International Journal of Molecular Sciences

21 pages, 1205 KiB

Open AccessReview

Mutations Associated with Functional Disorder of Xanthine Oxidoreductase and Hereditary Xanthinuria in Humans

by Kimiyoshi Ichida¹, Yoshihiro Amaya², Ken Okamoto³ and Takeshi Nishino^3,4,*

¹ Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences 1432-1, Horinouchi, Hachioji, Tokyo 192-0392, Japan

² Division of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, 2-5274 Gakkocho-dori, Chuo-ku, Niigata 951-8514, Japan

³ Department of Biochemistry and Molecular Biology, Nippon Medical School, 1-1-5 Sendagi, Bunkyou-ku, Tokyo 113-8602, Japan

⁴ Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-Ku, Tokyo 113-8657, Japan

Int. J. Mol. Sci. 2012, 13(11), 15475-15495; https://doi.org/10.3390/ijms131115475 - 21 Nov 2012

Cited by 95 | Viewed by 14474

Abstract

Xanthine oxidoreductase (XOR) catalyzes the conversion of hypoxanthine to xanthine and xanthine to uric acid with concomitant reduction of either NAD⁺ or O₂. The enzyme is a target of drugs to treat hyperuricemia, gout and reactive oxygen-related diseases. Human diseases [...] Read more.

Xanthine oxidoreductase (XOR) catalyzes the conversion of hypoxanthine to xanthine and xanthine to uric acid with concomitant reduction of either NAD⁺ or O₂. The enzyme is a target of drugs to treat hyperuricemia, gout and reactive oxygen-related diseases. Human diseases associated with genetically determined dysfunction of XOR are termed xanthinuria, because of the excretion of xanthine in urine. Xanthinuria is classified into two subtypes, type I and type II. Type I xanthinuria involves XOR deficiency due to genetic defect of XOR, whereas type II xanthinuria involves dual deficiency of XOR and aldehyde oxidase (AO, a molybdoflavo enzyme similar to XOR) due to genetic defect in the molybdenum cofactor sulfurase. Molybdenum cofactor deficiency is associated with triple deficiency of XOR, AO and sulfite oxidase, due to defective synthesis of molybdopterin, which is a precursor of molybdenum cofactor for all three enzymes. The present review focuses on mutation or chemical modification studies of mammalian XOR, as well as on XOR mutations identified in humans, aimed at understanding the reaction mechanism of XOR and the relevance of mutated XORs as models to estimate the possible side effects of clinical application of XOR inhibitors. Full article

(This article belongs to the Special Issue Flavins)

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11 pages, 219 KiB

Open AccessArticle

Associations between Endogenous Dimethylarginines and Renal Function in Healthy Children and Adolescents

by Aleksandra Jaźwińska-Kozuba¹, Jens Martens-Lobenhoffer², Andrzej Surdacki^3,*, Olga Kruszelnicka⁴, Jarosław Rycaj⁵, Urszula Godula-Stuglik⁶ and Stefanie M. Bode-Böger²

¹ Almed-Elektra Medical Center, 41-710 Ruda Śląska, Poland

² Institute for Clinical Pharmacology, Otto-von-Guericke University, 39120 Magdeburg, Germany

³ Department of Cardiology, Jagiellonian University/University Hospital, 31-501 Cracow, Poland

⁴ Department of Coronary Artery Disease, the John Paul II Hospital, 31-202 Cracow, Poland

⁵ Department of Cardiology, Congenital Heart Defects and Electrotherapy, Silesian Center for Heart Diseases in Zabrze, 41-800 Zabrze, Medical University of Silesia, Poland

⁶ Department of Pediatrics in Zabrze, 41-800 Zabrze, Medical University of Silesia, Poland

Int. J. Mol. Sci. 2012, 13(11), 15464-15474; https://doi.org/10.3390/ijms131115464 - 21 Nov 2012

Cited by 6 | Viewed by 6131

Abstract

The structural isomer of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), is eliminated almost entirely by urinary excretion and considered a sensitive index of glomerular filtration rate (GFR). However, reports on this relationship in healthy subjects younger than 18 years of age are rare. [...] Read more.

The structural isomer of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), is eliminated almost entirely by urinary excretion and considered a sensitive index of glomerular filtration rate (GFR). However, reports on this relationship in healthy subjects younger than 18 years of age are rare. Therefore, our aim was to investigate relations between endogenous dimethylarginines and renal function indices in healthy children and adolescents. We studied 40 subjects aged 3–18 years free of coexistent diseases or subclinical carotid atherosclerosis. A serum creatinine-derived estimated GFR (eGFR) was calculated by the revised bedside Schwartz equation. L-arginine, ADMA and SDMA were measured by liquid chromatography-tandem mass spectrometry. Mean eGFR was 122 ± 22 (SD) mL/min per 1.73 m². Creatinine and eGFR exhibited closer correlations with the SDMA/ADMA ratio (r = 0.64, p < 0.0001; r = −0.63, p < 0.0001, respectively) than with SDMA (r = 0.31, p = 0.05; r = −0.35, p = 0.03). Neither creatinine nor eGFR correlated with ADMA or L-arginine. Adjustment for age or height only slightly attenuated the associations between the SDMA/ADMA ratio and eGFR or creatinine. Our findings suggest the superiority of the SDMA/ADMA ratio over SDMA as a renal function index in healthy children. Thus, further studies are warranted to verify our preliminary results in a larger group of subjects below 18 years of age. Full article

(This article belongs to the Special Issue ADMA and Nitrergic System)

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17 pages, 189 KiB

Open AccessReview

Dietary Docosahexaenoic Acid (22:6) Incorporates into Cardiolipin at the Expense of Linoleic Acid (18:2): Analysis and Potential Implications

by Colin H. Cortie^* and Paul L. Else

Metabolic Research Centre (in IHMRI), School of Health Sciences, University of Wollongong, Wollongong, NSW 2522, Australia

Int. J. Mol. Sci. 2012, 13(11), 15447-15463; https://doi.org/10.3390/ijms131115447 - 21 Nov 2012

Cited by 26 | Viewed by 9394

Abstract

Cardiolipin is a signature phospholipid of major functional significance in mitochondria. In heart mitochondria the fatty acid composition of cardiolipin is commonly viewed as highly regulated due to its high levels of linoleic acid (18:2n − 6) and the dominant presence of [...] Read more.

Cardiolipin is a signature phospholipid of major functional significance in mitochondria. In heart mitochondria the fatty acid composition of cardiolipin is commonly viewed as highly regulated due to its high levels of linoleic acid (18:2n − 6) and the dominant presence of a 4×18:2 molecular species. However, analysis of data from a comprehensive compilation of studies reporting changes in fatty acid composition of cardiolipin in heart and liver mitochondria in response to dietary fat shows that, in heart the accrual of 18:2 into cardiolipin conforms strongly to its dietary availability at up to 20% of total dietary fatty acid and thereafter is regulated. In liver, no dietary conformer trend is apparent for 18:2 with regulated lower levels across the dietary range for 18:2. When 18:2 and docosahexaenoic acid (22:6n − 3) are present in the same diet, 22:6 is incorporated into cardiolipin of heart and liver at the expense of 18:2 when 22:6 is up to ~20% and 10% of total dietary fatty acid respectively. Changes in fatty acid composition in response to dietary fat are also compared for the two other main mitochondrial phospholipids, phosphatidylcholine and phosphatidylethanolamine, and the potential consequences of replacement of 18:2 with 22:6 in cardiolipin are discussed. Full article

(This article belongs to the Special Issue Phospholipids: Molecular Sciences 2012)

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27 pages, 2386 KiB

Open AccessArticle

Errors in the Calculation of ²⁷Al Nuclear Magnetic Resonance Chemical Shifts

by Xianlong Wang^1,2,*, Chengfei Wang¹ and Hui Zhao¹

¹ Center of Bioinformatics, University of Electronic Science and Technology of China, No. 4, 2nd Section, Jianshe Road, Chengdu 610054, China

² Department of Chemistry, Bryn Mawr College, 101 North Merion Avenue, Bryn Mawr, PA 19010, USA

Int. J. Mol. Sci. 2012, 13(11), 15420-15446; https://doi.org/10.3390/ijms131115420 - 21 Nov 2012

Cited by 9 | Viewed by 8027

Abstract

Computational chemistry is an important tool for signal assignment of ²⁷Al nuclear magnetic resonance spectra in order to elucidate the species of aluminum(III) in aqueous solutions. The accuracy of the popular theoretical models for computing the ²⁷Al chemical shifts was evaluated [...] Read more.

