International Journal of Molecular Sciences

Editorial

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159 KiB

Open AccessEditorial

Transparency of Reporting in Molecular Diagnostics

by Stephen Bustin

Int. J. Mol. Sci. 2013, 14(8), 15878-15884; https://doi.org/10.3390/ijms140815878 - 30 Jul 2013

Cited by 14 | Viewed by 5897

Abstract

The major advances made over the past few years in molecular and cell biology are providing a progressively more detailed understanding of the molecular pathways that control normal processes and become dysregulated in disease [1]. This has resulted in the documentation of numerous [...] Read more.

The major advances made over the past few years in molecular and cell biology are providing a progressively more detailed understanding of the molecular pathways that control normal processes and become dysregulated in disease [1]. This has resulted in the documentation of numerous genetic, epigenetic, transcriptomic, proteomic and metabolomic biomarkers that promise earlier disease detection, more accurate patient stratification and better prognosis [2–5]. Furthermore, molecular fingerprinting of diseases can be predictive of drug response and so assist with specific targeting of drugs against disease-associated molecules and function [6]. [...] Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

Research

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311 KiB

Open AccessArticle

Anti-Inflammatory Activity of N-(3-Florophenyl)ethylcaffeamide in Mice

by Jung-Chun Liao, Jen-Chieh Tsai, Wen-Huang Peng, Yung-Jia Chiu, Ping-Jyun Sung, Minoru Tsuzoki and Yueh-Hsiung Kuo

Int. J. Mol. Sci. 2013, 14(8), 15199-15211; https://doi.org/10.3390/ijms140815199 - 24 Jul 2013

Cited by 18 | Viewed by 8109

Abstract

In this study, we evaluated the anti-inflammatory activity of one synthetic product, N-(3-Florophenyl)ethylcaffeamide (abbrev. FECA), by using animal model of λ-carrageenan-induced paw edema in mice. The anti-inflammatory mechanism of FECA was determined by measuring the levels of cyclooxygenase-2 (COX-2), nitric oxide (NO), [...] Read more.

In this study, we evaluated the anti-inflammatory activity of one synthetic product, N-(3-Florophenyl)ethylcaffeamide (abbrev. FECA), by using animal model of λ-carrageenan-induced paw edema in mice. The anti-inflammatory mechanism of FECA was determined by measuring the levels of cyclooxygenase-2 (COX-2), nitric oxide (NO), tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and malondialdehyde (MDA) in the edema paw tissue, and the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GRd) in the liver. The results showed that FECA reduced the paw edema at three, four and five hours after λ-carrageenan administration. The levels of COX-2, NO, TNF-α, and MDA in the λ-carrageenan-induced edema paws were reduced and the activities of SOD, GPx, and GRd in liver tissues were raised by FECA. These results suggested that FECA possessed anti-inflammatory activities and the anti-inflammatory mechanisms might be related to the decrease of the levels of COX-2, NO, and TNF-α in inflamed tissues and the increase in the MDA level by increasing the activities of SOD, GPx, and GRd. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Interaction between Dipolar Lipid Headgroups and Charged Nanoparticles Mediated by Water Dipoles and Ions

by Aljaž Velikonja, Poornima Budime Santhosh, Ekaterina Gongadze, Mukta Kulkarni, Kristina Eleršič, Šarka Perutkova, Veronika Kralj-Iglič, Nataša Poklar Ulrih and Aleš Iglič

Int. J. Mol. Sci. 2013, 14(8), 15312-15329; https://doi.org/10.3390/ijms140815312 - 24 Jul 2013

Cited by 37 | Viewed by 10455

Abstract

In this work, a theoretical model describing the interaction between a positivelyor negatively charged nanoparticle and neutral zwitterionic lipid bilayers is presented. It isshown that in the close vicinity of the positively charged nanoparticle, the zwitterionic lipidheadgroups are less extended in the direction [...] Read more.

In this work, a theoretical model describing the interaction between a positivelyor negatively charged nanoparticle and neutral zwitterionic lipid bilayers is presented. It isshown that in the close vicinity of the positively charged nanoparticle, the zwitterionic lipidheadgroups are less extended in the direction perpendicular to the membrane surface, whilein the vicinity of the negatively charged nanoparticle, the headgroups are more extended.This result coincides with the calculated increase in the osmotic pressure between the zwitterionic lipid surface and positively charged nanoparticle and the decrease of osmoticpressure between the zwitterionic lipid surface and the negatively charged nanoparticle.Our theoretical predictions agree well with the experimentally determined fluidity of alipid bilayer membrane in contact with positively or negatively charged nanoparticles. Theprospective significance of the present work is mainly to contribute to better understandingof the interactions of charged nanoparticles with a zwitterionic lipid bilayer, which may beimportant in the efficient design of the lipid/nanoparticle nanostructures (like liposomes withencapsulated nanoparticles), which have diverse biomedical applications, including targetedtherapy (drug delivery) and imaging of cancer cells. Full article

(This article belongs to the Special Issue Computational Modelling of Biological Membranes)

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Open AccessArticle

Identification and Phylogenetic Analysis of a CC-NBS-LRR Encoding Gene Assigned on Chromosome 7B of Wheat

by Caiyan Gong, Shuanghe Cao, Renchun Fan, Bo Wei, Guiping Chen, Xianping Wang, Yiwen Li and Xiangqi Zhang

Int. J. Mol. Sci. 2013, 14(8), 15330-15347; https://doi.org/10.3390/ijms140815330 - 24 Jul 2013

Cited by 10 | Viewed by 7853

Abstract

Hexaploid wheat displays limited genetic variation. As a direct A and B genome donor of hexaploid wheat, tetraploid wheat represents an important gene pool for cultivated bread wheat. Many disease resistant genes express conserved domains of the nucleotide-binding site and leucine-rich repeats (NBS-LRR). [...] Read more.

Hexaploid wheat displays limited genetic variation. As a direct A and B genome donor of hexaploid wheat, tetraploid wheat represents an important gene pool for cultivated bread wheat. Many disease resistant genes express conserved domains of the nucleotide-binding site and leucine-rich repeats (NBS-LRR). In this study, we isolated a CC-NBS-LRR gene locating on chromosome 7B from durum wheat variety Italy 363, and designated it TdRGA-7Ba. Its open reading frame was 4014 bp, encoding a 1337 amino acid protein with a complete NBS domain and 18 LRR repeats, sharing 44.7% identity with the PM3B protein. TdRGA-7Ba expression was continuously seen at low levels and was highest in leaves. TdRGA-7Ba has another allele TdRGA-7Bb with a 4 bp deletion at position +1892 in other cultivars of tetraploid wheat. In Ae. speltoides, as a B genome progenitor, both TdRGA-7Ba and TdRGA-7Bb were detected. In all six species of hexaploid wheats (AABBDD), only TdRGA-7Bb existed. Phylogenic analysis showed that all TdRGA-7Bb type genes were grouped in one sub-branch. We speculate that TdRGA-7Bb was derived from a TdRGA-7Ba mutation, and it happened in Ae. speltoides. Both types of TdRGA-7B participated in tetraploid wheat formation. However, only the TdRGA-7Bb was retained in hexaploid wheat. Full article

(This article belongs to the Special Issue Advances in Molecular Plant Biology)

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Open AccessArticle

Addition of Aliskiren to Angiotensin Receptor Blocker Improves Ambulatory Blood Pressure Profile and Cardiorenal Function Better than Addition of Benazepril in Chronic Kidney Disease

by Masato Ohsawa, Kouichi Tamura, Tomohiko Kanaoka, Hiromichi Wakui, Akinobu Maeda, Toru Dejima, Kengo Azushima, Kazushi Uneda, Ryu Kobayashi, Yuko Tsurumi-Ikeya, Yoshiyuki Toya, Tetsuya Fujikawa and Satoshi Umemura

Int. J. Mol. Sci. 2013, 14(8), 15361-15375; https://doi.org/10.3390/ijms140815361 - 24 Jul 2013

Cited by 6 | Viewed by 6959

Abstract

An altered ambulatory blood pressure (BP) and heart rate (HR) profile is related to chronic kidney disease (CKD) and cardiorenal syndrome. In this study, we examined the effects of aliskiren, when added to angiotensin II type 1 receptor blockers, on ambulatory BP and [...] Read more.

An altered ambulatory blood pressure (BP) and heart rate (HR) profile is related to chronic kidney disease (CKD) and cardiorenal syndrome. In this study, we examined the effects of aliskiren, when added to angiotensin II type 1 receptor blockers, on ambulatory BP and cardiorenal function in CKD. Thirty-six hypertensive CKD patients were randomly assigned to the aliskiren add-on group (n = 18) or the benazepril add-on group (n = 18). Ambulatory BP and cardiorenal function parameters were measured at baseline and 24 weeks after treatment. Compared with the benazepril group, nighttime systolic BP variability in the aliskiren group was lower after treatment. Albuminuria was decreased in the aliskiren group, but not in the benazepril group. In addition, left ventricular mass index (LVMI) was significantly lower in the aliskiren group than in the benazepril group after treatment. In the aliskiren group, multivariate linear regression analysis showed an association between changes in albuminuria and changes in nighttime systolic BP. Furthermore, there were associations between changes in LVMI and changes in daytime HR variability, as well as between changes in LVMI and changes in plasma aldosterone concentration. These results suggest that aliskiren add-on therapy may be beneficial for suppression of renal deterioration and pathological cardiac remodeling through an improvement that is effected in ambulatory BP and HR profiles. Full article

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Open AccessArticle

The L10P Polymorphism and Serum Levels of Transforming Growth Factor β1 in Human Breast Cancer

by Eva Taubenschuß, Erika Marton, Maurice Mogg, Barbara Frech, Lisa Ehart, Dana Muin and Martin Schreiber

Int. J. Mol. Sci. 2013, 14(8), 15376-15385; https://doi.org/10.3390/ijms140815376 - 24 Jul 2013

Cited by 23 | Viewed by 6522

Abstract

The L10P single nucleotide polymorphism (SNP) is located in the signal sequence of the transforming growth factor β1 (TGFβ1) gene. The proline-encoding (Pro-) allele of this SNP has been associated with an increased breast cancer risk, which has been attributed to [...] Read more.

The L10P single nucleotide polymorphism (SNP) is located in the signal sequence of the transforming growth factor β1 (TGFβ1) gene. The proline-encoding (Pro-) allele of this SNP has been associated with an increased breast cancer risk, which has been attributed to the elevated secretion of this TGFβ1 variant observed in vitro and in male subjects. Here we investigated the association of the L10P SNP with serum levels of TGFβ1 in female breast cancer patients and controls. We genotyped the L10P SNP in 276 breast cancer patients and 255 controls. Serum TGFβ1 concentrations were measured by enzyme-linked immunosorbent assay (ELISA) in a subset of the study population (n = 211). We found no evidence for an association of the L10P SNP with breast cancer risk (per-allele odds ratio: 0.91; 95% confidence interval: 0.71–1.16). However, patients with the Pro/Pro genotype exhibited a significantly younger age at breast cancer onset (55.2 ± 14.3 years) than Leu/Leu patients (60.6 ± 13.6 years; p = 0.04), which may reflect the ability of TGFβ to promote tumor progression. Mean TGFβ1 serum levels of Pro-allele carriers were 39.4 ± 7.4 ng/mL, whereas those of Leu/Leu subjects were 37.6 ± 6.0 ng/mL (p = 0.07). Thus, compared to a previous study of male subjects, we observed only a modest increase, if any, in TGFβ1 levels of female Pro-allele carriers. Full article

(This article belongs to the Special Issue Molecular Research of Carcinogenesis)

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Open AccessArticle

Apoptosis Signal-Regulating Kinase 1 Is Involved in Brain-Derived Neurotrophic Factor (BDNF)-Enhanced Cell Motility and Matrix Metalloproteinase 1 Expression in Human Chondrosarcoma Cells

by Chih-Yang Lin, Sunny Li-Yun Chang, Yi-Chin Fong, Chin-Jung Hsu and Chih-Hsin Tang

Int. J. Mol. Sci. 2013, 14(8), 15459-15478; https://doi.org/10.3390/ijms140815459 - 25 Jul 2013

Cited by 27 | Viewed by 7077

Abstract

Chondrosarcoma is the primary malignancy of bone that is characterized by a potent capacity to invade locally and cause distant metastasis, and is therefore associated with poor prognoses. Chondrosarcoma further shows a predilection for metastasis to the lungs. The brain-derived neurotrophic factor (BDNF) [...] Read more.

Chondrosarcoma is the primary malignancy of bone that is characterized by a potent capacity to invade locally and cause distant metastasis, and is therefore associated with poor prognoses. Chondrosarcoma further shows a predilection for metastasis to the lungs. The brain-derived neurotrophic factor (BDNF) is a small molecule in the neurotrophin family of growth factors that is associated with the disease status and outcome of cancers. However, the effect of BDNF on cell motility in human chondrosarcoma cells is mostly unknown. Here, we found that human chondrosarcoma cell lines had significantly higher cell motility and BDNF expression compared to normal chondrocytes. We also found that BDNF increased cell motility and expression of matrix metalloproteinase-1 (MMP-1) in human chondrosarcoma cells. BDNF-mediated cell motility and MMP-1 up-regulation were attenuated by Trk inhibitor (K252a), ASK1 inhibitor (thioredoxin), JNK inhibitor (SP600125), and p38 inhibitor (SB203580). Furthermore, BDNF also promoted Sp1 activation. Our results indicate that BDNF enhances the migration and invasion activity of chondrosarcoma cells by increasing MMP-1 expression through a signal transduction pathway that involves the TrkB receptor, ASK1, JNK/p38, and Sp1. BDNF thus represents a promising new target for treating chondrosarcoma metastasis. Full article

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Open AccessArticle

Protein Synthesis Inhibition Activity by Strawberry Tissue Protein Extracts during Plant Life Cycle and under Biotic and Abiotic Stresses

by Letizia Polito, Massimo Bortolotti, Daniele Mercatelli, Rossella Mancuso, Gianluca Baruzzi, Walther Faedi and Andrea Bolognesi

Int. J. Mol. Sci. 2013, 14(8), 15532-15545; https://doi.org/10.3390/ijms140815532 - 25 Jul 2013

Cited by 9 | Viewed by 8788

Abstract

Ribosome-inactivating proteins (RIPs), enzymes that are widely distributed in the plant kingdom, inhibit protein synthesis by depurinating rRNA and many other polynucleotidic substrates. Although RIPs show antiviral, antifungal, and insecticidal activities, their biological and physiological roles are not completely understood. Additionally, it has [...] Read more.

Ribosome-inactivating proteins (RIPs), enzymes that are widely distributed in the plant kingdom, inhibit protein synthesis by depurinating rRNA and many other polynucleotidic substrates. Although RIPs show antiviral, antifungal, and insecticidal activities, their biological and physiological roles are not completely understood. Additionally, it has been described that RIP expression is augmented under stressful conditions. In this study, we evaluated protein synthesis inhibition activity in partially purified basic proteins (hereafter referred to as RIP activity) from tissue extracts of Fragaria × ananassa (strawberry) cultivars with low (Dora) and high (Record) tolerance to root pathogens and fructification stress. Association between the presence of RIP activity and the crop management (organic or integrated soil), growth stage (quiescence, flowering, and fructification), and exogenous stress (drought) were investigated. RIP activity was found in every tissue tested (roots, rhizomes, leaves, buds, flowers, and fruits) and under each tested condition. However, significant differences in RIP distribution were observed depending on the soil and growth stage, and an increase in RIP activity was found in the leaves of drought-stressed plants. These results suggest that RIP expression and activity could represent a response mechanism against biotic and abiotic stresses and could be a useful tool in selecting stress-resistant strawberry genotypes. Full article

(This article belongs to the Special Issue Molecular Research in Plant Secondary Metabolism)

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Open AccessArticle

Effects of Fe₃O₄ Magnetic Nanoparticles on A549 Cells

by Masatoshi Watanabe, Misao Yoneda, Ayaka Morohashi, Yasuki Hori, Daiki Okamoto, Akiko Sato, Daisuke Kurioka, Tadashi Nittami, Yoshifumi Hirokawa, Taizo Shiraishi, Kazuaki Kawai, Hiroshi Kasai and Yukari Totsuka

Int. J. Mol. Sci. 2013, 14(8), 15546-15560; https://doi.org/10.3390/ijms140815546 - 25 Jul 2013

Cited by 76 | Viewed by 10110

Abstract

Fe₃O₄ magnetic nanoparticles (MgNPs-Fe₃O₄) are widely used in medical applications, including magnetic resonance imaging, drug delivery, and in hyperthermia. However, the same properties that aid their utility in the clinic may potentially induce toxicity. Therefore, the [...] Read more.

Fe₃O₄ magnetic nanoparticles (MgNPs-Fe₃O₄) are widely used in medical applications, including magnetic resonance imaging, drug delivery, and in hyperthermia. However, the same properties that aid their utility in the clinic may potentially induce toxicity. Therefore, the purpose of this study was to investigate the cytotoxicity and genotoxicity of MgNPs-Fe₃O₄ in A549 human lung epithelial cells. MgNPs-Fe₃O₄ caused cell membrane damage, as assessed by the release of lactate dehydrogenase (LDH), only at a high concentration (100 μg/mL); a lower concentration (10 μg/mL) increased the production of reactive oxygen species, increased oxidative damage to DNA, and decreased the level of reduced glutathione. MgNPs-Fe₃O₄ caused a dose-dependent increase in the CD44⁺ fraction of A549 cells. MgNPs-Fe₃O₄ induced the expression of heme oxygenase-1 at a concentration of 1 μg/mL, and in a dose-dependent manner. Despite these effects, MgNPs-Fe₃O₄ had minimal effect on cell viability and elicited only a small increase in the number of cells undergoing apoptosis. Together, these data suggest that MgNPs-Fe₃O₄ exert little or no cytotoxicity until a high exposure level (100 μg/mL) is reached. This dissociation between elevated indices of cell damage and a small effect on cell viability warrants further study. Full article

(This article belongs to the Special Issue Magnetic Nanoparticles 2013)

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Open AccessArticle

Genetic Analysis of Health-Related Secondary Metabolites in a Brassica rapa Recombinant Inbred Line Population

by Hedayat Bagheri, Mohamed El-Soda, Hye Kyong Kim, Steffi Fritsche, Christian Jung and Mark G. M. Aarts

Int. J. Mol. Sci. 2013, 14(8), 15561-15577; https://doi.org/10.3390/ijms140815561 - 25 Jul 2013

Cited by 9 | Viewed by 8484

Abstract

The genetic basis of the wide variation for nutritional traits in Brassica rapa is largely unknown. A new Recombinant Inbred Line (RIL) population was profiled using High Performance Liquid Chromatography (HPLC) and Nuclear Magnetic Resonance (NMR) analysis to detect quantitative trait [...] Read more.

The genetic basis of the wide variation for nutritional traits in Brassica rapa is largely unknown. A new Recombinant Inbred Line (RIL) population was profiled using High Performance Liquid Chromatography (HPLC) and Nuclear Magnetic Resonance (NMR) analysis to detect quantitative trait loci (QTLs) controlling seed tocopherol and seedling metabolite concentrations. RIL population parent L58 had a higher level of glucosinolates and phenylpropanoids, whereas levels of sucrose, glucose and glutamate were higher in the other RIL population parent, R-o-18. QTL related to seed tocopherol (α-, β-, γ-, δ-, α-⁄γ- and total tocopherol) concentrations were detected on chromosomes A3, A6, A9 and A10, explaining 11%–35% of the respective variation. The locus on A3 co-locates with the BrVTE1gene, encoding tocopherol cyclase. NMR spectroscopy identified the presence of organic/amino acid, sugar/glucosinolate and aromatic compounds in seedlings. QTL positions were obtained for most of the identified compounds. Compared to previous studies, novel loci were found for glucosinolate concentrations. This work can be used to design markers for marker-assisted selection of nutritional compounds in B. rapa. Full article

(This article belongs to the Special Issue Molecular Research in Plant Secondary Metabolism)

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Open AccessArticle

Phyto-SERM Constitutes from Flemingia macrophylla

by Wan-Chun Lai, Ya-Ting Tsui, Abdel Nasser B. Singab, Mohamed El-Shazly, Ying-Chi Du, Tsong-Long Hwang, Chin-Chung Wu, Ming-Hong Yen, Ching-Kuo Lee, Ming-Feng Hou, Yang-Chang Wu and Fang-Rong Chang

Int. J. Mol. Sci. 2013, 14(8), 15578-15594; https://doi.org/10.3390/ijms140815578 - 26 Jul 2013

Cited by 19 | Viewed by 7772

Abstract

The methanolic extract of Flemingia macrophylla roots exhibited significant estrogenic activity in the transgenic plant assay system which was comparable to the activity of soybean extract. Utilizing estrogenic activity-guided fractionation, one new compound, fleminigin, together with 23 known compounds were isolated from F. [...] Read more.

The methanolic extract of Flemingia macrophylla roots exhibited significant estrogenic activity in the transgenic plant assay system which was comparable to the activity of soybean extract. Utilizing estrogenic activity-guided fractionation, one new compound, fleminigin, together with 23 known compounds were isolated from F. macrophylla roots’ methanolic extract. The structure of the new compound was identified based on intensive spectroscopic analysis and the full spectral data for one of the isolated compounds, flemichin E, was introduced for the first time in the current investigation. The estrogenic and anti-estrogenic activities of the isolated compounds were evaluated revealing that the isolated isoflavonoids may act as partial estrogen agonists, as well as antagonists. Additionally, the anti-inflammatory and the cytotoxic activities of the isolated compounds were studied. These results suggested the potential applications of F. macrophylla extract and its isolated compounds as selective estrogen receptor modulators (SERMs). Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Molecular, Physicochemical and Rheological Characteristics of Introgressive Triticale/Triticum monococcum ssp. monococcum Lines with Wheat 1D/1A Chromosome Substitution

by Bolesław P. Salmanowicz, Monika Langner, Halina Wiśniewska, Barbara Apolinarska, Michał Kwiatek and Lidia Błaszczyk

Int. J. Mol. Sci. 2013, 14(8), 15595-15614; https://doi.org/10.3390/ijms140815595 - 26 Jul 2013

Cited by 10 | Viewed by 9012

Abstract

Three sets of hexaploid introgressive triticale lines, with Triticum monococcum ssp. monococcum (cultivated einkorn wheat) genes and a bread wheat chromosome 1D substituted for chromosome 1A, and one set of secondary triticale lines were evaluated for grain and flour physicochemical and dough rheological [...] Read more.

Three sets of hexaploid introgressive triticale lines, with Triticum monococcum ssp. monococcum (cultivated einkorn wheat) genes and a bread wheat chromosome 1D substituted for chromosome 1A, and one set of secondary triticale lines were evaluated for grain and flour physicochemical and dough rheological characteristics in two generations (F7 and F8). Genomic in situ hybridization (GISH) and fluorescence in situ hybridization (FISH) confirmed the 1D/1A chromosome substitution. The presence or absence of einkorn high-molecular-weight (HMW) glutenin subunits and the wheat Glu-D1d locus encoding the 5 + 10 subunits was assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), capillary zone electrophoresis, and allele-specific molecular markers. Significant differences were found among physicochemical properties (with the exception of the Hagberg falling number) of all introgressive Triticale/T. monococcum lines and the secondary triticale lines. The wheat 1D/1A chromosome substitution also affected these properties. The results showed that in all introgressive triticale lines, the protein and gluten content, Zeleny sedimentation value, and water absorption capacity, were increased. The rheological parameters estimated using micro-farinograph, reomixer, and Kieffer dough extensibility systems also showed an appreciable increase in dough-mixing properties, maximum resistance to extension (R_max), and dough extensibility. Introgressive Triticale/T. monococcum lines with 5 + 10 subunits have particularly favorable rheological parameters. The results obtained in this study suggest that the cultivated einkorn genome A^m, in the context of hexaploid secondary triticale lines and with a wheat 1D/1A substitution, has the potential to improve gluten polymer interactions and be a valuable genetic resource for triticale quality improvement. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Exploring the Glycosylation of Serum CA125

by Radka Saldova, Weston B. Struwe, Kieran Wynne, Giuliano Elia, Michael J. Duffy and Pauline M. Rudd

Int. J. Mol. Sci. 2013, 14(8), 15636-15654; https://doi.org/10.3390/ijms140815636 - 26 Jul 2013

Cited by 70 | Viewed by 10525

Abstract

Ovarian cancer is the most lethal gynaecologic cancer affecting women. The most widely used biomarker for ovarian cancer, CA125, lacks sensitivity and specificity. Here, we explored differences in glycosylation of CA125 between serum from patients with ovarian cancer and healthy controls. We found [...] Read more.

