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Int. J. Mol. Sci., Volume 20, Issue 6 (March-2 2019)

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Cover Story (view full-size image) Tetraploid wheat originated in the Fertile Crescent around 10,000 BP spread with human migrations [...] Read more.
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Open AccessReview Multifactorial Contribution of Notch Signaling in Head and Neck Squamous Cell Carcinoma
Int. J. Mol. Sci. 2019, 20(6), 1520; https://doi.org/10.3390/ijms20061520
Received: 28 February 2019 / Revised: 21 March 2019 / Accepted: 22 March 2019 / Published: 26 March 2019
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Abstract
Head and neck squamous cell carcinoma (HNSCC) defines a group of solid tumors originating from the mucosa of the upper aerodigestive tract, pharynx, larynx, mouth, and nasal cavity. It has a metastatic evolution and poor prognosis and is the sixth most common cancer [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) defines a group of solid tumors originating from the mucosa of the upper aerodigestive tract, pharynx, larynx, mouth, and nasal cavity. It has a metastatic evolution and poor prognosis and is the sixth most common cancer in the world, with 600,000 new cases reported every year. HNSCC heterogeneity and complexity is reflected in a multistep progression, involving crosstalk between several molecular pathways. The Notch pathway is associated with major events supporting cancerogenic evolution: cell proliferation, self-renewal, angiogenesis, and preservation of a pro-oncogenic microenvironment. Additionally, Notch is pivotal in tumor development and plays a dual role acting as both oncogene and tumor suppressor. In this review, we summarize the role of the Notch pathway in HNSCC, with a special focus on its compelling role in major events of tumor initiation and growth. Full article
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Open AccessArticle Wnt/β-Catenin Pathway Is Involved in Cadmium-Induced Inhibition of Osteoblast Differentiation of Bone Marrow Mesenchymal Stem Cells
Int. J. Mol. Sci. 2019, 20(6), 1519; https://doi.org/10.3390/ijms20061519
Received: 20 February 2019 / Revised: 18 March 2019 / Accepted: 22 March 2019 / Published: 26 March 2019
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Abstract
Cadmium is a common environmental pollutant that causes bone damage. However, the effects of cadmium on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs) and its mechanism of action in this process are unclear. Here, we determined the effects of cadmium [...] Read more.
Cadmium is a common environmental pollutant that causes bone damage. However, the effects of cadmium on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs) and its mechanism of action in this process are unclear. Here, we determined the effects of cadmium chloride (CdCl2) on the osteogenic differentiation of BMMSCs and the potential mechanism involved in this process. As determined in the present investigation, CdCl2, in a concentration-dependent manner, affected the viability of BMMSCs and their cytoskeletons. Exposure to 0.1 or 0.2 µM CdCl2 inhibited osteogenic differentiation of BMMSCs, which was reflected in the down-regulation of osteoblast-related genes (ALP, OCN, Runx2, OSX, and OPN); in suppression of the protein expression of alkaline phosphatase (ALP) and runt-related transcription factor 2 (Runx2); and in decreased ALP activity and capacity for mineralization. Moreover, mRNA microarray was performed to determine the roles of these factors in BMMSCs treated with CdCl2 in comparison to control BMMSCs. As determined with the microarrays, the Wingless-type (Wnt), mothers against decapentaplegic and the C. elegans gene Sam (SMAD), and Janus kinase-Signal Transducers and Activators of Transcription (JAK-STAT) signaling pathways were involved in the effects caused by CdCl2. Moreover, during differentiation, the protein levels of Wnt3a, β-catenin, lymphoid enhancer factor 1 (LEF1), and T-cell factor 1 (TCF1) were reduced by CdCl2. The current research shows that CdCl2 suppresses the osteogenesis of BMMSCs via inhibiting the Wnt/β-catenin pathway. The results establish a previously unknown mechanism for bone injury induced by CdCl2. Full article
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Open AccessArticle X-linked Retinitis Pigmentosa in Japan: Clinical and Genetic Findings in Male Patients and Female Carriers
Int. J. Mol. Sci. 2019, 20(6), 1518; https://doi.org/10.3390/ijms20061518
Received: 7 March 2019 / Revised: 23 March 2019 / Accepted: 25 March 2019 / Published: 26 March 2019
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Abstract
X-linked retinitis pigmentosa (XLRP) is a type of severe retinal dystrophy, and female carriers of XLRP demonstrate markedly variable clinical severity. In this study, we aimed to elucidate the clinical findings of male patients with and female carriers of XLRP in a Japanese [...] Read more.
X-linked retinitis pigmentosa (XLRP) is a type of severe retinal dystrophy, and female carriers of XLRP demonstrate markedly variable clinical severity. In this study, we aimed to elucidate the clinical findings of male patients with and female carriers of XLRP in a Japanese cohort and demonstrate the genetic contribution. Twelve unrelated families (13 male patients, 15 female carriers) harboring pathogenic mutations in RPGR or RP2 were included, and comprehensive ophthalmic examinations were performed. To identify potential pathogenic mutations, targeted next-generation sequencing was employed. Consequently, we identified 11 pathogenic mutations, of which five were novel. Six and five mutations were detected in RPGR and RP2, respectively. Only one mutation was detected in ORF15. Affected male patients with RP2 mutations tended to have lower visual function than those with RPGR mutations. Female carriers demonstrated varying visual acuities and visual fields. Among the female carriers, 92% had electroretinographical abnormalities and 63% had a radial autofluorescent pattern, and the carriers who had higher myopia showed worse visual acuity and more severe retinal degeneration. Our results expand the knowledge of the clinical phenotypes of male patients with and female carriers of XLRP and suggest the possibility that RP2 mutations are relatively highly prevalent in Japan. Full article
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Open AccessArticle Oral DhHP-6 for the Treatment of Type 2 Diabetes Mellitus
Int. J. Mol. Sci. 2019, 20(6), 1517; https://doi.org/10.3390/ijms20061517
Received: 24 February 2019 / Revised: 15 March 2019 / Accepted: 22 March 2019 / Published: 26 March 2019
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Abstract
Type 2 diabetes mellitus (T2DM) is associated with pancreatic β-cell dysfunction which can be induced by oxidative stress. Deuterohemin-βAla-His-Thr-Val-Glu-Lys (DhHP-6) is a microperoxidase mimetic that can scavenge reactive oxygen species (ROS) in vivo. In our previous studies, we demonstrated an increased stability of [...] Read more.
