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Metformin, the primary therapy for type 2 diabetes mellitus (T2DM), showed limitations such as varying absorption, rapid system clearance, required large amount, resistance, longstanding side effects. Use of Nano formulations for pharmaceuticals is emerging as a viable technique to reduce negative consequences of drug, while simultaneously attaining precise release and targeted distribution. This study developed a Polyethylene Glycol conjugated Graphene Oxide Quantum dots (GOQD-PEG) nanocomposite for the sustained release of metformin. Herein, we evaluated the effectiveness of metformin-loaded nanoconjugate in in vitro insulin resistance model. Results demonstrated drug loaded nanoconjugate successfully restored glucose uptake and reversed insulin resistance in in vitro conditions at reduced dosage compared to free metformin.
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Preparações de Ação Retardada , Grafite , Resistência à Insulina , Metformina , Nanoconjugados , Polietilenoglicóis , Pontos Quânticos , Grafite/química , Pontos Quânticos/química , Metformina/administração & dosagem , Metformina/farmacologia , Metformina/farmacocinética , Metformina/química , Polietilenoglicóis/química , Nanoconjugados/química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Sistemas de Liberação de Medicamentos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose/metabolismo , Glucose/químicaRESUMO
Arsenic (As) contamination of rice grain poses a serious threat to human health. Therefore, it is crucial to reduce the bioavailability of As in the soil and its accumulation in rice grains to ensure the safety of food and human health. In this study, mango (Mangifera indica) leaf-derived biochars (MBC) were synthesized and modified with iron (Fe) to produce FeMBC. In this study, 0.5 and 1% (w/w) doses of MBC and FeMBC were used. The results showed that 1% FeMBC enhanced the percentage of filled grains/panicle and biomass yield by 17 and 27%, respectively, compared to the control. The application of 0.5 and 1% FeMBC significantly (p < 0.05) reduced bioavailable soil As concentration by 33 and 48%, respectively, in comparison to the control. The even higher As flux in the control group as compared to the biochar-treated groups indicates the lower As availability to biochar-treated rice plant. The concentration of As in rice grains was reduced by 6 and 31% in 1% MBC and 1% FeMBC, respectively, compared to the control. The reduction in As concentration in rice grain under 1% FeMBC was more pronounced due to reduced bioavailability of As and enhanced formation of Fe-plaque. This may restrict the entry of As through the rice plant. The concentrations of micronutrients (such as Fe, Zn, Se, and Mn) in brown rice were also improved after the application of both MBC and FeMBC in comparison to the control. This study indicates that the consumption of parboiled rice reduces the health risk associated with As compared to cooked sunned rice. It emphasizes that 1% MBC and 1% FeMBC have great potential to decrease the uptake of As in rice grains.
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Arsênio , Oryza , Poluentes do Solo , Humanos , Ferro/análise , Oryza/metabolismo , Arsênio/análise , Carvão Vegetal/metabolismo , Solo , Poluentes do Solo/análise , Cádmio/análiseRESUMO
INTRODUCTION: One of the most fatal urological malignancies is clear cell renal cell carcinoma (ccRCC), yet little is known about its pathophysiology or prognosis. This study is aimed at obtaining some novel biomarkers with diagnostic and prognostic meaning and may find out potential therapeutic targets for ccRCC. MATERIAL AND METHODS: Using three publically accessible ccRCC gene expression profiles acquired from the Gene Expression Omnibus database, differentially expressed genes (DEG) were discovered and function enrichment analyses were carried out. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted by using the DAVID tool and a protein-protein interaction (PPI) network was constructed and visualized by Cytoscape. Then we identified 10 hub genes using the cytohubba plugin of Cytoscape based on degree score. The mRNA and protein expression of hub genes was analyzed by GEPIA and Human Protein Atlas (HPA) database. Then, prognosis analysis of hub genes was conducted using GEPIA 3.0 which consists of data from The Cancer Genome Atlas (TCGA). RESULTS: We discovered 293 DEG which is highly enriched in several biological processes connected to immune-regulation and pathways linked to tumors, including HIF-1, PI3K-AKT, and metabolic pathways. In particular, C1QA, C1QB, FCER1G, and TYROBP were related to advanced clinical stage, high pathological grade, and poor survival in patients with ccRCC. CONCLUSIONS: Further molecular biological studies are required to confirm the role of the putative biomarkers in human ccRCC. Our work highlighted the hub genes and pathways involved in the progression of ccRCC.