Computational chemistry is an important tool for signal assignment of ²⁷Al nuclear magnetic resonance spectra in order to elucidate the species of aluminum(III) in aqueous solutions. The accuracy of the popular theoretical models for computing the ²⁷Al chemical shifts was evaluated by comparing the calculated and experimental chemical shifts in more than one hundred aluminum(III) complexes. In order to differentiate the error due to the chemical shielding tensor calculation from that due to the inadequacy of the molecular geometry prediction, single-crystal X-ray diffraction determined structures were used to build the isolated molecule models for calculating the chemical shifts. The results were compared with those obtained using the calculated geometries at the B3LYP/6-31G(d) level. The isotropic chemical shielding constants computed at different levels have strong linear correlations even though the absolute values differ in tens of ppm. The root-mean-square difference between the experimental chemical shifts and the calculated values is approximately 5 ppm for the calculations based on the X-ray structures, but more than 10 ppm for the calculations based on the computed geometries. The result indicates that the popular theoretical models are adequate in calculating the chemical shifts while an accurate molecular geometry is more critical. Full article

(This article belongs to the Special Issue Atoms in Molecules and in Nanostructures)

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19 pages, 585 KiB

Open AccessReview

Marine Omega-3 Phospholipids: Metabolism and Biological Activities

by Lena Burri¹, Nils Hoem¹, Sebastiano Banni² and Kjetil Berge^1,*

¹ Aker BioMarine ASA, Fjordalléen 16, NO-0115 Oslo, Norway

² Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy

Int. J. Mol. Sci. 2012, 13(11), 15401-15419; https://doi.org/10.3390/ijms131115401 - 21 Nov 2012

Cited by 228 | Viewed by 24815

Abstract

The biological activities of omega-3 fatty acids (n-3 FAs) have been under extensive study for several decades. However, not much attention has been paid to differences of dietary forms, such as triglycerides (TGs) versus ethyl esters or phospholipids (PLs). New innovative marine raw [...] Read more.

The biological activities of omega-3 fatty acids (n-3 FAs) have been under extensive study for several decades. However, not much attention has been paid to differences of dietary forms, such as triglycerides (TGs) versus ethyl esters or phospholipids (PLs). New innovative marine raw materials, like krill and fish by-products, present n-3 FAs mainly in the PL form. With their increasing availability, new evidence has emerged on n-3 PL biological activities and differences to n-3 TGs. In this review, we describe the recently discovered nutritional properties of n-3 PLs on different parameters of metabolic syndrome and highlight their different metabolic bioavailability in comparison to other dietary forms of n-3 FAs. Full article

(This article belongs to the Special Issue Phospholipids: Molecular Sciences 2012)

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14 pages, 414 KiB

Open AccessArticle

Predicting Retention Times of Naturally Occurring Phenolic Compounds in Reversed-Phase Liquid Chromatography: A Quantitative Structure-Retention Relationship (QSRR) Approach

by Jamshed Akbar¹, Shahid Iqbal¹, Fozia Batool¹, Abdul Karim¹ and Kim Wei Chan^2,*

¹ Department of Chemistry, University of Sargodha, Sargodha 40100, Pakistan

² Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400, Malaysia

Int. J. Mol. Sci. 2012, 13(11), 15387-15400; https://doi.org/10.3390/ijms131115387 - 20 Nov 2012

Cited by 22 | Viewed by 7516

Abstract

Quantitative structure-retention relationships (QSRRs) have successfully been developed for naturally occurring phenolic compounds in a reversed-phase liquid chromatographic (RPLC) system. A total of 1519 descriptors were calculated from the optimized structures of the molecules using MOPAC2009 and DRAGON softwares. The data set of [...] Read more.

Quantitative structure-retention relationships (QSRRs) have successfully been developed for naturally occurring phenolic compounds in a reversed-phase liquid chromatographic (RPLC) system. A total of 1519 descriptors were calculated from the optimized structures of the molecules using MOPAC2009 and DRAGON softwares. The data set of 39 molecules was divided into training and external validation sets. For feature selection and mapping we used step-wise multiple linear regression (SMLR), unsupervised forward selection followed by step-wise multiple linear regression (UFS-SMLR) and artificial neural networks (ANN). Stable and robust models with significant predictive abilities in terms of validation statistics were obtained with negation of any chance correlation. ANN models were found better than remaining two approaches. HNar, IDM, Mp, GATS2v, DISP and 3D-MoRSE (signals 22, 28 and 32) descriptors based on van der Waals volume, electronegativity, mass and polarizability, at atomic level, were found to have significant effects on the retention times. The possible implications of these descriptors in RPLC have been discussed. All the models are proven to be quite able to predict the retention times of phenolic compounds and have shown remarkable validation, robustness, stability and predictive performance. Full article

(This article belongs to the Section Biochemistry)

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14 pages, 2170 KiB

Open AccessArticle

Tenomodulin Inhibits Retinal Neovascularization in a Mouse Model of Oxygen-Induced Retinopathy

by Wei Wang^1,*, Zhongqiu Li¹, Tatsuhiko Sato² and Yusuke Oshima²

¹ Department of Ophthalmology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China

² Department of Ophthalmology and Visual Science, Osaka University Medical School, Yamadaoka, Suita, Osaka 5650871, Japan

Int. J. Mol. Sci. 2012, 13(11), 15373-15386; https://doi.org/10.3390/ijms131115373 - 20 Nov 2012

Cited by 10 | Viewed by 7157

Abstract

We aimed to determine the anti-angiogenic effect of tenomodulin (TeM) on retinal neovascularization in an oxygen-induced retinopathy (OIR) mouse model. OIR was induced in C57BL/6 mice by exposing seven-day-old mice to 75% oxygen for five days followed by room air for five days. [...] Read more.

We aimed to determine the anti-angiogenic effect of tenomodulin (TeM) on retinal neovascularization in an oxygen-induced retinopathy (OIR) mouse model. OIR was induced in C57BL/6 mice by exposing seven-day-old mice to 75% oxygen for five days followed by room air for five days. Control mice were exposed to room air from birth until postnatal day 17. Mice received intravitreal injections of 1 μg of TeM in one eye and PBS in the contralateral eye at P7 before being exposed to 75% oxygen. Eyes were collected at postnatal day 17. Retinal blood vessel patterns were visualized by fluorescein angiography. We quantified the number of neovascular nuclei that were present beyond the inner limiting membrane (ILM) using histological methods with a masked approach. Furthermore, double immunohistochemical staining of TeM was performed on retinas to identify nuclei protruding into the vitreous cavity. Western blot was used to detect exogenous TeM protein. The central nonperfusion area (NPA, mm²) of TeM-injected eyes was significantly different from that of OIR and PBS-injected eyes, and the number of nuclei in new blood vessels breaking through the ILM in each retinal cross-section significantly differed from that of OIR eyes and PBS-injected control eyes. Cellular nuclei of new blood vessels protruding into the vitreous cavity were also observed in TeM-injected retinas by immunohistochemistry. Western blotting revealed a 16-kDa immunoreactive protein, indicating incorporation of an exogenous TeM fragment into the retina. Our data shows that TeM can effectively inhibit pathological angiogenesis in mouse eyes; indicating its potential role in prevention and treatment of ocular neovascularization. Full article

(This article belongs to the Section Biochemistry)

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13 pages, 547 KiB

Open AccessArticle

Eclipsed Acetaldehyde as a Precursor for Producing Vinyl Alcohol

by Osman I. Osman^*

, Abdulrahman O. Alyoubi, Shabaan A. K. Elroby

, Rifaat H. Hilal and Saadullah G. Aziz

Chemistry Department, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia

Int. J. Mol. Sci. 2012, 13(11), 15360-15372; https://doi.org/10.3390/ijms131115360 - 20 Nov 2012

Cited by 5 | Viewed by 8248

Abstract

The MP2 and DFT/B3LYP methods at 6-311++G(d,p) and aug-cc-pdz basis sets have been used to probe the origin of relative stability preference for eclipsed acetaldehyde over its bisected counterpart. A relative energy stability range of 1.02 to 1.20 kcal/mol, in favor of the [...] Read more.

