Department Of Biochemistry And Microbial Sciences
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Item Identification of potential natural inhibitors of SARS-CoV2 main protease by molecular docking and simulation studies(Taylor and Francis Ltd., 2020) Gupta, S; Singh, A.K; Kushwaha, P.P; Prajapati, K.S; Shuaib, M; Senapati, S; Kumar, S.Coronaviruses are contagious pathogens primarily responsible for respiratory and intestinal infections. Research efforts to develop antiviral agents against coronavirus demonstrated the main protease (Mpro) protein may represent effective drug target. X-ray crystallographic structure of the SARS-CoV2 Mpro protein demonstrated the significance of Glu166, Cys141, and His41 residues involved in protein dimerization and its catalytic function. We performed in silico screening of compounds from Curcuma longa L. (Zingiberaceae family) against Mpro protein inhibition. Employing a combination of molecular docking, scoring functions, and molecular dynamics simulations, 267 compounds were screened by docking on Mpro crystallographic structure. Docking score and interaction profile analysis exhibited strong binding on the Mpro catalytic domain with compounds C1 (1E,6E)-1,2,6,7-tetrahydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione) and C2 (4Z,6E)?1,5?dihydroxy?1,7?bis(4?hydroxyphenyl)hepta?4,6?dien?3?one as lead agents. Compound C1 and C2 showed minimum binding score (�9.08 and �8.07 kcal/mole) against Mpro protein in comparison to shikonin and lopinavir (? ?5.4 kcal/mole) a standard Mpro inhibitor. Furthermore, principal component analysis, free energy landscape and protein-ligand energy calculation studies revealed that these two compounds strongly bind to the catalytic core of the Mpro protein with higher efficacy than lopinavir, a standard antiretroviral of the protease inhibitor class. Taken together, this structure based optimization has provided lead on two natural Mpro inhibitors for further testing and development as therapeutics against human coronavirus. Communicated by Ramaswamy H. Sarma. � 2020, � 2020 Informa UK Limited, trading as Taylor & Francis Group.Item Primary metabolites from overproducing microbial system using sustainable substrates(Wiley-Blackwell Publishing Ltd, 2020) Srivastava, R.K; Akhtar, N; Verma, M; Imandi, S.B.Primary (or secondary) metabolites are produced by animals, plants, or microbial cell systems either intracellularly or extracellularly. Production capabilities of microbial cell systems for many types of primary metabolites have been exploited at a commercial scale. But the high production cost of metabolites is a big challenge for most of the bioprocess industries and commercial production needs to be achieved. This issue can be solved to some extent by screening and developing the engineered microbial systems via reconstruction of the genome-scale metabolic model. The predicted genetic modification is applied for an increased flux in biosynthesis pathways toward the desired product. Wherein the resulting microbial strain is capable of converting a large amount of carbon substrate to the expected product with minimum by-product formation in the optimal operating conditions. Metabolic engineering efforts have also resulted in significant improvement of metabolite yields, depending on the nature of the products, microbial cell factory modification, and the types of substrate used. The objective of this review is to comprehend the state of art for the production of various primary metabolites by microbial strains system, focusing on the selection of efficient strain and genetic or pathway modifications, applied during strain engineering. � 2020 International Union of Biochemistry and Molecular Biology, Inc.Item Drug-metabolizing enzymes: role in drug resistance in cancer(Springer, 2020) Kaur, G; Gupta, S.K; Singh, P; Ali, V; Kumar, V; Verma, M.Although continuous researches are going on for the discovery of new chemotherapeutic agents, resistance to these anticancer agents has made it really difficult to reach the fruitful results. There are many causes for this resistance that are being studied by the researchers across the world, but still, success is far because there are several factors that are going along unattended or have been studied less. Drug-metabolizing