Ovarian cancer is the most lethal gynaecologic cancer affecting women. The most widely used biomarker for ovarian cancer, CA125, lacks sensitivity and specificity. Here, we explored differences in glycosylation of CA125 between serum from patients with ovarian cancer and healthy controls. We found differences between CA125 N-glycans from patient sera compared to controls. These include increases in core-fucosylated bi-antennary monosialylated glycans, as well as decreases in mostly bisecting bi-antennary and non-fucosylated glycans in patients compared to controls. Measurement of the glycosylated state of CA125 may therefore provide a more specific biomarker for patients with ovarian cancer. Full article

(This article belongs to the Special Issue Advances in Cancer Diagnosis)

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Open AccessArticle

Resveratrol Sensitizes Tamoxifen in Antiestrogen-Resistant Breast Cancer Cells with Epithelial-Mesenchymal Transition Features

by Xiao-Peng Shi, Shan Miao, Yin Wu, Wei Zhang, Xiao-Fang Zhang, Hua-Zhao Ma, Hai-Li Xin, Juan Feng, Ai-Dong Wen and Yan Li

Int. J. Mol. Sci. 2013, 14(8), 15655-15668; https://doi.org/10.3390/ijms140815655 - 26 Jul 2013

Cited by 66 | Viewed by 11516

Abstract

Tamoxifen resistance remains to be a huge obstacle in the treatment of hormone-dependent breast cancer, and this therefore highlights the dire need to explore the underlying mechanisms. The epithelial-mesenchymal transition (EMT) is a molecular process through which an epithelial cell transfers into a [...] Read more.

Tamoxifen resistance remains to be a huge obstacle in the treatment of hormone-dependent breast cancer, and this therefore highlights the dire need to explore the underlying mechanisms. The epithelial-mesenchymal transition (EMT) is a molecular process through which an epithelial cell transfers into a mesenchymal phenotype. Roles of EMT in embryo development, cancer invasion and metastasis have been extensively reported. Herein, we established tamoxifen-resistant MCF-7/TR breast cancer cells and showed that MCF-7/TR cells underwent EMT driven by enhanced endogenous TGF-β/Smad signaling. Ectopic supplement of TGF-β promoted in MCF-7 cells a mesenchymal and resistant phenotype. In parallel, we demonstrated that resveratrol was capable of synergizing with tamoxifen and triggering apoptosis in MCF-7/TR cells. Further Western blot analysis indicated that the chemosensitizing effects of resveratrol were conferred with its modulation on endogenous TGF-β production and Smad phosphorylation. In particular, 50 μM resveratrol had minor effects on MCF-7/TR cell proliferation, but could significantly attenuate endogenous TGF-β production and the Smad pathway, ultimately leading to reversion of EMT. Collectively, our study highlighted distinct roles of EMT in tamoxifen resistance and resveratrol as a potential agent to overcome acquired tamoxifen resistance. The molecular mechanism of resveratrol chemosensitizing effects is, at least in part, TGF-β/Smad-dependent. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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Open AccessArticle

Hydrogenation of the Exocyclic Olefinic Bond at C-16/C-17 Position of ent-Kaurane Diterpene Glycosides of Stevia rebaudiana Using Various Catalysts

by Venkata Sai Prakash Chaturvedula and Indra Prakash

Int. J. Mol. Sci. 2013, 14(8), 15669-15680; https://doi.org/10.3390/ijms140815669 - 26 Jul 2013

Cited by 3 | Viewed by 6179

Abstract

Catalytic hydrogenation of the exocyclic double bond present between C16 and C17 carbons of the four ent-kaurane diterpene glycosides namely rebaudioside A, rebaudioside B, rebaudioside C, and rebaudioside D isolated from Stevia rebaudiana has been carried out using Pt/C, Pd(OH)₂, [...] Read more.

Catalytic hydrogenation of the exocyclic double bond present between C16 and C17 carbons of the four ent-kaurane diterpene glycosides namely rebaudioside A, rebaudioside B, rebaudioside C, and rebaudioside D isolated from Stevia rebaudiana has been carried out using Pt/C, Pd(OH)₂, Rh/C, Raney Ni, PtO₂, and 5% Pd/BaCO₃ to their corresponding dihydro derivatives with 17α and 17β methyl group isomers. Reactions were performed using the above-mentioned catalysts with the solvents methanol, water, and ethanol/water (8:2) under various conditions. Synthesis of reduced steviol glycosides was performed using straightforward chemistry and their structures were characterized on the basis of 1D and 2D NMR spectral data, including a comparison with reported spectral data. Full article

(This article belongs to the Section Biochemistry)

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Mild Oxidative Damage in the Diabetic Rat Heart Is Attenuated by Glyoxalase-1 Overexpression

by Olaf Brouwers, Joyce M. J. de Vos-Houben, Petra M. G. Niessen, Toshio Miyata, Frans Van Nieuwenhoven, Ben J. A. Janssen, Geja Hageman, Coen D. A. Stehouwer and Casper G. Schalkwijk

Int. J. Mol. Sci. 2013, 14(8), 15724-15739; https://doi.org/10.3390/ijms140815724 - 29 Jul 2013

Cited by 26 | Viewed by 8288

Abstract

Diabetes significantly increases the risk of heart failure. The increase in advanced glycation endproducts (AGEs) and oxidative stress have been associated with diabetic cardiomyopathy. We recently demonstrated that there is a direct link between AGEs and oxidative stress. Therefore, the aim of the [...] Read more.

Diabetes significantly increases the risk of heart failure. The increase in advanced glycation endproducts (AGEs) and oxidative stress have been associated with diabetic cardiomyopathy. We recently demonstrated that there is a direct link between AGEs and oxidative stress. Therefore, the aim of the current study was to investigate if a reduction of AGEs by overexpression of the glycation precursor detoxifying enzyme glyoxalase-I (GLO-I) can prevent diabetes-induced oxidative damage, inflammation and fibrosis in the heart. Diabetes was induced in wild-type and GLO-I transgenic rats by streptozotocin. After 24-weeks of diabetes, cardiac function was monitored with ultrasound under isoflurane anesthesia. Blood was drawn and heart tissue was collected for further analysis. Analysis with UPLC-MSMS showed that the AGE N^ε-(1-carboxymethyl)lysine and its precursor 3-deoxyglucosone were significantly elevated in the diabetic hearts. Markers of oxidative damage, inflammation, and fibrosis were mildly up-regulated in the heart of the diabetic rats and were attenuated by GLO-I overexpression. In this model of diabetes, these processes were not accompanied by significant changes in systolic heart function, i.e., stroke volume, fractional shortening and ejection fraction. This study shows that 24-weeks of diabetes in rats induce early signs of mild cardiac alterations as indicated by an increase of oxidative stress, inflammation and fibrosis which are mediated, at least partially, by glycation. Full article

(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)

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Open AccessArticle

Insulin-Dependent H₂O₂ Production Is Higher in Muscle Fibers of Mice Fed with a High-Fat Diet

by Alejandra Espinosa, Cristian Campos, Alexis Díaz-Vegas, José E. Galgani, Nevenka Juretic, César Osorio-Fuentealba, José L. Bucarey, Gladys Tapia, Rodrigo Valenzuela, Ariel Contreras-Ferrat, Paola Llanos and Enrique Jaimovich

Int. J. Mol. Sci. 2013, 14(8), 15740-15754; https://doi.org/10.3390/ijms140815740 - 29 Jul 2013

Cited by 39 | Viewed by 9704

Abstract

Insulin resistance is defined as a reduced ability of insulin to stimulate glucose utilization. C57BL/6 mice fed with a high-fat diet (HFD) are a model of insulin resistance. In skeletal muscle, hydrogen peroxide (H₂O₂) produced by NADPH oxidase 2 [...] Read more.

Insulin resistance is defined as a reduced ability of insulin to stimulate glucose utilization. C57BL/6 mice fed with a high-fat diet (HFD) are a model of insulin resistance. In skeletal muscle, hydrogen peroxide (H₂O₂) produced by NADPH oxidase 2 (NOX2) is involved in signaling pathways triggered by insulin. We evaluated oxidative status in skeletal muscle fibers from insulin-resistant and control mice by determining H₂O₂ generation (HyPer probe), reduced-to-oxidized glutathione ratio and NOX2 expression. After eight weeks of HFD, insulin-dependent glucose uptake was impaired in skeletal muscle fibers when compared with control muscle fibers. Insulin-resistant mice showed increased insulin-stimulated H₂O₂ release and decreased reduced-to-oxidized glutathione ratio (GSH/GSSG). In addition, p47^phox and gp91^phox (NOX2 subunits) mRNA levels were also high (~3-fold in HFD mice compared to controls), while protein levels were 6.8- and 1.6-fold higher, respectively. Using apocynin (NOX2 inhibitor) during the HFD feeding period, the oxidative intracellular environment was diminished and skeletal muscle insulin-dependent glucose uptake restored. Our results indicate that insulin-resistant mice have increased H₂O₂ release upon insulin stimulation when compared with control animals, which appears to be mediated by an increase in NOX2 expression. Full article

(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)

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Open AccessArticle

Galactosylated Chitosan Oligosaccharide Nanoparticles for Hepatocellular Carcinoma Cell-Targeted Delivery of Adenosine Triphosphate

by Xiu Liang Zhu, Yong Zhong Du, Ri Sheng Yu, Ping Liu, Dan Shi, Ying Chen, Ying Wang and Fang Fang Huang

Int. J. Mol. Sci. 2013, 14(8), 15755-15766; https://doi.org/10.3390/ijms140815755 - 29 Jul 2013

Cited by 46 | Viewed by 9633

Abstract

Nanoparticles composed of galactosylated chitosan oligosaccharide (Gal-CSO) and adenosine triphosphate (ATP) were prepared for hepatocellular carcinoma cell-specific uptake, and the characteristics of Gal-CSO/ATP nanoparticles were evaluated. CSO/ATP nanoparticles were prepared as a control. The average diameter and zeta potential of Gal-CSO/ATP nanoparticles were [...] Read more.

Nanoparticles composed of galactosylated chitosan oligosaccharide (Gal-CSO) and adenosine triphosphate (ATP) were prepared for hepatocellular carcinoma cell-specific uptake, and the characteristics of Gal-CSO/ATP nanoparticles were evaluated. CSO/ATP nanoparticles were prepared as a control. The average diameter and zeta potential of Gal-CSO/ATP nanoparticles were 51.03 ± 3.26 nm and 30.50 ± 1.25 mV, respectively, suggesting suitable properties for a drug delivery system. Subsequently, the cytotoxicity of Gal-CSO/ATP nanoparticles were examined by the methyl tetrazolium (MTT) assay, and the half maximal inhibitory concentration (IC₅₀) values were calculated with HepG2 (human hepatocellular carcinoma cell line) cells. The results showed that the cytotoxic effect of nanoparticles on HepG2 cells was low. In the meantime, it was also found that the Gal-CSO/ATP nanoparticles could be uptaken by HepG2 cells, due to expression of the asialoglycoprotein receptor (ASGP-R) on their surfaces. The presented results indicate that the Gal-CSO nanoparticles might be very attractive to be used as an intracellular drug delivery carrier for hepatocellular carcinoma cell targeting, thus warranting further in vivo or clinical investigations. Full article

(This article belongs to the Special Issue Bioactive Nanoparticles 2013)

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Post-Traumatic Caspase-3 Expression in the Adjacent Areas of Growth Plate Injury Site: A Morphological Study

by Giuseppe Musumeci, Paola Castrogiovanni, Carla Loreto, Sergio Castorina, Karin Pichler and Annelie Martina Weinberg

Int. J. Mol. Sci. 2013, 14(8), 15767-15784; https://doi.org/10.3390/ijms140815767 - 29 Jul 2013

Cited by 61 | Viewed by 11572

Abstract

The epiphyseal plate is a hyaline cartilage plate that sits between the diaphysis and the epiphysis. The objective of this study was to determine the impact of an injury in the growth plate chondrocytes through the study of histological morphology, immunohistochemistry, histomorphometry and [...] Read more.

The epiphyseal plate is a hyaline cartilage plate that sits between the diaphysis and the epiphysis. The objective of this study was to determine the impact of an injury in the growth plate chondrocytes through the study of histological morphology, immunohistochemistry, histomorphometry and Western Blot analyses of the caspase-3 and cleaved PARP-1, and levels of the inflammatory cytokines, Interleukin-6 (IL-6) and Tumor Necrosis Factor alpha (TNF-α), in order to acquire more information about post-injury reactions of physeal cell turnover. In our results, morphological analysis showed that in experimental bones, neo-formed bone trabeculae—resulting from bone formation repair—invaded the growth plate and reached the metaphyseal bone tissue (bone bridge), and this could result in some growth arrest. We demonstrated, by ELISA, increased expression levels of the inflammatory cytokines IL-6 and TNF-α. Immunohistochemistry, histomorphometry and Western Blot analyses of the caspase-3 and cleaved PARP-1 showed that the physeal apoptosis rate of the experimental bones was significantly higher than that of the control ones. In conclusion, we could assume that the inflammation process causes stress to chondrocytes that will die as a biological defense mechanism, and will also increase the survival of new chondrocytes for maintaining cell homeostasis. Nevertheless, the exact stimulus leading to the increased apoptosis rate, observed after injury, needs additional research to understand the possible contribution of chondrocyte apoptosis to growth disturbance. Full article

(This article belongs to the Special Issue The Chondrocyte Phenotype in Cartilage Biology)

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Highly Sensitive Automated Method for DNA Damage Assessment: Gamma-H2AX Foci Counting and Cell Cycle Sorting

by Laia Hernández, Mariona Terradas, Marta Martín, Laura Tusell and Anna Genescà

Int. J. Mol. Sci. 2013, 14(8), 15810-15826; https://doi.org/10.3390/ijms140815810 - 30 Jul 2013

Cited by 34 | Viewed by 13166

Abstract

Phosphorylation of the H2AX protein is an early step in the double strand break (DSB) repair pathway; therefore, phosphorylated histone (γH2AX) foci scoring is widely used as a measure for DSBs. Foci scoring is performed either manually or semi-automatically using hand-operated capturing and [...] Read more.

Phosphorylation of the H2AX protein is an early step in the double strand break (DSB) repair pathway; therefore, phosphorylated histone (γH2AX) foci scoring is widely used as a measure for DSBs. Foci scoring is performed either manually or semi-automatically using hand-operated capturing and image analysis software. In general, both techniques are laborious and prone to artifacts associated with manual scoring. While a few fully automated methods have been described in the literature, none of them have been used to quantify γH2AX foci in combination with a cell cycle phase analysis. Adding this feature to a rapid automated γH2AX foci quantification method would reduce the scoring uncertainty that arises from the variations in the background level of the γH2AX signal throughout the cell cycle. The method was set up to measure DNA damage induced in human mammary epithelial cells by irradiation under a mammogram device. We adapted a FISH (fluorescent in situ hybridization) Spot-counting system, which has a slide loader with automatic scanning and cell capture system throughout the thickness of each cell (z-stack), to meet our assay requirements. While scanning the sample, the system classifies the selected nuclei according to the signal patterns previously described by the user. For our purposes, a double staining immunofluorescence was carried out with antibodies to detect γH2AX and pericentrin, an integral component of the centrosome. We could thus distinguish both the number of γH2AX foci per cell and the cell cycle phase. Furthermore, restrictive settings of the program classifier reduced the “touching nuclei” problem described in other image analysis software. The automated scoring was faster than and as sensitive as its manually performed counterpart. This system is a reliable tool for γH2AX radio-induced foci counting and provides essential information about the cell cycle stage. It thus offers a more complete and rapid assessment of DNA damage. Full article

(This article belongs to the Collection Radiation Toxicity in Cells)

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Cinnamtannin B-1 Regulates Cell Proliferation of Spinal Cord Astrocytes and Protects the Cell from Oxygen-Glucose-Serum Deprivation/Reoxygenation-Induced Apoptosis

by Zhiyong Chi, Xueling Ma, Guofeng Cui, Mingchao Li and Fuchun Li

Int. J. Mol. Sci. 2013, 14(8), 15827-15837; https://doi.org/10.3390/ijms140815827 - 30 Jul 2013

Cited by 12 | Viewed by 6526

Abstract

Astrocytes are important for protecting neurons in the central nervous system. It has been reported that some antioxidants could protect astrocytes from ischemia/reperfusion-induced dysfunction. Cinnamtannin B-1 is a naturally occurring A-type proanthocyanidin that exhibits anti-oxidant properties. In this study, we investigated the effects [...] Read more.

Astrocytes are important for protecting neurons in the central nervous system. It has been reported that some antioxidants could protect astrocytes from ischemia/reperfusion-induced dysfunction. Cinnamtannin B-1 is a naturally occurring A-type proanthocyanidin that exhibits anti-oxidant properties. In this study, we investigated the effects of cinnamtannin B-1 on spinal cord astrocytes. Astrocytes were subjected to oxygen-glucose-serum deprivation for eight hours followed by reoxygenation with or without cinnamtannin B-1. We found that cinnamtannin B-1 protected astrocytes from oxygen-glucose-serum deprivation and reoxygenation-induced apoptosis. Concurrently, cinnamtannin B-1 promoted the proliferation of astrocytes whereas the extracellular regulated protein kinase (ERK) inhibitor reversed this effect. The results indicated that cinnamtannin B-1 protects astrocytes from oxygen-glucose-serum deprivation/reoxygenation-induced apoptosis by promoting astrocyte proliferation via an ERK pathway. Therefore, as an anti-oxidant, cinnamtannin B-1 might provide extra benefit for astrocyte protection during ischemia/reperfusion in the central nervous system. Full article

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Comparative Analysis of Mafriwal (Bos taurus × Bos indicus) and Kedah Kelantan (Bos indicus) Sperm Proteome Identifies Sperm Proteins Potentially Responsible for Higher Fertility in a Tropical Climate

by Ali Ashrafzadeh, Sheila Nathan and Saiful Anuar Karsani

Int. J. Mol. Sci. 2013, 14(8), 15860-15877; https://doi.org/10.3390/ijms140815860 - 30 Jul 2013

Cited by 17 | Viewed by 8106

Abstract

The fertility of zebu cattle (Bos indicus) is higher than that of the European purebred (Bos taurus) and crossbred (Bos taurus × Bos indicus) cattle in tropical areas. To identify proteins related to the higher thermo-tolerance and [...] Read more.

The fertility of zebu cattle (Bos indicus) is higher than that of the European purebred (Bos taurus) and crossbred (Bos taurus × Bos indicus) cattle in tropical areas. To identify proteins related to the higher thermo-tolerance and fertility of Zebu cattle, this study was undertaken to identify differences in sperm proteome between the high fertile Malaysian indigenous zebu cattle (Kedah Kelantan) and the sub-fertile crossbred cattle (Mafriwal). Frozen semen from three high performance bulls from each breed were processed to obtain live and pure sperm. Sperm proteins were then extracted, and two-dimensional gel electrophoresis performed to compare proteome profiles. Gel image analysis identified protein spots of interest which were then identified by liquid chromatography mass spectrometry quadrupole time-of-flight (LC MS/MS Q-TOF). STRING network analysis predicted interactions between at least 20 of the identified proteins. Among the identified proteins, a number of motility and energy related proteins were present in greater abundance in Kedah Kelantan. Sperm motility evaluation by Computer Assisted Semen Analysis (CASA) confirmed significantly higher motility in Kedah Kelantan. While results from this study do identify proteins that may be responsible for the higher fertility of Kedah Kelantan, functional characterization of these proteins is warranted to reinforce our understanding of their roles in sperm fertility. Full article

(This article belongs to the Section Biochemistry)

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Effect of δ-Opioid Receptor Activation on BDNF-TrkB vs. TNF-α in the Mouse Cortex Exposed to Prolonged Hypoxia

by Xuesong Tian, Fei Hua, Harleen K Sandhu, Dongman Chao, Gianfranco Balboni, Severo Salvadori, Xiaozhou He and Ying Xia

Int. J. Mol. Sci. 2013, 14(8), 15959-15976; https://doi.org/10.3390/ijms140815959 - 31 Jul 2013

Cited by 37 | Viewed by 9495

Abstract

We investigated whether δ-opioid receptor (DOR)-induced neuroprotection involves the brain-derived neurotrophic factor (BDNF) pathway. We studied the effect of DOR activation on the expression of BDNF and other proteins in the cortex of C57BL/6 mice exposed to hypoxia (10% of oxygen) for 1–10 [...] Read more.

We investigated whether δ-opioid receptor (DOR)-induced neuroprotection involves the brain-derived neurotrophic factor (BDNF) pathway. We studied the effect of DOR activation on the expression of BDNF and other proteins in the cortex of C57BL/6 mice exposed to hypoxia (10% of oxygen) for 1–10 days. The results showed that: (1) 1-day hypoxia had no appreciable effect on BDNF expression, while 3- and 10-day hypoxia progressively decreased BDNF expression, resulting in 37.3% reduction (p < 0.05) after 10-day exposure; (2) DOR activation with UFP-512 (1 mg/kg, i.p., daily) partially reversed the hypoxia-induced reduction of BDNF expression in the 3- or 10-day exposed cortex; (3) DOR activation partially reversed the hypoxia-induced reduction in functional TrkB (140-kDa) and attenuated hypoxia-induced increase in truncated TrkB (90-kDa) in the 3- or 10-day hypoxic cortex; and (4) prolonged hypoxia (10 days) significantly increased TNF-α level and decreased CD11b expression in the cortex, which was completely reversed following DOR activation; and (5) there was no significant change in pCREB and pATF-1 levels in the hypoxic cortex. We conclude that prolonged hypoxia down-regulates BDNF-TrkB signaling leading to an increase in TNF-α in the cortex, while DOR activation up-regulates BDNF-TrkB signaling thereby decreasing TNF-α levels in the hypoxic cortex. Full article

(This article belongs to the Special Issue Molecular Research in Neurotoxicology)

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Matrine Activates PTEN to Induce Growth Inhibition and Apoptosis in ^V600EBRAF Harboring Melanoma Cells

by Hui Jin, Yu Sun, Shuiying Wang and Xiaodong Cheng

Int. J. Mol. Sci. 2013, 14(8), 16040-16057; https://doi.org/10.3390/ijms140816040 - 31 Jul 2013

Cited by 27 | Viewed by 7085

Abstract

Here, we report a natural chemical Matrine, which exhibits anti-melanoma potential with its PTEN activation mechanism. Matrine effectively inhibited proliferation of several carcinoma cell lines, including melanoma ^V600EBRAF harboring M21 cells. Flow cytometry analysis showed Matrine induced G₀/G₁ [...] Read more.

Here, we report a natural chemical Matrine, which exhibits anti-melanoma potential with its PTEN activation mechanism. Matrine effectively inhibited proliferation of several carcinoma cell lines, including melanoma ^V600EBRAF harboring M21 cells. Flow cytometry analysis showed Matrine induced G₀/G₁ cell cycle arrest in M21 cells dose-dependently. Apoptosis in M21 cells induced by Matrine was identified by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis and Annexin-V/FITC staining. Molecular mechanistic study suggested that Matrine upregulated both mRNA level and protein expression level of phosphatase and tensin homolog deleted on chromosome ten (PTEN), leading to inhibition of the PI3K/Akt pathway. Downregulation of phosphor-Akt^ser473 by Matrine activated p21 and Bax, which contributed to G₀/G₁ cell cycle and apoptosis. Besides, Matrine enhanced the PI3K/Akt inhibition effects to inhibit the cell proliferation with PI3K inhibitor, LY2940002. In summary, our findings suggest Matrine is a promising antitumor drug candidate with its possible PTEN activation mechanisms for treating cancer diseases, such as melanomas. Full article

(This article belongs to the Section Biochemistry)

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Transition Pathway and Its Free-Energy Profile: A Protocol for Protein Folding Simulations

by In-Ho Lee, Seung-Yeon Kim and Jooyoung Lee

Int. J. Mol. Sci. 2013, 14(8), 16058-16075; https://doi.org/10.3390/ijms140816058 - 2 Aug 2013

Cited by 3 | Viewed by 7503

Abstract

We propose a protocol that provides a systematic definition of reaction coordinate and related free-energy profile as the function of temperature for the protein-folding simulation. First, using action-derived molecular dynamics (ADMD), we investigate the dynamic folding pathway model of a protein between a [...] Read more.