Type 2 diabetes mellitus (T2DM) is associated with pancreatic β-cell dysfunction which can be induced by oxidative stress. Deuterohemin-βAla-His-Thr-Val-Glu-Lys (DhHP-6) is a microperoxidase mimetic that can scavenge reactive oxygen species (ROS) in vivo. In our previous studies, we demonstrated an increased stability of linear peptides upon their covalent attachment to porphyrins. In this study, we assessed the utility of DhHP-6 as an oral anti-diabetic drug in vitro and in vivo. DhHP-6 showed high resistance to proteolytic degradation in vitro and in vivo. The degraded DhHP-6 product in gastrointestinal (GI) fluid retained the enzymatic activity of DhHP-6, but displayed a higher permeability coefficient. DhHP-6 protected against the cell damage induced by H2O2 and promoted insulin secretion in INS-1 cells. In the T2DM model, DhHP-6 reduced blood glucose levels and facilitated the recovery of blood lipid disorders. DhHP-6 also mitigated both insulin resistance and glucose tolerance. Most importantly, DhHP-6 promoted the recovery of damaged pancreas islets. These findings suggest that DhHP-6 in physiological environments has high stability against enzymatic degradation and maintains enzymatic activity. As DhHP-6 lowered the fasting blood glucose levels of T2DM mice, it thus represents a promising candidate for oral administration and clinical therapy. Full article
(This article belongs to the Special Issue Nutrition and Diabetes)
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Open AccessArticle Computational Study for the Unbinding Routes of β-N-Acetyl-d-Hexosaminidase Inhibitor: Insight from Steered Molecular Dynamics Simulations
Int. J. Mol. Sci. 2019, 20(6), 1516; https://doi.org/10.3390/ijms20061516
Received: 19 February 2019 / Revised: 20 March 2019 / Accepted: 22 March 2019 / Published: 26 March 2019
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Abstract
β-N-Acetyl-d-hexosaminidase from Ostrinia furnacalis (OfHex1) is a new target for the design of insecticides. Although some of its inhibitors have been found, there is still no commercial drug available at present. The residence time of the ligand [...] Read more.
β-N-Acetyl-d-hexosaminidase from Ostrinia furnacalis (OfHex1) is a new target for the design of insecticides. Although some of its inhibitors have been found, there is still no commercial drug available at present. The residence time of the ligand may be important for its pharmacodynamic effect. However, the unbinding routes of ligands from OfHex1 still remain largely unexplored. In the present study, we first simulated the six dissociation routes of N,N,N-trimethyl-d-glucosamine-chitotriomycin (TMG-chitotriomycin, a highly selective inhibitor of OfHex1) from the active pocket of OfHex1 by steered molecular dynamics simulations. By comparing the potential of mean forces (PMFs) of six routes, Route 1 was considered as the most possible route with the lowest energy barrier. Furthermore, the structures of six different states for Route 1 were snapshotted, and the key amino acid residues affecting the dissociated time were analyzed in the unbinding pathway. Moreover, we also analyzed the “open–close” mechanism of Glu368 and Trp448 and found that their conformational changes directly affected the dissociation of TMG-chitotriomycin. Our findings would be helpful to understanding and identifying novel inhibitors against OfHex1 from virtual screening or lead-optimization. Full article
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Open AccessCommunication Autophosphorylation of Orphan Receptor ERBB2 Can Be Induced by Extracellular Treatment with Mildly Alkaline Media
Int. J. Mol. Sci. 2019, 20(6), 1515; https://doi.org/10.3390/ijms20061515
Received: 15 January 2019 / Revised: 20 March 2019 / Accepted: 21 March 2019 / Published: 26 March 2019
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Abstract
ErbB2 is an oncogene receptor tyrosine kinase linked to breast cancer. It is a member of the epidermal growth factor receptor (EGFR) minifamily. ErbB2 is currently viewed as an orphan receptor since, by itself, it does not bind EGF-like ligands and can be [...] Read more.
ErbB2 is an oncogene receptor tyrosine kinase linked to breast cancer. It is a member of the epidermal growth factor receptor (EGFR) minifamily. ErbB2 is currently viewed as an orphan receptor since, by itself, it does not bind EGF-like ligands and can be activated only when overexpressed in malignant cells or complexed with ErbB3, another member of the EGFR minifamily. Here, we report that ErbB2 can be activated by extracellular application of mildly alkaline (pH 8–9) media to ErbB2-transfected cells. We also show that the activation of the ErbB2 receptor by alkali is dose-dependent and buffer-independent. The endogenous ErbB2 receptor of A431 cell line can also undergo alkali-dependent autophosphorylation. Thus, we describe a novel ligand-independent mechanism of ErbB2 receptor activation. Full article
(This article belongs to the Special Issue Kinase Signal Transduction 2019)
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Open AccessArticle Analysis of 50 Neurodegenerative Genes in Clinically Diagnosed Early-Onset Alzheimer’s Disease
Int. J. Mol. Sci. 2019, 20(6), 1514; https://doi.org/10.3390/ijms20061514
Received: 20 February 2019 / Revised: 19 March 2019 / Accepted: 20 March 2019 / Published: 26 March 2019
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Abstract
Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), and prion diseases have a certain degree of clinical, pathological, and molecular overlapping. Previous studies revealed that many causative mutations in AD, PD, and FTD/ALS genes could [...] Read more.
Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), and prion diseases have a certain degree of clinical, pathological, and molecular overlapping. Previous studies revealed that many causative mutations in AD, PD, and FTD/ALS genes could be found in clinical familial and sporadic AD. To further elucidate the missing heritability in early-onset Alzheimer’s disease (EOAD), we genetically characterized a Thai EOAD cohort by Next-Generation Sequencing (NGS) with a high depth of coverage, capturing variants in 50 previously recognized AD and other related disorders’ genes. A novel mutation, APP p.V604M, and the known causative variant, PSEN1 p.E184G, were found in two of the familiar cases. Remarkably, among 61 missense variants were additionally discovered from 21 genes out of 50 genes, six potential mutations including MAPT P513A, LRRK2 p.R1628P, TREM2 p.L211P, and CSF1R (p.P54Q and pL536V) may be considered to be probably/possibly pathogenic and risk factors for other dementia leading to neuronal degeneration. All allele frequencies of the identified missense mutations were compared to 622 control individuals. Our study provides initial evidence that AD and other neurodegenerative diseases may represent shades of the same disease spectrum, and consideration should be given to offer exactly embracing genetic testing to patients diagnosed with EOAD. Our results need to be further confirmed with a larger cohort from this area. Full article
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Open AccessComment Vitamin D Supplementation as Add-on Therapy in Multiple Sclerosis—Balance between Benefit and Risk?: A Commentary on Vitamin D Supplementation in Central Nervous System Demyelinating Disease—Enough Is Enough
Int. J. Mol. Sci. 2019, 20(6), 1513; https://doi.org/10.3390/ijms20061513
Received: 13 February 2019 / Accepted: 25 March 2019 / Published: 26 March 2019
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Abstract
The excellent publication by Häusler and Weber [...] Full article
Open AccessReview Connecting Western and Eastern Medicine from an Energy Perspective
Int. J. Mol. Sci. 2019, 20(6), 1512; https://doi.org/10.3390/ijms20061512
Received: 12 February 2019 / Revised: 19 March 2019 / Accepted: 22 March 2019 / Published: 26 March 2019
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Abstract
Although Western medicine and Eastern medicine are worlds apart, there is a striking overlap in the basic principle of these types of medicine when we look at them from the perspective of energy. In both worlds, opposing forces provide the energy that flows [...] Read more.