enzymes (DMEs) are one of these factors, on which less study has been conducted. DMEs include Phase I and Phase II enzymes. Cytochrome P450s (CYPs) are major Phase I enzymes while glutathione-S-transferases (GSTs), UDP-glucuronosyltransferases (UGTs), dihydropyrimidine dehydrogenases are the major enzymes belonging to the Phase II enzymes. These enzymes play an important role in detoxification of the xenobiotics as well as the metabolism of drugs, depending upon the tissue in which they are expressed. When present in tumorous tissues, they cause resistance by metabolizing the drugs and rendering them inactive. In this review, the role of these various enzymes in anticancer drug metabolism and the possibilities for overcoming the resistance have been discussed. � 2020, Federaci�n de Sociedades Espa�olas de Oncolog�a (FESEO).Item Phytochemical ginkgolide b protects cultured neuroblastoma SH-SY5Y cells against a?(25-35) induced oxidative stress responses by maintaining the mitochondrial integrity(Rasayan Journal of Chemistry, c/o Dr. Pratima Sharma, 2020) Kaur, N; Kaur, S; Saini, M; Dhiman, M; Mantha, A.K.Alzheimer�s disease is associated with oxidative stress induced by accumulation of A? peptide, by disrupting the mitochondrial function. In this study, the oxidative stress responses induced by A?(25-35) and protective effects of diterpenoid phytochemical Ginkgolide B (GB) were evaluated by the determination of cellular oxidant/antioxidant status, oxidative DNA base damage and repair capacity of cells through evaluation of mitochondrial BER pathway status and the multifunctional enzyme APE1 in human neuroblastoma SH-SY5Y cells, and evaluation of mitochondrial membrane potential and changes in apoptotic pathway. It was found that A?(25-35) treatment increased ROS/RNS production, increased the activities of antioxidant SOD and Catalase enzymes, decreased the expression of mitochondrial SOD (SOD2), induced oxidative DNA base damage, might be altered the repair capacity as analyzed by the transcriptional and translational expression of APE1 and other BER pathway enzymes in the mitochondria, disrupted the mitochondrial membrane potential and induced apoptosis as a result of these responses. Phytochemical modulation by the pre-treatment of GB for 3 hr followed by the treatment of A?(25-35) for a period of 24 hr caused decrease in ROS/RNS, increase in activities of antioxidant enzymes and expression of SOD2, decreased oxidative DNA base damage and increased transcriptional and translational expression of APE1, increased/restored expression of APE1 and polymerase gamma (?) in the mitochondria, restored mitochondrial membrane potential and rescued the SH-SY5Y cells from mitochondrial-mediated apoptosis against A?(25-35) induced oxidative stress responses. Taken together, GB showed neuroprotection by restoring cellular antioxidant defense system, repair capacity of cells and restoring mitochondrial integrity (genome and membrane potential), thus rescuing the SH-SY5Y cells from A?(25-35) induced oxidative stress responses. � RAS?YAN. All rights reserved.Item Circulating microRNA-590-5p functions as a liquid biopsy marker in non-small cell lung cancer(Blackwell Publishing Ltd, 2020) Khandelwal, A; Seam, R.K; Gupta, M; Rana, M.K; Prakash, H; Vasquez, K.M; Jain, A.Despite the availability of various diagnostic procedures, a tissue biopsy is still indispensable for the routine diagnosis of lung cancer. However, inaccurate diagnoses can occur, leading to inefficient cancer management. In this context, use of circulating microRNAs (miRNAs) may serve as diagnostic tools as liquid biopsies, and as biomarkers to better understand the molecular mechanisms involved in the progression of cancer. We identified miR-590-5p as a potential prognostic marker in the progression of non-small cell lung cancer (NSCLC). We were able to detect this miRNA in blood plasma samples of NSCLC patients through quantitative real-time PCR. Our data showed an ~7.5-fold downregulation of miR-590-5p in NSCLC patients compared to healthy controls, which correlated with several clinicopathological features. Further, overexpression of miR-590-5p led to decreased cell viability, proliferation, colony formation, migration, and invasion potential of lung cancer cells, whereas its knockdown showed the opposite effect. In addition, the levels of several proteins involved in the epithelial-to-mesenchymal transition negatively correlated with miR-590-5p levels in lung adenocarcinoma cells and tumors of NSCLC patients. Further, dual-luciferase reporter assays identified STAT3 as a direct target of miR-590-5p, which negatively regulated STAT3 activation and its downstream signaling molecules (eg, Cyclin D1, c-Myc, Vimentin, and ?