We propose a protocol that provides a systematic definition of reaction coordinate and related free-energy profile as the function of temperature for the protein-folding simulation. First, using action-derived molecular dynamics (ADMD), we investigate the dynamic folding pathway model of a protein between a fixed extended conformation and a compact conformation. We choose the pathway model to be the reaction coordinate, and the folding and unfolding processes are characterized by the ADMD step index, in contrast to the common a priori reaction coordinate as used in conventional studies. Second, we calculate free-energy profile as the function of temperature, by employing the replica-exchange molecular dynamics (REMD) method. The current method provides efficient exploration of conformational space and proper characterization of protein folding/unfolding dynamics from/to an arbitrary extended conformation. We demonstrate that combination of the two simulation methods, ADMD and REMD, provides understanding on molecular conformational changes in proteins. The protocol is tested on a small protein, penta-peptide of met-enkephalin. For the neuropeptide met-enkephalin system, folded, extended, and intermediate sates are well-defined through the free-energy profile over the reaction coordinate. Results are consistent with those in the literature. Full article

(This article belongs to the Special Issue Protein Folding)

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Acetylcholinesterase Reactivators (HI-6, Obidoxime, Trimedoxime, K027, K075, K127, K203, K282): Structural Evaluation of Human Serum Albumin Binding and Absorption Kinetics

by Filip Zemek, Jana Karasova Zdarova, Vendula Sepsova and Kamil Kuca

Int. J. Mol. Sci. 2013, 14(8), 16076-16086; https://doi.org/10.3390/ijms140816076 - 2 Aug 2013

Cited by 14 | Viewed by 7141

Abstract

Acetylcholinesterase (AChE) reactivators (oximes) are compounds predominantly targeting the active site of the enzyme. Toxic effects of organophosphates nerve agents (OPNAs) are primarily related to their covalent binding to AChE and butyrylcholinesterase (BChE), critical detoxification enzymes in the blood and in the central [...] Read more.

Acetylcholinesterase (AChE) reactivators (oximes) are compounds predominantly targeting the active site of the enzyme. Toxic effects of organophosphates nerve agents (OPNAs) are primarily related to their covalent binding to AChE and butyrylcholinesterase (BChE), critical detoxification enzymes in the blood and in the central nervous system (CNS). After exposure to OPNAs, accumulation of acetylcholine (ACh) overstimulates receptors and blocks neuromuscular junction transmission resulting in CNS toxicity. Current efforts at treatments for OPNA exposure are focused on non-quaternary reactivators, monoisonitrosoacetone oximes (MINA), and diacylmonoxime reactivators (DAM). However, so far only quaternary oximes have been approved for use in cases of OPNA intoxication. Five acetylcholinesterase reactivator candidates (K027, K075, K127, K203, K282) are presented here, together with pharmacokinetic data (plasma concentration, human serum albumin binding potency). Pharmacokinetic curves based on intramuscular application of the tested compounds are given, with binding information and an evaluation of structural relationships. Human Serum Albumin (HSA) binding studies have not yet been performed on any acetylcholinesterase reactivators, and correlations between structure, concentration curves and binding are vital for further development. HSA bindings of the tested compounds were 1% (HI-6), 7% (obidoxime), 6% (trimedoxime), and 5%, 10%, 4%, 15%, and 12% for K027, K075, K127, K203, and K282, respectively. Full article

(This article belongs to the Section Biochemistry)

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MicroRNA Expression Changes during Interferon-Beta Treatment in the Peripheral Blood of Multiple Sclerosis Patients

by Michael Hecker, Madhan Thamilarasan, Dirk Koczan, Ina Schröder, Kristin Flechtner, Sherry Freiesleben, Georg Füllen, Hans-Jürgen Thiesen and Uwe Klaus Zettl

Int. J. Mol. Sci. 2013, 14(8), 16087-16110; https://doi.org/10.3390/ijms140816087 - 5 Aug 2013

Cited by 114 | Viewed by 12162

Abstract

MicroRNAs (miRNAs) are small non-coding RNA molecules acting as post-transcriptional regulators of gene expression. They are involved in many biological processes, and their dysregulation is implicated in various diseases, including multiple sclerosis (MS). Interferon-beta (IFN-beta) is widely used as a first-line immunomodulatory treatment [...] Read more.

MicroRNAs (miRNAs) are small non-coding RNA molecules acting as post-transcriptional regulators of gene expression. They are involved in many biological processes, and their dysregulation is implicated in various diseases, including multiple sclerosis (MS). Interferon-beta (IFN-beta) is widely used as a first-line immunomodulatory treatment of MS patients. Here, we present the first longitudinal study on the miRNA expression changes in response to IFN-beta therapy. Peripheral blood mononuclear cells (PBMC) were obtained before treatment initiation as well as after two days, four days, and one month, from patients with clinically isolated syndrome (CIS) and patients with relapsing-remitting MS (RRMS). We measured the expression of 651 mature miRNAs and about 19,000 mRNAs in parallel using real-time PCR arrays and Affymetrix microarrays. We observed that the up-regulation of IFN-beta-responsive genes is accompanied by a down-regulation of several miRNAs, including members of the mir-29 family. These differentially expressed miRNAs were found to be associated with apoptotic processes and IFN feedback loops. A network of miRNA-mRNA target interactions was constructed by integrating the information from different databases. Our results suggest that miRNA-mediated regulation plays an important role in the mechanisms of action of IFN-beta, not only in the treatment of MS but also in normal immune responses. miRNA expression levels in the blood may serve as a biomarker of the biological effects of IFN-beta therapy that may predict individual disease activity and progression. Full article

(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)

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Gender-Dependent Effects of Enriched Environment and Social Isolation in Ischemic Retinal Lesion in Adult Rats

by Peter Kiss, Krisztina Szabadfi, Gabor Horvath, Andrea Tamas, Jozsef Farkas, Robert Gabriel and Dora Reglodi

Int. J. Mol. Sci. 2013, 14(8), 16111-16123; https://doi.org/10.3390/ijms140816111 - 5 Aug 2013

Cited by 13 | Viewed by 7112

Abstract

Exposure to an enriched environment has been shown to have many positive effects on brain structure and function. Numerous studies have proven that enriched environment can reduce the lesion induced by toxic and traumatic injuries. Impoverished environment, on the other hand, can have [...] Read more.

Exposure to an enriched environment has been shown to have many positive effects on brain structure and function. Numerous studies have proven that enriched environment can reduce the lesion induced by toxic and traumatic injuries. Impoverished environment, on the other hand, can have deleterious effects on the outcome of neuronal injuries. We have previously shown that enriched conditions have protective effects in retinal injury in newborn rats. It is well-known that the efficacy of neuroprotective strategies can depend on age and gender. The aim of the present study, therefore, was to examine the effects of environmental enrichment and social isolation in retinal ischemia. We used bilateral common carotid artery occlusion to induce retinal hypoperfusion in adult Wistar rats of both genders. Groups were housed in standard, enriched or impoverished conditions. Impoverished environment was induced by social isolation. Retinas were processed for histological analysis after two weeks of survival. In the present study, we show that (1) enriched environment has protective effects in adult ischemic retinal lesion, while (2) impoverished environment further increases the degree of ischemic injury, and (3) that these environmental effects are gender-dependent: females are less responsive to the positive effects of environmental enrichment and more vulnerable to retinal ischemia in social isolation. In summary, our present study shows that the effects of both positive and negative environmental stimuli are gender-dependent in ischemic retinal lesions. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2014)

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Comparative Analysis of Osteogenic/Chondrogenic Differentiation Potential in Primary Limb Bud-Derived and C3H10T1/2 Cell Line-Based Mouse Micromass Cultures

by Roland Takács, Csaba Matta, Csilla Somogyi, Tamás Juhász and Róza Zákány

Int. J. Mol. Sci. 2013, 14(8), 16141-16167; https://doi.org/10.3390/ijms140816141 - 5 Aug 2013

Cited by 27 | Viewed by 11885

Abstract

Murine micromass models have been extensively applied to study chondrogenesis and osteogenesis to elucidate pathways of endochondral bone formation. Here we provide a detailed comparative analysis of the differentiation potential of micromass cultures established from either BMP-2 overexpressing C3H10T1/2 cells or mouse embryonic [...] Read more.

Murine micromass models have been extensively applied to study chondrogenesis and osteogenesis to elucidate pathways of endochondral bone formation. Here we provide a detailed comparative analysis of the differentiation potential of micromass cultures established from either BMP-2 overexpressing C3H10T1/2 cells or mouse embryonic limb bud-derived chondroprogenitor cells, using micromass cultures from untransfected C3H10T1/2 cells as controls. Although the BMP-2 overexpressing C3H10T1/2 cells failed to form chondrogenic nodules, cells of both models expressed mRNA transcripts for major cartilage-specific marker genes including Sox9, Acan, Col2a1, Snorc, and Hapln1 at similar temporal sequence, while notable lubricin expression was only detected in primary cultures. Furthermore, mRNA transcripts for markers of osteogenic differentiation including Runx2, Osterix, alkaline phosphatase, osteopontin and osteocalcin were detected in both models, along with matrix calcification. Although the adipogenic lineage-specific marker gene FABP4 was also expressed in micromass cultures, Oil Red O-positive cells along with PPARγ2 transcripts were only detected in C3H10T1/2-derived micromass cultures. Apart from lineage-specific marker genes, pluripotency factors (Nanog and Sox2) were also expressed in these models, reflecting on the presence of various mesenchymal lineages as well as undifferentiated cells. This cellular heterogeneity has to be taken into consideration for the interpretation of data obtained by using these models. Full article

(This article belongs to the Special Issue The Chondrocyte Phenotype in Cartilage Biology)

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Arbuscular Mycorrhizal Fungi and Plant Growth-Promoting Pseudomonads Increases Anthocyanin Concentration in Strawberry Fruits (Fragaria x ananassa var. Selva) in Conditions of Reduced Fertilization

by Guido Lingua, Elisa Bona, Paola Manassero, Francesco Marsano, Valeria Todeschini, Simone Cantamessa, Andrea Copetta, Giovanni D'Agostino, Elisa Gamalero and Graziella Berta

Int. J. Mol. Sci. 2013, 14(8), 16207-16225; https://doi.org/10.3390/ijms140816207 - 6 Aug 2013

Cited by 134 | Viewed by 12446

Abstract

Anthocyanins are a group of common phenolic compounds in plants. They are mainly detected in flowers and fruits, are believed to play different important roles such as in the attraction of animals and seed dispersal, and also in the increase of the antioxidant [...] Read more.

Anthocyanins are a group of common phenolic compounds in plants. They are mainly detected in flowers and fruits, are believed to play different important roles such as in the attraction of animals and seed dispersal, and also in the increase of the antioxidant response in tissues directly or indirectly affected by biotic or abiotic stress factors. As a major group of secondary metabolites in plants commonly consumed as food, they are of importance in both the food industry and human nutrition. It is known that arbuscular mycorrhizal (AM) fungi can influence the plant secondary metabolic pathways such as the synthesis of essential oils in aromatic plants, of secondary metabolites in roots, and increase flavonoid concentration. Plant Growth-Promoting Bacteria (PGPB) are able to increase plant growth, improving plant nutrition and supporting plant development under natural or stressed conditions. Various studies confirmed that a number of bacterial species living on and inside the root system are beneficial for plant growth, yield and crop quality. In this work it is shown that inoculation with AM fungi and/or with selected and tested Pseudomonas strains, under conditions of reduced fertilization, increases anthocyanin concentration in the fruits of strawberry. Full article

(This article belongs to the Special Issue Molecular Research in Plant Secondary Metabolism)

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Involvement of miR-20a in Promoting Gastric Cancer Progression by Targeting Early Growth Response 2 (EGR2)

by Xiangsheng Li, Zhichao Zhang, Ming Yu, Liqi Li, Guangsheng Du, Weidong Xiao and Hua Yang

Int. J. Mol. Sci. 2013, 14(8), 16226-16239; https://doi.org/10.3390/ijms140816226 - 6 Aug 2013

Cited by 82 | Viewed by 8928

Abstract

Gastric cancer (GC) is one of the most common cancers, with high incidences in East Asia. microRNAs (miRNAs) play essential roles in the carcinogenesis of GC. miR-20a was elevated in GC, while the potential function of miR-20a was poorly understood. miR-20a expression was [...] Read more.

Gastric cancer (GC) is one of the most common cancers, with high incidences in East Asia. microRNAs (miRNAs) play essential roles in the carcinogenesis of GC. miR-20a was elevated in GC, while the potential function of miR-20a was poorly understood. miR-20a expression was examined in GC tissues and cell lines. The effects of miR-20a on the growth, migration, invasion, and chemoresistance of GC cells were examined. Luciferase reporter assay and Western blot were used to screen the target of miR-20a. miR-20a was increased in GC tissues and cell lines. miR-20a promoted the growth, migration and invasion of GC cells, enhanced the chemoresistance of GC cells to cisplatin and docetaxel. Luciferase activity and Western blot confirmed that miR-20a negatively regulated EGR2 expression. Overexpression of EGR2 significantly attenuated the oncogenic effect of miR-20a. miR-20a was involved in the carcinogenesis of GC through modulation of the EGR2 signaling pathway. Full article

(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)

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Domain Structures in Nematic Liquid Crystals on a Polycarbonate Surface

by Alexander M. Parshin, Vladimir A. Gunyakov, Victor Y. Zyryanov and Vasily F. Shabanov

Int. J. Mol. Sci. 2013, 14(8), 16303-16320; https://doi.org/10.3390/ijms140816303 - 7 Aug 2013

Cited by 30 | Viewed by 9805

Abstract

Alignment of nematic liquid crystals on polycarbonate films obtained with the use of solvents with different solvations is studied. Domain structures occurring during the growth on the polymer surface against the background of the initial thread-like or schlieren texture are demonstrated. It is [...] Read more.

Alignment of nematic liquid crystals on polycarbonate films obtained with the use of solvents with different solvations is studied. Domain structures occurring during the growth on the polymer surface against the background of the initial thread-like or schlieren texture are demonstrated. It is established by optical methods that the domains are stable formations visualizing the polymer surface structures. In nematic droplets, the temperature-induced transition from the domain structure with two extinction bands to the structure with four bands is observed. This transition is shown to be caused by reorientation of the nematic director in the liquid crystal volume from the planar alignment to the homeotropic state with the pronounced radial configuration of nematic molecules on the surface. The observed textures are compared with different combinations of the volume LC orientations and the radial distribution of the director field and the disclination lines at the polycarbonate surface. Full article

(This article belongs to the Special Issue Experimental and Theoretical Studies of Liquid Crystalline Materials: Where Do We Stand after 120 Years?)

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The Efficacy of the Quorum Sensing Inhibitor FS8 and Tigecycline in Preventing Prosthesis Biofilm in an Animal Model of Staphylococcal Infection

by Oriana Simonetti, Oscar Cirioni, Federico Mocchegiani, Ivana Cacciatore, Carmela Silvestri, Leonardo Baldassarre, Fiorenza Orlando, Pamela Castelli, Mauro Provinciali, Marco Vivarelli, Erika Fornasari, Andrea Giacometti and Annamaria Offidani

Int. J. Mol. Sci. 2013, 14(8), 16321-16332; https://doi.org/10.3390/ijms140816321 - 7 Aug 2013

Cited by 38 | Viewed by 8322

Abstract

We investigated the efficacy of tigecycline and FS8, alone or combined, in preventing prosthesis biofilm in a rat model of staphylococcal vascular graft infection. Graft infections were established in the back subcutaneous tissue of adult male Wistar rats by implantation of Dacron prostheses [...] Read more.

We investigated the efficacy of tigecycline and FS8, alone or combined, in preventing prosthesis biofilm in a rat model of staphylococcal vascular graft infection. Graft infections were established in the back subcutaneous tissue of adult male Wistar rats by implantation of Dacron prostheses followed by topical inoculation with 2 x 10⁷ colony-forming units of Staphylococcus aureus, strain Smith diffuse. The study included a control group, a contaminated group that did not receive any antibiotic prophylaxis, and three contaminated groups that received: (i) intraperitoneal tigecycline, (ii) FS8-soaked graft, and (iii) tigecycline plus FS8-soaked graft, respectively. Each group included 15 animals. The infection burden was evaluated by using sonication and quantitative agar culture. Moreover, an in vitro binding-study was performed to quantify the how much FS8 was coated to the surface of the prosthesis. Tigecycline, combined with FS8, against the adherent bacteria showed MICs (2.00 mg/L) and MBCs (4.00 mg/L) four-fold lower with respect to tigecycline alone in in vitro studies. The rat groups treated with tigecycline showed the lowest bacterial numbers (4.4 x 10⁴ ± 1.2 x 10⁴ CFU/mL). The FS8-treated group showed a good activity and significant differences compared to control group with bacterial numbers of 6.8 x 10⁴ ± 2.0 x 10⁴ CFU/mL. A stronger inhibition of bacterial growth was observed in rats treated with a combined FS8 and tigecycline therapy than in those that were singly treated with bacterial numbers of 10¹ CFU/mL graft. In conclusion, the ability to affect biofilm formation as well, its property to be an antibiotic enhancer suggests FS8 as alternative or additional agent to use in conjunction with conventional antimicrobial for prevention of staphylococcal biofilm related infection. Full article

(This article belongs to the Special Issue Quorum Sensing Research in Microbial Systems)

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The Effects of Biopolymer Encapsulation on Total Lipids and Cholesterol in Egg Yolk during in Vitro Human Digestion

by Sun-Jin Hur, Young-Chan Kim, Inwook Choi and Si-Kyung Lee

Int. J. Mol. Sci. 2013, 14(8), 16333-16347; https://doi.org/10.3390/ijms140816333 - 7 Aug 2013

Cited by 22 | Viewed by 7385

Abstract

The purpose of this study was to examine the effect of biopolymer encapsulation on the digestion of total lipids and cholesterol in egg yolk using an in vitro human digestion model. Egg yolks were encapsulated with 1% cellulose, pectin, or chitosan. The samples [...] Read more.

The purpose of this study was to examine the effect of biopolymer encapsulation on the digestion of total lipids and cholesterol in egg yolk using an in vitro human digestion model. Egg yolks were encapsulated with 1% cellulose, pectin, or chitosan. The samples were then passed through an in vitro human digestion model that simulated the composition of mouth saliva, stomach acid, and the intestinal juice of the small intestine by using a dialysis tubing system. The change in digestion of total lipids was monitored by confocal fluorescence microscopy. The digestion rate of total lipids and cholesterol in all egg yolk samples dramatically increased after in vitro human digestion. The digestion rate of total lipids and cholesterol in egg yolks encapsulated with chitosan or pectin was reduced compared to the digestion rate of total lipids and cholesterol in other egg yolk samples. Egg yolks encapsulated with pectin or chitosan had lower free fatty acid content, and lipid oxidation values than samples without biopolymer encapsulation. Moreover, the lipase activity decreased, after in vitro digestion, in egg yolks encapsulated with biopolymers. These results improve our understanding of the effects of digestion on total lipids and cholesterol in egg yolk within the gastrointestinal tract. Full article

(This article belongs to the Section Biochemistry)

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Liquid Crystal Phase Behaviour of Attractive Disc-Like Particles

by Liang Wu, George Jackson and Erich A. Müller

Int. J. Mol. Sci. 2013, 14(8), 16414-16442; https://doi.org/10.3390/ijms140816414 - 8 Aug 2013

Cited by 10 | Viewed by 8314

Abstract

We employ a generalized van der Waals-Onsager perturbation theory to construct a free energy functional capable of describing the thermodynamic properties and orientational order of the isotropic and nematic phases of attractive disc particles. The model mesogen is a hard (purely repulsive) cylindrical [...] Read more.

We employ a generalized van der Waals-Onsager perturbation theory to construct a free energy functional capable of describing the thermodynamic properties and orientational order of the isotropic and nematic phases of attractive disc particles. The model mesogen is a hard (purely repulsive) cylindrical disc particle decorated with an anisotropic square-well attractive potential placed at the centre of mass. Even for isotropic attractive interactions, the resulting overall inter-particle potential is anisotropic, due to the orientation-dependent excluded volume of the underlying hard core. An algebraic equation of state for attractive disc particles is developed by adopting the Onsager trial function to characterize the orientational order in the nematic phase. The theory is then used to represent the fluid-phase behaviour (vapour-liquid, isotropic-nematic, and nematic-nematic) of the oblate attractive particles for varying values of the molecular aspect ratio and parameters of the attractive potential. When compared to the phase diagram of their athermal analogues, it is seen that the addition of an attractive interaction facilitates the formation of orientationally-ordered phases. Most interestingly, for certain aspect ratios, a coexistence between two anisotropic nematic phases is exhibited by the attractive disc-like fluids. Full article

(This article belongs to the Special Issue Experimental and Theoretical Studies of Liquid Crystalline Materials: Where Do We Stand after 120 Years?)

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A Nitric Oxide-Responsive Quorum Sensing Circuit in Vibrio harveyi Regulates Flagella Production and Biofilm Formation

by Bernadette M. Henares, Yueming Xu and Elizabeth M. Boon

Int. J. Mol. Sci. 2013, 14(8), 16473-16484; https://doi.org/10.3390/ijms140816473 - 8 Aug 2013

Cited by 50 | Viewed by 8463

Abstract

Cell signaling plays an important role in the survival of bacterial colonies. They use small molecules to coordinate gene expression in a cell density dependent manner. This process, known as quorum sensing, helps bacteria regulate diverse functions such as bioluminescence, biofilm formation and [...] Read more.

Cell signaling plays an important role in the survival of bacterial colonies. They use small molecules to coordinate gene expression in a cell density dependent manner. This process, known as quorum sensing, helps bacteria regulate diverse functions such as bioluminescence, biofilm formation and virulence. In Vibrio harveyi, a bioluminescent marine bacterium, four parallel quorum-sensing systems have been identified to regulate light production. We have previously reported that nitric oxide (NO), through the H-NOX/HqsK quorum sensing pathway contributes to light production in V. harveyi through the LuxU/LuxO/LuxR quorum sensing pathway. In this study, we show that nitric oxide (NO) also regulates flagellar production and enhances biofilm formation. Our data suggest that V. harveyi is capable of switching between lifestyles to be able to adapt to changes in the environment. Full article

(This article belongs to the Special Issue Quorum Sensing Research in Microbial Systems)

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Correlation of Dual Colour Single Particle Trajectories for Improved Detection and Analysis of Interactions in Living Cells

by Hendrik Deschout, Thomas Martens, Dries Vercauteren, Katrien Remaut, Jo Demeester, Stefaan C. De Smedt, Kristiaan Neyts and Kevin Braeckmans

Int. J. Mol. Sci. 2013, 14(8), 16485-16514; https://doi.org/10.3390/ijms140816485 - 8 Aug 2013

Cited by 13 | Viewed by 7345

Abstract

Interactions between objects inside living cells are often investigated by looking for colocalization between fluorescence microscopy images that are recorded in separate colours corresponding to the fluorescent label of each object. The fundamental limitation of this approach in the case of dynamic objects [...] Read more.