The MP2 and DFT/B3LYP methods at 6-311++G(d,p) and aug-cc-pdz basis sets have been used to probe the origin of relative stability preference for eclipsed acetaldehyde over its bisected counterpart. A relative energy stability range of 1.02 to 1.20 kcal/mol, in favor of the eclipsed conformer, was found and discussed. An NBO study at these chemistry levels complemented these findings and assigned the eclipsed acetaldehyde preference mainly to the vicinal antiperiplanar hyperconjugative interactions. The tautomeric interconversion between the more stable eclipsed acetaldehyde and vinyl alcohol has been achieved through a four-membered ring transition state (TS). The obtained barrier heights and relative stabilities of eclipsed acetaldehyde and the two conformers of vinyl alchol at these model chemistries have been estimated and discussed. Full article

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

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17 pages, 453 KiB

Open AccessArticle

Targeting Death Receptor TRAIL-R2 by Chalcones for TRAIL-Induced Apoptosis in Cancer Cells

by Ewelina Szliszka^†, Dagmara Jaworska^†

, Małgorzata Ksek, Zenon P. Czuba and Wojciech Król^*

¹ Chair and Department of Microbiology and Immunology, Medical University of Silesia in Katowice, Jordana 19, 41-808 Zabrze, Poland

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2012, 13(11), 15343-15359; https://doi.org/10.3390/ijms131115343 - 20 Nov 2012

Cited by 58 | Viewed by 8903

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells without toxicity to normal cells. TRAIL binds to death receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5) expressed on cancer cell surface and activates apoptotic pathways. Endogenous TRAIL plays an important role in immune [...] Read more.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells without toxicity to normal cells. TRAIL binds to death receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5) expressed on cancer cell surface and activates apoptotic pathways. Endogenous TRAIL plays an important role in immune surveillance and defense against cancer cells. However, as more tumor cells are reported to be resistant to TRAIL mediated death, it is important to search for and develop new strategies to overcome this resistance. Chalcones can sensitize cancer cells to TRAIL-induced apoptosis. We examined the cytotoxic and apoptotic effects of TRAIL in combination with four chalcones: chalcone, isobavachalcone, licochalcone A and xanthohumol on HeLa cancer cells. The cytotoxicity was measured by MTT and LDH assays. The apoptosis was detected using annexin V-FITC staining by flow cytometry and fluorescence microscopy. Death receptor expression was analyzed using flow cytometry. The decreased expression of death receptors in cancer cells may be the cause of TRAIL-resistance. Chalcones enhance TRAIL-induced apoptosis in HeLa cells through increased expression of TRAIL-R2. Our study has indicated that chalcones augment the antitumor activity of TRAIL and confirm their cancer chemopreventive properties. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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22 pages, 266 KiB

Open AccessArticle

Primary, Secondary Metabolites, Photosynthetic Capacity and Antioxidant Activity of the Malaysian Herb Kacip Fatimah (Labisia Pumila Benth) Exposed to Potassium Fertilization under Greenhouse Conditions

by Mohd Hafiz Ibrahim, Hawa Z. E. Jaafar^*, Ehsan Karimi

and Ali Ghasemzadeh

Department of Crop Science, Faculty of Agriculture, University Putra Malaysia, 43400 Serdang, Selangor, Malaysia

Int. J. Mol. Sci. 2012, 13(11), 15321-15342; https://doi.org/10.3390/ijms131115321 - 20 Nov 2012

Cited by 94 | Viewed by 9342

Abstract

A randomized complete block design was used to characterize the relationship between production of total phenolics, flavonoids, ascorbic acid, carbohydrate content, leaf gas exchange, phenylalanine ammonia-lyase (PAL), soluble protein, invertase and antioxidant enzyme activities (ascorbate peroxidase (APX), catalase (CAT) and superoxide dismutase (SOD) [...] Read more.

A randomized complete block design was used to characterize the relationship between production of total phenolics, flavonoids, ascorbic acid, carbohydrate content, leaf gas exchange, phenylalanine ammonia-lyase (PAL), soluble protein, invertase and antioxidant enzyme activities (ascorbate peroxidase (APX), catalase (CAT) and superoxide dismutase (SOD) in Labisia pumila Benth var. alata under four levels of potassium fertilization experiments (0, 90, 180 and 270 kg K/ha) conducted for 12 weeks. It was found that the production of total phenolics, flavonoids, ascorbic acid and carbohydrate content was affected by the interaction between potassium fertilization and plant parts. As the potassium fertilization levels increased from 0 to 270 kg K/ha, the production of soluble protein and PAL activity increased steadily. At the highest potassium fertilization (270 kg K/ha) L. pumila exhibited signiﬁcantly higher net photosynthesis (A), stomatal conductance (g_s), intercellular CO₂ (C_i), apparent quantum yield (ɸ) and lower dark respiration rates (R_d), compared to the other treatments. It was found that the production of total phenolics, flavonoids and ascorbic acid are also higher under 270 kg K/ha compared to 180, 90 and 0 kg K/ha. Furthermore, from the present study, the invertase activity was also found to be higher in 270 kg K/ha treatment. The antioxidant enzyme activities (APX, CAT and SOD) were lower under high potassium fertilization (270 kg K/ha) and have a significant negative correlation with total phenolics and flavonoid production. From this study, it was observed that the up-regulation of leaf gas exchange and downregulation of APX, CAT and SOD activities under high supplementation of potassium fertilizer enhanced the carbohydrate content that simultaneously increased the production of L. pumila secondary metabolites, thus increasing the health promoting effects of this plant. Full article

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16 pages, 761 KiB

Open AccessArticle

Pharmacological Evaluation and Preliminary Pharmacokinetics Studies of a New Diclofenac Prodrug without Gastric Ulceration Effect

by Jean Leandro dos Santos^1,*, Vanessa Moreira², Michel Leandro Campos³, Rafael Consolin Chelucci¹, Karina Pereira Barbieri¹, Pollyana Cristina Maggio de Castro Souto², Márcio Hideki Matsubara², Catarina Teixeira², Priscila Longhin Bosquesi¹, Rosângela Gonçalves Peccinini³ and Chung Man Chin^1,*

¹ Lapdesf—Laboratory of Research and Drug Development, Drugs and Medicines Department, School of Pharmaceutical Science—UNESP Rodovia Araraquara Jaú Km. 01, 14801-902, Araraquara, SP, Brazil

² Pharmacology Laboratory, Inflammation unit, Butantan Institute, Vital Brazil Avenue 1500, 05503-900, São Paulo, Brazil

³ Natural Active Principles and Toxicology Department, School of Pharmaceutical Science—UNESP Rodovia Araraquara Jaú Km. 01, 14801-902, Araraquara, SP, Brazil

Int. J. Mol. Sci. 2012, 13(11), 15305-15320; https://doi.org/10.3390/ijms131115305 - 19 Nov 2012

Cited by 13 | Viewed by 7994

Abstract

Long-term nonsteroidal anti-inflammatory drugs (NSAIDs) therapy has been associated with several adverse effects such as gastric ulceration and cardiovascular events. Among the molecular modifications strategies, the prodrug approach is a useful tool to discover new safe NSAIDs. The 1-(2,6-dichlorophenyl)indolin-2-one is a diclofenac prodrug [...] Read more.