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Carcinoma de Células Renais , Biologia Computacional , Neoplasias Renais , Carcinoma de Células Renais/genética , Humanos , Neoplasias Renais/genética , Prognóstico , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão GênicaRESUMO
Asymmetric scaffolds were developed through electrospinning by utilizing biocompatible materials for effective wound healing applications. First of all, the chitosan surface was modified with decanoyl chloride and crosslinked with collagen to synthesize collagen crosslinked modified-chitosan (CG-cross-CS-g-Dc). Then, the asymmetric scaffolds were fabricated through electrospinning, where the top layer was a monoaxial nanofiber of the PCL/graphene oxide quantum dot (GOQD) nanocomposite and the bottom layer was a coaxial nanofiber having PCL in the core and the CG-cross-CS-g-Dc/GOQD nanocomposite in the shell layer. The formation of monoaxial (â¼130 ± 50 nm) and coaxial (â¼320 ± 40 nm) nanofibers was confirmed by transmission electron microscopy (TEM). The presence of GOQDs contributed to antioxidant and antimicrobial efficacy. These scaffolds showed substantial antibacterial activity against the common wound pathogens Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The scaffolds exhibited excellent cytocompatibility (MTT assay) and anti-inflammatory behaviour as analysed via the cytokine assay and biochemical analysis. The in vivo wound healing potential of the nanofibrous scaffolds was assessed with full-thickness excisional wounds in a rat model. The scaffolds accelerated the re-epithelialization as well as the collagen deposition, thereby facilitating the wound healing process in a very short span of time (10 days). Both in vitro and in vivo analyses thus provide a compelling argument for the use of these scaffolds as therapeutic biomaterials and their suitability for application in rapid wound regeneration and repair.
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Type 2 diabetes mellitus (T2DM) predominantly considered a metabolic disease is now being considered an inflammatory disease as well due to the involvement of meta-inflammation. Obesity-induced adipose tissue inflammation (ATI) is one of the earliest phenomena in the case of meta-inflammation, leading to the advent of insulin resistance (IR) and T2DM. The key events of ATI are orchestrated by macrophages, which aggravate the inflammatory state in the tissue upon activation, ultimately leading to systemic chronic low-grade inflammation and Non-Alcoholic Steatohepatitis (NASH) through the involvement of proinflammatory cytokines. The CD44 receptor on macrophages is overexpressed in ATI, NASH, and IR. Therefore, we developed a CD44 targeted Hyaluronic Acid functionalized Graphene Oxide Quantum Dots (GOQD-HA) nanocomposite for tissue-specific delivery of metformin. Metformin-loaded GOQD-HA (GOQD-HA-Met) successfully downregulated the expression of proinflammatory cytokines and restored antioxidant status at lower doses than free metformin in both palmitic acid-induced RAW264.7 cells and diet induced obese mice. Our study revealed that the GOQD-HA nanocarrier enhanced the efficacy of Metformin primarily by acting as a therapeutic agent apart from being a drug delivery platform. The therapeutic properties of GOQD-HA stem from both HA and GOQD having anti-inflammatory and antioxidant properties respectively. This study unravels the function of GOQD-HA as a targeted drug delivery option for metformin in meta-inflammation where the nanocarrier itself acts as a therapeutic agent.