Interactions between objects inside living cells are often investigated by looking for colocalization between fluorescence microscopy images that are recorded in separate colours corresponding to the fluorescent label of each object. The fundamental limitation of this approach in the case of dynamic objects is that coincidental colocalization cannot be distinguished from true interaction. Instead, correlation between motion trajectories obtained by dual colour single particle tracking provides a much stronger indication of interaction. However, frequently occurring phenomena in living cells, such as immobile phases or transient interactions, can limit the correlation to small parts of the trajectories. The method presented here, developed for the detection of interaction, is based on the correlation inside a window that is scanned along the trajectories, covering different subsets of the positions. This scanning window method was validated by simulations and, as an experimental proof of concept, it was applied to the investigation of the intracellular trafficking of polymeric gene complexes by endosomes in living retinal pigment epithelium cells, which is of interest to ocular gene therapy. Full article

(This article belongs to the Special Issue Frontiers of Micro-Spectroscopy in Biological Applications)

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Structural Variations in Articular Cartilage Matrix Are Associated with Early-Onset Osteoarthritis in the Spondyloepiphyseal Dysplasia Congenita (Sedc) Mouse

by David W. Macdonald, Ryan S. Squires, Shaela A. Avery, Jason Adams, Melissa Baker, Christopher R. Cunningham, Nicholas B. Heimann, David L. Kooyman and Robert E. Seegmiller

Int. J. Mol. Sci. 2013, 14(8), 16515-16531; https://doi.org/10.3390/ijms140816515 - 9 Aug 2013

Cited by 13 | Viewed by 10164

Abstract

Heterozgyous spondyloepiphyseal dysplasia congenita (sedc/+) mice expressing a missense mutation in col2a1 exhibit a normal skeletal morphology but early-onset osteoarthritis (OA). We have recently examined knee articular cartilage obtained from homozygous (sedc/sedc) mice, which express a Stickler-like phenotype including [...] Read more.

Heterozgyous spondyloepiphyseal dysplasia congenita (sedc/+) mice expressing a missense mutation in col2a1 exhibit a normal skeletal morphology but early-onset osteoarthritis (OA). We have recently examined knee articular cartilage obtained from homozygous (sedc/sedc) mice, which express a Stickler-like phenotype including dwarfism. We examined sedc/sedc mice at various levels to better understand the mechanistic process resulting in OA. Mutant sedc/sedc, and control (+/+) cartilages were compared at two, six and nine months of age. Tissues were fixed, decalcified, processed to paraffin sections, and stained with hematoxylin/eosin and safranin O/fast green. Samples were analyzed under the light microscope and the modified Mankin and OARSI scoring system was used to quantify the OA-like changes. Knees were stained with 1C10 antibody to detect the presence and distribution of type II collagen. Electron microscopy was used to study chondrocyte morphology and collagen fibril diameter. Compared with controls, mutant articular cartilage displayed decreased fibril diameter concomitant with increases in size of the pericellular space, Mankin and OARSI scores, cartilage thickness, chondrocyte clustering, proteoglycan staining and horizontal fissuring. In conclusion, homozygous sedc mice are subject to early-onset knee OA. We conclude that collagen in the mutant’s articular cartilage (both heterozygote and homozygote) fails to provide the normal meshwork required for matrix integrity and overall cartilage stability. Full article

(This article belongs to the Section Biochemistry)

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Skp2 Regulates Subcellular Localization of PPARγ by MEK Signaling Pathways in Human Breast Cancer

by Hongge Cheng, Jie Meng, Guisheng Wang, Yuming Meng, Yu Li, Dong Wei, Chunyun Fu, Kaifeng Deng, Aiguo Shen, Huimin Wang and Shengming Dai

Int. J. Mol. Sci. 2013, 14(8), 16554-16569; https://doi.org/10.3390/ijms140816554 - 9 Aug 2013

Cited by 10 | Viewed by 7515

Abstract

Nuclear hormone receptor family member PPARγ plays an important role in mammary gland tumorigenesis. Previous studies have shown PPARγ has cytoplasmic activities upon tetradecanoyl phorbol acetate (TPA) stimulation. However, the clinical pathological significance of cytoplasmic PPARγ is not completely understood in human breast [...] Read more.

Nuclear hormone receptor family member PPARγ plays an important role in mammary gland tumorigenesis. Previous studies have shown PPARγ has cytoplasmic activities upon tetradecanoyl phorbol acetate (TPA) stimulation. However, the clinical pathological significance of cytoplasmic PPARγ is not completely understood in human breast cancer. Skp2 is oncogenic, and its frequent amplification and overexpression correlated with the grade of malignancy. In this study, the role of cytoplasmic PPARγ and Skp2 expression was investigated in human breast cancer progression. Therefore, immunohistochemical analysis was performed on formalin-fixed paraffin sections of 70 specimens. Furthermore, Western blot and immunofluorescence microscopy analysis were used to study the relationship between expression of cytoplasmic PPARγ and Skp2 expression in human breast cancer cells in vitro. Results showed that the expression of cytoplasmic PPARγ was positively correlated with Skp2 expression (p < 0.05), and correlated significantly with estrogen receptor (p = 0.026) and pathological grade (p = 0.029), respectively. In addition, Skp2 overexpression can provoke cytoplasmic localization of PPARγ upon MEK1-dependent mechanisms in human breast cancer cells by nuclear-cytosolic fractionation technology and immunofluorescence microscopy analysis. Using RNA interference technology, we also found that down-regulated Skp2 reduced the phosphorylation level of MEK1 and significantly reversed TPA-induced nuclear export of PPARγ in MDA-MB-231 cells. The changes in the subcellular localization of PPARγ may represent a novel target for selective interference in patients with breast cancer. Full article

(This article belongs to the Section Biochemistry)

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Cadmium Modifies the Cell Cycle and Apoptotic Profiles of Human Breast Cancer Cells Treated with 5-Fluorouracil

by Yolande Asara, Juan A. Marchal, Esther Carrasco, Houria Boulaiz, Giuliana Solinas, Pasquale Bandiera, Maria A. Garcia, Cristiano Farace, Andrea Montella and Roberto Madeddu

Int. J. Mol. Sci. 2013, 14(8), 16600-16616; https://doi.org/10.3390/ijms140816600 - 12 Aug 2013

Cited by 53 | Viewed by 8721

Abstract

Industrialisation, the proximity of factories to cities, and human work activities have led to a disproportionate use of substances containing heavy metals, such as cadmium (Cd), which may have deleterious effects on human health. Carcinogenic effects of Cd and its relationship with breast [...] Read more.

Industrialisation, the proximity of factories to cities, and human work activities have led to a disproportionate use of substances containing heavy metals, such as cadmium (Cd), which may have deleterious effects on human health. Carcinogenic effects of Cd and its relationship with breast cancer, among other tumours, have been reported. 5-Fluorouracil (5-FU) is a fluoropyrimidine anticancer drug used to treat solid tumours of the colon, breast, stomach, liver, and pancreas. The purpose of this work was to study the effects of Cd on cell cycle, apoptosis, and gene and protein expression in MCF-7 breast cancer cells treated with 5-FU. Cd altered the cell cycle profile, and its effects were greater when used either alone or in combination with 5-FU compared with 5-FU alone. Cd significantly suppressed apoptosis of MCF-7 cells pre-treated with 5-FU. Regarding gene and protein expression, bcl2 expression was mainly upregulated by all treatments involving Cd. The expression of caspase 8 and caspase 9 was decreased by most of the treatments and at all times evaluated. C-myc expression was increased by all treatments involving Cd, especially 5-FU plus Cd at the half time of treatment. Cd plus 5-FU decreased cyclin D1 and increased cyclin A1 expression. In conclusion, our results indicate that exposure to Cd blocks the anticancer effects of 5-FU in MCF-7 cells. These results could have important clinical implications in patients treated with 5-FU-based therapies and who are exposed to high levels of Cd. Full article

(This article belongs to the Section Molecular Toxicology)

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Glycogen Synthase Kinase 3β Inhibition as a Therapeutic Approach in the Treatment of Endometrial Cancer

by Yan Yin, Nora T. Kizer, Premal H. Thaker, Katherine B. Chiappinelli, Kathryn M. Trinkaus, Paul J. Goodfellow and Liang Ma

Int. J. Mol. Sci. 2013, 14(8), 16617-16637; https://doi.org/10.3390/ijms140816617 - 12 Aug 2013

Cited by 17 | Viewed by 8005

Abstract

Alternative strategies beyond current chemotherapy and radiation therapy regimens are needed in the treatment of advanced stage and recurrent endometrial cancers. There is considerable promise for biologic agents targeting the extracellular signal-regulated kinase (ERK) pathway for treatment of these cancers. Many downstream substrates [...] Read more.

Alternative strategies beyond current chemotherapy and radiation therapy regimens are needed in the treatment of advanced stage and recurrent endometrial cancers. There is considerable promise for biologic agents targeting the extracellular signal-regulated kinase (ERK) pathway for treatment of these cancers. Many downstream substrates of the ERK signaling pathway, such as glycogen synthase kinase 3β (GSK3β), and their roles in endometrial carcinogenesis have not yet been investigated. In this study, we tested the importance of GSK3β inhibition in endometrial cancer cell lines and in vivo models. Inhibition of GSK3β by either lithium chloride (LiCl) or specific GSK3β inhibitor VIII showed cytostatic and cytotoxic effects on multiple endometrial cancer cell lines, with little effect on the immortalized normal endometrial cell line. Flow cytometry and immunofluorescence revealed a G2/M cell cycle arrest in both type I (AN3CA, KLE, and RL952) and type II (ARK1) endometrial cancer cell lines. In addition, LiCl pre-treatment sensitized AN3CA cells to the chemotherapy agent paclitaxel. Administration of LiCl to AN3CA tumor-bearing mice resulted in partial or complete regression of some tumors. Thus, GSK3β activity is associated with endometrial cancer tumorigenesis and its pharmacologic inhibition reduces cell proliferation and tumor growth. Full article

(This article belongs to the Special Issue Molecular Research of Carcinogenesis)

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Physico-Chemical Properties and Phase Behavior of the Ionic Liquid-β-Cyclodextrin Complexes

by Marek Rogalski, Ali Modaressi, Pierre Magri, Fabrice Mutelet, Aleksandra Grydziuszko, Michał Wlazło and Urszula Domańska

Int. J. Mol. Sci. 2013, 14(8), 16638-16655; https://doi.org/10.3390/ijms140816638 - 13 Aug 2013

Cited by 10 | Viewed by 7225

Abstract

The solubility of β-cyclodextrin (β-CD) in ionic liquids (ILs) and the activity coefficients at infinite dilution () of more than 20 solutes (alkanes, aromatic hydrocarbons, alcohols) were measured in four chosen ionic liquids, their mixtures with β-CD, and in the β-CD at high [...] Read more.

The solubility of β-cyclodextrin (β-CD) in ionic liquids (ILs) and the activity coefficients at infinite dilution () of more than 20 solutes (alkanes, aromatic hydrocarbons, alcohols) were measured in four chosen ionic liquids, their mixtures with β-CD, and in the β-CD at high temperatures from 338 to 398 K using the inverse gas chromatography. The intermolecular interactions, inclusion complexes and the possible increasing of the solubility of β-CD in water using the IL are presented. The solubility of β-CD in ten chosen hydrophobic ILs at the temperature T = 423 K was detected. The solid-liquid phase diagrams (SLE) of {IL (1) + β-CD (2)} binary systems at the high mole fraction of the IL were measured for three systems (1-ethyl-3-methylimidazolium chloride, [EMIM][Cl], 1-ethyl-3-methylimidazolium bromide, [EMIM][Br]; and for 1-butyl-3-methylimidazolium chloride, [BMIM][Cl]). The eutectic points were determined at the high IL concentration for all binary systems. The intermolecular interaction and the possibility of inclusion complexes of the IL and/or solvents with β-CD were discussed. The infrared spectroscopy, IR was used for the description of the intermolecular interactions in the (β-CD + IL) systems. It was shown via the activity coefficients at infinite dilution results that the inclusion complexes are dependent on the temperature. The addition of β-CD to the IL does not improve the selectivity of the separation of the aliphatics from aromatics. Full article

(This article belongs to the Section Physical Chemistry, Theoretical and Computational Chemistry)

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Open AccessArticle

Androgen Receptor Phosphorylation at Serine 308 and Serine 791 Predicts Enhanced Survival in Castrate Resistant Prostate Cancer Patients

by Pamela McCall, Claire E. Adams, Jennifer M. Willder, Lindsay Bennett, Tahir Qayyum, Clare Orange, Mark A. Underwood and Joanne Edwards

Int. J. Mol. Sci. 2013, 14(8), 16656-16671; https://doi.org/10.3390/ijms140816656 - 13 Aug 2013

Cited by 14 | Viewed by 7658

Abstract

We previously reported that AR phosphorylation at serine 213 was associated with poor outcome and may contribute to prostate cancer development and progression. This study investigates if specific AR phosphorylation sites have differing roles in the progression of hormone naïve prostate cancer (HNPC) [...] Read more.

We previously reported that AR phosphorylation at serine 213 was associated with poor outcome and may contribute to prostate cancer development and progression. This study investigates if specific AR phosphorylation sites have differing roles in the progression of hormone naïve prostate cancer (HNPC) to castrate resistant disease (CRPC). A panel of phosphospecific antibodies were employed to study AR phosphorylation in 84 matched HNPC and CRPC tumours. Immunohistochemistry measured Androgen receptor expression phosphorylated at serine residues 94 (pAR⁹⁴), 308 (pAR³⁰⁸), 650(pAR⁶⁵⁰) and 791 (pAR⁷⁹¹). No correlations with clinical parameters were observed for pAR⁹⁴ or pAR⁶⁵⁰ in HNPC or CRPC tumours. In contrast to our previous observation with serine 213, high pAR³⁰⁸ is significantly associated with a longer time to disease specific death (p = 0.011) and high pAR⁷⁹¹ expression significantly associated with a longer time to disease recurrence (p = 0.018) in HNPC tumours and longer time to death from disease recurrence (p = 0.040) in CRPC tumours. This observation in CRPC tumours was attenuated in high apoptotic tumours (p = 0.022) and low proliferating tumours (p = 0.004). These results demonstrate that understanding the differing roles of AR phosphorylation is necessary before this can be exploited as a target for castrate resistant prostate cancer. Full article

(This article belongs to the Special Issue Molecular Research in Urology)

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Molecular and Functional Analyses of the Fast Skeletal Myosin Light Chain2 Gene of the Korean Oily Bitterling, Acheilognathus koreensis

by Hee Jeong Kong, Ye-Ji Lee, Woo-Jin Kim, Hyung Soo Kim, Bong-Seok Kim, Cheul Min An, Sang-Yeob Yeo and Hyun Kook Cho

Int. J. Mol. Sci. 2013, 14(8), 16672-16684; https://doi.org/10.3390/ijms140816672 - 13 Aug 2013

Cited by 3 | Viewed by 6743

Abstract

We identified and characterized the primary structure of the Korean oily bitterling Acheilognathus koreensis fast skeletal myosin light chain 2 (Akmlc2f), gene. Encoded by seven exons spanning 3955 bp, the deduced 168-amino acid AkMLC2f polypeptide contained an EF-hand calcium-binding motif and [...] Read more.

We identified and characterized the primary structure of the Korean oily bitterling Acheilognathus koreensis fast skeletal myosin light chain 2 (Akmlc2f), gene. Encoded by seven exons spanning 3955 bp, the deduced 168-amino acid AkMLC2f polypeptide contained an EF-hand calcium-binding motif and showed strong homology (80%–98%) with the MLC2 proteins of Ictalurus punctatus and other species, including mammals. Akmlc2f mRNA was highly enriched in skeletal muscles, and was detectable in other tissues. The upstream regions of Akmlc2f included a TATA box, one copy of a putative MEF-2 binding site and several putative C/EBPβ binding sites. The functional activity of the promoter region of Akmlc2f was examined using luciferase and red fluorescent protein reporters. The Akmlc2f promoter-driven reporter expressions were detected and increased by the C/EBPβ transcription factor in HEK293T cells. The activity of the promoter of Akmlc2f was also confirmed in the developing zebrafish embryo. Although the detailed mechanism underlying the expression of Akmlc2f remains unknown, these results suggest the muscle-specific expression of Akmlc2f transcript and the functional activation of Akmlc2f promoter by C/EBPβ. Full article

(This article belongs to the Section Biochemistry)

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Using Synchrotron Radiation-Based Infrared Microspectroscopy to Reveal Microchemical Structure Characterization: Frost Damaged Wheat vs. Normal Wheat

by Hangshu Xin, Xuewei Zhang and Peiqiang Yu

Int. J. Mol. Sci. 2013, 14(8), 16706-16718; https://doi.org/10.3390/ijms140816706 - 14 Aug 2013

Cited by 22 | Viewed by 6835

Abstract

This study was conducted to compare: (1) protein chemical characteristics, including the amide I and II region, as well as protein secondary structure; and (2) carbohydrate internal structure and functional groups spectral intensities between the frost damaged wheat and normal wheat using synchrotron [...] Read more.

This study was conducted to compare: (1) protein chemical characteristics, including the amide I and II region, as well as protein secondary structure; and (2) carbohydrate internal structure and functional groups spectral intensities between the frost damaged wheat and normal wheat using synchrotron radiation-based Fourier transform infrared microspectroscopy (SR-FTIRM). Fingerprint regions of specific interest in our study involved protein and carbohydrate functional group band assignments, including protein amide I and II (ca. 1774–1475 cm⁻¹), structural carbohydrates (SCHO, ca. 1498–1176 cm⁻¹), cellulosic compounds (CELC, ca. 1295–1176 cm⁻¹), total carbohydrates (CHO, ca. 1191–906 cm⁻¹) and non-structural carbohydrates (NSCHO, ca. 954–809 cm⁻¹). The results showed that frost did cause variations in spectral profiles in wheat grains. Compared with healthy wheat grains, frost damaged wheat had significantly lower (p < 0.05) spectral intensities in height and area ratios of amide I to II and almost all the spectral parameters of carbohydrate-related functional groups, including SCHO, CHO and NSCHO. Furthermore, the height ratio of protein amide I to the third peak of CHO and the area ratios of protein amide (amide I + II) to carbohydrate compounds (CHO and SCHO) were also changed (p < 0.05) in damaged wheat grains. It was concluded that the SR-FTIR microspectroscopic technique was able to examine inherent molecular structure features at an ultra-spatial resolution (10 × 10 μm) between different wheat grains samples. The structural characterization of wheat was influenced by climate conditions, such as frost damage, and these structural variations might be a major reason for the decreases in nutritive values, nutrients availability and milling and baking quality in wheat grains. Full article

(This article belongs to the Special Issue Frontiers of Micro-Spectroscopy in Biological Applications)

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Endogenous Protease Nexin-1 Protects against Cerebral Ischemia

by Osvaldo Mirante, Melanie Price, Wilfredo Puentes, Ximena Castillo, Corinne Benakis, Jonathan Thevenet, Denis Monard and Lorenz Hirt

Int. J. Mol. Sci. 2013, 14(8), 16719-16731; https://doi.org/10.3390/ijms140816719 - 14 Aug 2013

Cited by 13 | Viewed by 8385

Abstract

The serine protease thrombin plays a role in signalling ischemic neuronal death in the brain. Paradoxically, endogenous neuroprotective mechanisms can be triggered by preconditioning with thrombin (thrombin preconditioning, TPC), leading to tolerance to cerebral ischemia. Here we studied the role of thrombin’s endogenous [...] Read more.

The serine protease thrombin plays a role in signalling ischemic neuronal death in the brain. Paradoxically, endogenous neuroprotective mechanisms can be triggered by preconditioning with thrombin (thrombin preconditioning, TPC), leading to tolerance to cerebral ischemia. Here we studied the role of thrombin’s endogenous potent inhibitor, protease nexin-1 (PN-1), in ischemia and in tolerance to cerebral ischemia induced by TPC. Cerebral ischemia was modelled in vitro in organotypic hippocampal slice cultures from rats or genetically engineered mice lacking PN-1 or with the reporter gene lacZ knocked into the PN-1 locus PN-1HAPN-1-lacZ/HAPN-1-lacZ (PN-1 KI) exposed to oxygen and glucose deprivation (OGD). We observed increased thrombin enzyme activity in culture homogenates 24 h after OGD. Lack of PN-1 increased neuronal death in the CA1, suggesting that endogenous PN-1 inhibits thrombin-induced neuronal damage after ischemia. OGD enhanced β-galactosidase activity, reflecting PN-1 expression, at one and 24 h, most strikingly in the stratum radiatum, a glial cell layer adjacent to the CA1 layer of ischemia sensitive neurons. TPC, 24 h before OGD, additionally increased PN-1 expression 1 h after OGD, compared to OGD alone. TPC failed to induce tolerance in cultures from PN-1^−/− mice confirming PN-1 as an important TPC target. PN-1 upregulation after TPC was blocked by the c-Jun N-terminal kinase (JNK) inhibitor, L-JNKI1, known to block TPC. This work suggests that PN-1 is an endogenous neuroprotectant in cerebral ischemia and a potential target for neuroprotection. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2014)

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Protein Structures among Bio-Ethanol Co-Products and Its Relationships with Ruminal and Intestinal Availability of Protein in Dairy Cattle

by Arash Azarfar, Arjan Jonker and Peiqiang Yu

Int. J. Mol. Sci. 2013, 14(8), 16802-16816; https://doi.org/10.3390/ijms140816802 - 15 Aug 2013

Cited by 5 | Viewed by 6800

Abstract

The objectives of this study were to reveal molecular structures of protein among different types of the dried distillers grains with solubles (100% wheat DDGS (WDDGS); DDGS blend1 (BDDGS1, corn to wheat ratio 30:70%); DDGS blend2 (BDDGS2, corn to wheat ratio 50:50 percent)) [...] Read more.

The objectives of this study were to reveal molecular structures of protein among different types of the dried distillers grains with solubles (100% wheat DDGS (WDDGS); DDGS blend1 (BDDGS1, corn to wheat ratio 30:70%); DDGS blend2 (BDDGS2, corn to wheat ratio 50:50 percent)) and different batches within DDGS type using diffuse reflectance infrared Fourier transform spectroscopy (DRIFT). Compared with BDDGS1 and BDDGS2, wheat DDGS had higher (p < 0.05) peak area intensities of protein amide I and II and amide I to II intensity ratio. Increasing the corn to wheat ratio form 30:70 to 50:50 in the blend DDGS did not affect amide I and II area intensities and their ratio. Amide I to II peak intensity ratio differed (p < 0.05) among the different batches within WDDGS and BDDGS1. Compared with both blend DDGS types, WDDGS had higher α-helix and β-sheet ratio (p < 0.05), while α-helix to β-sheet ratio was similar among the three DDGS types. The α-helix to β-sheet ratio differed significantly among batches within WDDGS. Principal component analysis (PCA) revealed that protein molecular structures in WDDGS differed from those of BDDGS1 and between different batches within BDDGS1 and BDDGS2. The α-helix to β-sheet ratios of protein in all DDGS types had an influence on availability of protein at the ruminal level as well as at the intestinal level. The α-helix to β-sheet ratio was positively correlated to rumen undegraded protein (r = 0.41, p < 0.05) and unavailable protein (PC; r = 0.59, p < 0.05). Full article

(This article belongs to the Section Biochemistry)

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Trastuzumab-Peptide Interactions: Mechanism and Application in Structure-Based Ligand Design

by Tian-Yang Sun, Qi Wang, Jin Zhang, Tao Wu and Fan Zhang

Int. J. Mol. Sci. 2013, 14(8), 16836-16850; https://doi.org/10.3390/ijms140816836 - 15 Aug 2013

Cited by 24 | Viewed by 9119

Abstract

Understanding of protein-ligand interactions and its influences on protein stability is necessary in the research on all biological processes and correlative applications, for instance, the appropriate affinity ligand design for the purification of bio-drugs. In this study, computational methods were applied to identify [...] Read more.

Understanding of protein-ligand interactions and its influences on protein stability is necessary in the research on all biological processes and correlative applications, for instance, the appropriate affinity ligand design for the purification of bio-drugs. In this study, computational methods were applied to identify binding site interaction details between trastuzumab and its natural receptor. Trastuzumab is an approved antibody used in the treatment of human breast cancer for patients whose tumors overexpress the HER2 (human epidermal growth factor receptor 2) protein. However, rational design of affinity ligands to keep the stability of protein during the binding process is still a challenge. Herein, molecular simulations and quantum mechanics were used on protein-ligand interaction analysis and protein ligand design. We analyzed the structure of the HER2-trastuzumab complex by molecular dynamics (MD) simulations. The interaction energies of the mutated peptides indicate that trastuzumab binds to ligand through electrostatic and hydrophobic interactions. Quantitative investigation of interactions shows that electrostatic interactions play the most important role in the binding of the peptide ligand. Prime/MM-GBSA calculations were carried out to predict the binding affinity of the designed peptide ligands. A high binding affinity and specificity peptide ligand is designed rationally with equivalent interaction energy to the wild-type octadecapeptide. The results offer new insights into affinity ligand design. Full article

(This article belongs to the Special Issue Proteins and Protein-Ligand Interactions)

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Design, Synthesis and DNA Interaction Study of New Potential DNA Bis-Intercalators Based on Glucuronic Acid

by Jiuyang Zhao, Wei Li, Rui Ma, Shaopeng Chen, Sumei Ren and Tao Jiang

Int. J. Mol. Sci. 2013, 14(8), 16851-16865; https://doi.org/10.3390/ijms140816851 - 15 Aug 2013

Cited by 37 | Viewed by 7614

Abstract

A series of novel potential DNA bis-intercalators were designed and synthesized, in which two glucuronic acids were linked by ethylenediamine, and the glucuronic acid was coupled with various chromophores, including quinoline, acridine, indole and purine, at the C-1 position. The preliminary binding properties [...] Read more.