Although Western medicine and Eastern medicine are worlds apart, there is a striking overlap in the basic principle of these types of medicine when we look at them from the perspective of energy. In both worlds, opposing forces provide the energy that flows through networks in an organism, which fuels life. In this concept, health is the ability of an organism to maintain the balance between these opposing forces, i.e., homeostasis (West) and harmony (East), which creates resilience. Moreover, strategies used to treat diseases are strikingly alike, namely adjusting the flow of energy by changing the connections in the network. The energy perspective provides a basis to integrate Eastern and Western medicine, and opens new directions for research to get the best of both worlds. Full article
(This article belongs to the Special Issue Traditional Medicine – Unraveling Its Molecular Mechanism, Volume 2)
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Open AccessReview Therapeutic Targeting Steroid Resistant Pro-Inflammatory NK and NKT-Like Cells in Chronic Inflammatory Lung Disease
Int. J. Mol. Sci. 2019, 20(6), 1511; https://doi.org/10.3390/ijms20061511
Received: 6 February 2019 / Revised: 5 March 2019 / Accepted: 21 March 2019 / Published: 26 March 2019
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Abstract
The innate immune system drives the initiation of inflammation and progression to chronic inflammation in two important chronic inflammatory lung diseases involving the small airways, chronic obstructive pulmonary disease (COPD) and bronchiolitis obliterans syndrome (BOS), following lung transplantation. Recently natural killer T cell [...] Read more.
The innate immune system drives the initiation of inflammation and progression to chronic inflammation in two important chronic inflammatory lung diseases involving the small airways, chronic obstructive pulmonary disease (COPD) and bronchiolitis obliterans syndrome (BOS), following lung transplantation. Recently natural killer T cell like (NKT-like) cells, which represent a bridge between the innate and adaptive immune response as well as the innate natural killer cell (NK) cells, have been shown to be important cells in these two chronic lung diseases. Importantly these cells have been shown to be resistant to commonly used anti-inflammatory drugs such as glucocorticoids and as such their inflammatory nature has been difficult to suppress. Mechanisms leading to steroid resistance in both diseases has recently been shown. Glucocorticoids switch off inflammatory genes by first entering the cell and binding to glucocorticoid receptors (GCRs). The steroid-GCR complex must then be chaperoned into the nucleus via several heat shock proteins, where they engage histone deacetylase 2 to switch off pro-inflammatory gene transcription. Many of these mechanisms are altered in NK and NKT-like cells in COPD and BOS requiring novel intervention using combinations of currently available drugs. Evidence will be presented to show how these drugs can overcome these mechanisms of drug resistance ex vivo advising novel therapeutic strategies for the treatment these two important chronic inflammatory lung diseases. Full article
(This article belongs to the Section Molecular Immunology)
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Open AccessArticle Placenta Transcriptome Profiling in Intrauterine Growth Restriction (IUGR)
Int. J. Mol. Sci. 2019, 20(6), 1510; https://doi.org/10.3390/ijms20061510
Received: 5 March 2019 / Revised: 22 March 2019 / Accepted: 24 March 2019 / Published: 26 March 2019
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Abstract
Intrauterine growth restriction (IUGR) is a serious pathological complication associated with compromised fetal development during pregnancy. The aim of the study was to broaden knowledge about the transcriptomic complexity of the human placenta by identifying genes potentially involved in IUGR pathophysiology. RNA-Seq data [...] Read more.
Intrauterine growth restriction (IUGR) is a serious pathological complication associated with compromised fetal development during pregnancy. The aim of the study was to broaden knowledge about the transcriptomic complexity of the human placenta by identifying genes potentially involved in IUGR pathophysiology. RNA-Seq data were used to profile protein-coding genes, detect alternative splicing events (AS), single nucleotide variant (SNV) calling, and RNA editing sites prediction in IUGR-affected placental transcriptome. The applied methodology enabled detection of 37,501 transcriptionally active regions and the selection of 28 differentially-expressed genes (DEGs), among them 10 were upregulated and 18 downregulated in IUGR-affected placentas. Functional enrichment annotation indicated that most of the DEGs were implicated in the processes of inflammation and immune disorders related to IUGR and preeclampsia. Additionally, we revealed that some genes (S100A13, GPR126, CTRP1, and TFPI) involved in the alternation of splicing events were mainly implicated in angiogenic-related processes. Significant SNVs were overlapped with 6533 transcripts and assigned to 2386 coding sequence (CDS), 1528 introns, 345 5’ untranslated region (UTR), 1260 3’UTR, 918 non-coding RNA (ncRNA), and 10 intergenic regions. Within CDS regions, 543 missense substitutions with functional effects were recognized. Two known mutations (rs4575, synonymous; rs3817, on the downstream region) were detected within the range of AS and DEG candidates: PA28β and PINLYP, respectively. Novel genes that are dysregulated in IUGR were detected in the current research. Investigating genes underlying the IUGR is crucial for identification of mechanisms regulating placental development during a complicated pregnancy. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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Open AccessArticle Telomerase Impinges on the Cellular Response to Oxidative Stress Through Mitochondrial ROS-Mediated Regulation of Autophagy
Int. J. Mol. Sci. 2019, 20(6), 1509; https://doi.org/10.3390/ijms20061509
Received: 24 January 2019 / Revised: 15 March 2019 / Accepted: 15 March 2019 / Published: 26 March 2019
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Abstract
Telomerase has cellular functions beyond telomere stabilization, including a role in mitochondria. The function of the catalytic component—TERT—in mitochondria is still unknown, but it seems to play a role in the response to oxidative stress. Here, we interrogated the role of the subcellular [...] Read more.