Long-term nonsteroidal anti-inflammatory drugs (NSAIDs) therapy has been associated with several adverse effects such as gastric ulceration and cardiovascular events. Among the molecular modifications strategies, the prodrug approach is a useful tool to discover new safe NSAIDs. The 1-(2,6-dichlorophenyl)indolin-2-one is a diclofenac prodrug which demonstrated relevant anti-inflammatory properties without gastro ulceration effect. In addition, the prodrug decreases PGE₂ levels, COX-2 expression and cellular influx into peritoneal cavity induced by carrageenan treatment. Preliminary pharmacokinetic studies have shown in vivo bioconversion of prodrug to diclofenac. This prodrug is a new nonulcerogenic NSAID useful to treat inflammatory events by long-term therapy. Full article

(This article belongs to the Section Biochemistry)

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14 pages, 3436 KiB

Open AccessArticle

Clinicopathological Signiﬁcance of NMIIA Overexpression in Human Gastric Cancer

by Dongning Liu^†, Lei Zhang^†, Zhiyong Shen, Fei Tan, Yanfeng Hu, Jiang Yu and Guoxin Li^*

¹ Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2012, 13(11), 15291-15304; https://doi.org/10.3390/ijms131115291 - 19 Nov 2012

Cited by 34 | Viewed by 8481

Abstract

Altered expressions of nonmuscle myosin IIA (NMIIA) have been observed in certain types of cancers, but the impact of the alterations in gastric cancer (GC) remains unclear. The purpose of this study was to evaluate the expression of NMIIA at the mRNA and [...] Read more.

Altered expressions of nonmuscle myosin IIA (NMIIA) have been observed in certain types of cancers, but the impact of the alterations in gastric cancer (GC) remains unclear. The purpose of this study was to evaluate the expression of NMIIA at the mRNA and protein level in patients with GC and to assess its clinical significance. We investigated the expression of NMIIA in fresh, paired GC tissues by reverse transcriptase polymerase chain reaction (RT-PCR; n = 14) and Western blot analysis (n = 36). Simultaneously, we performed immunohistochemistry (IHC) on paraffin embedded specimens, including 96 GC specimens, 30 matched normal specimens and 30 paired metastatic lymph node samples. NMIIA is overexpressed in GC compared with the adjacent normal gastric epithelium (p < 0.001) and high-level NMIIA expression is significantly correlated with the depth of wall invasion, lymph node metastasis, distant metastasis and Tumor Node Metastasis (TNM) stage. Furthermore, elevated NMIIA expression is an independent prognostic factor in multivariate analysis using the Cox regression model (p = 0.021). These findings indicate that overexpression of NMIIA may contribute to the progression and poor prognosis of GC. Full article

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

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12 pages, 2789 KiB

Open AccessArticle

Molecular Mechanisms of RADA16-1 Peptide on Fast Stop Bleeding in Rat Models

by Ting Wang¹, Xiaozhong Zhong², Songtao Wang^1,3, Fei Lv¹ and Xiaojun Zhao^1,*

¹ Institute for NanoBiomedical Technology and Membrane Biology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China

² College of Life Science, Jianghan University, Wuhan 430056, Hubei, China

³ National Engineering Research Center for solid state fermentation, Luzhou 640040, Sichuan, China

Int. J. Mol. Sci. 2012, 13(11), 15279-15290; https://doi.org/10.3390/ijms131115279 - 19 Nov 2012

Cited by 51 | Viewed by 10318

Abstract

Ionic self-assembly of the peptide RADARADARADARADA (RADA16-1) may form a well-defined nanofiber and eventually a hydrogel scaffold, with a water content of over 99.5%. This leads to the establishment of a nanofiber barrier that can be used to achieve complete hemostasis in less [...] Read more.

Ionic self-assembly of the peptide RADARADARADARADA (RADA16-1) may form a well-defined nanofiber and eventually a hydrogel scaffold, with a water content of over 99.5%. This leads to the establishment of a nanofiber barrier that can be used to achieve complete hemostasis in less than 20 s in multiple tissues and in a variety of different wounds. In the present study, the nanofiber scaffolds of RADA16-1 peptide were sonicated into smaller fragments to identify possible molecular mechanisms underlying the rapid cessation of bleeding associated with these materials. Atomic force microscopy (AFM), circular dichroism (CD), and rheometry were also used to evaluate the re-assembly kinetics of this peptide. A bleeding control experiment was performed in animal models to uncover the molecular mechanisms underlying this fast hemostasis. In this way, these sonicated fragments not only quickly reassembled into nanofibers indistinguishable from the original material, but the degree of reassembly was also correlated with an increase in the rigidity of the scaffold and increased as the time required for hemostasis increased. Full article

(This article belongs to the Section Biochemistry)

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8 pages, 225 KiB

Open AccessReview

Role of Oxidative Stress in Hepatocarcinogenesis Induced by Hepatitis C Virus

by Kyoko Tsukiyama-Kohara

Department of Animal Hygiene, Transboundary Animal Diseases Center, Joint Faculty of Veterinary Medicine Kagoshima University, 1-21-24 Korimoto, Kagoshima 890-0065, Japan

Int. J. Mol. Sci. 2012, 13(11), 15271-15278; https://doi.org/10.3390/ijms131115271 - 19 Nov 2012

Cited by 37 | Viewed by 8404

Abstract

Hepatitis C virus (HCV) easily establishes chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). During the progression of HCV infections, reactive oxygen species (ROS) are generated, and these ROS then induce significant DNA damage. The role of ROS in the pathogenesis of HCV infection [...] Read more.

Hepatitis C virus (HCV) easily establishes chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). During the progression of HCV infections, reactive oxygen species (ROS) are generated, and these ROS then induce significant DNA damage. The role of ROS in the pathogenesis of HCV infection is still not fully understood. Recently, we found that HCV induced the expression of 3β-hydroxysterol ∆24-reductase (DHCR24). We also found that a HCV responsive region is present in the 5'-flanking genomic promoter region of DHCR24 and the HCV responsive region was characterized as (−167/−140). Moreover, the transcription factor Sp1 was found to bind to this region in response to oxidative stress under the regulation of ataxia telangiectasia mutated (ATM) kinase. Overexpression of DHCR24 impaired p53 activity by suppression of acetylation and increased interaction with MDM2. This impairment of p53 suppressed the hydrogen peroxide-induced apoptotic response in hepatocytes. Thus, a target of oxidative stress in HCV infection is DHCR24 through Sp1, which suppresses apoptotic responses and increases tumorigenicity. Full article

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

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19 pages, 368 KiB

Open AccessArticle

Simple Estimation of Förster Resonance Energy Transfer (FRET) Orientation Factor Distribution in Membranes

by Luís M. S. Loura^1,2

¹ Faculty of Pharmacy, University of Coimbra, Health Sciences Campus, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal

² Centre for Chemistry-Coimbra, Rua Larga, 3004-535 Coimbra, Portugal

Int. J. Mol. Sci. 2012, 13(11), 15252-15270; https://doi.org/10.3390/ijms131115252 - 19 Nov 2012

Cited by 65 | Viewed by 9764

Abstract

Because of its acute sensitivity to distance in the nanometer scale, Förster resonance energy transfer (FRET) has found a large variety of applications in many fields of chemistry, physics, and biology. One important issue regarding the correct usage of FRET is its dependence [...] Read more.