A series of novel potential DNA bis-intercalators were designed and synthesized, in which two glucuronic acids were linked by ethylenediamine, and the glucuronic acid was coupled with various chromophores, including quinoline, acridine, indole and purine, at the C-1 position. The preliminary binding properties of these compounds to calf thymus DNA (CT-DNA) have been investigated by UV-absorption and fluorescence spectroscopy. The results indicated that all the target compounds can interact with CT-DNA, and the acridine derivative, 3b, showed the highest key selection vector (KSV) value, which suggested that compound 3b binds most strongly to CT-DNA. Full article

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L/N-Type Calcium Channel Blocker Cilnidipine Added to Renin-Angiotensin Inhibition Improves Ambulatory Blood Pressure Profile and Suppresses Cardiac Hypertrophy in Hypertension with Chronic Kidney Disease

by Tomohiko Kanaoka, Kouichi Tamura, Hiromichi Wakui, Masato Ohsawa, Kengo Azushima, Kazushi Uneda, Ryu Kobayashi, Tetsuya Fujikawa, Yuko Tsurumi-Ikeya, Akinobu Maeda, Mai Yanagi, Yoshiyuki Toya and Satoshi Umemura

Int. J. Mol. Sci. 2013, 14(8), 16866-16881; https://doi.org/10.3390/ijms140816866 - 16 Aug 2013

Cited by 14 | Viewed by 9402

Abstract

Ambulatory blood pressure (BP) and heart rate (HR) profile are proposed to be related to renal deterioration and cardiovascular complication in hypertension and chronic kidney disease (CKD). In this study, we examined the beneficial effects cilnidipine, a unique L/N-type calcium channel blocker (CCB), [...] Read more.

Ambulatory blood pressure (BP) and heart rate (HR) profile are proposed to be related to renal deterioration and cardiovascular complication in hypertension and chronic kidney disease (CKD). In this study, we examined the beneficial effects cilnidipine, a unique L/N-type calcium channel blocker (CCB), in addition to renin-angiotensin system inhibitors, on ambulatory BP and HR profile, as well as cardiorenal function in hypertensive CKD patients. Forty-five patients were randomly assigned to the cilnidipine replacement group (n = 21) or the control CCBs group (n = 24) during a 24-week active treatment period. Although clinical BP values were similar in the cilnidipine and control CCBs groups after the treatment period, the results of ambulatory BP monitoring showed that the 24-h and daytime systolic BP levels in the cilnidipine group were significantly lower compared with the control group after the study. Furthermore, the left ventricular mass index (LVMI) was significantly decreased in the cilnidipine group compared to the control group after the study (LVMI, 135.3 ± 26.4 versus 181.2 ± 88.4, p = 0.031), with a significant difference in the changes in the LVMI between the cilnidipine and control groups (change in LVMI, −12.4 ± 23.7 versus 26.2 ± 64.4, p = 0.007). These results indicate that cilnidipine is beneficial for the suppression of pathological cardiac remodeling, at least partly, via a superior improving effect on ambulatory BP profile compared with control CCBs in hypertensive CKD patients. Full article

(This article belongs to the Section Biochemistry)

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Oximes: Inhibitors of Human Recombinant Acetylcholinesterase. A Structure-Activity Relationship (SAR) Study

by Vendula Sepsova, Jana Zdarova Karasova, Jan Korabecny, Rafael Dolezal, Filip Zemek, Brian J. Bennion and Kamil Kuca

Int. J. Mol. Sci. 2013, 14(8), 16882-16900; https://doi.org/10.3390/ijms140816882 - 16 Aug 2013

Cited by 42 | Viewed by 9499

Abstract

Acetylcholinesterase (AChE) reactivators were developed for the treatment of organophosphate intoxication. Standard care involves the use of anticonvulsants (e.g., diazepam), parasympatolytics (e.g., atropine) and oximes that restore AChE activity. However, oximes also bind to the active site of AChE, simultaneously acting as reversible [...] Read more.

Acetylcholinesterase (AChE) reactivators were developed for the treatment of organophosphate intoxication. Standard care involves the use of anticonvulsants (e.g., diazepam), parasympatolytics (e.g., atropine) and oximes that restore AChE activity. However, oximes also bind to the active site of AChE, simultaneously acting as reversible inhibitors. The goal of the present study is to determine how oxime structure influences the inhibition of human recombinant AChE (hrAChE). Therefore, 24 structurally different oximes were tested and the results compared to the previous eel AChE (EeAChE) experiments. Structural factors that were tested included the number of pyridinium rings, the length and structural features of the linker, and the number and position of the oxime group on the pyridinium ring. Full article

(This article belongs to the Collection Computational, Structural and Spectroscopic Studies of Enzyme Mechanisms, Inhibition and Dynamics)

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Bioinformatic Prediction of Gene Functions Regulated by Quorum Sensing in the Bioleaching Bacterium Acidithiobacillus ferrooxidans

by Alvaro Banderas and Nicolas Guiliani

Int. J. Mol. Sci. 2013, 14(8), 16901-16916; https://doi.org/10.3390/ijms140816901 - 16 Aug 2013

Cited by 23 | Viewed by 9353

Abstract

The biomining bacterium Acidithiobacillus ferrooxidans oxidizes sulfide ores and promotes metal solubilization. The efficiency of this process depends on the attachment of cells to surfaces, a process regulated by quorum sensing (QS) cell-to-cell signalling in many Gram-negative bacteria. At. ferrooxidans has a functional [...] Read more.

The biomining bacterium Acidithiobacillus ferrooxidans oxidizes sulfide ores and promotes metal solubilization. The efficiency of this process depends on the attachment of cells to surfaces, a process regulated by quorum sensing (QS) cell-to-cell signalling in many Gram-negative bacteria. At. ferrooxidans has a functional QS system and the presence of AHLs enhances its attachment to pyrite. However, direct targets of the QS transcription factor AfeR remain unknown. In this study, a bioinformatic approach was used to infer possible AfeR direct targets based on the particular palindromic features of the AfeR binding site. A set of Hidden Markov Models designed to maintain palindromic regions and vary non-palindromic regions was used to screen for putative binding sites. By annotating the context of each predicted binding site (PBS), we classified them according to their positional coherence relative to other putative genomic structures such as start codons, RNA polymerase promoter elements and intergenic regions. We further used the Multiple EM for Motif Elicitation algorithm (MEME) to further filter out low homology PBSs. In summary, 75 target-genes were identified, 34 of which have a higher confidence level. Among the identified genes, we found afeR itself, zwf, genes encoding glycosyltransferase activities, metallo-beta lactamases, and active transport-related proteins. Glycosyltransferases and Zwf (Glucose 6-phosphate-1-dehydrogenase) might be directly involved in polysaccharide biosynthesis and attachment to minerals by At. ferrooxidans cells during the bioleaching process. Full article

(This article belongs to the Special Issue Quorum Sensing Research in Microbial Systems)

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ACE Inhibition with Captopril Retards the Development of Signs of Neurodegeneration in an Animal Model of Alzheimer’s Disease

by Said AbdAlla, Andreas Langer, Xuebin Fu and Ursula Quitterer

Int. J. Mol. Sci. 2013, 14(8), 16917-16942; https://doi.org/10.3390/ijms140816917 - 16 Aug 2013

Cited by 77 | Viewed by 11864

Abstract

Increased generation of reactive oxygen species (ROS) is a significant pathological feature in the brains of patients with Alzheimer’s disease (AD). Experimental evidence indicates that inhibition of brain ROS could be beneficial in slowing the neurodegenerative process triggered by amyloid-beta (Abeta) aggregates. The [...] Read more.

Increased generation of reactive oxygen species (ROS) is a significant pathological feature in the brains of patients with Alzheimer’s disease (AD). Experimental evidence indicates that inhibition of brain ROS could be beneficial in slowing the neurodegenerative process triggered by amyloid-beta (Abeta) aggregates. The angiotensin II AT1 receptor is a significant source of brain ROS, and AD patients have an increased brain angiotensin-converting enzyme (ACE) level, which could account for an excessive angiotensin-dependent AT1-induced ROS generation. Therefore, we analyzed the impact of ACE inhibition on signs of neurodegeneration of aged Tg2576 mice as a transgenic animal model of AD. Whole genome microarray gene expression profiling and biochemical analyses demonstrated that the centrally active ACE inhibitor captopril normalized the excessive hippocampal ACE activity of AD mice. Concomitantly, the development of signs of neurodegeneration was retarded by six months of captopril treatment. The neuroprotective profile triggered by captopril was accompanied by reduced amyloidogenic processing of the amyloid precursor protein (APP), and decreased hippocampal ROS, which is known to enhance Abeta generation by increased activation of beta- and gamma-secretases. Taken together, our data present strong evidence that ACE inhibition with a widely used cardiovascular drug could interfere with Abeta-dependent neurodegeneration. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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The Association of IFI27 Expression and Fatigue Intensification during Localized Radiation Therapy: Implication of a Para-Inflammatory Bystander Response

by Chao-Pin Hsiao, Maria Araneta, Xiao Min Wang and Leorey N. Saligan

Int. J. Mol. Sci. 2013, 14(8), 16943-16957; https://doi.org/10.3390/ijms140816943 - 16 Aug 2013

Cited by 25 | Viewed by 8369

Abstract

The mechanisms behind fatigue intensification during cancer therapy remain elusive. The interferon alpha-inducible protein 27 (IFI27) was the most up-regulated gene based on our previous microarray data in fatigued men with non-metastatic prostate cancer receiving localized external beam radiation therapy (EBRT). [...] Read more.

The mechanisms behind fatigue intensification during cancer therapy remain elusive. The interferon alpha-inducible protein 27 (IFI27) was the most up-regulated gene based on our previous microarray data in fatigued men with non-metastatic prostate cancer receiving localized external beam radiation therapy (EBRT). The purpose of this study was to confirm the IFI27 up-regulation and determine its association with fatigue intensification during EBRT. Peripheral blood samples and fatigue scores were collected at three time points—prior to EBRT, at midpoint, and at completion of EBRT. Confirmatory quantitative real time polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) were utilized to verify the microarray results. Subjects were a total of 40 Caucasian men with prostate cancer; 20 scheduled for EBRT (65.6 ± 7.5 years old), and 20 on active surveillance as controls (62.8 ± 6.1 years old). Significant IFI27 expression overtime during EBRT was confirmed by qPCR (p < 0.5), which correlated with fatigue scores during EBRT (R = −0.90, p = 0.006). Alterations in mechanisms associated with immune response and mitochondrial function that explain the up-regulation of IFI27 may provide an understanding of the pathways related to the intensification of fatigue during localized radiation therapy. Full article

(This article belongs to the Collection Radiation Toxicity in Cells)

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MicroRNA-143 Downregulates Interleukin-13 Receptor Alpha1 in Human Mast Cells

by Shaoqing Yu, Ruxin Zhang, Chunshen Zhu, Jianqiu Cheng, Hong Wang and Jing Wu

Int. J. Mol. Sci. 2013, 14(8), 16958-16969; https://doi.org/10.3390/ijms140816958 - 19 Aug 2013

Cited by 25 | Viewed by 8071

Abstract

MicroRNA-143 (miR-143) was found to be downregulated in allergic rhinitis, and bioinformatics analysis predicted that IL-13Rα1 was a target gene of miR-143. To understand the molecular mechanisms of miR-143 involved in the pathogenesis of allergic inflammation, recombinant miR-143 plasmid vectors were constructed, and [...] Read more.

MicroRNA-143 (miR-143) was found to be downregulated in allergic rhinitis, and bioinformatics analysis predicted that IL-13Rα1 was a target gene of miR-143. To understand the molecular mechanisms of miR-143 involved in the pathogenesis of allergic inflammation, recombinant miR-143 plasmid vectors were constructed, and human mast cell-1(HMC-1) cells which play a central role in the allergic response were used for study. The plasmids were transfected into HMC-1 cells using a lentiviral vector. Expression of IL-13Rα1 mRNA was then detected by reverse transcriptase polymerase chain reaction (RT-PCR) and Western Blotting. The miR-143 lentiviral vector was successfully stably transfected in HMC-1 cells for target gene expression. Compared to the control, the target gene IL-13Rα1 was less expressed in HMC-1 transfected with miR-143 as determined by RT-PCR and Western Blotting (p < 0.05); this difference in expression was statistically significant and the inhibition efficiency was 71%. It indicates that miR-143 directly targets IL-13Rα1 and suppresses IL-13Rα1 expression in HMC-1 cells. Therefore, miR-143 may be associated with allergic reaction in human mast cells. Full article

(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)

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Structural Properties of Polyphenols Causing Cell Cycle Arrest at G1 Phase in HCT116 Human Colorectal Cancer Cell Lines

by Soon Young Shin, Hyuk Yoon, Seunghyun Ahn, Dong-Wook Kim, Dong-Ho Bae, Dongsoo Koh, Young Han Lee and Yoongho Lim

Int. J. Mol. Sci. 2013, 14(8), 16970-16985; https://doi.org/10.3390/ijms140816970 - 19 Aug 2013

Cited by 31 | Viewed by 9141

Abstract

Plant-derived polyphenols are being tested as chemopreventive agents; some polyphenols arrest the cell cycle at G1 phase, whereas others inhibit cell cycle proliferation at G2/M phase. Therefore, polyphenols have been proposed to inhibit cell cycle progression at different phases via distinct mechanisms. Indeed, [...] Read more.

Plant-derived polyphenols are being tested as chemopreventive agents; some polyphenols arrest the cell cycle at G1 phase, whereas others inhibit cell cycle proliferation at G2/M phase. Therefore, polyphenols have been proposed to inhibit cell cycle progression at different phases via distinct mechanisms. Indeed, our previous studies showed that small structural differences in polyphenols cause large differences in their biological activities; however, the details of the structural properties causing G1 cell cycle arrest remain unknown. In this study, we prepared 27 polyphenols, including eight different scaffolds, to gain insight into the structural conditions that arrest the cell cycle at G1 phase in a quantitative structure–activity relationship study. We used cell cycle profiles to determine the biophores responsible for G1 cell cycle arrest and believe that the biophores identified in this study will help design polyphenols that cause G1 cell cycle arrest. Full article

(This article belongs to the Special Issue Pathogenesis and Prevention of Colorectal Cancer)

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Decreased Expression of Alpha-L-Fucosidase Gene FUCA1 in Human Colorectal Tumors

by Olalla Otero-Estévez, Mónica Martínez-Fernández, Lorena Vázquez-Iglesias, María Páez de la Cadena, Francisco J. Rodríguez-Berrocal and Vicenta S. Martínez-Zorzano

Int. J. Mol. Sci. 2013, 14(8), 16986-16998; https://doi.org/10.3390/ijms140816986 - 19 Aug 2013

Cited by 25 | Viewed by 8460

Abstract

In previous studies we described a decreased alpha-L-fucosidase activity in colorectal tumors, appearing as a prognostic factor of tumoral recurrence. The aim of this work was to extend the knowledge about tissue alpha-L-fucosidase in colorectal cancer by quantifying the expression of its encoding [...] Read more.

In previous studies we described a decreased alpha-L-fucosidase activity in colorectal tumors, appearing as a prognostic factor of tumoral recurrence. The aim of this work was to extend the knowledge about tissue alpha-L-fucosidase in colorectal cancer by quantifying the expression of its encoding gene FUCA1 in tumors and healthy mucosa. FUCA1 mRNA levels were measured by RT-qPCR in paired tumor and normal mucosa tissues from 31 patients. For the accuracy of the RT-qPCR results, five candidate reference genes were validated in those samples. In addition, activity and expression of alpha-L-fucosidase in selected matched tumor and healthy mucosa samples were analyzed. According to geNorm and NormFinder algorithms, RPLP0 and HPRT1 were the best reference genes in colorectal tissues. These genes were used for normalization of FUCA1 expression levels. A significant decrease of more than 60% in normalized FUCA1 expression was detected in tumors compared to normal mucosa (p = 0.002). Moreover, a gradual decrease in FUCA1 expression was observed with progression of disease from earlier to advanced stages. These findings were confirmed by Western blot analysis of alpha-L-fucosidase expression. Our results demonstrated diminished FUCA1 mRNA levels in tumors, suggesting that expression of tissue alpha-L-fucosidase could be regulated at transcriptional level in colorectal cancer. Full article

(This article belongs to the Special Issue Glycosylation and Glycoproteins)

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Regulation of Huntingtin Gene Expression by miRNA-137, -214, -148a, and Their Respective isomiRs

by Emilia Kozlowska, Wlodzimierz J. Krzyzosiak and Edyta Koscianska

Int. J. Mol. Sci. 2013, 14(8), 16999-17016; https://doi.org/10.3390/ijms140816999 - 19 Aug 2013

Cited by 42 | Viewed by 9932

Abstract

With the advent of deep sequencing technology, a variety of miRNA length and sequence variants, termed isomiRNAs (isomiRs), have been discovered. However, the functional roles of these commonly detected isomiRs remain unknown. In this paper, we demonstrated that miRNAs regulate the expression of [...] Read more.

With the advent of deep sequencing technology, a variety of miRNA length and sequence variants, termed isomiRNAs (isomiRs), have been discovered. However, the functional roles of these commonly detected isomiRs remain unknown. In this paper, we demonstrated that miRNAs regulate the expression of the HTT gene, whose mutation leads to Huntington’s disease (HD), a hereditary degenerative disorder. Specifically, we validated the interactions of canonical miRNAs, miR-137, miR-214, and miR-148a, with the HTT 3'UTR using a luciferase assay. Moreover, we applied synthetic miRNA mimics to examine whether a slight shifting of miRNA seed regions might alter the regulation of the HTT transcript. We also examined miR-137, miR-214, and miR-148a isomiRs and showed the activity of these isoforms on reporter constructs bearing appropriate sequences from the HTT 3'UTR. Hence, we demonstrated that certain 5'-end variants of miRNAs might be functional for the regulation of the same targets as canonical miRNAs. Full article

(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)

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Inhibition of NADPH Oxidase by Apocynin Attenuates Progression of Atherosclerosis

by Kara Kinkade, Jennifer Streeter and Francis J. Miller

Int. J. Mol. Sci. 2013, 14(8), 17017-17028; https://doi.org/10.3390/ijms140817017 - 19 Aug 2013

Cited by 48 | Viewed by 8843

Abstract

Of the multiple sources of reactive oxygen species (ROS) in the blood vessel, NADPH oxidases are the primary source. Whereas several studies have implicated NADPH oxidases in the initiation of atherosclerosis, their roles in disease progression are incompletely understood. Our objective was to [...] Read more.

Of the multiple sources of reactive oxygen species (ROS) in the blood vessel, NADPH oxidases are the primary source. Whereas several studies have implicated NADPH oxidases in the initiation of atherosclerosis, their roles in disease progression are incompletely understood. Our objective was to determine the potential clinical relevance of inhibiting NADPH oxidase in established atherosclerosis. Using a hypercholesteremic murine model of atherosclerosis (ApoE^−/−/LDLR^−/− (AS) mice on normal chow diet), we first established a time-dependent relationship between superoxide levels and lesion size in AS mice. Next, we identified NADPH oxidase as the primary source of ROS in atherosclerotic lesions. Treatment of aortic segments from AS mice with apocynin, which interferes with NADPH oxidase activation in part by preventing translocation of the subunit p47^phox, significantly reduced superoxide levels. Moreover, addition of apocynin to the drinking water of AS mice produced a decrease in lesion size as compared to untreated AS mice, with the effect most pronounced in the thoracoabdominal aorta but absent from the aortic arch. Granulocyte function in AS+apocynin mice was suppressed, confirming efficacy of apocynin treatment. We conclude that apocynin attenuates the progression of atherosclerosis in hypercholesterolemic mice, potentially by its ability to inhibit generation of superoxide by NADPH oxidase. Full article

(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)

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UVB-Stimulated TNFα Release from Human Melanocyte and Melanoma Cells Is Mediated by p38 MAPK

by Visalini Muthusamy and Terrence J. Piva

Int. J. Mol. Sci. 2013, 14(8), 17029-17054; https://doi.org/10.3390/ijms140817029 - 19 Aug 2013

Cited by 9 | Viewed by 7772

Abstract

Ultraviolet (UV) radiation activates cell signaling pathways in melanocytes. As a result of altered signaling pathways and UV-induced cellular damage, melanocytes can undergo oncogenesis and develop into melanomas. In this study, we investigated the effect of UV-radiation on p38 MAPK (mitogen-activated protein kinase), [...] Read more.

Ultraviolet (UV) radiation activates cell signaling pathways in melanocytes. As a result of altered signaling pathways and UV-induced cellular damage, melanocytes can undergo oncogenesis and develop into melanomas. In this study, we investigated the effect of UV-radiation on p38 MAPK (mitogen-activated protein kinase), JNK and NFκB pathways to determine which plays a major role in stimulating TNFα secretion in human HEM (melanocytes) and MM96L (melanoma) cells. MM96L cells exhibited 3.5-fold higher p38 activity than HEM cells at 5 min following UVA + B radiation and 1.6-fold higher JNK activity at 15–30 min following UVB+A radiation, while NFκB was minimally activated in both cells. Irradiated HEM cells had the greatest fold of TNFα secretion (UVB: 109-fold, UVA + B: 103-fold & UVB+A: 130-fold) when co-exposed to IL1α. The p38 inhibitor, SB202190, inhibited TNFα release by 93% from UVB-irradiated HEM cells. In the UVB-irradiated MM96L cells, both SB202190 and sulfasalazine (NFκB inhibitor) inhibited TNFα release by 52%. Although, anisomycin was a p38 MAPK activator, it inhibited TNFα release in UV-irradiated cells. This suggests that UV-mediated TNFα release may occur via different p38 pathway intermediates compared to those stimulated by anisomycin. As such, further studies into the functional role p38 MAPK plays in regulating TNFα release in UV-irradiated melanocyte-derived cells are warranted. Full article

(This article belongs to the Collection Radiation Toxicity in Cells)

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Molecular Cloning, Characterization and mRNA Expression of a Chitin Synthase 2 Gene from the Oriental Fruit Fly, Bactrocera dorsalis (Diptera: Tephritidae)

by Li Chen, Wen-Jia Yang, Lin Cong, Kang-Kang Xu and Jin-Jun Wang

Int. J. Mol. Sci. 2013, 14(8), 17055-17072; https://doi.org/10.3390/ijms140817055 - 19 Aug 2013

Cited by 17 | Viewed by 6793

Abstract

Chitin synthase (CHS), a potential target for eco-friendly insecticides, plays an essential role in chitin formation in insects. In this study, a full-length cDNA encoding chitin synthase 2 (BdCHS2) was cloned and characterized in the oriental fruit fly, Bactrocera dorsalis. [...] Read more.