Telomerase has cellular functions beyond telomere stabilization, including a role in mitochondria. The function of the catalytic component—TERT—in mitochondria is still unknown, but it seems to play a role in the response to oxidative stress. Here, we interrogated the role of the subcellular localization of TERT to the response to hydrogen peroxide (H2O2) treatment. Using normal human fibroblasts (NHF) expressing non-tagged wild type (WT) human TERT (hTERT) or nuclear localization and function (nuchTERT), a mutant that we previously described as being competent in telomere elongation, while not being able to localize to mitochondria, we found the differential activation of autophagy as a function of hTERT’s subcellular localization. Specifically, we found that only cells expressing the mutant had significant increases in autophagy markers as a response to H2O2 challenge. Either the reintroduction of the mitochondrial pool of hTERT or the expression of mitochondrially-targeted catalase in mutant cells blunted the autophagic response under oxidative stress. Interestingly, autophagy activation was also associated with decreased levels of mitochondrial DNA damage. Taken together, these results suggest that the loss of hTERT in mitochondria initiates a signaling cascade that allows for cells to adapt to and cope with the lack of mitochondrial telomerase. Such effects also influence the cellular response to oxidative damage. Full article
(This article belongs to the Special Issue mtDNA and Mitochondrial Stress Signaling in Human Diseases)
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Open AccessArticle Tomentosin Displays Anti-Carcinogenic Effect in Human Osteosarcoma MG-63 Cells via the Induction of Intracellular Reactive Oxygen Species
Int. J. Mol. Sci. 2019, 20(6), 1508; https://doi.org/10.3390/ijms20061508
Received: 11 February 2019 / Revised: 19 March 2019 / Accepted: 22 March 2019 / Published: 26 March 2019
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Abstract
Tomentosin is a natural sesquiterpene lactone extracted from various plants and is widely used as a medicine because it exhibits essential therapeutic properties. In this study, we investigated the anti-carcinogenic effects of tomentosin in human osteosarcoma MG-63 cells by performing cell migration/viability/proliferation, apoptosis, [...] Read more.
Tomentosin is a natural sesquiterpene lactone extracted from various plants and is widely used as a medicine because it exhibits essential therapeutic properties. In this study, we investigated the anti-carcinogenic effects of tomentosin in human osteosarcoma MG-63 cells by performing cell migration/viability/proliferation, apoptosis, and reactive oxygen species (ROS) analysis assays. MG-63 cells were treated with various doses of tomentosin. After treatment with tomentosin, MG-63 cells were analyzed using the MTT assay, colony formation assay, cell counting assay, wound healing assay, Boyden chamber assay, zymography assay, cell cycle analysis, FITC Annexin V apoptosis assay, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, western blot analysis, and ROS detection analysis. Our results indicated that tomentosin decreased cell viability and migration ability in MG-63 cells. Moreover, tomentosin induced apoptosis, cell cycle arrest, DNA damage, and ROS production in MG-63 cells. Furthermore, tomentosin-induced intracellular ROS decreased cell viability and induced apoptosis, cell cycle arrest, and DNA damage in MG-63 cells. Taken together, our results suggested that tomentosin exerted anti-carcinogenic effects in MG-63 cells by induction of intracellular ROS. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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Open AccessArticle Comparison the Effect of Ferutinin and 17β-Estradiol on Bone Mineralization of Developing Zebrafish (Danio rerio) Larvae
Int. J. Mol. Sci. 2019, 20(6), 1507; https://doi.org/10.3390/ijms20061507
Received: 28 January 2019 / Revised: 21 February 2019 / Accepted: 25 February 2019 / Published: 26 March 2019
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Abstract
There is an urgent need to develop novel drugs for osteoporosis which occurs due to estrogen deficiency. Phytoestrogens derived from medicinal plants would be the best alternative to chemical drugs with harmful side effects. The main purpose of the present study was to [...] Read more.
There is an urgent need to develop novel drugs for osteoporosis which occurs due to estrogen deficiency. Phytoestrogens derived from medicinal plants would be the best alternative to chemical drugs with harmful side effects. The main purpose of the present study was to investigate the effect of ferutinin compared to 17β-estradiol (E2) on bone mineralization of zebrafish larvae. Regarding the lack of publications, the histology analysis was performed after exposure to E2 to find effective treatment on bone mineralization of developing zebrafish larvae. Then, the larvae were exposed to four concentrations of ferutinin at three time points to assess the mortality, the expression of some related genes and histology of the ceratohyal and hyomandibular of treated larvae. The RT-PCR result of the treatment groups demonstrated the similar expression pattern in the larvae which were exposed to 1.25 μg/mL of ferutinin and 2 µM of E2 at 2 dpf, which confirmed the result of histology analysis. In addition, RT-qPCR of high concentration of ferutinin and E2 demonstrated that bmp2a/b and esr1 were downregulated and upregulated when the larvae were exposed to 5 μg/mL of ferutinin and 10 µM of E2, respectively. Full article
(This article belongs to the Special Issue Zebrafish 2.0: A Model for Toxicological Research)
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Open AccessArticle Cell Signaling Pathways in Mammary Carcinoma Induced in Rats with Low versus High Inherent Aerobic Capacity
Int. J. Mol. Sci. 2019, 20(6), 1506; https://doi.org/10.3390/ijms20061506
Received: 20 February 2019 / Revised: 20 March 2019 / Accepted: 22 March 2019 / Published: 26 March 2019
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Abstract
An inverse association exists between physical activity and breast cancer incidence and outcomes. An objective indicator of an individual’s recent physical activity exposure is aerobic capacity. We took advantage of the fact that there is an inherited as well as inducible component of [...] Read more.
An inverse association exists between physical activity and breast cancer incidence and outcomes. An objective indicator of an individual’s recent physical activity exposure is aerobic capacity. We took advantage of the fact that there is an inherited as well as inducible component of aerobic capacity to show that experimentally induced mammary cancer is inversely related to inherent aerobic capacity (IAC). The objective of this study was to determine whether cell signaling pathways involved in the development of mammary cancer differed in rats with low inherent aerobic capacity (LIAC, n = 55) versus high inherent aerobic capacity (HIAC, n = 57). Cancer burden was 0.21 ± 0.16 g/rat in HIAC versus 1.14 ± 0.45 in LIAC, p < 0.001. Based on protein expression, cancer in LIAC animals was associated with upregulated glucose utilization, and protein and fatty acid synthesis. Signaling in cancers from HIAC rats was associated with energy sensing, fatty acid oxidation and cell cycle arrest. These findings support the thesis that pro-glycolytic, metabolic inflexibility in LIAC favors not only insulin resistance and obesity but also tumor development and growth. This provides an unappreciated framework for understanding how obesity and low aerobic fitness, hallmarks of physical inactivity, are associated with higher cancer risk and poorer prognosis. Full article
(This article belongs to the Special Issue Molecular Research on Metabolic Disorders)
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Open AccessReview Associations between Adipokines in Arthritic Disease and Implications for Obesity
Int. J. Mol. Sci. 2019, 20(6), 1505; https://doi.org/10.3390/ijms20061505
Received: 4 March 2019 / Revised: 18 March 2019 / Accepted: 21 March 2019 / Published: 26 March 2019
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Abstract
Secretion from adipose tissue of adipokines or adipocytokines, comprising of bioactive peptides or proteins, immune molecules and inflammatory mediators, exert critical roles in inflammatory arthritis and obesity. This review considers the evidence generated over the last decade regarding the effects of several adipokines [...] Read more.