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Diabetes Mellitus Tipo 2 , Metformina , Hepatopatia Gordurosa não Alcoólica , Pontos Quânticos , Animais , Camundongos , Ácido Hialurônico/uso terapêutico , Pontos Quânticos/uso terapêutico , Nanoconjugados/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Antioxidantes/uso terapêutico , Inflamação/tratamento farmacológico , Citocinas , Metformina/farmacologia , Metformina/uso terapêuticoRESUMO
Bifenthrin (BF), a synthetic pyrethroid is used worldwide for both agricultural and non-agricultural purposes due to its high insecticidal activity and low toxicity in mammals. However, its improper usage implies a possible risk to aquatic life. The study was aimed to correlate the association of BF toxicity with mitochondrial DNA copy number variation in edible fish Punitus sophore. The 96-h LC50 of BF in P. sophore was 3.4 µg/L, fish was treated with sub-lethal doses ((â and â of LC50;0.34 µg/L, 0.68 µg/L) of BF for 15 days. The activity and expression level of cytochrome c oxidase (Mt-COI) were measured to assess mitochondrial dysfunction caused by BF. Results showed BF reduced the level of Mt-COI mRNA in treated groups, hindered complex IV activity and increased ROS generation leading to oxidative damage. mtDNAcn was decreased in the muscle, brain and liver after BF treatment. Furthermore, BF induced neurotoxicity in brain and muscle cells through the inhibition of AchE activity. The treated groups showed elevated level of malondialdehyde (MDA) and an imbalance of antioxidant enzymes activity. Molecular docking and simulation analysis also predicted that BF binds to the active sites of the enzyme and restricts the fluctuation of its residues. Hence, outcome of the study suggests reduction of mtDNAcn could be a potential biomarker to assess Bifenthrin induced toxicity in aquatic ecosystem.
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Cyprinidae , Piretrinas , Animais , Complexo IV da Cadeia de Transporte de Elétrons/genética , Variações do Número de Cópias de DNA , DNA Mitocondrial/genética , Ecossistema , Simulação de Acoplamento Molecular , Piretrinas/toxicidade , Piretrinas/química , Estresse Oxidativo , Antioxidantes , Mitocôndrias , MamíferosRESUMO
Aim: The functionalization and characterization of antibacterial nanoceria with folic acid (FA) and elucidation of their in vivo wound-healing application. Materials & methods: Functionalization of nanoceria were done with FA using a chemical method and their antibacterial activity, cellular biocompatibility and in vivo wound-healing application were evaluated. Results: The functionalization of nanoceria with FA was done with 10-20 nm size and -20.1 mV zeta potential. The nanoformulation showed a bacteriostatic effect along with biocompatibility to different cell lines; 0.1% w/v spray of FA-nanoceria demonstrated excellent wound-healing capacity within 14 days in a Wister rat model. Conclusion: The antioxidant and reactive oxygen species scavenging activity of the FA-nanoceria make it a promising therapeutic agent as a unique spray formulation in wound-healing applications.
The emergence of chronic wounds is a main reason for mortality in patients with diabetes and other severe pathological complications. Advances in the use of nanotechnology have resulted in beneficial technology for tailoring of pharmacokinetic properties of different drug-delivery vehicles for different biomedical applications. In this study, folic acid (FA) functionalized nanoceria (FA-nanoceria) were formulated and their potential efficacy in the wound-healing process was explored. The nanoformulation showed a remarkable bacteriostatic effect on both Gram-negative and Gram-positive bacteria. In vitro cell line studies showed satisfactory biocompatibility in three different types of cell lines. In addition, a 0.1% w/v spray of FA-nanoceria was applied to full-thickness wounds in an in vivo mice model where it demonstrated excellent wound-healing capacity within 14 days. The combined antioxidant and reactive oxygen species scavenging activity of both the FA and nanoceria makes FA-nanoceria a promising therapeutic agent as a unique spray formulation in wound-healing applications.
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Antioxidantes , Ácido Fólico , Ratos , Animais , Ácido Fólico/química , Ratos Wistar , Antioxidantes/química , Antibacterianos/farmacologia , Antibacterianos/químicaRESUMO
Gastric cancer has emerged as a key challenge in oncology research as a malignant tumour with advanced stage detection. Apart from surgical management, a pharmacotherapeutic approach to stomach cancer treatment is an appealing option to consider. Andrographolide has been shown to have anticancer and chemosensitizer properties in a variety of solid tumors, including stomach cancer but the exact molecular mechanism is skeptical. In this study, we identified and validated pharmacological mechanism involved in the treatment of GC with integrated approach of network pharmacology and molecular docking. The targets of andrographolide and GC were obtained from databases. The intersected targets between andrographolide and GC-related genes were used to construct protein-protein interaction (PPI) network. Furthermore, mechanism of action of the targets was predicted by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Finally, these results were validated by molecular docking experiments, mRNA and protein expression level. A total of 197 targets were obtained for andrographolide treating GC. Functional enrichment analysis revealed that the target genes were exerted promising therapeutic effects on GC by HIF-1 and PI3K-Akt signaling pathway. The possible mechanism of action is by inactivation of HIF-1 signaling pathway which is dependent on the inhibition of upstream PI3K-AKT pathway. The PPI network identified SRC, AKT1, TP53, STAT3, PIK3CA, MAPK1, MAPK3, VEGFA, JUN and HSP90AA1 as potential hub targets. In addition, these results were further validated with molecular docking experiments. Survival analysis indicated that the expression levels of the hub genes were significantly associated with the clinical prognosis of GC. This study provided a novel approach to reveal the therapeutic mechanisms of andrographolide on GC, making future clinical application of andrographolide in the treatment of GC.