Chitin synthase (CHS), a potential target for eco-friendly insecticides, plays an essential role in chitin formation in insects. In this study, a full-length cDNA encoding chitin synthase 2 (BdCHS2) was cloned and characterized in the oriental fruit fly, Bactrocera dorsalis. The BdCHS2 cDNA had 4417 nucleotides, containing an open reading frame of 4122 nucleotides, which encoded 1373 amino acid residues with a predicted molecular weight of 158.5 kDa. Phylogenetic analysis with other insect CHSs suggested that BdCHS2 belongs to insect CHS2. The BdCHS2 transcript was predominately found in midgut but was detected at low levels in fat body, Malpighian tubules, integument, and trachea. Moreover, BdCHS2 was expressed in all developmental stages, and highly expressed in the feeding stages. There was a positive relationship between BdCHS2 expression and total chitin content during development. Furthermore, both the gene expression and chitin content in midgut decreased when the insect was fed for 24 h, then starved for 24 h, while they increased dramatically and rapidly under the condition of starvation for 24 h then feeding for 24 h. These results suggest that BdCHS2 may play an important role in regulating chitin content of the midgut, and subsequently affect the growth and development of B. dorsalis. Full article

(This article belongs to the Section Biochemistry)

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Effects of Reduced Prolamin on Seed Storage Protein Composition and the Nutritional Quality of Rice

by Hyun-Jung Kim, Jong-Yeol Lee, Ung-Han Yoon, Sun-Hyung Lim and Young-Mi Kim

Int. J. Mol. Sci. 2013, 14(8), 17073-17084; https://doi.org/10.3390/ijms140817073 - 19 Aug 2013

Cited by 27 | Viewed by 9185

Abstract

Rice seed storage proteins accumulate in two types of protein body (PB-I and PB-II) that are nutrient sources for animals. PB-I is indigestible and negatively affects rice protein quality. To improve the nutritional value of rice seeds we are aiming to engineer the [...] Read more.

Rice seed storage proteins accumulate in two types of protein body (PB-I and PB-II) that are nutrient sources for animals. PB-I is indigestible and negatively affects rice protein quality. To improve the nutritional value of rice seeds we are aiming to engineer the composition and accumulation of endogenous seed storage proteins. In this study we generated transgenic rice plants in which 13 kD prolamin genes were suppressed by RNA interference (13 kD pro-RNAi). Analysis based on qRT-PCR confirmed that the targeted 13 kD prolamins were markedly suppressed, and were compensated for by an increase in other storage proteins including 10 kD prolamin, glutelins, and chaperone proteins. The storage protein profiles further revealed that the levels of 13 kD prolamins were significantly reduced, while that of the glutelin precursor was slightly increased and the remaining storage proteins did not change. Amino acid analysis showed that the reduction of 13 kD prolamins resulted in a 28% increase in the lysine content relative to the wild type, indicating that the 13 kD pro-RNAi rice seeds are more nutritious. Furthermore, a reduction in the levels of 13 kD prolamins resulted in abnormal formation of PB-I, which was small and had no lamellar structure. These results suggest that alteration of prolamins can contribute to improving the nutritional quality of rice. Full article

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Homoserine Lactones Influence the Reaction of Plants to Rhizobia

by Azhar A. Zarkani, Elke Stein, Christian R. Röhrich, Marek Schikora, Elena Evguenieva-Hackenberg, Thomas Degenkolb, Andreas Vilcinskas, Gabriele Klug, Karl-Heinz Kogel and Adam Schikora

Int. J. Mol. Sci. 2013, 14(8), 17122-17146; https://doi.org/10.3390/ijms140817122 - 20 Aug 2013

Cited by 68 | Viewed by 10438

Abstract

Bacterial quorum sensing molecules not only grant the communication within bacterial communities, but also influence eukaryotic hosts. N-acyl-homoserine lactones (AHLs) produced by pathogenic or beneficial bacteria were shown to induce diverse reactions in animals and plants. In plants, the reaction to AHLs [...] Read more.

Bacterial quorum sensing molecules not only grant the communication within bacterial communities, but also influence eukaryotic hosts. N-acyl-homoserine lactones (AHLs) produced by pathogenic or beneficial bacteria were shown to induce diverse reactions in animals and plants. In plants, the reaction to AHLs depends on the length of the lipid side chain. Here we investigated the impact of two bacteria on Arabidopsis thaliana, which usually enter a close symbiosis with plants from the Fabaceae (legumes) family and produce a long-chain AHL (Sinorhizobium meliloti) or a short-chain AHL (Rhizobium etli). We demonstrate that, similarly to the reaction to pure AHL molecules, the impact, which the inoculation with rhizosphere bacteria has on plants, depends on the type of the produced AHL. The inoculation with oxo-C14-HSL-producing S. meliloti strains enhanced plant resistance towards pathogenic bacteria, whereas the inoculation with an AttM lactonase-expressing S. meliloti strain did not. Inoculation with the oxo-C8-HSL-producing R. etli had no impact on the resistance, which is in agreement with our previous hypothesis. In addition, plants seem to influence the availability of AHLs in the rhizosphere. Taken together, this report provides new insights in the role of N-acyl-homoserine lactones in the inter-kingdom communication at the root surface. Full article

(This article belongs to the Special Issue Quorum Sensing Research in Microbial Systems)

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Open AccessArticle

Cucurbitacin E as Inducer of Cell Death and Apoptosis in Human Oral Squamous Cell Carcinoma Cell Line SAS

by Chao-Ming Hung, Chi-Chang Chang, Chen-Wei Lin, Shun-Yao Ko and Yi-Chiang Hsu

Int. J. Mol. Sci. 2013, 14(8), 17147-17156; https://doi.org/10.3390/ijms140817147 - 20 Aug 2013

Cited by 34 | Viewed by 7198

Abstract

Human oral squamous cell carcinoma (OSCC) is a common form of malignant cancer, for which radiotherapy or chemotherapy are the main treatment methods. Cucurbitacin E (CuE) is a natural compound previously shown to be an antifeedant as well as a potent chemopreventive agent [...] Read more.

Human oral squamous cell carcinoma (OSCC) is a common form of malignant cancer, for which radiotherapy or chemotherapy are the main treatment methods. Cucurbitacin E (CuE) is a natural compound previously shown to be an antifeedant as well as a potent chemopreventive agent against several types of cancer. The present study investigates anti-proliferation (using MTT assay, CuE demonstrated cytotoxic activity against SAS cell with IC₅₀ values at 3.69 µM) and induced apoptosis of human oral squamous cell carcinoma SAS cells after 24 h treatment with CuE. Mitochondrial membrane potential (MMP) and caspase activity were studied and our results indicate that CuE inhibits cell proliferation as well as the activation of apoptois in SAS cells. Both effects increased in proportion to the dosage of CuE and apoptosis was induced via mitochondria- and caspase-dependent pathways. CuE can induce cell death by a mechanism that is not dependent on apoptosis induction, and thus represents a promising anticancer agent for prevention and treatment of OSCC. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Design, Synthesis and Antiviral Activity Studies of Schizonepetin Derivatives

by Beihua Bao, Zheng Meng, Nianguang Li, Zhengjie Meng, Li Zhang, Yudan Cao, Weifeng Yao, Mingqiu Shan and Anwei Ding

Int. J. Mol. Sci. 2013, 14(8), 17193-17203; https://doi.org/10.3390/ijms140817193 - 20 Aug 2013

Cited by 2 | Viewed by 5989

Abstract

A series of schizonepetin derivatives have been designed and synthesized in order to obtain potent antivirus agents. The antiviral activity against HSV-1 and influenza virus H3N2 as well as the cytotoxicity of these derivatives was evaluated by using cytopathic effect (CPE) inhibition assay [...] Read more.

A series of schizonepetin derivatives have been designed and synthesized in order to obtain potent antivirus agents. The antiviral activity against HSV-1 and influenza virus H3N2 as well as the cytotoxicity of these derivatives was evaluated by using cytopathic effect (CPE) inhibition assay in vitro. Compounds M2, M4, M5 and M34 showed higher inhibitory activity against HSV-1 virus with the TC₅₀ values being in micromole. Compounds M28, M33, and M35 showed higher inhibitory activity against influenza virus H3N2 with their TC₅₀ values being 96.4, 71.0 and 75.4 μM, respectively. Preliminary biological activity evaluation indicated that the anti-H3N2 and anti-HSV-1 activities improved obviously through the introduction of halogen into the structure of schizonepetin. Full article

(This article belongs to the Section Biochemistry)

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Review

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Open AccessReview

S-Glutathionylation in Monocyte and Macrophage (Dys)Function

by Sarah Ullevig, Hong Seok Kim and Reto Asmis

Int. J. Mol. Sci. 2013, 14(8), 15212-15232; https://doi.org/10.3390/ijms140815212 - 24 Jul 2013

Cited by 26 | Viewed by 8176

Abstract

Atherosclerosis is a chronic inflammatory disease involving the accumulation of monocytes and macrophages in the vascular wall. Monocytes and macrophages play a central role in the initiation and progression of atherosclerotic lesion development. Oxidative stress, which occurs when reactive oxygen species (ROS) overwhelm [...] Read more.

Atherosclerosis is a chronic inflammatory disease involving the accumulation of monocytes and macrophages in the vascular wall. Monocytes and macrophages play a central role in the initiation and progression of atherosclerotic lesion development. Oxidative stress, which occurs when reactive oxygen species (ROS) overwhelm cellular antioxidant systems, contributes to the pathophysiology of many chronic inflammatory diseases, including atherosclerosis. Major targets of ROS are reactive thiols on cysteine residues in proteins, which when oxidized can alter cellular processes, including signaling pathways, metabolic pathways, transcription, and translation. Protein-S-glutathionylation is the process of mixed disulfide formation between glutathione (GSH) and protein thiols. Until recently, protein-S-glutathionylation was associated with increased cellular oxidative stress, but S-glutathionylation of key protein targets has now emerged as a physiologically important redox signaling mechanism, which when dysregulated contributes to a variety of disease processes. In this review, we will explore the role of thiol oxidative stress and protein-S-glutathionylation in monocyte and macrophage dysfunction as a mechanistic link between oxidative stress associated with metabolic disorders and chronic inflammatory diseases, including atherosclerosis. Full article

(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)

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How Can Plant DNA Viruses Evade siRNA-Directed DNA Methylation and Silencing?

by Mikhail M. Pooggin

Int. J. Mol. Sci. 2013, 14(8), 15233-15259; https://doi.org/10.3390/ijms140815233 - 24 Jul 2013

Cited by 79 | Viewed by 16877

Abstract

Plants infected with DNA viruses produce massive quantities of virus-derived, 24-nucleotide short interfering RNAs (siRNAs), which can potentially direct viral DNA methylation and transcriptional silencing. However, growing evidence indicates that the circular double-stranded DNA accumulating in the nucleus for Pol II-mediated transcription of [...] Read more.

Plants infected with DNA viruses produce massive quantities of virus-derived, 24-nucleotide short interfering RNAs (siRNAs), which can potentially direct viral DNA methylation and transcriptional silencing. However, growing evidence indicates that the circular double-stranded DNA accumulating in the nucleus for Pol II-mediated transcription of viral genes is not methylated. Hence, DNA viruses most likely evade or suppress RNA-directed DNA methylation. This review describes the specialized mechanisms of replication and silencing evasion evolved by geminiviruses and pararetoviruses, which rescue viral DNA from repressive methylation and interfere with transcriptional and post-transcriptional silencing of viral genes. Full article

(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)

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The Role of AKT/mTOR Pathway in Stress Response to UV-Irradiation: Implication in Skin Carcinogenesis by Regulation of Apoptosis, Autophagy and Senescence

by Elwira Strozyk and Dagmar Kulms

Int. J. Mol. Sci. 2013, 14(8), 15260-15285; https://doi.org/10.3390/ijms140815260 - 24 Jul 2013

Cited by 130 | Viewed by 19328

Abstract

Induction of DNA damage by UVB and UVA radiation may generate mutations and genomic instability leading to carcinogenesis. Therefore, skin cells being repeatedly exposed to ultraviolet (UV) light have acquired multilayered protective mechanisms to avoid malignant transformation. Besides extensive DNA repair mechanisms, the [...] Read more.

Induction of DNA damage by UVB and UVA radiation may generate mutations and genomic instability leading to carcinogenesis. Therefore, skin cells being repeatedly exposed to ultraviolet (UV) light have acquired multilayered protective mechanisms to avoid malignant transformation. Besides extensive DNA repair mechanisms, the damaged skin cells can be eliminated by induction of apoptosis, which is mediated through the action of tumor suppressor p53. In order to prevent the excessive loss of skin cells and to maintain the skin barrier function, apoptotic pathways are counteracted by anti-apoptotic signaling including the AKT/mTOR pathway. However, AKT/mTOR not only prevents cell death, but is also active in cell cycle transition and hyper-proliferation, thereby also counteracting p53. In turn, AKT/mTOR is tuned down by the negative regulators being controlled by the p53. This inhibition of AKT/mTOR, in combination with transactivation of damage-regulated autophagy modulators, guides the p53-mediated elimination of damaged cellular components by autophagic clearance. Alternatively, p53 irreversibly blocks cell cycle progression to prevent AKT/mTOR-driven proliferation, thereby inducing premature senescence. Conclusively, AKT/mTOR via an extensive cross talk with p53 influences the UV response in the skin with no black and white scenario deciding over death or survival. Full article

(This article belongs to the Collection Radiation Toxicity in Cells)

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Exposure to Environmental Toxicants and Pathogenesis of Amyotrophic Lateral Sclerosis: State of the Art and Research Perspectives

by Francesca Trojsi, Maria Rosaria Monsurrò and Gioacchino Tedeschi

Int. J. Mol. Sci. 2013, 14(8), 15286-15311; https://doi.org/10.3390/ijms140815286 - 24 Jul 2013

Cited by 58 | Viewed by 12625

Abstract

There is a broad scientific consensus that amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease, is caused by gene-environment interactions. In fact, given that only about 10% of all ALS diagnosis has a genetic basis, gene-environmental interaction may give account for the remaining [...] Read more.

There is a broad scientific consensus that amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease, is caused by gene-environment interactions. In fact, given that only about 10% of all ALS diagnosis has a genetic basis, gene-environmental interaction may give account for the remaining percentage of cases. However, relatively little attention has been paid to environmental and lifestyle factors that may trigger the cascade of motor neuron degeneration leading to ALS, although exposure to chemicals—including lead and pesticides—agricultural environments, smoking, intense physical activity, trauma and electromagnetic fields have been associated with an increased risk of ALS. This review provides an overview of our current knowledge of potential toxic etiologies of ALS with emphasis on the role of cyanobacteria, heavy metals and pesticides as potential risk factors for developing ALS. We will summarize the most recent evidence from epidemiological studies and experimental findings from animal and cellular models, revealing that potential causal links between environmental toxicants and ALS pathogenesis have not been fully ascertained, thus justifying the need for further research. Full article

(This article belongs to the Special Issue Molecular Research in Neurotoxicology)

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Functional Diversity of RNAi-Associated sRNAs in Fungi

by Francisco E. Nicolás and Rosa M. Ruiz-Vázquez

Int. J. Mol. Sci. 2013, 14(8), 15348-15360; https://doi.org/10.3390/ijms140815348 - 24 Jul 2013

Cited by 61 | Viewed by 8980

Abstract

Yeast and filamentous fungi have been essential model systems for unveiling the secrets of RNA interference (RNAi). Research on these organisms has contributed to identifying general mechanisms and conserved eukaryotic RNAi machinery that can be found from fungi to mammals. The development of [...] Read more.

Yeast and filamentous fungi have been essential model systems for unveiling the secrets of RNA interference (RNAi). Research on these organisms has contributed to identifying general mechanisms and conserved eukaryotic RNAi machinery that can be found from fungi to mammals. The development of deep sequencing technologies has brought on the last wave of studies on RNAi in fungi, which has been focused on the identification of new types of functional small RNAs (sRNAs). These studies have discovered an unexpected diversity of sRNA, biogenesis pathways and new functions that are the focus of this review. Full article

(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)

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Open AccessReview

Long Non-Coding RNAs in Haematological Malignancies

by Andoni Garitano-Trojaola, Xabier Agirre, Felipe Prósper and Puri Fortes

Int. J. Mol. Sci. 2013, 14(8), 15386-15422; https://doi.org/10.3390/ijms140815386 - 24 Jul 2013

Cited by 42 | Viewed by 12548

Abstract

Long non-coding RNAs (lncRNAs) are functional RNAs longer than 200 nucleotides in length. LncRNAs are as diverse as mRNAs and they normally share the same biosynthetic machinery based on RNA polymerase II, splicing and polyadenylation. However, lncRNAs have low coding potential. Compared to [...] Read more.

Long non-coding RNAs (lncRNAs) are functional RNAs longer than 200 nucleotides in length. LncRNAs are as diverse as mRNAs and they normally share the same biosynthetic machinery based on RNA polymerase II, splicing and polyadenylation. However, lncRNAs have low coding potential. Compared to mRNAs, lncRNAs are preferentially nuclear, more tissue specific and expressed at lower levels. Most of the lncRNAs described to date modulate the expression of specific genes by guiding chromatin remodelling factors; inducing chromosomal loopings; affecting transcription, splicing, translation or mRNA stability; or serving as scaffolds for the organization of cellular structures. They can function in cis, cotranscriptionally, or in trans, acting as decoys, scaffolds or guides. These functions seem essential to allow cell differentiation and growth. In fact, many lncRNAs have been shown to exert oncogenic or tumor suppressor properties in several cancers including haematological malignancies. In this review, we summarize what is known about lncRNAs, the mechanisms for their regulation in cancer and their role in leukemogenesis, lymphomagenesis and hematopoiesis. Furthermore, we discuss the potential of lncRNAs in diagnosis, prognosis and therapy in cancer, with special attention to haematological malignancies. Full article

(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)

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Open AccessReview

Detecting and Comparing Non-Coding RNAs in the High-Throughput Era

by Giovanni Bussotti, Cedric Notredame and Anton J. Enright

Int. J. Mol. Sci. 2013, 14(8), 15423-15458; https://doi.org/10.3390/ijms140815423 - 24 Jul 2013

Cited by 21 | Viewed by 12404

Abstract

In recent years there has been a growing interest in the field of non-coding RNA. This surge is a direct consequence of the discovery of a huge number of new non-coding genes and of the finding that many of these transcripts are involved [...] Read more.

In recent years there has been a growing interest in the field of non-coding RNA. This surge is a direct consequence of the discovery of a huge number of new non-coding genes and of the finding that many of these transcripts are involved in key cellular functions. In this context, accurately detecting and comparing RNA sequences has become important. Aligning nucleotide sequences is a key requisite when searching for homologous genes. Accurate alignments reveal evolutionary relationships, conserved regions and more generally any biologically relevant pattern. Comparing RNA molecules is, however, a challenging task. The nucleotide alphabet is simpler and therefore less informative than that of amino-acids. Moreover for many non-coding RNAs, evolution is likely to be mostly constrained at the structural level and not at the sequence level. This results in very poor sequence conservation impeding comparison of these molecules. These difficulties define a context where new methods are urgently needed in order to exploit experimental results to their full potential. This review focuses on the comparative genomics of non-coding RNAs in the context of new sequencing technologies and especially dealing with two extremely important and timely research aspects: the development of new methods to align RNAs and the analysis of high-throughput data. Full article

(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)

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Open AccessReview

Early Lung Cancer Diagnosis by Biosensors

by Yuqian Zhang, Dongliang Yang, Lixing Weng and Lianhui Wang

Int. J. Mol. Sci. 2013, 14(8), 15479-15509; https://doi.org/10.3390/ijms140815479 - 25 Jul 2013

Cited by 48 | Viewed by 9775

Abstract

Lung cancer causes an extreme threat to human health, and the mortality rate due to lung cancer has not decreased during the last decade. Prognosis or early diagnosis could help reduce the mortality rate. If microRNA and tumor-associated antigens (TAAs), as well as [...] Read more.

Lung cancer causes an extreme threat to human health, and the mortality rate due to lung cancer has not decreased during the last decade. Prognosis or early diagnosis could help reduce the mortality rate. If microRNA and tumor-associated antigens (TAAs), as well as the corresponding autoantibodies, can be detected prior to clinical diagnosis, such high sensitivity of biosensors makes the early diagnosis and prognosis of cancer realizable. This review provides an overview of tumor-associated biomarker identifying methods and the biosensor technology available today. Laboratorial researches utilizing biosensors for early lung cancer diagnosis will be highlighted. Full article

(This article belongs to the Special Issue Advances in Cancer Diagnosis)

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Open AccessReview

Genetic and Molecular Differences in Prostate Carcinogenesis between African American and Caucasian American Men

by James Farrell, Gyorgy Petrovics, David G. McLeod and Shiv Srivastava

Int. J. Mol. Sci. 2013, 14(8), 15510-15531; https://doi.org/10.3390/ijms140815510 - 25 Jul 2013

Cited by 64 | Viewed by 8333

Abstract

Prostate cancer is the most common non-skin cancer and the second leading cause of cancer-related death for men in the United States. Prostate cancer incidence and associated mortality are highest in African American men in comparison to other races. The observed differences in [...] Read more.

Prostate cancer is the most common non-skin cancer and the second leading cause of cancer-related death for men in the United States. Prostate cancer incidence and associated mortality are highest in African American men in comparison to other races. The observed differences in incidence and disease aggressiveness at presentation support a potential role for different pathways of prostate carcinogenesis between African American and Caucasian men. This review focuses on some of the recent molecular biology discoveries, which have been investigated in prostate carcinogenesis and their likely contribution to the known discrepancies across race and ethnicity. Key discussion points include the androgen receptor gene structure and function, genome-wide association studies and epigenetics. The new observations of the ethnic differences of the ERG oncogene, the most common prostate cancer gene, are providing new insights into ERG based stratification of prostate cancers in the context of ethnically diverse patient populations. This rapidly advancing knowledge has the likely potential to benefit clinical practice. Current and future work will improve the ability to sub-type prostate cancers by molecular alterations and lead to targeted therapy against this common malignancy. Full article

(This article belongs to the Special Issue Molecular Research in Urology)

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Open AccessReview

Experimental Evidence of Persistent Androgen-Receptor-Dependency in Castration-Resistant Prostate Cancer

by Takashi Kobayashi, Takahiro Inoue, Tomomi Kamba and Osamu Ogawa

Int. J. Mol. Sci. 2013, 14(8), 15615-15635; https://doi.org/10.3390/ijms140815615 - 26 Jul 2013

Cited by 38 | Viewed by 9476

Abstract

In the majority of castration-resistant prostate cancer (CRPC), prostate-specific antigen (PSA), product of a gene that is almost exclusively regulated by the androgen receptor (AR), still acts as a serum marker reflecting disease burden, indicating that AR signaling is activated even under castrate [...] Read more.

In the majority of castration-resistant prostate cancer (CRPC), prostate-specific antigen (PSA), product of a gene that is almost exclusively regulated by the androgen receptor (AR), still acts as a serum marker reflecting disease burden, indicating that AR signaling is activated even under castrate level of serum androgen. Accumulated evidence shows that transcriptional ability of AR is activated both in ligand-dependent and -independent manners in CRPC cells. Some androgen-independent sublines derived from originally androgen-dependent LNCaP prostate cancer cells overexpress the AR and PSA, for which silencing the AR gene suppresses cellular proliferation. The overexpression of the AR confers androgen-independent growth ability on androgen-dependent prostate cancer cells. Some patient-derived prostate cancer xenograft lines also acquire castration-resistant growth ability secreting PSA. More recent publications have shown that the AR activated in CRPC cells regulates distinct gene sets from that in androgen-dependent status. This concept provides very important insights in the development of novel anti-prostate cancer drugs such as new generation anti-androgens and CYP17 inhibitors. Full article

(This article belongs to the Special Issue Molecular Research in Urology)

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Open AccessReview

Impaired Pre-mRNA Processing and Altered Architecture of 3' Untranslated Regions Contribute to the Development of Human Disorders

by Eva Michalova, Borivoj Vojtesek and Roman Hrstka

Int. J. Mol. Sci. 2013, 14(8), 15681-15694; https://doi.org/10.3390/ijms140815681 - 26 Jul 2013

Cited by 28 | Viewed by 7818

Abstract

The biological fate of each mRNA and consequently, the protein to be synthesised, is highly dependent on the nature of the 3' untranslated region. Despite its non-coding character, the 3' UTR may affect the final mRNA stability, the localisation, the export from the [...] Read more.

The biological fate of each mRNA and consequently, the protein to be synthesised, is highly dependent on the nature of the 3' untranslated region. Despite its non-coding character, the 3' UTR may affect the final mRNA stability, the localisation, the export from the nucleus and the translation efficiency. The conserved regulatory sequences within 3' UTRs and the specific elements binding to them enable gene expression control at the posttranscriptional level and all these processes reflect the actual state of the cell including proliferation, differentiation, cellular stress or tumourigenesis. Through this article, we briefly outline how the alterations in the establishment and final architecture of 3' UTRs may contribute to the development of various disorders in humans. Full article

(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)

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Lessons Learned about Human Stem Cell Responses to Ionizing Radiation Exposures: A Long Road Still Ahead of Us

by Mykyta Sokolov and Ronald Neumann

Int. J. Mol. Sci. 2013, 14(8), 15695-15723; https://doi.org/10.3390/ijms140815695 - 29 Jul 2013

Cited by 23 | Viewed by 8689

Abstract

Human stem cells (hSC) possess several distinct characteristics that set them apart from other cell types. First, hSC are self-renewing, capable of undergoing both asymmetric and symmetric cell divisions. Second, these cells can be coaxed to differentiate into various specialized cell types and, [...] Read more.