Secretion from adipose tissue of adipokines or adipocytokines, comprising of bioactive peptides or proteins, immune molecules and inflammatory mediators, exert critical roles in inflammatory arthritis and obesity. This review considers the evidence generated over the last decade regarding the effects of several adipokines including leptin, adiponectin, visfatin, resistin, chemerin and apelin, in cartilage and bone homeostasis in the pathogenesis of rheumatoid arthritis and osteoarthritis, which has important implications for obesity. Full article
(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis)
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Open AccessArticle Unique Regulation of Enterocyte Brush Border Membrane Na-Glutamine and Na-Alanine Co-Transport by Peroxynitrite during Chronic Intestinal Inflammation
Int. J. Mol. Sci. 2019, 20(6), 1504; https://doi.org/10.3390/ijms20061504
Received: 25 February 2019 / Revised: 20 March 2019 / Accepted: 22 March 2019 / Published: 26 March 2019
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Abstract
Na-amino acid co-transporters (NaAAcT) are uniquely affected in rabbit intestinal villus cell brush border membrane (BBM) during chronic intestinal inflammation. Specifically, Na-alanine co-transport (ASCT1) is inhibited secondary to a reduction in the affinity of the co-transporter for alanine, whereas Na-glutamine co-transport (B0AT1) is [...] Read more.
Na-amino acid co-transporters (NaAAcT) are uniquely affected in rabbit intestinal villus cell brush border membrane (BBM) during chronic intestinal inflammation. Specifically, Na-alanine co-transport (ASCT1) is inhibited secondary to a reduction in the affinity of the co-transporter for alanine, whereas Na-glutamine co-transport (B0AT1) is inhibited secondary to a reduction in BBM co-transporter numbers. During chronic intestinal inflammation, there is abundant production of the potent oxidant peroxynitrite (OONO). However, whether OONO mediates the unique alteration in NaAAcT in intestinal epithelial cells during chronic intestinal inflammation is unknown. In this study, ASCT1 and B0AT1 were inhibited by OONO in vitro. The mechanism of inhibition of ASCT1 by OONO was secondary to a reduction in the affinity of the co-transporter for alanine, and secondary to a reduction in the number of co-transporters for B0AT1, which were further confirmed by Western blot analyses. In conclusion, peroxynitrite inhibited both BBM ASCT1 and B0AT1 in intestinal epithelial cells but by different mechanisms. These alterations in the villus cells are similar to those seen in the rabbit model of chronic enteritis. Therefore, this study indicates that peroxynitrite may mediate the inhibition of ASCT1 and B0AT1 during inflammation, when OONO levels are known to be elevated in the mucosa. Full article
(This article belongs to the Special Issue Amino Acids Transport and Metabolism 2.0)
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Open AccessArticle Role of SIRT-3, p-mTOR and HIF-1α in Hepatocellular Carcinoma Patients Affected by Metabolic Dysfunctions and in Chronic Treatment with Metformin
Int. J. Mol. Sci. 2019, 20(6), 1503; https://doi.org/10.3390/ijms20061503
Received: 31 January 2019 / Revised: 13 March 2019 / Accepted: 22 March 2019 / Published: 26 March 2019
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Abstract
The incidence of hepatocellular carcinoma deriving from metabolic dysfunctions has increased in the last years. Sirtuin- (SIRT-3), phospho-mammalian target of rapamycin (p-mTOR) and hypoxia-inducible factor- (HIF-1α) are involved in metabolism and cancer. However, their role in hepatocellular carcinoma (HCC) metabolism, drug resistance and [...] Read more.
The incidence of hepatocellular carcinoma deriving from metabolic dysfunctions has increased in the last years. Sirtuin- (SIRT-3), phospho-mammalian target of rapamycin (p-mTOR) and hypoxia-inducible factor- (HIF-1α) are involved in metabolism and cancer. However, their role in hepatocellular carcinoma (HCC) metabolism, drug resistance and progression remains unclear. This study aimed to better clarify the biological and clinical function of these markers in HCC patients, in relation to the presence of metabolic alterations, metformin therapy and clinical outcome. A total of 70 HCC patients were enrolled: 48 and 22 of whom were in early stage and advanced stage, respectively. The expression levels of the three markers were assessed by immunohistochemistry and summarized using descriptive statistics. SIRT-3 expression was higher in diabetic than non-diabetic patients, and in metformin-treated than insulin-treated patients. Interestingly, p-mTOR was higher in patients with metabolic syndrome than those with different etiology, and, similar to SIRT-3, in metformin-treated than insulin-treated patients. Moreover, our results describe a slight, albeit not significant, benefit of high SIRT-3 and a significant benefit of high nuclear HIF-1α expression in early-stage patients, whereas high levels of p-mTOR correlated with worse prognosis in advanced-stage patients. Our study highlighted the involvement of SIRT-3 and p-mTOR in metabolic dysfunctions that occur in HCC patients, and suggested SIRT-3 and HIF-1α as predictors of prognosis in early-stage HCC patients, and p-mTOR as target for the treatment of advanced-stage HCC. Full article
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Open AccessArticle Levan-Capped Silver Nanoparticles for Bactericidal Formulations: Release and Activity Modelling
Int. J. Mol. Sci. 2019, 20(6), 1502; https://doi.org/10.3390/ijms20061502
Received: 27 February 2019 / Revised: 20 March 2019 / Accepted: 22 March 2019 / Published: 26 March 2019
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Abstract
An environmentally friendly technique was used to produce levan-capped silver nanoparticles of about 30 nm (with a loading of 30%) that showed bactericide effect, for E. coli and B. subtilis. That effect was mathematically studied with a dose-response model (lethal dose of [...] Read more.
An environmentally friendly technique was used to produce levan-capped silver nanoparticles of about 30 nm (with a loading of 30%) that showed bactericide effect, for E. coli and B. subtilis. That effect was mathematically studied with a dose-response model (lethal dose of 12.4 ppm and 6.8 ppm respectively). These silver nanoparticles were subsequently introduced in a gel to create a silver release system with bacteria inhibition activity. Silver release from the gel and its bactericidal activity was theoretically studied to develop a unique model that is able to predict accurately both silver release and lethal dose for any type of bacteria. This model will be useful for performing predictions for future silver in gel applications. Full article
(This article belongs to the Special Issue Surface-Functionalized Nanoparticles as Drug Carriers)
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Open AccessArticle Metabolic Inhibition Induces Transient Increase of L-type Ca2+ Current in Human and Rat Cardiac Myocytes
Int. J. Mol. Sci. 2019, 20(6), 1501; https://doi.org/10.3390/ijms20061501
Received: 19 February 2019 / Revised: 15 March 2019 / Accepted: 23 March 2019 / Published: 26 March 2019
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Abstract
Metabolic inhibition is a common condition observed during ischemic heart disease and heart failure. It is usually accompanied by a reduction in L-type Ca2+ channel (LTCC) activity. In this study, however, we show that metabolic inhibition results in a biphasic effect on [...] Read more.