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Medicamentos de Ervas Chinesas , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , Simulação de Acoplamento Molecular , Farmacologia em Rede , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Medicamentos de Ervas Chinesas/farmacologiaRESUMO
Neural tube defects (NTDs) are significant congenital deformities of the central nervous system among which spina bifida is the most common form that occurs due to defect in the neurulation process of embryogenesis. NTDs are among the most common type of birth defects occurring at a range of 0.5-10 in every 1000 live births worldwide and are thought to have multifactorial etiology, including multigenetic and epigenetic notions. Epigenetic regulations control differential gene expression in normal and disease phenotypes. DNA methylation is a significant epigenetic process, guided by DNMT1, one of the most important maintenance methylating agents. However, the relationship between DNMT1 and NTDs had always been inconclusive and poorly understood. In the present study, by utilizing in silico methodologies we tried to figure out potent single nucleotide variants (SNVs) that could play roles in generating functional differences in DNMT1 expression and we also tried to check (by in vitro method) if there is any connection between DNMT1 expression and spina bifida condition. A number of coding and non-coding (both intragenic and intergenic) SNVs of DNMT1 were found (using the in silico methods) that have potentials to alter its expression. From the in vitro experimentations, differential DNMT1 RNA expressions were found between spina bifida affected newborns and their respective mothers when compared with controls. It is the first report of NTD from Eastern India precisely showing inverse correlation between DNMT1 expression and occurrence of NTD. The findings of the present study could be further considered for early prognosis and future experimental designs.
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DNA (Citosina-5-)-Metiltransferase 1 , Defeitos do Tubo Neural , Humanos , Índia , Defeitos do Tubo Neural/diagnóstico , Defeitos do Tubo Neural/genética , DNA (Citosina-5-)-Metiltransferase 1/genética , Variação Genética , PrognósticoRESUMO
PI3K/AKT/mTOR pathway is one of the frequently disrupted signaling pathways in renal cell carcinoma (RCC) that plays a significant role in tumor formation, disease progression and therapeutic resistance. Therefore, novel natural molecules targeting the critical proteins of this pathway will provide the best alternative to existing drugs, which are toxic and develops resistance. Recent studies have recognized the anti-cancer therapeutic potential of mycocompounds. The current study is focused on screening various mycocompounds from Astraeus hygrometricus against key cancer signaling proteins phosphoinositide 3-kinase (PI3K), protein kinase B, PKB (AKT1) and mammalian target of rapamycin (mTOR). We also studied in-silico cancer cells cytotoxicity and ADMET (absorption, distribution, metabolism, excretion and toxicity) profiles to elucidate the molecular mechanism against RCC and also to uncover the pharmacokinetic profile of these compounds. Astrakurkurone and Ergosta-4,6, 8-(14) 22-tetraene-3-one were the two most efficacious compounds with highest interaction scores and bonding. These compounds were both active against RCC4 and VMRC-RCZ cell lines of RCC. The ADME profiles of both were satisfactory based on druglikeness and bioavailability score criteria. Thus, this proposed study identified astrakurkurone and ergosta-4,6, 8-(14) 22-tetraene-3-one as potential anticancer drug candidates, and provides comparative structural insight into their binding to the 3 protein kinases.