Human stem cells (hSC) possess several distinct characteristics that set them apart from other cell types. First, hSC are self-renewing, capable of undergoing both asymmetric and symmetric cell divisions. Second, these cells can be coaxed to differentiate into various specialized cell types and, as such, hold great promise for regenerative medicine. Recent progresses in hSC biology fostered the characterization of the responses of hSC to genotoxic stresses, including ionizing radiation (IR). Here, we examine how different types of hSC respond to IR, with a special emphasis on their radiosensitivity, cell cycle, signaling networks, DNA damage response (DDR) and DNA repair. We show that human embryonic stem cells (hESCs) possess unique characteristics in how they react to IR that clearly distinguish these cells from all adult hSC studied thus far. On the other hand, a manifestation of radiation injuries/toxicity in human bodies may depend to a large extent on hSC populating corresponding tissues, such as human mesenchymal stem cells (hMSC), human hematopoietic stem cells (hHSC), neural hSC, intestine hSC, etc. We discuss here that hSC responses to IR differ notably across many types of hSC which may represent the distinct roles these cells play in development, regeneration and/or maintenance of homeostasis. Full article

(This article belongs to the Collection Radiation Toxicity in Cells)

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Post-Transcriptional Regulation of Iron Homeostasis in Saccharomyces cerevisiae

by María Teresa Martínez-Pastor, Rosa De Llanos, Antonia María Romero and Sergi Puig

Int. J. Mol. Sci. 2013, 14(8), 15785-15809; https://doi.org/10.3390/ijms140815785 - 30 Jul 2013

Cited by 22 | Viewed by 10174

Abstract

Iron is an essential micronutrient for all eukaryotic organisms because it participates as a redox cofactor in a wide variety of biological processes. Recent studies in Saccharomyces cerevisiae have shown that in response to iron deficiency, an RNA-binding protein denoted Cth2 coordinates a [...] Read more.

Iron is an essential micronutrient for all eukaryotic organisms because it participates as a redox cofactor in a wide variety of biological processes. Recent studies in Saccharomyces cerevisiae have shown that in response to iron deficiency, an RNA-binding protein denoted Cth2 coordinates a global metabolic rearrangement that aims to optimize iron utilization. The Cth2 protein contains two Cx₈Cx₅Cx₃H tandem zinc fingers (TZFs) that specifically bind to adenosine/uridine-rich elements within the 3' untranslated region of many mRNAs to promote their degradation. The Cth2 protein shuttles between the nucleus and the cytoplasm. Once inside the nucleus, Cth2 binds target mRNAs and stimulates alternative 3' end processing. A Cth2/mRNA-containing complex is required for export to the cytoplasm, where the mRNA is degraded by the 5' to 3' degradation pathway. This post-transcriptional regulatory mechanism limits iron utilization in nonessential pathways and activates essential iron-dependent enzymes such as ribonucleotide reductase, which is required for DNA synthesis and repair. Recent findings indicate that the TZF-containing tristetraprolin protein also functions in modulating human iron homeostasis. Elevated iron concentrations can also be detrimental for cells. The Rnt1 RNase III exonuclease protects cells from excess iron by promoting the degradation of a subset of the Fe acquisition system when iron levels rise. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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The Role of Bacterial Biofilms and Surface Components in Plant-Bacterial Associations

by Pablo C. Bogino, María De las Mercedes Oliva, Fernando G. Sorroche and Walter Giordano

Int. J. Mol. Sci. 2013, 14(8), 15838-15859; https://doi.org/10.3390/ijms140815838 - 30 Jul 2013

Cited by 352 | Viewed by 18342

Abstract

The role of bacterial surface components in combination with bacterial functional signals in the process of biofilm formation has been increasingly studied in recent years. Plants support a diverse array of bacteria on or in their roots, transport vessels, stems, and leaves. These [...] Read more.

The role of bacterial surface components in combination with bacterial functional signals in the process of biofilm formation has been increasingly studied in recent years. Plants support a diverse array of bacteria on or in their roots, transport vessels, stems, and leaves. These plant-associated bacteria have important effects on plant health and productivity. Biofilm formation on plants is associated with symbiotic and pathogenic responses, but how plants regulate such associations is unclear. Certain bacteria in biofilm matrices have been found to induce plant growth and to protect plants from phytopathogens (a process termed biocontrol), whereas others are involved in pathogenesis. In this review, we systematically describe the various components and mechanisms involved in bacterial biofilm formation and attachment to plant surfaces and the relationships of these mechanisms to bacterial activity and survival. Full article

(This article belongs to the Special Issue Biofilms: Extracellular Bastions of Bacteria)

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Angiogenesis-Related Pathways in the Pathogenesis of Ovarian Cancer

by Nikos G. Gavalas, Michalis Liontos, Sofia-Paraskevi Trachana, Tina Bagratuni, Calliope Arapinis, Christine Liacos, Meletios A. Dimopoulos and Aristotle Bamias

Int. J. Mol. Sci. 2013, 14(8), 15885-15909; https://doi.org/10.3390/ijms140815885 - 30 Jul 2013

Cited by 114 | Viewed by 15059

Abstract

Ovarian Cancer represents the most fatal type of gynecological malignancies. A number of processes are involved in the pathogenesis of ovarian cancer, especially within the tumor microenvironment. Angiogenesis represents a hallmark phenomenon in cancer, and it is responsible for tumor spread and metastasis [...] Read more.

Ovarian Cancer represents the most fatal type of gynecological malignancies. A number of processes are involved in the pathogenesis of ovarian cancer, especially within the tumor microenvironment. Angiogenesis represents a hallmark phenomenon in cancer, and it is responsible for tumor spread and metastasis in ovarian cancer, among other tumor types, as it leads to new blood vessel formation. In recent years angiogenesis has been given considerable attention in order to identify targets for developing effective anti-tumor therapies. Growth factors have been identified to play key roles in driving angiogenesis and, thus, the formation of new blood vessels that assist in “feeding” cancer. Such molecules include the vascular endothelial growth factor (VEGF), the platelet derived growth factor (PDGF), the fibroblast growth factor (FGF), and the angiopoietin/Tie2 receptor complex. These proteins are key players in complex molecular pathways within the tumor cell and they have been in the spotlight of the development of anti-angiogenic molecules that may act as stand-alone therapeutics, or in concert with standard treatment regimes such as chemotherapy. The pathways involved in angiogenesis and molecules that have been developed in order to combat angiogenesis are described in this paper. Full article

(This article belongs to the Special Issue Genes and Pathways in the Pathogenesis of Ovarian Cancer)

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Magnetic Iron Oxide Nanoparticles for Multimodal Imaging and Therapy of Cancer

by Reju Thomas, In-Kyu Park and Yong Yeon Jeong

Int. J. Mol. Sci. 2013, 14(8), 15910-15930; https://doi.org/10.3390/ijms140815910 - 31 Jul 2013

Cited by 223 | Viewed by 16586

Abstract

Superparamagnetic iron oxide nanoparticles (SPION) have emerged as an MRI contrast agent for tumor imaging due to their efficacy and safety. Their utility has been proven in clinical applications with a series of marketed SPION-based contrast agents. Extensive research has been performed to [...] Read more.

Superparamagnetic iron oxide nanoparticles (SPION) have emerged as an MRI contrast agent for tumor imaging due to their efficacy and safety. Their utility has been proven in clinical applications with a series of marketed SPION-based contrast agents. Extensive research has been performed to study various strategies that could improve SPION by tailoring the surface chemistry and by applying additional therapeutic functionality. Research into the dual-modal contrast uses of SPION has developed because these applications can save time and effort by reducing the number of imaging sessions. In addition to multimodal strategies, efforts have been made to develop multifunctional nanoparticles that carry both diagnostic and therapeutic cargos specifically for cancer. This review provides an overview of recent advances in multimodality imaging agents and focuses on iron oxide based nanoparticles and their theranostic applications for cancer. Furthermore, we discuss the physiochemical properties and compare different synthesis methods of SPION for the development of multimodal contrast agents. Full article

(This article belongs to the Special Issue Magnetic Nanoparticles 2013)

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Mechanisms of Radiation Toxicity in Transformed and Non-Transformed Cells

by Ronald-Allan M. Panganiban, Andrew L. Snow and Regina M. Day

Int. J. Mol. Sci. 2013, 14(8), 15931-15958; https://doi.org/10.3390/ijms140815931 - 31 Jul 2013

Cited by 89 | Viewed by 13787

Abstract

Radiation damage to biological systems is determined by the type of radiation, the total dosage of exposure, the dose rate, and the region of the body exposed. Three modes of cell death—necrosis, apoptosis, and autophagy—as well as accelerated senescence have been demonstrated to [...] Read more.

Radiation damage to biological systems is determined by the type of radiation, the total dosage of exposure, the dose rate, and the region of the body exposed. Three modes of cell death—necrosis, apoptosis, and autophagy—as well as accelerated senescence have been demonstrated to occur in vitro and in vivo in response to radiation in cancer cells as well as in normal cells. The basis for cellular selection for each mode depends on various factors including the specific cell type involved, the dose of radiation absorbed by the cell, and whether it is proliferating and/or transformed. Here we review the signaling mechanisms activated by radiation for the induction of toxicity in transformed and normal cells. Understanding the molecular mechanisms of radiation toxicity is critical for the development of radiation countermeasures as well as for the improvement of clinical radiation in cancer treatment. Full article

(This article belongs to the Collection Radiation Toxicity in Cells)

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Tuning the Magnetic Properties of Nanoparticles

by Arati G. Kolhatkar, Andrew C. Jamison, Dmitri Litvinov, Richard C. Willson and T. Randall Lee

Int. J. Mol. Sci. 2013, 14(8), 15977-16009; https://doi.org/10.3390/ijms140815977 - 31 Jul 2013

Cited by 637 | Viewed by 35075

Abstract

The tremendous interest in magnetic nanoparticles (MNPs) is reflected in published research that ranges from novel methods of synthesis of unique nanoparticle shapes and composite structures to a large number of MNP characterization techniques, and finally to their use in many biomedical and [...] Read more.

The tremendous interest in magnetic nanoparticles (MNPs) is reflected in published research that ranges from novel methods of synthesis of unique nanoparticle shapes and composite structures to a large number of MNP characterization techniques, and finally to their use in many biomedical and nanotechnology-based applications. The knowledge gained from this vast body of research can be made more useful if we organize the associated results to correlate key magnetic properties with the parameters that influence them. Tuning these properties of MNPs will allow us to tailor nanoparticles for specific applications, thus increasing their effectiveness. The complex magnetic behavior exhibited by MNPs is governed by many factors; these factors can either improve or adversely affect the desired magnetic properties. In this report, we have outlined a matrix of parameters that can be varied to tune the magnetic properties of nanoparticles. For practical utility, this review focuses on the effect of size, shape, composition, and shell-core structure on saturation magnetization, coercivity, blocking temperature, and relaxation time. Full article

(This article belongs to the Special Issue Magnetic Nanoparticles 2013)

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Non-Coding RNAs: Multi-Tasking Molecules in the Cell

by Anita Quintal Gomes, Sofia Nolasco and Helena Soares

Int. J. Mol. Sci. 2013, 14(8), 16010-16039; https://doi.org/10.3390/ijms140816010 - 31 Jul 2013

Cited by 206 | Viewed by 19504

Abstract

In the last years it has become increasingly clear that the mammalian transcriptome is highly complex and includes a large number of small non-coding RNAs (sncRNAs) and long noncoding RNAs (lncRNAs). Here we review the biogenesis pathways of the three classes of sncRNAs, [...] Read more.

In the last years it has become increasingly clear that the mammalian transcriptome is highly complex and includes a large number of small non-coding RNAs (sncRNAs) and long noncoding RNAs (lncRNAs). Here we review the biogenesis pathways of the three classes of sncRNAs, namely short interfering RNAs (siRNAs), microRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs). These ncRNAs have been extensively studied and are involved in pathways leading to specific gene silencing and the protection of genomes against virus and transposons, for example. Also, lncRNAs have emerged as pivotal molecules for the transcriptional and post-transcriptional regulation of gene expression which is supported by their tissue-specific expression patterns, subcellular distribution, and developmental regulation. Therefore, we also focus our attention on their role in differentiation and development. SncRNAs and lncRNAs play critical roles in defining DNA methylation patterns, as well as chromatin remodeling thus having a substantial effect in epigenetics. The identification of some overlaps in their biogenesis pathways and functional roles raises the hypothesis that these molecules play concerted functions in vivo, creating complex regulatory networks where cooperation with regulatory proteins is necessary. We also highlighted the implications of biogenesis and gene expression deregulation of sncRNAs and lncRNAs in human diseases like cancer. Full article

(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)

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Neuron Biomechanics Probed by Atomic Force Microscopy

by Elise Spedden and Cristian Staii

Int. J. Mol. Sci. 2013, 14(8), 16124-16140; https://doi.org/10.3390/ijms140816124 - 5 Aug 2013

Cited by 64 | Viewed by 10409

Abstract

Mechanical interactions play a key role in many processes associated with neuronal growth and development. Over the last few years there has been significant progress in our understanding of the role played by the substrate stiffness in neuronal growth, of the cell-substrate adhesion [...] Read more.

Mechanical interactions play a key role in many processes associated with neuronal growth and development. Over the last few years there has been significant progress in our understanding of the role played by the substrate stiffness in neuronal growth, of the cell-substrate adhesion forces, of the generation of traction forces during axonal elongation, and of the relationships between the neuron soma elastic properties and its health. The particular capabilities of the Atomic Force Microscope (AFM), such as high spatial resolution, high degree of control over the magnitude and orientation of the applied forces, minimal sample damage, and the ability to image and interact with cells in physiologically relevant conditions make this technique particularly suitable for measuring mechanical properties of living neuronal cells. This article reviews recent advances on using the AFM for studying neuronal biomechanics, provides an overview about the state-of-the-art measurements, and suggests directions for future applications. Full article

(This article belongs to the Special Issue Frontiers of Micro-Spectroscopy in Biological Applications)

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Post-Transcriptional Regulation by Poly(ADP-ribosyl)ation of the RNA-Binding Proteins

by Yingbiao Ji and Alexei V. Tulin

Int. J. Mol. Sci. 2013, 14(8), 16168-16183; https://doi.org/10.3390/ijms140816168 - 5 Aug 2013

Cited by 50 | Viewed by 10711

Abstract

Gene expression is intricately regulated at the post-transcriptional level by RNA-binding proteins (RBPs) via their interactions with pre-messenger RNA (pre-mRNA) and mRNA during development. However, very little is known about the mechanism regulating RBP activities in RNA metabolism. During the past few years, [...] Read more.

Gene expression is intricately regulated at the post-transcriptional level by RNA-binding proteins (RBPs) via their interactions with pre-messenger RNA (pre-mRNA) and mRNA during development. However, very little is known about the mechanism regulating RBP activities in RNA metabolism. During the past few years, a large body of evidence has suggested that many RBPs, such as heterogeneous nuclear ribonucleoproteins (hnRNPs), undergo post-translational modification through poly(ADP-ribosyl)ation to modulate RNA processing, including splicing, polyadenylation, translation, miRNA biogenesis and rRNA processing. Accordingly, RBP poly(ADP-ribosyl)ation has been shown to be involved in stress responses, stem cell differentiation and retinal morphogenesis. Here, we summarize recent advances in understanding the biological roles of RBP poly(ADP-ribosyl)ation, as controlled by Poly(ADP-ribose) Polymerases (PARPs) and Poly(ADP-ribose) Glycohydrolase (PARG). In addition, we discuss the potential of PARP and PARG inhibitors for the treatment of RBP-related human diseases, including cancer and neurodegenerative disorders. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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Contributions of Microdialysis to New Alternative Therapeutics for Hepatic Encephalopathy

by Liliana Rivera-Espinosa, Esaú Floriano-Sánchez, José Pedraza-Chaverrí, Elvia Coballase-Urrutia, Aristides III Sampieri, Daniel Ortega-Cuellar, Noemí Cárdenas-Rodríguez and Liliana Carmona-Aparicio

Int. J. Mol. Sci. 2013, 14(8), 16184-16206; https://doi.org/10.3390/ijms140816184 - 5 Aug 2013

Cited by 7 | Viewed by 7242

Abstract

Hepatic encephalopathy (HE) is a common complication of cirrhosis, of largely reversible impairment of brain function occurring in patients with acute or chronic liver failure or when the liver is bypassed by portosystemic shunts. The mechanisms causing this brain dysfunction are still largely [...] Read more.

Hepatic encephalopathy (HE) is a common complication of cirrhosis, of largely reversible impairment of brain function occurring in patients with acute or chronic liver failure or when the liver is bypassed by portosystemic shunts. The mechanisms causing this brain dysfunction are still largely unclear. The need to avoid complications caused by late diagnosis has attracted interest to understand the mechanisms underlying neuronal damage in order to find markers that will allow timely diagnosis and to propose new therapeutic alternatives to improve the care of patients. One of the experimental approaches to study HE is microdialysis; this technique allows evaluation of different chemical substances in several organs through the recollection of samples in specific places by semi-permeable membranes. In this review we will discuss the contributions of microdialysis in the understanding of the physiological alterations in human hepatic encephalopathy and experimental models and the studies to find novel alternative therapies for this disease. Full article

(This article belongs to the Section Biochemistry)

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The Role of Thyroid Hormone Signaling in the Prevention of Digestive System Cancers

by Adam R. Brown, Rosalia C. M. Simmen and Frank A. Simmen

Int. J. Mol. Sci. 2013, 14(8), 16240-16257; https://doi.org/10.3390/ijms140816240 - 6 Aug 2013

Cited by 40 | Viewed by 9048

Abstract

Thyroid hormones play a critical role in the growth and development of the alimentary tract in vertebrates. Their effects are mediated by nuclear receptors as well as the cell surface receptor integrin α_Vβ₃. Systemic thyroid hormone levels are controlled [...] Read more.

Thyroid hormones play a critical role in the growth and development of the alimentary tract in vertebrates. Their effects are mediated by nuclear receptors as well as the cell surface receptor integrin α_Vβ₃. Systemic thyroid hormone levels are controlled via activation and deactivation by iodothyronine deiodinases in the liver and other tissues. Given that thyroid hormone signaling has been characterized as a major effector of digestive system growth and homeostasis, numerous investigations have examined its role in the occurrence and progression of cancers in various tissues of this organ system. The present review summarizes current findings regarding the effects of thyroid hormone signaling on cancers of the esophagus, stomach, liver, pancreas, and colon. Particular attention is given to the roles of different thyroid hormone receptor isoforms, the novel integrin α_Vβ₃ receptor, and thyroid hormone-related nutrients as possible protective agents and therapeutic targets. Future investigations geared towards a better understanding of thyroid hormone signaling in digestive system cancers may provide preventive or therapeutic strategies to diminish risk, improve outcome and avert recurrence in afflicted individuals. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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The Role of Antioxidation and Immunomodulation in Postnatal Multipotent Stem Cell-Mediated Cardiac Repair

by Arman Saparov, Chien-Wen Chen, Sarah A. Beckman, Yadong Wang and Johnny Huard

Int. J. Mol. Sci. 2013, 14(8), 16258-16279; https://doi.org/10.3390/ijms140816258 - 6 Aug 2013

Cited by 25 | Viewed by 7997

Abstract

Oxidative stress and inflammation play major roles in the pathogenesis of coronary heart disease including myocardial infarction (MI). The pathological progression following MI is very complex and involves a number of cell populations including cells localized within the heart, as well as cells [...] Read more.

Oxidative stress and inflammation play major roles in the pathogenesis of coronary heart disease including myocardial infarction (MI). The pathological progression following MI is very complex and involves a number of cell populations including cells localized within the heart, as well as cells recruited from the circulation and other tissues that participate in inflammatory and reparative processes. These cells, with their secretory factors, have pleiotropic effects that depend on the stage of inflammation and regeneration. Excessive inflammation leads to enlargement of the infarction site, pathological remodeling and eventually, heart dysfunction. Stem cell therapy represents a unique and innovative approach to ameliorate oxidative stress and inflammation caused by ischemic heart disease. Consequently, it is crucial to understand the crosstalk between stem cells and other cells involved in post-MI cardiac tissue repair, especially immune cells, in order to harness the beneficial effects of the immune response following MI and further improve stem cell-mediated cardiac regeneration. This paper reviews the recent findings on the role of antioxidation and immunomodulation in postnatal multipotent stem cell-mediated cardiac repair following ischemic heart disease, particularly acute MI and focuses specifically on mesenchymal, muscle and blood-vessel-derived stem cells due to their antioxidant and immunomodulatory properties. Full article

(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease)

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Principles of miRNA-Target Regulation in Metazoan Models

by Epaminondas Doxakis

Int. J. Mol. Sci. 2013, 14(8), 16280-16302; https://doi.org/10.3390/ijms140816280 - 7 Aug 2013

Cited by 23 | Viewed by 11221

Abstract

MicroRNAs (miRs) are key post-transcriptional regulators that silence gene expression by direct base pairing to target sites of RNAs. They have a wide variety of tissue expression patterns and are differentially expressed during development and disease. Their activity and abundance is subject to [...] Read more.

MicroRNAs (miRs) are key post-transcriptional regulators that silence gene expression by direct base pairing to target sites of RNAs. They have a wide variety of tissue expression patterns and are differentially expressed during development and disease. Their activity and abundance is subject to various levels of control ranging from transcription and biogenesis to miR response elements on RNAs, target cellular levels and miR turnover. This review summarizes and discusses current knowledge on the regulation of miR activity and concludes with novel non-canonical functions that have recently emerged. Full article

(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)

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The Role of Mitochondrial DNA Damage and Repair in the Resistance of BCR/ABL-Expressing Cells to Tyrosine Kinase Inhibitors

by Sylwester Glowacki, Ewelina Synowiec and Janusz Blasiak

Int. J. Mol. Sci. 2013, 14(8), 16348-16364; https://doi.org/10.3390/ijms140816348 - 7 Aug 2013

Cited by 19 | Viewed by 11800

Abstract

Chronic myeloid leukemia (CML) is a hematological malignancy that arises from the transformation of stem hematopoietic cells by the fusion oncogene BCR/ABL and subsequent clonal expansion of BCR/ABL-positive progenitor leukemic cells. The BCR/ABL protein displays a constitutively increased tyrosine kinase activity that alters [...] Read more.

Chronic myeloid leukemia (CML) is a hematological malignancy that arises from the transformation of stem hematopoietic cells by the fusion oncogene BCR/ABL and subsequent clonal expansion of BCR/ABL-positive progenitor leukemic cells. The BCR/ABL protein displays a constitutively increased tyrosine kinase activity that alters many regulatory pathways, leading to uncontrolled growth, impaired differentiation and increased resistance to apoptosis featured by leukemic cells. Current CML therapy is based on tyrosine kinase inhibitors (TKIs), primarily imatinib, which induce apoptosis in leukemic cells. However, some patients show primary resistance to TKIs while others develop it in the course of therapy. In both cases, resistance may be underlined by perturbations in apoptotic signaling in leukemic cells. As mitochondria may play an important role in such signaling, alteration in mitochondrial metabolism may change resistance to pro-apoptotic action of TKIs in BCR/ABL-positive cells. Because BCR/ABL may induce reactive oxygen species and unfaithful DNA repair, it may affect the stability of mitochondrial DNA, influencing mitochondrial apoptotic signaling and in this way change the sensitivity of CML cells to TKIs. Moreover, cancer cells, including BCR/ABL-positive cells, show an increased level of glucose metabolism, resulting from the shift from oxidative phosphorylation to glycolysis to supply ATP for extensive proliferation. Enhanced level of glycolysis may be associated with TKI resistance and requires change in the expression of several genes regulated mostly by hypoxia-inducible factor-1α, HIF-1α. Such regulation may be associated with the impaired mitochondrial respiratory system in CML cells. In summary, mitochondria and mitochondria-associated molecules and pathways may be attractive targets to overcome TKI resistance in CML. Full article

(This article belongs to the Section Biochemistry)

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Molecular Pathways Involved in Colorectal Cancer: Implications for Disease Behavior and Prevention

by Dora Colussi, Giovanni Brandi, Franco Bazzoli and Luigi Ricciardiello

Int. J. Mol. Sci. 2013, 14(8), 16365-16385; https://doi.org/10.3390/ijms140816365 - 7 Aug 2013

Cited by 352 | Viewed by 17995

Abstract

Research conducted during the past 30 years has increased our understanding of the mechanisms involved in colorectal cancer initiation and development. The findings have demonstrated the existence of at least three pathways: chromosomal instability, microsatellite instability and CpG island methylator phenotype. Importantly, new [...] Read more.