-catenin) involved in tumorigenesis. Taken together, our study suggests that miR-590-5p functions as a tumor suppressor in NSCLC through regulating the STAT3 pathway, and may serve as a useful biomarker for the diagnosis/prognosis of NSCLC, and as a potential therapeutic target for the treatment of NSCLC. � 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.Item MicroRNA Targeting Nicotinamide Adenine Dinucleotide Phosphate Oxidases in Cancer(Mary Ann Liebert Inc., 2020) Kushwaha P.P.; Gupta S.; Singh A.K.; Prajapati K.S.; Shuaib M.; Kumar S.Significance: Reactive oxygen species (ROS) production occurs primarily in the mitochondria as a by-product of cellular metabolism. ROS are also produced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidases in response to growth factors and cytokines by normal physiological signaling pathways. NADPH oxidase, a member of NADPH oxidase (NOX) family, utilizes molecular oxygen (O2) to generate ROS such as hydrogen peroxide and superoxide. Imbalance between ROS production and its elimination is known to be the major cause of various human diseases. NOX family proteins are exclusively involved in ROS production, which makes them attractive target(s) for the treatment of ROS-mediated diseases including cancer. Recent Advances: Molecules such as Keap1/nuclear factor erythroid 2-related factor 2 (Nrf2), N-methyl-d-aspartic acid (NMDA) receptors, nuclear factor-kappaB, KRAS, kallistatin, gene associated with retinoic-interferon-induced mortality-19, and deregulated metabolic pathways are involved in ROS production in association with NADPH oxidase. Critical Issues: Therapeutic strategies targeting NADPH oxidases in ROS-driven cancers are not very effective due to its complex regulatory circuit. Tumor suppressor microRNAs (miRNAs) viz. miR-34a, miR-137, miR-99a, and miR-21a-3p targeting NADPH oxidases are predominantly downregulated in ROS-driven cancers. miRNAs also regulate other cellular machineries such as Keap1/Nrf2 pathway and NMDA receptors involved in ROS production and consequently drug resistance. Here, we discuss the structure, function, and metabolic role of NADPH oxidase, NOX family protein-protein interaction, their association with other pathways, and NADPH oxidase alteration by miRNAs. Moreover, we also discuss and summarize studies on NADPH oxidase associated with various malignancies and their therapeutic implications. Future Directions: Targeting NADPH oxidases through miRNAs appears to be a promising strategy for the treatment of ROS-driven cancer.Item Brown gold of marginal soil: Plant growth promoting bacteria to overcome plant abiotic stress for agriculture, biofuels and carbon sequestration(Elsevier B.V., 2020) Ramakrishna W.; Rathore P.; Kumari R.; Yadav R.Marginal land is defined as land with poor soil characteristics and low crop productivity with no potential for profit. Poor soil quality due to the presence of xenobiotics or climate change is of great concern. Sustainable food production with increasing population is a challenge which becomes more difficult due to poor soil quality. Marginal soil can be made productive with the use of Plant Growth Promoting Bacteria (PGPB). This review outlines how PGPB can be used to improve marginal soil quality and its implications on agriculture, rhizoremediation, abiotic stress (drought, salinity and heavy metals) tolerance, carbon sequestration and production of biofuels. The feasibility of the idea is supported by several studies which showed maximal increase in the growth of plants inoculated with PGPB than to uninoculated plants grown in marginal soil when compared to the growth of plants inoculated with PGPB in healthy soil. The combination of PGPB and plants grown in marginal soil will serve as a green technology leading to the next green revolution, reduction in soil pollution and fossil fuel use, neutralizing