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Produtos Biológicos , Carcinoma de Células Renais , Fungos , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Neoplasias Renais/patologia , Fosfatidilinositol 3-Quinase , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Serina-Treonina Quinases TOR/genética , Fungos/química , Produtos Biológicos/farmacologiaRESUMO
Synthesized organometallic gold-based folate nanoparticles (FAuNPs) were characterized, and its defense against lipopolysaccharide (LPS)-induced brain inflammation in Zebra fish was proven. Vitamin entrapment efficiency of these particles was found to be nearly 70%. The in vitro pH-dependent drug release dialysis study of FAuNPs confirmed a slow, sustained, and gradual release of folate for a period of 24 h. Both AuNPs and FAuNPs did not cause any marked changes in food intake, body weight, color, behavioral pattern, blood parameters, and hepatotoxicity. Histology of liver showed no changes between treated and control groups of fishes. The ex vivo study showed significant uptake of FAuNPs to free folate in folate receptor negative Hek293 cells, confirming a strategy to overcome folate deficiency in the brain. Antioxidant status and activities of few crucial brain enzymes were also measured to assess the brain function and found to be returned to the basal level, following FAuNP treatment. The transcription factor NRF2-Keap 1 expression pattern was also noted, and a prominent modulation was observed in the LPS-treated and FAuNP-administered group. Decisive brain enzymes like AChE and Na+K+ATPase were decreased significantly after LPS treatment, which is restored with FAuNP treatment. Caspases increased sharply after LPS treatment and diminished following FAuNP treatment. We conclude that FAuNP due to its high physical stability and uptake could be utilized against severe brain inflammation, leading to brain injury and neurodegeneration.
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PURPOSE: Graves' disease (GD) is an autoimmune disorder affecting primarily the thyroid gland. The most common extrathyroidal manifestation of GD is known as Graves' orbitopathy (GO). Bone marrow-derived fibrocytes represent a subset of monocytes in peripheral blood mononuclear cells (PBMCs), infiltrate the orbital tissues, and contribute to the pathogenesis of GO. Hence objectives of the study included whether the concentration of fibrocytes in peripheral blood was higher in GO, whether TSHR m RNA expression and TSHR surface expression in peripheral blood were higher in GO in comparison to Graves' Disease (GD) and Control subjects. METHODS: The percentage of circulating fibrocytes (FC) along with TSHR on its cell surface (CD 34+, CD 45+, CXCR4+, Collagen 1+, TSHR+) were assessed by flow cytometry of 50 patients with GD and GO and 15 healthy donors (Control). TSHR mRNA expression was measured by q RT PCR. RESULT: The concentration of circulating fibrocytes was significantly higher in GO compared to GD and control [GO 17% vs GD 3% vs control 0.7% (p < 0.05)]. Moreover, these fibrocytes express a significantly higher level of TSHR in GO. This was corroborated by the measure of TSH mRNA; in GD it was 2.3-fold higher and in GO it was 3.9 fold higher than in control, in GO this transcript level was 1.7fold higher than GD (p < 0.05). TSHR+ fibrocytes were significantly positively correlated with CAS (p = 0.004) and negatively correlated with age (p = 0.01) and duration of disease (p = 0.01) in GO. CONCLUSION: This study sheds further light on the pathogenesis of GO.
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Doença de Graves , Oftalmopatia de Graves , Doença de Graves/metabolismo , Oftalmopatia de Graves/metabolismo , Humanos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Receptores da TireotropinaRESUMO
Pediatric nephrolithiasis (NL) or Kidney stone disease (KSD) is an untethered topic in Asian population. In Western countries, the annual incidence of paediatric NL is around 6-10%. Here, we present data from West Bengal, India, on lower age (LA, 0-20 years) NL and its prevalence for the first time. To discover the mutations associated with KSD, twenty-four (18 + 6) rare LA-NL patients were selected for Whole Exome Sequencing (WES) and Sanger sequencing, respectively. It was found that GRHPR c. 494G>A mutation (MZ826703) is predominant in our study cohort. This specific homozygous mutation is functionally studied for the first time directly from human peripheral mononuclear cell (PBMC) samples. Using expression study with biochemical activity and computational analysis we assumed that the mutation is pathogenic with loss of function. Moreover, three genes, AGXT, HOGA1 and GRHPR with Novel variants known to cause hyperoxaluria were found frequently in the study cohort. Our study analyses the genes and variations that cause LA-NL, as well as the molecular function of the GRHPR mutation, which may serve as a clinical marker in the population of West Bengal, Eastern India.