Because of its acute sensitivity to distance in the nanometer scale, Förster resonance energy transfer (FRET) has found a large variety of applications in many fields of chemistry, physics, and biology. One important issue regarding the correct usage of FRET is its dependence on the donor-acceptor relative orientation, expressed as the orientation factor κ². Different donor/acceptor conformations can lead to κ² values in the 0 ≤ κ² ≤ 4 range. Because the characteristic distance for FRET, R₀, is proportional to (κ²)^1/6, uncertainties in the orientation factor are reflected in the quality of information that can be retrieved from a FRET experiment. In most cases, the average value of κ² corresponding to the dynamic isotropic limit (<κ²> = 2/3) is used for computation of R₀ and hence donor-acceptor distances and acceptor concentrations. However, this can lead to significant error in unfavorable cases. This issue is more critical in membrane systems, because of their intrinsically anisotropic nature and their reduced fluidity in comparison to most common solvents. Here, a simple numerical simulation method for estimation of the probability density function of κ² for membrane-embedded donor and acceptor fluorophores in the dynamic regime is presented. In the simplest form, the proposed procedure uses as input the most probable orientations of the donor and acceptor transition dipoles, obtained by experimental (including linear dichroism) or theoretical (such as molecular dynamics simulation) techniques. Optionally, information about the widths of the donor and/or acceptor angular distributions may be incorporated. The methodology is illustrated for special limiting cases and common membrane FRET pairs. Full article

(This article belongs to the Special Issue Förster Resonance Energy Transfer (FRET))

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11 pages, 227 KiB

Open AccessArticle

Synthesis Method for Thiosulfonate and Report of Its Insecticidal Activity in Anagasta kuehniella (Lepidoptera: Pyralidae)

by Edson Dos A. Dos Santos¹, Fernando M. Gonçalves², Paulo César Prado¹, Daniele Y. Sasaki², Dênis P. De Lima¹ and Maria Lígia Rodrigues Macedo^2,*

¹ Laboratory of Synthesis and Transformation of Organic Molecules, Chemistry Section of CCET, Federal University of Mato Grosso do Sul, CP 549, CEP 79070-900, Campo Grande-MS, Brazil

² Laboratory of Protein Purification and its Biological Functions, CCBS, Federal University of Mato Grosso do Sul, CP 549, CEP 79070-900, Campo Grande-MS, Brazil

Int. J. Mol. Sci. 2012, 13(11), 15241-15251; https://doi.org/10.3390/ijms131115241 - 19 Nov 2012

Cited by 19 | Viewed by 6737

Abstract

Insect pests have caused economic losses valued at billions of dollars in agricultural production. Anagasta kuehniella (Zeller), the Mediterranean flour moth, is of major economic importance as a flour and grain feeder and is often a severe pest in flourmills. This study provides [...] Read more.

Insect pests have caused economic losses valued at billions of dollars in agricultural production. Anagasta kuehniella (Zeller), the Mediterranean flour moth, is of major economic importance as a flour and grain feeder and is often a severe pest in flourmills. This study provides a suitable route for the direct preparation of thiosulfonates 2 and 3 from thiols, under mild conditions, with good yields; these thiosulfonates were tested for their regulatory effect on insect growth. The chronic ingestion of thiosulfonates resulted in a significant reduction in larval survival and weight. In addition, the tryptic activity of larvae was sensitive to these thiosulfonates. Results suggest that thiosulfonates 2 and 3 have a potential antimetabolic effect when ingested by A. kuehniella. The use of AgNO₃/BF₃·OEt₂ and Al(H₂PO₄)₃/HNO₃ provides a suitable route for the direct preparation of thiosulfonates from thiols under mild conditions with good yields. These thiosulfonates were toxic for A. kuehniella larvae, suggesting their potential as biotechnological tools. Full article

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14 pages, 1162 KiB

Open AccessArticle

Modification of Förster Resonance Energy Transfer Efficiencyat Interfaces

by Jörg Enderlein

III. Institute of Physics – Biophysics, Georg August University, Friedrich-Hund-Platz 1, D-37077 Göttingen, Germany

Int. J. Mol. Sci. 2012, 13(11), 15227-15240; https://doi.org/10.3390/ijms131115227 - 19 Nov 2012

Cited by 14 | Viewed by 6699

Abstract

We present a theoretical study on the impact of an interface on the FRET efficiency of a surface-bound acceptor-donor system. The FRET efficiency can be modified by two effects. Firstly, the donor’s electromagnetic field at the acceptor’s position is changed due to the [...] Read more.

We present a theoretical study on the impact of an interface on the FRET efficiency of a surface-bound acceptor-donor system. The FRET efficiency can be modified by two effects. Firstly, the donor’s electromagnetic field at the acceptor’s position is changed due to the partial reflection of the donor’s field. Secondly, both the donor’s and the acceptor’s quantum yield of fluorescence can be changed due to the interface-induced enhancement of the radiative emission rate (Purcell effect). Numerical results for a FRET-pair at a glass-water interface are given. Full article

(This article belongs to the Special Issue Förster Resonance Energy Transfer (FRET))

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18 pages, 589 KiB

Open AccessArticle

Isolation and Structural Characterization of Lignin from Cotton Stalk Treated in an Ammonia Hydrothermal System

by Sumin Kang¹, Lingping Xiao¹

, Lingyan Meng¹, Xueming Zhang^1,*

and Runcang Sun^1,2,*

¹ Institute of Biomass Chemistry and Technology, Beijing Forestry University, Beijing 100083, China

² State Key Laboratory of Pulp and Paper Engineering, South China University of Technology, Guangzhou 510640, China

Int. J. Mol. Sci. 2012, 13(11), 15209-15226; https://doi.org/10.3390/ijms131115209 - 16 Nov 2012

Cited by 73 | Viewed by 8376

Abstract

To investigate the potential for the utilization of cotton stalk, ammonia hydrothermal treatment was applied to fractionate the samples into aqueous ammonia-soluble and ammonia-insoluble portions. The ammonia-soluble portion was purified to yield lignin fractions. The lignin fractions obtained were characterized by wet chemistry [...] Read more.

To investigate the potential for the utilization of cotton stalk, ammonia hydrothermal treatment was applied to fractionate the samples into aqueous ammonia-soluble and ammonia-insoluble portions. The ammonia-soluble portion was purified to yield lignin fractions. The lignin fractions obtained were characterized by wet chemistry (carbohydrate analysis) and spectroscopy methods (FT-IR, ¹³C and ¹H-¹³C HSQC NMR spectroscopy) as well as gel permeation chromatography (GPC). The results showed that the cotton stalk lignin fractions were almost absent of neutral sugars (0.43%–1.29%) and had relatively low average molecular weights (1255–1746 g/mol). The lignin fractions belonged to typical G-S lignin, which was composed predominately of G-type units (59%) and noticeable amounts of S-type units (40%) together with a small amount of H-type units (~1%). Furthermore, the ammonia-extractable lignin fractions were mainly composed of β-O-4' inter-unit linkages (75.6%), and small quantities of β-β' (12.2%), together with lower amounts of β-5' carbon-carbon linkages (7.4%) and p-hydroxycinnamyl alcohol end groups. Full article

(This article belongs to the Section Materials Science)

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16 pages, 249 KiB

Open AccessArticle

Nitric Oxide-Dependent Posttranslational Modification in Plants: An Update

by Jeremy Astier^* and Christian Lindermayr^*

Institute of Biochemical Plant Pathology, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany

Int. J. Mol. Sci. 2012, 13(11), 15193-15208; https://doi.org/10.3390/ijms131115193 - 16 Nov 2012

Cited by 190 | Viewed by 11878

Abstract

Nitric oxide (NO) has been demonstrated as an essential regulator of several physiological processes in plants. The understanding of the molecular mechanism underlying its critical role constitutes a major field of research. NO can exert its biological function through different ways, such as [...] Read more.

Nitric oxide (NO) has been demonstrated as an essential regulator of several physiological processes in plants. The understanding of the molecular mechanism underlying its critical role constitutes a major field of research. NO can exert its biological function through different ways, such as the modulation of gene expression, the mobilization of second messengers, or interplays with protein kinases. Besides this signaling events, NO can be responsible of the posttranslational modifications (PTM) of target proteins. Several modifications have been identified so far, whereas metal nitrosylation, the tyrosine nitration and the S-nitrosylation can be considered as the main ones. Recent data demonstrate that these PTM are involved in the control of a wide range of physiological processes in plants, such as the plant immune system. However, a great deal of effort is still necessary to pinpoint the role of each PTM in plant physiology. Taken together, these new advances in proteomic research provide a better comprehension of the role of NO in plant signaling. Full article

(This article belongs to the Special Issue Advances in Proteomic Research)

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16 pages, 515 KiB

Open AccessArticle

Detection of Glycomic Alterations Induced by Overexpression of P-Glycoprotein on the Surfaces of L1210 Cells Using Sialic Acid Binding Lectins

by Tatiana Bubencíkova¹, Dana Cholujová², Lucia Messingerová¹, Danica Mislovicova³, Mario Seres¹, Albert Breier^1,* and Zdena Sulova^1,*

¹ Institute of Molecular Physiology and Genetics, Center of Excellence of the Slovak Research and Development Agency “BIOMEMBRANES2008”, Slovak Academy of Sciences, Vlarska 5, Bratislava 83334, Slovakia

² Cancer Research Institute, Slovak Academy of Sciences, Vlarska 7, Bratislava 83391, Slovakia

³ Institute of Chemistry, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava 84538, Slovakia

Int. J. Mol. Sci. 2012, 13(11), 15177-15192; https://doi.org/10.3390/ijms131115177 - 16 Nov 2012

Cited by 13 | Viewed by 7263

Abstract

P-glycoprotein (P-gp) overexpression is the most frequently observed cause of multidrug resistance in neoplastic cells. In our experiments, P-gp was expressed in L1210 mice leukemia cells (S cells) by selection with vincristine (R cells) or transfection with the gene encoding human P-gp (T [...] Read more.