abiotic stress and climate change effects.Item Exosomes from nischarin-expressing cells reduce breast cancer cell motility and tumor growth(American Association for Cancer Research Inc., 2019) Maziveyi M.; Dong S.; Baranwal S.; Mehrnezhad A.; Rathinam R.; Huckaba T.M.; Mercante D.E.; Park K.; Alahari S.K.Exosomes are small extracellular microvesicles that are secreted by cells when intracellular multivesicular bodies fuse with the plasma membrane. We have previously demonstrated that Nischarin inhibits focal adhesion formation, cell migration, and invasion, leading to reduced activation of focal adhesion kinase. In this study, we propose that the tumor suppressor Nischarin regulates the release of exosomes. When cocultured on exosomes from Nischarin-positive cells, breast cancer cells exhibited reduced survival, migration, adhesion, and spreading. The same cocultures formed xenograft tumors of significantly reduced volumefollowing injectionintomice. Exosomes secreted by Nischarin-expressing tumors inhibited tumor growth. Expression of only one allele of Nischarin increased secretion of exosomes, and Rab14 activity modulated exosome secretions and cell growth. Taken together, this study reveals a novel role for Nischarin in preventing cancer cell motility, which contributes to our understanding of exosome biology. Significance: Regulation of Nischarin-mediated exosome secretion by Rab14 seems to play an important role in controlling tumor growth and migration.Item Anti-inflammatory Effects of Northern Highbush Blueberry Extract on an In Vitro Inflammatory Bowel Disease Model(Routledge, 2019) Driscoll K.; Deshpande A.; Datta R.; Ramakrishna W.Blueberry anthocyanins have the ability to efficiently reach the GI tract and exhibit a broad range of biochemical effects. In the context of inflammatory bowel disease (IBD), they remain a promising complement to current IBD treatments. Here, we investigated the anti-inflammatory and antioxidant capabilities of Highbush blueberries in-vitro on two normal colon epithelial cell lines, NCM 356 and CCD 841 CoN using fluorescent microscopy and flow cytometry following stimulation with a pro-inflammatory cytokine cocktail. Treatment with blueberry extract revealed a significant decrease in nuclear and cytoplasmic generated reactive oxygen species (ROS) compared to controls. Additionally, the blueberry extract increased cell viability following treatment with the pro-inflammatory cytokine cocktail. A comparison with previous report on rice callus suspension culture (RCSC) revealed opposing trend with reference to the levels of nuclear and cytoplasmic ROS. It is likely that blueberry extract and RCSC employ different players and pathways to mitigate inflammation.Item Association of elevated levels of C-reactive protein with breast cancer, breast cancer subtypes, and poor outcome(Mosby Inc., 2019) Kaur R.P.; Rubal; Banipal R.P.S.; Vashistha R.; Dhiman M.; Munshi A.Background and Purpose: Inflammation and caner are linked in a bidirectional manner. C-reactive protein (CRP) is an important inflammatory marker. The aim of the study was to test whether the inflammatory marker, CRP at the time of diagnosis of breast cancer is associated with metastasis, recurrence, and death in breast cancer patients from Malwa region of Punjab where breast cancer is widely feared. Material and Methods: Two hundred and forty-two breast cancer patients and 242 age and sex matched controls were included in the study. CRP levels were estimated using fully automated bio analyzer Erba200. Follow up interviews were conducted at an interval of 3, 6, 9, 12, 15, 18, 21, 24, and 27 months to determine the outcome among breast cancer patients. Results: Elevated levels of CRP were found among the diseased in comparison with controls (P < 0.0001). Higher CRP levels associated significantly with poor outcome including metastasis and recurrence among breast cancer patients [P = 0.03; 95% confidence interval; odds ratio: 2.954 (0.9125-9.561)]. Conclusion: Elevated levels of CRP associated significantly with increased risk of breast cancer and poor outcome. CRP estimation may be a simple and inexpensive tool for the risk assessment and outcome of the disease in Malwa region of Punjab where incidence of breast cancer is reported to be very high.