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Several traits related to positive and negative affect show a high genetic as well as phenotypic correlation with well-being in humans, and are therefore collectively termed as "Well-being spectrum". Genome-Wide Association studies (GWA studies) on "well-being measurement" have led to identification of several genomic variants (Single Nucleotide Variants - SNVs), but very little has been explained with respect to their functionality and mode of alteration of well-being. Utilizing a pool of 1258 GWA studies based SNVs on "well-being measurement", we prioritized the SNVs and tried to annotate well-being related functionality through several bioinformatic tools to predict whether a protein sequence variation affects protein function, as well as experimentally validated datasets available in ENCODE based web-tools namely rSNPBase, RegulomeDB, Haploreg, along with GTEx Portal and STRING based protein interaction networks. Prioritization yielded three key SNVs; rs3781627-A, rs13072536-T and 5877-C potentially regulating three genes, PSMC3, ITIH4 and SERPINC1, respectively. Interestingly, the genes showed well clustered protein-protein interaction (maximum combined confidence score >0.4) with other well-being candidate genes, namely TNF and CRP genes suggesting their important role in modulation of well-being. PSMC3 and ITIH4 genes are also involved in driving acute phase responses signifying a probable cross-talk between well-being and psychoneuroimmunological system. To best of our knowledge this study is the first of its kind where the well-being associated GWA studies-SNVs were prioritized and functionally annotated, majorly based on functional data available in public domain, which revealed PSMC3, ITIH4 and SERPINC1 genes as probable candidates in regulation of well-being spectrum.
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Neural tube defects (NTDs) are among the common and severe congenital malformations in neonates. According to a WHO report, nearly three lakh babies are affected per year worldwide by NTDs. Most studies revealed that folate deficiency is the key element to promote NTD with other oligogenic and multifactorial elements. This folate is metabolized by the FOCM (folate one-carbon metabolism) pathway. The most important step in the FOCM pathway is the conversion of methionine to homocysteine, which is guided by the enzyme MTRR. Several single-nucleotide polymorphisms (SNPs) in the MTRR gene are strongly associated with the progression of NTD. A nonsynonymous allelic variant (rs1532268) of the protein leads to a missense mutation at the 202nd position from serine to leucine (S202L) and is associated with a higher disease prevalence in different populations. In our study, this SNP indicates a 2-fold increase in the risk of disease progression (p-value of 0.03; OR 2.76; 95% CI 1.08-7.11). Here, extensive molecular dynamics simulations and interaction network analysis reveal that the change of 202nd serine to leucine alters the structures of the FAD and NAD binding domains, which restricts the ligand binding. The S202L variation alters the functional dynamics that might impede the electron transport chain along the NADP(H)â FADâ FMN pathway and hamper phosphorylation by kinases like GSK-3 and CaM-II during the posttranscriptional modification of the protein. The present study provides functional insights into the effect of the genetic variations of the MTRR gene on the NTD disease pathogenesis.
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The pathophysiological mechanism(s) driving non-alcoholic fatty liver disease, the most prevalent chronic liver disease globally, have yet to be fully elucidated. Here, we identify regulator of G protein signaling 6 (RGS6), up-regulated in the livers of NAFLD patients, as a critical mediator of hepatic steatosis, fibrosis, inflammation, and cell death. Human patients with high hepatic RGS6 expression exhibited a corresponding high inflammatory burden, pronounced insulin resistance, and poor liver function. In mice, liver-specific RGS6 knockdown largely ameliorated high fat diet (HFD)-driven oxidative stress, fibrotic remodeling, inflammation, lipid deposition and cell death. RGS6 depletion allowed for maintenance of mitochondrial integrity restoring redox balance, improving fatty acid oxidation, and preventing loss of insulin receptor sensitivity in hepatocytes. RGS6 is both induced by ROS and increases ROS generation acting as a key amplification node to exacerbate oxidative stress. In liver, RGS6 forms a direct complex with ATM kinase supported by key aspartate residues in the RGS domain and is both necessary and sufficient to drive hyperlipidemia-dependent ATM phosphorylation. pATM and markers of DNA damage (γH2AX) were also elevated in livers from NAFLD patients particularly in samples with high RGS6 protein content. Unsurprisingly, RGS6 knockdown prevented ATM phosphorylation in livers from HFD-fed mice. Further, RGS6 mutants lacking the capacity for ATM binding fail to facilitate palmitic acid-dependent hepatocyte apoptosis underscoring the importance of the RGS6-ATM complex in hyperlipidemia-dependent cell death. Inhibition of RGS6, then, may provide a viable means to prevent or reverse liver damage by mitigating oxidative liver damage.