P-glycoprotein (P-gp) overexpression is the most frequently observed cause of multidrug resistance in neoplastic cells. In our experiments, P-gp was expressed in L1210 mice leukemia cells (S cells) by selection with vincristine (R cells) or transfection with the gene encoding human P-gp (T cells). Remodeling of cell surface sugars is associated with P-gp expression in L1210 cells as a secondary cellular response. In this study, we monitored the alteration of cell surface saccharides by Sambucus nigra agglutinin (SNA), wheat germ agglutinin (WGA) and Maackia amurensis agglutinin (MAA). Sialic acid is predominantly linked to the surface of S, R and T cells via α-2,6 branched sugars that tightly bind SNA. The presence of sialic acid linked to the cell surface via α-2,3 branched sugars was negligible, and the binding of MAA (recognizing this branch) was much less pronounced than SNA. WGA induced greater cell death than SNA, which was bound to the cell surface and agglutinated all three L1210 cell-variants more effectively than WGA. Thus, the ability of lectins to induce cell death did not correlate with their binding efficiency and agglutination potency. Compared to S cells, P-gp positive R and T cells contain a higher amount of N-acetyl-glucosamine on their cell surface, which is associated with improved WGA binding. Both P-gp positive variants of L1210 cells are strongly resistant to vincristine as P-gp prototypical drug. This resistance could not be altered by liberalization of terminal sialyl residues from the cell surface by sialidase. Full article

(This article belongs to the Section Molecular Toxicology)

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15 pages, 639 KiB

Open AccessArticle

The Characterization of SaPIN2b, a Plant Trichome-Localized Proteinase Inhibitor from Solanum americanum

by Ming Luo^1,2,†, Ling-Wen Ding^1,†, Zhi-Juan Ge^1,†, Zhen-Yu Wang¹, Bo-Lun Hu¹, Xiao-Bei Yang¹, Qiao-Yang Sun¹ and Zeng-Fu Xu^1,3,*

¹ State Key Laboratory of Biocontrol and Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China

² Key Laboratory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, China

³ Key Laboratory of Tropical Plant Resource and Sustainable Use, Xishuangbanna Tropical Botanical Garden, Chinese Academy of Sciences, Menglun, Yunnan 666303, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2012, 13(11), 15162-15176; https://doi.org/10.3390/ijms131115162 - 16 Nov 2012

Cited by 17 | Viewed by 7149

Abstract

Proteinase inhibitors play an important role in plant resistance of insects and pathogens. In this study, we characterized the serine proteinase inhibitor SaPIN2b, which is constitutively expressed in Solanum americanum trichomes and contains two conserved motifs of the proteinase inhibitor II (PIN2) family. [...] Read more.

Proteinase inhibitors play an important role in plant resistance of insects and pathogens. In this study, we characterized the serine proteinase inhibitor SaPIN2b, which is constitutively expressed in Solanum americanum trichomes and contains two conserved motifs of the proteinase inhibitor II (PIN2) family. The recombinant SaPIN2b (rSaPIN2b), which was expressed in Escherichia coli, was demonstrated to be a potent proteinase inhibitor against a panel of serine proteinases, including subtilisin A, chymotrypsin and trypsin. Moreover, rSaPIN2b also effectively inhibited the proteinase activities of midgut trypsin-like proteinases that were extracted from the devastating pest Helicoverpa armigera. Furthermore, the overexpression of SaPIN2b in transgenic tobacco plants resulted in enhanced resistance against H. armigera. Taken together, our results demonstrated that SaPIN2b is a potent serine proteinase inhibitor that may act as a protective protein in plant defense against insect attacks. Full article

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

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25 pages, 869 KiB

Open AccessReview

Förster Resonance Energy Transfer (FRET) as a Tool for Dissecting the Molecular Mechanisms for Maturation of the Shigella Type III Secretion Needle Tip Complex

by Nicholas E. Dickenson^* and William D. Picking

Department of Microbiology and Molecular Genetics, Oklahoma State University, Stillwater, OK 74078, USA

Int. J. Mol. Sci. 2012, 13(11), 15137-15161; https://doi.org/10.3390/ijms131115137 - 16 Nov 2012

Cited by 13 | Viewed by 7353

Abstract

Förster resonance energy transfer (FRET) provides a powerful tool for monitoring intermolecular interactions and a sensitive technique for studying Å-level protein conformational changes. One system that has particularly benefited from the sensitivity and diversity of FRET measurements is the maturation of the Shigella [...] Read more.

Förster resonance energy transfer (FRET) provides a powerful tool for monitoring intermolecular interactions and a sensitive technique for studying Å-level protein conformational changes. One system that has particularly benefited from the sensitivity and diversity of FRET measurements is the maturation of the Shigella type III secretion apparatus (T3SA) needle tip complex. The Shigella T3SA delivers effector proteins into intestinal cells to promote bacterial invasion and spread. The T3SA is comprised of a basal body that spans the bacterial envelope and a needle with an exposed tip complex that matures in response to environmental stimuli. FRET measurements demonstrated bile salt binding by the nascent needle tip protein IpaD and also mapped resulting structural changes which led to the recruitment of the translocator IpaB. At the needle tip IpaB acts as a sensor for host cell contact but prior to secretion, it is stored as a heterodimeric complex with the chaperone IpgC. FRET analyses showed that chaperone binding to IpaB’s N-terminal domain causes a conformational change in the latter. These FRET analyses, with other biophysical methods, have been central to understanding T3SA maturation and will be highlighted, focusing on the details of the FRET measurements and the relevance to this particular system. Full article

(This article belongs to the Special Issue Förster Resonance Energy Transfer (FRET))

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11 pages, 284 KiB

Open AccessArticle

Catalytic Hydrogenation of the Sweet Principles of Stevia rebaudiana, Rebaudioside B, Rebaudioside C, and Rebaudioside D and Sensory Evaluation of Their Reduced Derivatives

by Indra Prakash¹, Mary Campbell² and Venkata Sai Prakash Chaturvedula^1,*

¹ Organic Chemistry Department, Global Research and Development, The Coca-Cola Company, One Coca-Cola Plaza, Atlanta, GA 30313, USA

² Product Development, Coca-Cola North America Division, The Coca-Cola Company, One Coca-Cola Plaza, Atlanta, GA 30313, USA

Int. J. Mol. Sci. 2012, 13(11), 15126-15136; https://doi.org/10.3390/ijms131115126 - 16 Nov 2012

Cited by 30 | Viewed by 8635

Abstract

Catalytic hydrogenation of rebaudioside B, rebaudioside C, and rebaudioside D; the three ent-kaurane diterpene glycosides isolated from Stevia rebaudiana was carried out using Pd(OH)₂. Reduction of steviol glycosides was performed using straightforward synthetic chemistry with the catalyst Pd(OH)₂ and [...] Read more.