Metabolic inhibition is a common condition observed during ischemic heart disease and heart failure. It is usually accompanied by a reduction in L-type Ca2+ channel (LTCC) activity. In this study, however, we show that metabolic inhibition results in a biphasic effect on LTCC current (ICaL) in human and rat cardiac myocytes: an initial increase of ICaL is observed in the early phase of metabolic inhibition which is followed by the more classical and strong inhibition. We studied the mechanism of the initial increase of ICaL in cardiac myocytes during β-adrenergic stimulation by isoprenaline, a non-selective agonist of β-adrenergic receptors. The whole-cell patch–clamp technique was used to record the ICaL in single cardiac myocytes. The initial increase of ICaL was induced by a wide range of metabolic inhibitors (FCCP, 2,4-DNP, rotenone, antimycin A). In rat cardiomyocytes, the initial increase of ICaL was eliminated when the cells were pre-treated with thapsigargin leading to the depletion of Ca2+ from the sarcoplasmic reticulum (SR). Similar results were obtained when Ca2+ release from the SR was blocked with ryanodine. These data suggest that the increase of ICaL in the early phase of metabolic inhibition is due to a reduced calcium dependent inactivation (CDI) of LTCCs. This was further confirmed in human atrial myocytes where FCCP failed to induce the initial stimulation of ICaL when Ca2+ was replaced by Ba2+, eliminating CDI of LTCCs. We conclude that the initial increase in ICaL observed during the metabolic inhibition in human and rat cardiomyocytes is a consequence of an acute reduction of Ca2+ release from SR resulting in reduced CDI of LTCCs. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling)
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Open AccessArticle Neuromuscular Plasticity in a Mouse Neurotoxic Model of Spinal Motoneuronal Loss
Int. J. Mol. Sci. 2019, 20(6), 1500; https://doi.org/10.3390/ijms20061500
Received: 1 March 2019 / Revised: 19 March 2019 / Accepted: 24 March 2019 / Published: 26 March 2019
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Abstract
Despite the relevant research efforts, the causes of amyotrophic lateral sclerosis (ALS) are still unknown and no effective cure is available. Many authors suggest that ALS is a multi-system disease caused by a network failure instead of a cell-autonomous pathology restricted to motoneurons. [...] Read more.
Despite the relevant research efforts, the causes of amyotrophic lateral sclerosis (ALS) are still unknown and no effective cure is available. Many authors suggest that ALS is a multi-system disease caused by a network failure instead of a cell-autonomous pathology restricted to motoneurons. Although motoneuronal loss is the critical hallmark of ALS given their specific vulnerability, other cell populations, including muscle and glial cells, are involved in disease onset and progression, but unraveling their specific role and crosstalk requires further investigation. In particular, little is known about the plastic changes of the degenerating motor system. These spontaneous compensatory processes are unable to halt the disease progression, but their elucidation and possible use as a therapeutic target represents an important aim of ALS research. Genetic animal models of disease represent useful tools to validate proven hypotheses or to test potential therapies, and the conception of novel hypotheses about ALS causes or the study of pathogenic mechanisms may be advantaged by the use of relatively simple in vivo models recapitulating specific aspects of the disease, thus avoiding the inclusion of too many confounding factors in an experimental setting. Here, we used a neurotoxic model of spinal motoneuron depletion induced by injection of cholera toxin-B saporin in the gastrocnemius muscle to investigate the possible occurrence of compensatory changes in both the muscle and spinal cord. The results showed that, following the lesion, the skeletal muscle became atrophic and displayed electromyographic activity similar to that observed in ALS patients. Moreover, the changes in muscle fiber morphology were different from that observed in ALS models, thus suggesting that some muscular effects of disease may be primary effects instead of being simply caused by denervation. Notably, we found plastic changes in the surviving motoneurons that can produce a functional restoration probably similar to the compensatory changes occurring in disease. These changes could be at least partially driven by glutamatergic signaling, and astrocytes contacting the surviving motoneurons may support this process. Full article
(This article belongs to the Section Molecular Neurobiology)
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Open AccessArticle MicroRNA-29a Disrupts DNMT3b to Ameliorate Diet-Induced Non-Alcoholic Steatohepatitis in Mice
Int. J. Mol. Sci. 2019, 20(6), 1499; https://doi.org/10.3390/ijms20061499
Received: 26 February 2019 / Revised: 18 March 2019 / Accepted: 24 March 2019 / Published: 26 March 2019
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Abstract
MicroRNA-29 (miR-29) has been found to reduce liver inflammation and fibrosis following a liver injury. Meanwhile, DNA methyltransferase has been reported to participate in the development of non-alcoholic steatohepatitis (NASH). The aim of this study is to investigate the miR-29a regulation of methyltransferase [...] Read more.
MicroRNA-29 (miR-29) has been found to reduce liver inflammation and fibrosis following a liver injury. Meanwhile, DNA methyltransferase has been reported to participate in the development of non-alcoholic steatohepatitis (NASH). The aim of this study is to investigate the miR-29a regulation of methyltransferase signaling and epigenetic program in NASH progression. Methods: miR-29a transgenic mice (miR-29aTg mice) and wild-type littermates were subjected to the methionine-choline-deficient (MCD) diet-induced animal model of NASH. Primary hepatic stellate cells were transfected with a miR-29a mimic and antisense inhibitor. We then analyzed gene expressions with qRT-PCR, immunohistochemical stain, Western blot, and luciferase reporter assay. The results demonstrated that increased miR-29a alleviated the MCD diet-induced body weight loss and steatosis and decreased aspartate aminotransferase (AST) levels in mice. Furthermore, hepatic tissue in miR-29aTg mice displayed a weak fibrotic matrix, as shown with Sirius Red staining concomitant with low fibrotic α-SMA expression within affected tissues compared to the wild-type mice fed the MCD diet. Forced miR-29a expression reduced the MCD diet exaggeration of reactive oxygen species (ROS) production by immunohistochemically staining 8-OHdG. Increased miR-29a signaling also resulted in the downregulation of DNMT3b, TGF-β, IL-6, heme oxygenase-1 (HO-1), p-SMAD3, PI3K, and L3BII expression within the liver tissue. An in vitro luciferase reporter assay further confirmed that miR-29a mimic transfection reduced DNMT3b expression in primary HSCs. Our data provide new insights that miR-29a improves MCD diet-induced liver inflammation, steatosis and fibrosis, and highlight the potential of miR-29a targeted therapy for treating NASH. Full article
(This article belongs to the Section Biochemistry)
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Open AccessReview The Role of Tyrosine Phosphorylation of Protein Kinase C Delta in Infection and Inflammation
Int. J. Mol. Sci. 2019, 20(6), 1498; https://doi.org/10.3390/ijms20061498
Received: 7 March 2019 / Revised: 15 March 2019 / Accepted: 22 March 2019 / Published: 26 March 2019
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Abstract
Protein Kinase C (PKC) is a family composed of phospholipid-dependent serine/threonine kinases that are master regulators of inflammatory signaling. The activity of different PKCs is context-sensitive and these kinases can be positive or negative regulators of signaling pathways. The delta isoform (PKCδ) is [...] Read more.