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Hepatopatia Gordurosa não Alcoólica , Proteínas RGS , Animais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Morte Celular , Dieta Hiperlipídica/efeitos adversos , Proteínas de Ligação ao GTP/metabolismo , Hepatócitos , Humanos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse Oxidativo , Proteínas RGS/genética , Proteínas RGS/metabolismoRESUMO
The countrywide COVID-19 pandemic lockdown accomplished what aggressive plans could not do throughout the long-term cleaning of the Ganga River. Here, we illustrated Hooghly River surface water quality [physico-chemical parameters, biological parameters, dissolved heavy metals] improvement by analyzing eight sampling station before and during the lockdown. Because of shutdown of industrial units and individuals staying at home, a complete decrease in industrial wastes, contaminants, and self-purging of the stream improved significantly water quality by about 40% to 50%. Among dissolved heavy metals, the concentrations of Cd (50%), Pb (53%), demonstrated noteworthy variations during the lockdown. Diminishing trends were also observed for TDS (62%), and BOD (52%), with significant reduction in the total coliform (63%), faecal coliform (61%), notably. Principal component analysis and paired t-test signify the alteration of water quality. The study concludes that the aquatic ecosystem can be revived if wastewater, and anthropogenic activities are properly managed by environmental surveillance.
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COVID-19 , Metais Pesados , Poluentes Químicos da Água , Controle de Doenças Transmissíveis , Ecossistema , Monitoramento Ambiental , Estuários , Humanos , Índia , Metais Pesados/análise , Pandemias , Melhoria de Qualidade , Rios , SARS-CoV-2 , Água , Poluentes Químicos da Água/análise , Qualidade da ÁguaRESUMO
The outbreak of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a global catastrophe. The elderly and people with comorbidity are facing a serious complication of the disease. The entry and infection strategy of SARS-CoV-2 in a host cell is raised by an amazing way of angiotensin-converting enzyme (ACE) 2 (ACE2) receptor recognition and imbalance of ACE/ACE2 in various organs, especially in the lungs. Here it has been discussed the role of interferon and protease during the receptor recognition (begining of infection) and followed by the impact of cytokine and hypoxia in the context of the balance of ACE/ACE2. It has also very concisely delineated the biochemistry and mechanism of ACE/ACE2 balance in different stages of infection and its role in comorbidity.
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Enzima de Conversão de Angiotensina 2/sangue , COVID-19/epidemiologia , COVID-19/etiologia , Peptidil Dipeptidase A/sangue , SARS-CoV-2/patogenicidade , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Comorbidade , Citocinas/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Sistema Renina-Angiotensina/fisiologia , Internalização do Vírus , Tratamento Farmacológico da COVID-19RESUMO
Isolated growth hormone deficiency (IGHD) type 1A is a rare, autosomal recessive disorder caused by deletion of the GH1 gene and characterized by early onset severe short stature and typical phenotype. Lack of exposure to GH during fetal life often leads to formation of anti-GH antibody following exposure even the least immunogenic recombinant human GH (rhGH). Some patients with circulating anti-GH antibodies demonstrate lack of growth response to GH while others do not. However, the clinical significance of this antibody is unclear; hence testing is not routinely recommended. Three siblings, born of a consanguineous union, were referred with severe short stature. They were evaluated and IGHD was diagnosed in all of them. Genetic analysis revealed that all three had homozygous 6.7 Kb deletion in GH1 gene, while their parents displayed a pattern of heterozygous 6.7 Kb deletions. rhGH was started at 10, 6 and 1.58 years of age, respectively. Growth and hormonal parameters were monitored throughout the course of treatment. The eldest sibling demonstrated expected growth velocity (9.5 cm/year) for the first year of rhGH that rapidly waned thereafter (2.5 cm/year). The youngest sibling experienced excellent growth response even after the third year (10.3 cm/year) while the middle sibling displayed sub-optimal response from rhGH initiation (6.3 cm/year). Change of rhGH brand did not work in the two elder sisters. Such a different growth response with rhGH in three siblings harbouring similar genetic abnormality has not been described previously.