Research conducted during the past 30 years has increased our understanding of the mechanisms involved in colorectal cancer initiation and development. The findings have demonstrated the existence of at least three pathways: chromosomal instability, microsatellite instability and CpG island methylator phenotype. Importantly, new studies have shown that inflammation and microRNAs contribute to colorectal carcinogenesis. Recent data have demonstrated that several genetic and epigenetic changes are important in determining patient prognosis and survival. Furthermore, some of these mechanisms are related to patients’ response to drugs, such as aspirin, which could be used for both chemoprevention and treatment in specific settings. Thus, in the near future, we could be able to predict disease behavior based on molecular markers found on tumors, and direct the best treatment options for patients. Full article

(This article belongs to the Special Issue Pathogenesis and Prevention of Colorectal Cancer)

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Quorum Sensing in the Squid-Vibrio Symbiosis

by Subhash C. Verma and Tim Miyashiro

Int. J. Mol. Sci. 2013, 14(8), 16386-16401; https://doi.org/10.3390/ijms140816386 - 7 Aug 2013

Cited by 88 | Viewed by 15005

Abstract

Quorum sensing is an intercellular form of communication that bacteria use to coordinate group behaviors such as biofilm formation and the production of antibiotics and virulence factors. The term quorum sensing was originally coined to describe the mechanism underlying the onset of luminescence [...] Read more.

Quorum sensing is an intercellular form of communication that bacteria use to coordinate group behaviors such as biofilm formation and the production of antibiotics and virulence factors. The term quorum sensing was originally coined to describe the mechanism underlying the onset of luminescence production in cultures of the marine bacterium Vibrio fischeri. Luminescence and, more generally, quorum sensing are important for V. fischeri to form a mutualistic symbiosis with the Hawaiian bobtail squid, Euprymna scolopes. The symbiosis is established when V. fischeri cells migrate via flagella-based motility from the surrounding seawater into a specialized structure injuvenile squid called the light organ. The cells grow to high cell densities within the light organ where the infection persists over the lifetime of the animal. A hallmark of a successful symbiosis is the luminescence produced by V. fischeri that camouflages the squid at night by eliminating its shadow within the water column. While the regulatory networks governing quorum sensing are critical for properly regulating V. fischeri luminescence within the squid light organ, they also regulate luminescence-independent processes during symbiosis. In this review, we discuss the quorum-sensing network of V. fischeri and highlight its impact at various stages during host colonization. Full article

(This article belongs to the Special Issue Quorum Sensing Research in Microbial Systems)

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Exploring the Role of Genetic Variability and Lifestyle in Oxidative Stress Response for Healthy Aging and Longevity

by Serena Dato, Paolina Crocco, Patrizia D'Aquila, Francesco De Rango, Dina Bellizzi, Giuseppina Rose and Giuseppe Passarino

Int. J. Mol. Sci. 2013, 14(8), 16443-16472; https://doi.org/10.3390/ijms140816443 - 8 Aug 2013

Cited by 77 | Viewed by 13011

Abstract

Oxidative stress is both the cause and consequence of impaired functional homeostasis characterizing human aging. The worsening efficiency of stress response with age represents a health risk and leads to the onset and accrual of major age-related diseases. In contrast, centenarians seem to [...] Read more.

Oxidative stress is both the cause and consequence of impaired functional homeostasis characterizing human aging. The worsening efficiency of stress response with age represents a health risk and leads to the onset and accrual of major age-related diseases. In contrast, centenarians seem to have evolved conservative stress response mechanisms, probably derived from a combination of a diet rich in natural antioxidants, an active lifestyle and a favorable genetic background, particularly rich in genetic variants able to counteract the stress overload at the level of both nuclear and mitochondrial DNA. The integration of these factors could allow centenarians to maintain moderate levels of free radicals that exert beneficial signaling and modulator effects on cellular metabolism. Considering the hot debate on the efficacy of antioxidant supplementation in promoting healthy aging, in this review we gathered the existing information regarding genetic variability and lifestyle factors which potentially modulate the stress response at old age. Evidence reported here suggests that the integration of lifestyle factors (moderate physical activity and healthy nutrition) and genetic background could shift the balance in favor of the antioxidant cellular machinery by activating appropriate defense mechanisms in response to exceeding external and internal stress levels, and thus possibly achieving the prospect of living a longer life. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

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Mechanisms of Lin28-Mediated miRNA and mRNA Regulation—A Structural and Functional Perspective

by Florian Mayr and Udo Heinemann

Int. J. Mol. Sci. 2013, 14(8), 16532-16553; https://doi.org/10.3390/ijms140816532 - 9 Aug 2013

Cited by 90 | Viewed by 15453

Abstract

Lin28 is an essential RNA-binding protein that is ubiquitously expressed in embryonic stem cells. Its physiological function has been linked to the regulation of differentiation, development, and oncogenesis as well as glucose metabolism. Lin28 mediates these pleiotropic functions by inhibiting let-7 miRNA biogenesis [...] Read more.

Lin28 is an essential RNA-binding protein that is ubiquitously expressed in embryonic stem cells. Its physiological function has been linked to the regulation of differentiation, development, and oncogenesis as well as glucose metabolism. Lin28 mediates these pleiotropic functions by inhibiting let-7 miRNA biogenesis and by modulating the translation of target mRNAs. Both activities strongly depend on Lin28’s RNA-binding domains (RBDs), an N-terminal cold-shock domain (CSD) and a C-terminal Zn-knuckle domain (ZKD). Recent biochemical and structural studies revealed the mechanisms of how Lin28 controls let-7 biogenesis. Lin28 binds to the terminal loop of pri- and pre-let-7 miRNA and represses their processing by Drosha and Dicer. Several biochemical and structural studies showed that the specificity of this interaction is mainly mediated by the ZKD with a conserved GGAGA or GGAGA-like motif. Further RNA crosslinking and immunoprecipitation coupled to high-throughput sequencing (CLIP-seq) studies confirmed this binding motif and uncovered a large number of new mRNA binding sites. Here we review exciting recent progress in our understanding of how Lin28 binds structurally diverse RNAs and fulfills its pleiotropic functions. Full article

(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)

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Development of Quorum-Based Anti-Virulence Therapeutics Targeting Gram-Negative Bacterial Pathogens

by Song Buck Tay and Wen Shan Yew

Int. J. Mol. Sci. 2013, 14(8), 16570-16599; https://doi.org/10.3390/ijms140816570 - 9 Aug 2013

Cited by 103 | Viewed by 13141

Abstract

Quorum sensing is a cell density-dependent signaling phenomenon used by bacteria for coordination of population-wide phenotypes, such as expression of virulence genes, antibiotic resistance and biofilm formation. Lately, disruption of bacterial communication has emerged as an anti-virulence strategy with enormous therapeutic potential given [...] Read more.

Quorum sensing is a cell density-dependent signaling phenomenon used by bacteria for coordination of population-wide phenotypes, such as expression of virulence genes, antibiotic resistance and biofilm formation. Lately, disruption of bacterial communication has emerged as an anti-virulence strategy with enormous therapeutic potential given the increasing incidences of drug resistance in pathogenic bacteria. The quorum quenching therapeutic approach promises a lower risk of resistance development, since interference with virulence generally does not affect the growth and fitness of the bacteria and, hence, does not exert an associated selection pressure for drug-resistant strains. With better understanding of bacterial communication networks and mechanisms, many quorum quenching methods have been developed against various clinically significant bacterial pathogens. In particular, Gram-negative bacteria are an important group of pathogens, because, collectively, they are responsible for the majority of hospital-acquired infections. Here, we discuss the current understanding of existing quorum sensing mechanisms and present important inhibitory strategies that have been developed against this group of pathogenic bacteria. Full article

(This article belongs to the Special Issue Quorum Sensing Research in Microbial Systems)

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Folding and Biogenesis of Mitochondrial Small Tim Proteins

by Efrain Ceh-Pavia, Michael P. Spiller and Hui Lu

Int. J. Mol. Sci. 2013, 14(8), 16685-16705; https://doi.org/10.3390/ijms140816685 - 13 Aug 2013

Cited by 19 | Viewed by 9469

Abstract

Correct and timely folding is critical to the function of all proteins. The importance of this is illustrated in the biogenesis of the mitochondrial intermembrane space (IMS) “small Tim” proteins. Biogenesis of the small Tim proteins is regulated by dedicated systems or pathways, [...] Read more.

Correct and timely folding is critical to the function of all proteins. The importance of this is illustrated in the biogenesis of the mitochondrial intermembrane space (IMS) “small Tim” proteins. Biogenesis of the small Tim proteins is regulated by dedicated systems or pathways, beginning with synthesis in the cytosol and ending with assembly of individually folded proteins into functional complexes in the mitochondrial IMS. The process is mostly centered on regulating the redox states of the conserved cysteine residues: oxidative folding is crucial for protein function in the IMS, but oxidized (disulfide bonded) proteins cannot be imported into mitochondria. How the redox-sensitive small Tim precursor proteins are maintained in a reduced, import-competent form in the cytosol is not well understood. Recent studies suggest that zinc and the cytosolic thioredoxin system play a role in the biogenesis of these proteins. In the IMS, the mitochondrial import and assembly (MIA) pathway catalyzes both import into the IMS and oxidative folding of the small Tim proteins. Finally, assembly of the small Tim complexes is a multistep process driven by electrostatic and hydrophobic interactions; however, the chaperone function of the complex might require destabilization of these interactions to accommodate the substrate. Here, we review how folding of the small Tim proteins is regulated during their biogenesis, from maintenance of the unfolded precursors in the cytosol, to their import, oxidative folding, complex assembly and function in the IMS. Full article

(This article belongs to the Special Issue Protein Folding)

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The Effects of Nanomaterials as Endocrine Disruptors

by Ivo Iavicoli, Luca Fontana, Veruscka Leso and Antonio Bergamaschi

Int. J. Mol. Sci. 2013, 14(8), 16732-16801; https://doi.org/10.3390/ijms140816732 - 14 Aug 2013

Cited by 174 | Viewed by 15421

Abstract

In recent years, nanoparticles have been increasingly used in several industrial, consumer and medical applications because of their unique physico-chemical properties. However, in vitro and in vivo studies have demonstrated that these properties are also closely associated with detrimental health effects. There is [...] Read more.

In recent years, nanoparticles have been increasingly used in several industrial, consumer and medical applications because of their unique physico-chemical properties. However, in vitro and in vivo studies have demonstrated that these properties are also closely associated with detrimental health effects. There is a serious lack of information on the potential nanoparticle hazard to human health, particularly on their possible toxic effects on the endocrine system. This topic is of primary importance since the disruption of endocrine functions is associated with severe adverse effects on human health. Consequently, in order to gather information on the hazardous effects of nanoparticles on endocrine organs, we reviewed the data available in the literature regarding the endocrine effects of in vitro and in vivo exposure to different types of nanoparticles. Our aim was to understand the potential endocrine disrupting risks posed by nanoparticles, to assess their underlying mechanisms of action and identify areas in which further investigation is needed in order to obtain a deeper understanding of the role of nanoparticles as endocrine disruptors. Current data support the notion that different types of nanoparticles are capable of altering the normal and physiological activity of the endocrine system. However, a critical evaluation of these findings suggests the need to interpret these results with caution since information on potential endocrine interactions and the toxicity of nanoparticles is quite limited. Full article

(This article belongs to the Special Issue Bioactive Nanoparticles 2013)

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Gene Expression Profiling as a Tool to Investigate the Molecular Machinery Activated during Hippocampal Neurodegeneration Induced by Trimethyltin (TMT) Administration

by Wanda Lattanzi, Valentina Corvino, Valentina Di Maria, Fabrizio Michetti and Maria Concetta Geloso

Int. J. Mol. Sci. 2013, 14(8), 16817-16835; https://doi.org/10.3390/ijms140816817 - 15 Aug 2013

Cited by 31 | Viewed by 8663

Abstract

Trimethyltin (TMT) is an organotin compound exhibiting neurotoxicant effects selectively localized in the limbic system and especially marked in the hippocampus, in both experimental animal models and accidentally exposed humans. TMT administration causes selective neuronal death involving either the granular neurons of the [...] Read more.

Trimethyltin (TMT) is an organotin compound exhibiting neurotoxicant effects selectively localized in the limbic system and especially marked in the hippocampus, in both experimental animal models and accidentally exposed humans. TMT administration causes selective neuronal death involving either the granular neurons of the dentate gyrus or the pyramidal cells of the Cornu Ammonis, with a different pattern of localization depending on the different species studied or the dosage schedule. TMT is broadly used to realize experimental models of hippocampal neurodegeneration associated with cognitive impairment and temporal lobe epilepsy, though the molecular mechanisms underlying the associated selective neuronal death are still not conclusively clarified. Experimental evidence indicates that TMT-induced neurodegeneration is a complex event involving different pathogenetic mechanisms, probably acting differently in animal and cell models, which include neuroinflammation, intracellular calcium overload, and oxidative stress. Microarray-based, genome-wide expression analysis has been used to investigate the molecular scenario occurring in the TMT-injured brain in different in vivo and in vitro models, producing an overwhelming amount of data. The aim of this review is to discuss and rationalize the state-of-the-art on TMT-associated genome wide expression profiles in order to identify comparable and reproducible data that may allow focusing on significantly involved pathways. Full article

(This article belongs to the Special Issue Molecular Research in Neurotoxicology)

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Non-Coding RNAs and Cancer

by Federica Calore, Francesca Lovat and Michela Garofalo

Int. J. Mol. Sci. 2013, 14(8), 17085-17110; https://doi.org/10.3390/ijms140817085 - 19 Aug 2013

Cited by 48 | Viewed by 11756

Abstract

The discovery of the biological relevance of non-coding RNA (ncRNAs) molecules represents one of the most significant advances in contemporary molecular biology. Expression profiling of human tumors, based on the expression of miRNAs and other short or long ncRNAs, has identified signatures associated [...] Read more.

The discovery of the biological relevance of non-coding RNA (ncRNAs) molecules represents one of the most significant advances in contemporary molecular biology. Expression profiling of human tumors, based on the expression of miRNAs and other short or long ncRNAs, has identified signatures associated with diagnosis, staging, progression, prognosis, and response to treatment. In this review we will discuss the recent remarkable advancement in the understanding the biological functions of human ncRNAs in cancer, the mechanisms of expression and the therapeutic potential. Full article

(This article belongs to the Special Issue Regulation by non-coding RNAs 2013)

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NF90 in Posttranscriptional Gene Regulation and MicroRNA Biogenesis

by Kiyoshi Masuda, Yuki Kuwano, Kensei Nishida, Kazuhito Rokutan and Issei Imoto

Int. J. Mol. Sci. 2013, 14(8), 17111-17121; https://doi.org/10.3390/ijms140817111 - 19 Aug 2013

Cited by 37 | Viewed by 9238

Abstract

Gene expression patterns are effectively regulated by turnover and translation regulatory (TTR) RNA-binding proteins (RBPs). The TTR-RBPs control gene expression at posttranscriptional levels, such as pre-mRNA splicing, mRNA cytoplasmic export, turnover, storage, and translation. Double-stranded RNA binding proteins (DSRBPs) are known to regulate [...] Read more.

Gene expression patterns are effectively regulated by turnover and translation regulatory (TTR) RNA-binding proteins (RBPs). The TTR-RBPs control gene expression at posttranscriptional levels, such as pre-mRNA splicing, mRNA cytoplasmic export, turnover, storage, and translation. Double-stranded RNA binding proteins (DSRBPs) are known to regulate many processes of cellular metabolism, including transcriptional control, translational control, mRNA processing and localization. Nuclear factor 90 (NF90), one of the DSRBPs, is abundantly expressed in vertebrate tissue and participates in many aspects of RNA metabolism. NF90 was originally purified as a component of a DNA binding complex which binds to the antigen recognition response element 2 in the interleukin 2 promoter. Recent studies have provided us with interesting insights into its possible physiological roles in RNA metabolism, including transcription, degradation, and translation. In addition, it was shown that NF90 regulates microRNA expression. In this review, we try to focus on the function of NF90 in posttranscriptional gene regulation and microRNA biogenesis. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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Molecular Interactions in the Development of Brain Metastases

by Nina Martinez, Adrienne Boire and Lisa M. DeAngelis

Int. J. Mol. Sci. 2013, 14(8), 17157-17167; https://doi.org/10.3390/ijms140817157 - 20 Aug 2013

Cited by 11 | Viewed by 5859

Abstract

Brain metastases are a much-feared complication of cancer. The development of brain metastases requires a malignant cell to acquire characteristics that facilitate dissemination away from the primary site, entrance into the nervous system, and establishment in the brain. This review summarizes recent work [...] Read more.

Brain metastases are a much-feared complication of cancer. The development of brain metastases requires a malignant cell to acquire characteristics that facilitate dissemination away from the primary site, entrance into the nervous system, and establishment in the brain. This review summarizes recent work focused on the molecular derangements leading to brain metastases and outlines areas in need of greater understanding. Full article

(This article belongs to the Section Biochemistry)

254 KiB

Open AccessReview

Preventive or Potential Therapeutic Value of Nutraceuticals against Ionizing Radiation-Induced Oxidative Stress in Exposed Subjects and Frequent Fliers

by Maria Teresa Giardi, Eleftherios Touloupakis, Delfina Bertolotto and Gabriele Mascetti

Int. J. Mol. Sci. 2013, 14(8), 17168-17192; https://doi.org/10.3390/ijms140817168 - 20 Aug 2013

Cited by 26 | Viewed by 8607

Abstract

Humans are constantly exposed to ionizing radiation deriving from outer space sources or activities related to medical care. Absorption of ionizing radiation doses over a prolonged period of time can result in oxidative damage and cellular dysfunction inducing several diseases, especially in ageing [...] Read more.

Humans are constantly exposed to ionizing radiation deriving from outer space sources or activities related to medical care. Absorption of ionizing radiation doses over a prolonged period of time can result in oxidative damage and cellular dysfunction inducing several diseases, especially in ageing subjects. In this report, we analyze the effects of ionizing radiation, particularly at low doses, in relation to a variety of human pathologies, including cancer, and cardiovascular and retinal diseases. We discuss scientific data in support of protection strategies by safe antioxidant formulations that can provide preventive or potential therapeutic value in response to long-term diseases that may develop following exposure. Full article

(This article belongs to the Special Issue Oxidative Stress and Ageing)

198 KiB

Open AccessReview

Post-Transcriptional Controls by Ribonucleoprotein Complexes in the Acquisition of Drug Resistance

by Hoin Kang, Chongtae Kim, Heejin Lee, Wook Kim and Eun Kyung Lee

Int. J. Mol. Sci. 2013, 14(8), 17204-17220; https://doi.org/10.3390/ijms140817204 - 20 Aug 2013

Cited by 19 | Viewed by 7796

Abstract

Acquisition of drug resistance leads to failure of anti-cancer treatments and therapies. Although several successive chemotherapies are available, along with efforts towards clinical applications of new anti-cancer drugs, it is generally realized that there is a long way to go to treat cancers. [...] Read more.

Acquisition of drug resistance leads to failure of anti-cancer treatments and therapies. Although several successive chemotherapies are available, along with efforts towards clinical applications of new anti-cancer drugs, it is generally realized that there is a long way to go to treat cancers. Resistance to anti-cancer drugs results from various factors, including genetic as well as epigenetic differences in tumors. Determining the molecular and cellular mechanisms responsible for the acquisition of drug resistance may be a helpful approach for the development of new therapeutic strategies to overcome treatment failure. Several studies have shown that the acquisition of drug resistance is tightly regulated by post-transcriptional regulators such as RNA binding proteins (RBPs) and microRNAs (miRNAs), which change the stability and translation of mRNAs encoding factors involved in cell survival, proliferation, epithelial-mesenchymal transition, and drug metabolism. Here, we review our current understanding of ribonucleoprotein complexes, including RBPs and miRNAs, which play critical roles in the acquisition of drug resistance and have potential clinical implications for cancer. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

287 KiB

Open AccessReview

Environmental Stimuli Shape Biofilm Formation and the Virulence of Periodontal Pathogens

by Marja T. Pöllänen, Annamari Paino and Riikka Ihalin

Int. J. Mol. Sci. 2013, 14(8), 17221-17237; https://doi.org/10.3390/ijms140817221 - 20 Aug 2013

Cited by 27 | Viewed by 9112

Abstract

Periodontitis is a common inflammatory disease affecting the tooth-supporting structures. It is initiated by bacteria growing as a biofilm at the gingival margin, and communication of the biofilms differs in health and disease. The bacterial composition of periodontitis-associated biofilms has been well documented [...] Read more.

Periodontitis is a common inflammatory disease affecting the tooth-supporting structures. It is initiated by bacteria growing as a biofilm at the gingival margin, and communication of the biofilms differs in health and disease. The bacterial composition of periodontitis-associated biofilms has been well documented and is under continual investigation. However, the roles of several host response and inflammation driven environmental stimuli on biofilm formation is not well understood. This review article addresses the effects of environmental factors such as pH, temperature, cytokines, hormones, and oxidative stress on periodontal biofilm formation and bacterial virulence. Full article

(This article belongs to the Special Issue Biofilms: Extracellular Bastions of Bacteria)

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225 KiB

Open AccessBrief Report

Influence of Genetic Variations on Levels of Inflammatory Markers of Healthy Subjects at Baseline and One Week after Clopidogrel Therapy; Results of a Preliminary Study

by Payman Shahabi, Gérard Siest, Bernard Herbeth, Daniel Lambert, Christine Masson, Jean-Sébastien Hulot, Sébastien Bertil, Pascale Gaussem and Sophie Visvikis-Siest

Int. J. Mol. Sci. 2013, 14(8), 16402-16413; https://doi.org/10.3390/ijms140816402 - 8 Aug 2013

Cited by 3 | Viewed by 5803

Abstract

We aimed to assess the association between the most common polymorphisms of cytochrome P450 (CYP) epoxygenases on the plasma levels of inflammatory markers in a population of healthy subjects. We also sought to determine whether CYP2C19*2 polymorphism is associated with the anti-inflammatory response [...] Read more.

We aimed to assess the association between the most common polymorphisms of cytochrome P450 (CYP) epoxygenases on the plasma levels of inflammatory markers in a population of healthy subjects. We also sought to determine whether CYP2C19*2 polymorphism is associated with the anti-inflammatory response to clopidogrel. In a population of 49 healthy young males, the baseline plasma levels of inflammatory markers including C-reactive protein, haptoglobin, orosomucoid acid, CD-40 were compared in carriers vs. non-carriers of the most frequent CYP epoxygenase polymorphisms: CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C8*2 and CYP2J2*7. Also, the variation of inflammatory markers from baseline to 7 days after administration of 75 mg per day of clopidogrel were compared in carriers vs. non-carriers of CYP2C19* allele and also in responders vs. hypo-responders to clopidogrel, determined by platelet reactivity tests. There was no significant association between epoxygenase polymorphisms and the baseline levels of inflammatory markers. Likewise, CYP2C19* allele was not associated with anti-inflammatory response to clopidogrel. Our findings did not support the notion that the genetic variations of CYP epoxygenases are associated with the level of inflammatory markers. Moreover, our results did not support the hypothesis that CYP2C19*2 polymorphism is associated with the variability in response to the anti-inflammatory properties of clopidogrel. Full article

(This article belongs to the Special Issue Xenobiotic Metabolism)

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Int. J. Mol. Sci., Volume 14, Issue 8 (August 2013) – 106 articles , Pages 15199-17237

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