Protein Kinase C (PKC) is a family composed of phospholipid-dependent serine/threonine kinases that are master regulators of inflammatory signaling. The activity of different PKCs is context-sensitive and these kinases can be positive or negative regulators of signaling pathways. The delta isoform (PKCδ) is a critical regulator of the inflammatory response in cancer, diabetes, ischemic heart disease, and neurodegenerative diseases. Recent studies implicate PKCδ as an important regulator of the inflammatory response in sepsis. PKCδ, unlike other members of the PKC family, is unique in its regulation by tyrosine phosphorylation, activation mechanisms, and multiple subcellular targets. Inhibition of PKCδ may offer a unique therapeutic approach in sepsis by targeting neutrophil-endothelial cell interactions. In this review, we will describe the overall structure and function of PKCs, with a focus on the specific phosphorylation sites of PKCδ that determine its critical role in cell signaling in inflammatory diseases such as sepsis. Current genetic and pharmacological tools, as well as in vivo models, that are used to examine the role of PKCδ in inflammation and sepsis are presented and the current state of emerging tools such as microfluidic assays in these studies is described. Full article
(This article belongs to the Special Issue Protein Phosphorylation in Health and Disease)
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Open AccessReview Regulators of Rho GTPases in the Nervous System: Molecular Implication in Axon Guidance and Neurological Disorders
Int. J. Mol. Sci. 2019, 20(6), 1497; https://doi.org/10.3390/ijms20061497
Received: 5 March 2019 / Accepted: 18 March 2019 / Published: 25 March 2019
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Abstract
One of the fundamental steps during development of the nervous system is the formation of proper connections between neurons and their target cells—a process called neural wiring, failure of which causes neurological disorders ranging from autism to Down’s syndrome. Axons navigate through the [...] Read more.
One of the fundamental steps during development of the nervous system is the formation of proper connections between neurons and their target cells—a process called neural wiring, failure of which causes neurological disorders ranging from autism to Down’s syndrome. Axons navigate through the complex environment of a developing embryo toward their targets, which can be far away from their cell bodies. Successful implementation of neuronal wiring, which is crucial for fulfillment of all behavioral functions, is achieved through an intimate interplay between axon guidance and neural activity. In this review, our focus will be on axon pathfinding and the implication of some of its downstream molecular components in neurological disorders. More precisely, we will talk about axon guidance and the molecules implicated in this process. After, we will briefly review the Rho family of small GTPases, their regulators, and their involvement in downstream signaling pathways of the axon guidance cues/receptor complexes. We will then proceed to the final and main part of this review, where we will thoroughly comment on the implication of the regulators for Rho GTPases—GEFs (Guanine nucleotide Exchange Factors) and GAPs (GTPase-activating Proteins)—in neurological diseases and disorders. Full article
(This article belongs to the Special Issue Small GTPases 2019)
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Open AccessArticle Development of a Soy Protein Hydrolysate with an Antihypertensive Effect
Int. J. Mol. Sci. 2019, 20(6), 1496; https://doi.org/10.3390/ijms20061496
Received: 15 February 2019 / Revised: 12 March 2019 / Accepted: 21 March 2019 / Published: 25 March 2019
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Abstract
In this study, we combined enzymatic hydrolysis and lactic acid fermentation to generate an antihypertensive product. Soybean protein isolates were first hydrolyzed by Prozyme and subsequently fermented with Lactobacillus rhamnosus EBD1. After fermentation, the in vitro angiotensin-converting enzyme (ACE) inhibitory activity of the [...] Read more.
In this study, we combined enzymatic hydrolysis and lactic acid fermentation to generate an antihypertensive product. Soybean protein isolates were first hydrolyzed by Prozyme and subsequently fermented with Lactobacillus rhamnosus EBD1. After fermentation, the in vitro angiotensin-converting enzyme (ACE) inhibitory activity of the product (P-SPI) increased from 60.8 ± 2.0% to 88.24 ± 3.2%, while captopril (a positive control) had an inhibitory activity of 94.20 ± 5.4%. Mass spectrometry revealed the presence of three potent and abundant ACE inhibitory peptides, PPNNNPASPSFSSSS, GPKALPII, and IIRCTGC in P-SPI. Hydrolyzing P-SPI with gastrointestinal proteases did not significantly affect its ACE inhibitory ability. Also, oral administration of P-SPI (200 mg/kg body weight) to spontaneous hypertensive rats (SHRs) for 6 weeks significantly lowered systolic blood pressure (−19 ± 4 mm Hg, p < 0.05) and controlled body weight gain relative to control SHRs that were fed with physiological saline. Overall, P-SPI could be used as an antihypertensive functional food. Full article
(This article belongs to the Special Issue Peptides for Health Benefits 2019)
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Open AccessCorrection Correction: Akanda, M.R., et al., Anti-Inflammatory and Gastroprotective Roles of Rabdosia inflexa through Downregulation of Pro-Inflammatory Cytokines and MAPK/NF-κB Signaling Pathways. Int. J. Mol. Sci. 2018, 19, 584
Int. J. Mol. Sci. 2019, 20(6), 1495; https://doi.org/10.3390/ijms20061495
Received: 11 May 2018 / Accepted: 17 May 2018 / Published: 25 March 2019
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Abstract
The authors wish to make the following corrections to this paper [...] Full article
(This article belongs to the Section Biochemistry)
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Open AccessArticle Accelerated CO2 Hydration with Thermostable Sulfurihydrogenibium azorense Carbonic Anhydrase-Chitin Binding Domain Fusion Protein Immobilised on Chitin Support
Int. J. Mol. Sci. 2019, 20(6), 1494; https://doi.org/10.3390/ijms20061494
Received: 27 February 2019 / Revised: 20 March 2019 / Accepted: 22 March 2019 / Published: 25 March 2019
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Abstract
Carbonic anhydrases (CAs) represent a group of enzymes that catalyse important reactions of carbon dioxide hydration and dehydration, a reaction crucial to many biological processes and environmental biotechnology. In this study we successfully constructed a thermostable fusion enzyme composed of the Sulfurihydrogenibium azorense [...] Read more.