Catalytic hydrogenation of rebaudioside B, rebaudioside C, and rebaudioside D; the three ent-kaurane diterpene glycosides isolated from Stevia rebaudiana was carried out using Pd(OH)₂. Reduction of steviol glycosides was performed using straightforward synthetic chemistry with the catalyst Pd(OH)₂ and structures of the corresponding dihydro derivatives were characterized on the basis of 1D and 2D nuclear magnetic resonance (NMR) spectral data indicating that all are novel compounds being reported for the first time. Also, the taste properties of all reduced compounds were evaluated against their corresponding original steviol glycosides and sucrose. Full article

(This article belongs to the Section Biochemistry)

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19 pages, 201 KiB

Open AccessReview

Mast Cells in the Pathogenesis of Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

by Massimo Costanza¹, Mario P. Colombo² and Rosetta Pedotti^1,*

¹ Neuroimmunology and Neuromuscular Disorder Unit, Neurological Institute Foundation IRCCS C. Besta, via Amadeo 42, Milan 20133, Italy

² Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133, Italy

Int. J. Mol. Sci. 2012, 13(11), 15107-15125; https://doi.org/10.3390/ijms131115107 - 16 Nov 2012

Cited by 32 | Viewed by 8644

Abstract

Mast cells (MCs) are best known as key immune players in immunoglobulin E (IgE)-dependent allergic reactions. In recent years, several lines of evidence have suggested that MCs might play an important role in several pathological conditions, including autoimmune disorders such as multiple sclerosis [...] Read more.

Mast cells (MCs) are best known as key immune players in immunoglobulin E (IgE)-dependent allergic reactions. In recent years, several lines of evidence have suggested that MCs might play an important role in several pathological conditions, including autoimmune disorders such as multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Since their first description in MS plaques in the late 1800s, much effort has been put into elucidating the contribution of MCs to the development of central nervous system (CNS) autoimmunity. Mouse models of MC-deficiency have provided a valuable experimental tool for dissecting MC involvement in MS and EAE. However, to date there is still major controversy concerning the function of MCs in these diseases. Indeed, although MCs have been classically proposed as having a detrimental and pro-inflammatory role, recent literature has questioned and resized the contribution of MCs to the pathology of MS and EAE. In this review, we will present the main evidence obtained in MS and EAE on this topic, and discuss the critical and controversial aspects of such evidence. Full article

(This article belongs to the Special Issue Recent Advances in the Research of Multiple Sclerosis)

21 pages, 353 KiB

Open AccessReview

Bacterial Bio-Resources for Remediation of Hexachlorocyclohexane

by Analía Alvarez^1,2,†, Claudia S. Benimeli^1,3,†, Juliana M. Saez¹, María S. Fuentes¹, Sergio A. Cuozzo^1,2, Marta A. Polti^1,2 and María J. Amoroso^1,3,4,*

¹ Pilot Plant of Industrial and Microbiological Processes (PROIMI), CONICET, Av. Belgrano y Pasaje Caseros, 4000 Tucumán, Argentina

² Natural Sciences College and Miguel Lillo Institute, National University of Tucumán, Miguel Lillo 205, 4000 Tucumán, Argentina

³ North University of Saint Thomas Aquines, 9 de Julio 165, 4000 Tucumán, Argentina

⁴ Biochemistry, Chemistry and Pharmacy College, National University of Tucumán, Ayacucho 471, 4000 Tucumán, Argentina

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2012, 13(11), 15086-15106; https://doi.org/10.3390/ijms131115086 - 15 Nov 2012

Cited by 68 | Viewed by 10269

Abstract

In the last few decades, highly toxic organic compounds like the organochlorine pesticide (OP) hexachlorocyclohexane (HCH) have been released into the environment. All HCH isomers are acutely toxic to mammals. Although nowadays its use is restricted or completely banned in most countries, it [...] Read more.

In the last few decades, highly toxic organic compounds like the organochlorine pesticide (OP) hexachlorocyclohexane (HCH) have been released into the environment. All HCH isomers are acutely toxic to mammals. Although nowadays its use is restricted or completely banned in most countries, it continues posing serious environmental and health concerns. Since HCH toxicity is well known, it is imperative to develop methods to remove it from the environment. Bioremediation technologies, which use microorganisms and/or plants to degrade toxic contaminants, have become the focus of interest. Microorganisms play a significant role in the transformation and degradation of xenobiotic compounds. Many Gram-negative bacteria have been reported to have metabolic abilities to attack HCH. For instance, several Sphingomonas strains have been reported to degrade the pesticide. On the other hand, among Gram-positive microorganisms, actinobacteria have a great potential for biodegradation of organic and inorganic toxic compounds. This review compiles and updates the information available on bacterial removal of HCH, particularly by Streptomyces strains, a prolific genus of actinobacteria. A brief account on the persistence and deleterious effects of these pollutant chemical is also given. Full article

(This article belongs to the Special Issue Green Biocides)

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12 pages, 605 KiB

Open AccessArticle

Histone Deacetylase (HDAC) Inhibitors Down-Regulate Endothelial Lineage Commitment of Umbilical Cord Blood Derived Endothelial Progenitor Cells

by Florin Iordache, Cosmin Buzila, Andrei Constantinescu, Eugen Andrei and Horia Maniu^*

Institute of Cellular Biology and Pathology of Romanian Academy, “Nicolae Simionescu”, 8, B.P. Hasdeu, Bucharest 050568, Romania

Int. J. Mol. Sci. 2012, 13(11), 15074-15085; https://doi.org/10.3390/ijms131115074 - 15 Nov 2012

Cited by 19 | Viewed by 7376

Abstract

To test the involvement of histone deacetylases (HDACs) activity in endothelial lineage progression, we investigated the effects of HDAC inhibitors on endothelial progenitors cells (EPCs) derived from umbilical cord blood (UCB). Adherent EPCs, that expressed the endothelial marker proteins (PCAM-1, CD105, CD133, and [...] Read more.

To test the involvement of histone deacetylases (HDACs) activity in endothelial lineage progression, we investigated the effects of HDAC inhibitors on endothelial progenitors cells (EPCs) derived from umbilical cord blood (UCB). Adherent EPCs, that expressed the endothelial marker proteins (PCAM-1, CD105, CD133, and VEGFR₂) revealed by flow cytometry were treated with three HDAC inhibitors: Butyrate (BuA), Trichostatin A (TSA), and Valproic acid (VPA). RT-PCR assay showed that HDAC inhibitors down-regulated the expression of endothelial genes such as VE-cadherin, CD133, CXCR4 and Tie-2. Furthermore, flow cytometry analysis illustrated that HDAC inhibitors selectively reduce the expression of VEGFR₂, CD117, VE-cadherin, and ICAM-1, whereas the expression of CD34 and CD45 remained unchanged, demonstrating that HDAC is involved in endothelial differentiation of progenitor cells. Real-Time PCR demonstrated that TSA down-regulated telomerase activity probably via suppression of hTERT expression, suggesting that HDAC inhibitor decreased cell proliferation. Cell motility was also decreased after treatment with HDAC inhibitors as shown by wound-healing assay. The balance of acethylation/deacethylation kept in control by the activity of HAT (histone acetyltransferases)/HDAC enzymes play an important role in differentiation of stem cells by regulating proliferation and endothelial lineage commitment. Full article

(This article belongs to the Section Biochemistry)

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20 pages, 257 KiB

Open AccessReview

A Review of Molecular Mechanisms of the Anti-Leukemic Effects of Phenolic Compounds in Honey

by Murtala B. Abubakar^1,*, Wan Zaidah Abdullah², Siti Amrah Sulaiman³ and Ang Boon Suen¹

¹ Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia

² Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia

³ Department of Pharmacology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia

Int. J. Mol. Sci. 2012, 13(11), 15054-15073; https://doi.org/10.3390/ijms131115054 - 15 Nov 2012

Cited by 78 | Viewed by 12377

Abstract

Hematologic malignancies constitute about 9% of all new cases of cancers as reported via the GLOBOCAN series by International Agency for Research on Cancer (IARC) in 2008. So far, the conventional therapeutic and surgical approaches to cancer therapy have not been able to [...] Read more.

Hematologic malignancies constitute about 9% of all new cases of cancers as reported via the GLOBOCAN series by International Agency for Research on Cancer (IARC) in 2008. So far, the conventional therapeutic and surgical approaches to cancer therapy have not been able to curtail the rising incidence of cancers, including hematological malignancies, worldwide. The last decade has witnessed great research interest in biological activities of phenolic compounds that include anticancer, anti-oxidation and anti-inflammation, among other things. A large number of anticancer agents combat cancer through cell cycle arrest, induction of apoptosis and differentiation, as well as through inhibition of cell growth and proliferation, or a combination of two or more of these mechanisms. Various phenolic compounds from different sources have been reported to be promising anticancer agents by acting through one of these mechanisms. Honey, which has a long history of human consumption both for medicinal and nutritional uses, contains a variety of phenolic compounds such as flavonoids, phenolic acids, coumarins and tannins. This paper presents a review on the molecular mechanisms of the anti-leukemic activity of various phenolic compounds on cell cycle, cell growth and proliferation and apoptosis, and it advocates that more studies should be conducted to determine the potential role of honey in both chemoprevention and chemotherapy in leukemia. Full article

(This article belongs to the Section Biochemistry)

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12 pages, 2758 KiB

Open AccessArticle

Antifungal Activity of (KW)_n or (RW)_n Peptide against Fusarium solani and Fusarium oxysporum

by Ramamourthy Gopal¹, Hyungjong Na², Chang Ho Seo³ and Yoonkyung Park^1,2,*

¹ Research Center for Proteineous Materials, Chosun University, Gwangju 501-759, Korea

² Department of Biotechnology, Chosun University, Gwangju 501-759, Korea

³ Department of Bioinformatics, Kongju National University, Kongju 314-701, Korea

Int. J. Mol. Sci. 2012, 13(11), 15042-15053; https://doi.org/10.3390/ijms131115042 - 15 Nov 2012

Cited by 31 | Viewed by 8141

Abstract

The presence of lysine (Lys) or arginine (Arg) and tryptophan (Trp) are important for the antimicrobial effects of cationic peptides. Therefore, we designed and synthesized a series of antimicrobial peptides with various numbers of Lys (or Arg) and Trp repeats [(KW and RW) [...] Read more.

The presence of lysine (Lys) or arginine (Arg) and tryptophan (Trp) are important for the antimicrobial effects of cationic peptides. Therefore, we designed and synthesized a series of antimicrobial peptides with various numbers of Lys (or Arg) and Trp repeats [(KW and RW)_n-NH₂, where n equals 2, 3, 4, or 5]. Antifungal activities of these peptides increased with chain length. Light microscopy demonstrated that longer peptides (n = 4, 5) strongly inhibited in vitro growth of Fusarium solani, and Fusarium oxysporum, at 4–32 μM. Furthermore, longer peptides displayed potent fungicidal activities against a variety of agronomical important filamentous fungi, including F. solani and F. oxysporum, at their minimal inhibitory concentrations (MICs). However, RW series peptides showed slightly higher fungicidal activities than KW peptides against the two strains. Taken together, the results of this study indicate that these short peptides would be good candidates for use as synthetic or transgenic antifungal agents. Full article

(This article belongs to the Special Issue Green Biocides)

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30 pages, 1408 KiB

Open AccessReview

Dynamic Control of Electron Transfers in Diflavin Reductases

by Louise Aigrain¹, Fataneh Fatemi², Oriane Frances², Ewen Lescop² and Gilles Truan^3,4,5,*

¹ Gene Machines Group, Clarendon Laboratory, Department of Physics, University of Oxford, Parks Road, Oxford OX1 3PU, UK

² Institut de Chimie des Substances Naturelles, CNRS, UPR 2301, Centre de Recherche de Gif, 1 Av. de la Terrasse, 91198 Gif-sur-Yvette Cedex, France

³ Université de Toulouse; INSA, UPS, INP; LISBP, 135 Avenue de Rangueil, F-31077 Toulouse, France

⁴ Ingénierie des Systèmes Biologiques et des Procédés, F-31400 Toulouse, France

⁵ CNRS, UMR5504, F-31400 Toulouse, France

Int. J. Mol. Sci. 2012, 13(11), 15012-15041; https://doi.org/10.3390/ijms131115012 - 15 Nov 2012

Cited by 27 | Viewed by 8263

Abstract

Diflavin reductases are essential proteins capable of splitting the two-electron flux from reduced pyridine nucleotides to a variety of one electron acceptors. The primary sequence of diflavin reductases shows a conserved domain organization harboring two catalytic domains bound to the FAD and FMN [...] Read more.

Diflavin reductases are essential proteins capable of splitting the two-electron flux from reduced pyridine nucleotides to a variety of one electron acceptors. The primary sequence of diflavin reductases shows a conserved domain organization harboring two catalytic domains bound to the FAD and FMN flavins sandwiched by one or several non-catalytic domains. The catalytic domains are analogous to existing globular proteins: the FMN domain is analogous to flavodoxins while the FAD domain resembles ferredoxin reductases. The first structural determination of one member of the diflavin reductases family raised some questions about the architecture of the enzyme during catalysis: both FMN and FAD were in perfect position for interflavin transfers but the steric hindrance of the FAD domain rapidly prompted more complex hypotheses on the possible mechanisms for the electron transfer from FMN to external acceptors. Hypotheses of domain reorganization during catalysis in the context of the different members of this family were given by many groups during the past twenty years. This review will address the recent advances in various structural approaches that have highlighted specific dynamic features of diflavin reductases. Full article

(This article belongs to the Special Issue Flavins)

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Graphical abstract

20 pages, 2503 KiB

Open AccessArticle

Betulin Complex in γ-Cyclodextrin Derivatives: Properties and Antineoplasic Activities in In Vitro and In Vivo Tumor Models

by Codruta Şoica¹, Cristina Dehelean^1,*, Corina Danciu¹, Hai Ming Wang², Gerhard Wenz², Rita Ambrus³, Florina Bojin⁴

and Mariana Anghel⁴

¹ Faculty of Pharmacy, University of Medicine and Pharmacy, 2 Eftimie Murgu, Timisoara 300041, Romania

² Organic Macromolecular Chemistry, Saarland University, Campus Saarbrücken, Saarbrücken D-66123, Germany

³ Institute of Pharmaceutical Technology, University of Szeged, 6 Eotvos ut., Szeged H-6720, Hungary

⁴ Faculty of Medicine, University of Medicine and Pharmacy, 2 Eftimie Murgu, Timisoara 300041, Romania

Int. J. Mol. Sci. 2012, 13(11), 14992-15011; https://doi.org/10.3390/ijms131114992 - 15 Nov 2012

Cited by 70 | Viewed by 9610

Abstract

Given the present high incidence of melanoma and skin cancer, interest in potential drugs of plant origin has increased significantly. Pentacyclic lupane-type triterpenes are widely distributed in plants, offering numerous pharmacological benefits. Betulin is an important compound in the bark of Betula pendula [...] Read more.

Given the present high incidence of melanoma and skin cancer, interest in potential drugs of plant origin has increased significantly. Pentacyclic lupane-type triterpenes are widely distributed in plants, offering numerous pharmacological benefits. Betulin is an important compound in the bark of Betula pendula Roth and has important therapeutic properties, including antitumor activities. Its biological effect is limited by its poor water solubility, which can be improved by cyclodextrin complexation. The best results have been obtained by using a novel cyclodextrin derivative, octakis-[6-deoxy-6-(2-sulfanyl ethanesulfonate)]-γ-CD. The complexes between betulin and the previously mentioned cyclodextrin were analyzed by scanning electron microscopy (SEM)and differential scanning calorimetry (DSC) and pharmacologically evaluated in vitro (MTT and immunocytochemistry tests) and in vivo in C57BL/6J mice. The solubility of betulin is improved by cyclodextrin complexation, which creates a stable complex that improves the in vitro and in vivo properties of the active compound. Full article

(This article belongs to the Section Materials Science)

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Int. J. Mol. Sci., Volume 13, Issue 11 (November 2012) – 105 articles , Pages 13764-15495

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