Carbonic anhydrases (CAs) represent a group of enzymes that catalyse important reactions of carbon dioxide hydration and dehydration, a reaction crucial to many biological processes and environmental biotechnology. In this study we successfully constructed a thermostable fusion enzyme composed of the Sulfurihydrogenibium azorense carbonic anhydrase (Saz_CA), the fastest CA discovered to date, and the chitin binding domain (ChBD) of chitinase from Bacillus circulans. Introduction of ChBD to the Saz_CA had no major impact on the effect of ions or inhibitors on the enzymatic activity. The fusion protein exhibited no negative effects up to 60 °C, whilst the fusion partner appears to protect the enzyme from negative effects of magnesium. The prepared biocatalyst appears to be thermally activated at 60 °C and could be partially purified with heat treatment. Immobilisation attempts on different kinds of chitin-based support results have shown that the fusion enzyme preferentially binds to a cheap, untreated chitin with a large crystallinity index over more processed forms of chitin. It suggests significant potential economic benefits for large-scale deployment of immobilised CA technologies such as CO2 utilisation or mineralisation. Full article
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Open AccessArticle Transcriptome Analysis Reveals the Accumulation Mechanism of Anthocyanins in Buckwheat (Fagopyrum esculentum Moench) Cotyledons and Flowers
Int. J. Mol. Sci. 2019, 20(6), 1493; https://doi.org/10.3390/ijms20061493
Received: 4 March 2019 / Revised: 20 March 2019 / Accepted: 23 March 2019 / Published: 25 March 2019
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Abstract
Buckwheat (Fagopyrum esculentum) is a valuable crop which can produce multiple human beneficial secondary metabolites, for example, the anthocyanins in sprouts and flowers. However, as the predominant group of visible polyphenols in pigmentation, little is known about the molecular mechanisms underlying [...] Read more.
Buckwheat (Fagopyrum esculentum) is a valuable crop which can produce multiple human beneficial secondary metabolites, for example, the anthocyanins in sprouts and flowers. However, as the predominant group of visible polyphenols in pigmentation, little is known about the molecular mechanisms underlying the anthocyanin biosynthesis within buckwheat. In this study, a comparative transcriptome analysis of green and red common buckwheat cultivars was carried out through RNA sequencing. Overall, 3727 and 5323 differently expressed genes (DEGs) were identified in flowers and cotyledons, respectively. Through GO and KEGG analysis, we revealed that DEGs in flowers and cotyledons are predominately involved in biosynthesis of anthocyanin. A total of 42 unigenes encoding 11 structural enzymes of the anthocyanin biosynthesis were identified as DEGs. We also identified some transcription factor families involved in the regulation of anthocyanin biosynthesis. Real-time qPCR validation of candidate genes was performed in flowers and cotyledons, and the results suggested that the high expression level of structural genes involved in anthocyanin biosynthetic pathway promotes anthocyanin accumulation. Our results provide the insight understanding for coloration of red common buckwheat. Full article
(This article belongs to the Special Issue Transcriptional and Post-transcriptional Gene Regulation in Plants)
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Open AccessArticle Antidiabetic and Cardioprotective Effects of Pharmacological Inhibition of GRK2 in db/db Mice
Int. J. Mol. Sci. 2019, 20(6), 1492; https://doi.org/10.3390/ijms20061492
Received: 27 February 2019 / Revised: 17 March 2019 / Accepted: 20 March 2019 / Published: 25 March 2019
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Abstract
Despite the availability of several therapies for the management of blood glucose in diabetic patients, most of the treatments do not show benefits on diabetic cardiomyopathy, while others even favor the progression of the disease. New pharmacological targets are needed that might help [...] Read more.
Despite the availability of several therapies for the management of blood glucose in diabetic patients, most of the treatments do not show benefits on diabetic cardiomyopathy, while others even favor the progression of the disease. New pharmacological targets are needed that might help the management of diabetes and its cardiovascular complications at the same time. GRK2 appears a promising target, given its established role in insulin resistance and in systolic heart failure. Using a custom peptide inhibitor of GRK2, we assessed in vitro in L6 myoblasts the effects of GRK2 inhibition on glucose extraction and insulin signaling. Afterwards, we treated diabetic male mice (db/db) for 2 weeks. Glucose tolerance (IGTT) and insulin sensitivity (ITT) were ameliorated, as was skeletal muscle glucose uptake and insulin signaling. In the heart, at the same time, the GRK2 inhibitor ameliorated inflammatory and cytokine responses, reduced oxidative stress, and corrected patterns of fetal gene expression, typical of diabetic cardiomyopathy. GRK2 inhibition represents a promising therapeutic target for diabetes and its cardiovascular complications. Full article
(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions)
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Open AccessArticle Design and Synthesis of a New Soluble Natural β-Carboline Derivative for Preclinical Study by Intravenous Injection
Int. J. Mol. Sci. 2019, 20(6), 1491; https://doi.org/10.3390/ijms20061491
Received: 27 February 2019 / Revised: 20 March 2019 / Accepted: 21 March 2019 / Published: 25 March 2019
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Abstract
Harmine is a natural β-carboline compound showing several biological activities, including antiproliferative properties, but this soluble natural molecule lacks selectivity. Harmine derivatives were reported to overcome this problem, but they are usually poorly soluble. Here, we designed and synthesized a new 2, 7, [...] Read more.
Harmine is a natural β-carboline compound showing several biological activities, including antiproliferative properties, but this soluble natural molecule lacks selectivity. Harmine derivatives were reported to overcome this problem, but they are usually poorly soluble. Here, we designed and synthesized a new 2, 7, 9-trisubstituted molecule (1-methyl-7-(3-methylbutoxy)-9-propyl-2-[(pyridin-2-yl)methyl]-9H-pyrido[3,4-b]indol-2-ium bromide) with a solubility of 1.87 ± 0.07 mg/mL in a simulated injection vehicle. This compound is stable for at least 72 h in acidic and physiological conditions (pH 1.1 and 7.4) as well as in a simulated injection vehicle (physiological liquid + 0.1% Tween80®). Solubility in those media is 1.06 ± 0.08 mg/mL and 1.62 ± 0.13 mg/mL at pH 7.4 and 1. The synthesized molecule displays a significant activity on five different cancer cell lines (IC50 range from 0.2 to 2 µM on A549, MDA-MB-231, PANC-1, T98G and Hs683 cell lines). This compound is also more active on cancer cells (MDA-MB-231) than on normal cells (MCF-10a) at IC50 concentrations. Due to its high activity at low concentration, such solubility values should be sufficient for further in vivo antitumoral activity evaluation via intravenous injection. Full article
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