School Of Basic And Applied Sciences

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    Phytochemicals as Potential Therapeutics for SARS-CoV-2�Induced Cardiovascular Complications: Thrombosis and Platelet Perspective
    (Frontiers Media S.A., 2021-04-26T00:00:00) Beura, Samir K.; Panigrahi, Abhishek R.; Yadav, Pooja; Singh, Sunil K.
    After gaining entry through ACE2 aided by TMPRSS2, the SARS-CoV-2 causes serious complications of the cardiovascular system leading to myocarditis and other myocardial injuries apart from causing lung, kidney and brain dysfunctions. Here in this review, we are going to divulge the cellular and immunological mechanisms behind the cardiovascular, thrombotic and platelet impairments that are caused in COVID-19. In addition, we also propose the significance of various anti-platelet and anti-thrombotic phytochemicals in the treatment of COVID-19. The virus induces many immune-modulatory cytokines and chemokines which help in the intravascular coagulation and create a pro-thrombotic environment along with pulmonary embolism and thrombocytopenia. Different types of innate and adaptive immune cells and their granular contents regulate the pathophysiology of SARS-CoV-2 induced endothelial and platelet dysfunctions which correlate the involvement of platelets with myocardial injury and intravascular thrombi directly or indirectly. Hence, by exploiting the natural bioactive compounds from medicinal plants and inhibiting the platelet mediated thrombus formation can be beneficial for the treatment of SARS-CoV-2 infection. � Copyright � 2021 Beura, Panigrahi, Yadav and Singh.
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    A Perspective on Medicinal Chemistry Approaches for Targeting Pyruvate Kinase M2
    (American Chemical Society, 2021-11-02T00:00:00) Arora, Sahil; Joshi, Gaurav; Chaturvedi, Anuhar; Heuser, Michael; Patil, Santoshkumar; Kumar, Raj
    The allosteric regulation of pyruvate kinase M2 (PKM2) affects the switching of the PKM2 protein between the high-activity and low-activity states that allow ATP and lactate production, respectively. PKM2, in its low catalytic state (dimeric form), is chiefly active in metabolically energetic cells, including cancer cells. More recently, PKM2 has emerged as an attractive target due to its role in metabolic dysfunction and other interrelated conditions. PKM2 (dimer) activity can be inhibited by modulating PKM2 dimer�tetramer dynamics using either PKM2 inhibitors that bind at the ATP binding active site of PKM2 (dimer) or PKM2 activators that bind at the allosteric site of PKM2, thus activating PKM2 from the dimer formation to the tetrameric formation. The present perspective focuses on medicinal chemistry approaches to design and discover PKM2 inhibitors and activators and further provides a scope for the future design of compounds targeting PKM2 with better efficacy and selectivity. � 2021 American Chemical Society
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    Flavonoids as emerging notch signaling pathway modulators in cancer
    (Taylor and Francis Ltd., 2023-04-21T00:00:00) Singh, Atul Kumar; Kumar, Shashank
    Notch signaling is an evolutionary conserved pathway important for the developmental processes and implicated in the tumor formation. Notch signaling pathway (NSP) inhibitors have been tested in clinical trials alone or in combination with the chemotherapy but none got clinical approval due to severe toxicity in patients. Flavonoids inhibit NSP by inhibiting notch receptor cleavage and/or inhibiting transcriptional regulation by Notch intracellular domain (NICD). Interestingly, some flavonoids are reported to inhibit NSP by mediating the microRNA expression. NSP inhibitory flavonoid(s) in combination with standard therapy is might be an effective strategy in cancer treatment. � 2023 Informa UK Limited, trading as Taylor & Francis Group.
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    Discovery of Natural Anti-Apoptotic Protein Inhibitor Using Molecular Docking and MM-GBSA Approach: An Anticancer Intervention
    (AMG Transcend Association, 2022-12-27T00:00:00) Dey, Sarbjit; Singh, Atul Kumar; Kumar, Shashank
    Apoptosis is a programmed molecular phenomenon in normal cells, and "evading apoptosis" is a hallmark of cancer. Overexpression of anti-apoptotic BCL-2 promotes cancer cell survival, leading to tumor formation, its maintenance and progression, and further chemoresistance. Therefore, BCL-2 is considered an exciting drug target in clinical studies. The Cip/Kip family protein p21, which acts as an inhibitor of cyclin-CDK complexes, can also exert anti-apoptotic function and thus be involved in cancer initiation and progression. Preliminary research suggests that Piper chaba phytochemical(s) possess anticancer activity, but the underlying mechanism is yet to be established. For the first time, we explored Piper chaba phytochemicals for their anti-apoptotic protein (BCL-2 and p21) inhibition potential using molecular docking and MM-GBSA experiments. UC2288 and Venetoclax were known standards for BCL-2 and p21 proteins, respectively. We also explored the pharmacokinetics and drug-likeness properties of lead molecules using the SwissADME web tool. A total of 45 P. chaba phytochemicals were identified from published literature and docked at the drug-binding site of target proteins. Chabamide F, Piperchabaoside B, Piperundecalidiene, and Chabamide G showed ? binding affinity (-9.0 kcal/mole) than UC2288, while Brachystamide B showed lower binding affinity (-9.7 kcal/mole) than Venetoclax. MM-GBSA results revealed Chabamide F has a higher binding affinity for p21 than the standard compound. Therefore, P. chaba phytoconstituents qualify for further experiments on the drug discovery process to target anti-apoptosis proteins in cancer cells. � 2022 by the authors.
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    Natural Steroidal Lactone Induces G1/S Phase Cell Cycle Arrest and Intrinsic Apoptotic Pathway by Up-Regulating Tumor Suppressive miRNA in Triple-Negative Breast Cancer Cells
    (MDPI, 2022-12-27T00:00:00) Shuaib, Mohd; Prajapati, Kumari Sunita; Gupta, Sanjay; Kumar, Shashank
    Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with minimal treatment options. In the present work, Withaferin A (WA), a natural steroidal lactone found in Withania somnifera (Solanaceae), was studied to deduce the miRNA expression modulation mediated anticancer mode of action in TNBC cells. Small RNA next generation sequencing (NGS) of WA (2 �M) and vehicle (0.1% DMSO)-treated MDA-MB-231 cells revealed a total of 413 differentially expressed miRNAs (DEMs) and demonstrated that WA potentially up-regulates the miR-181c-5p, miR-15a-5p, miR-500b-5p, miR-191-3p, and miR-34a-5p and down-regulates miR-1275, miR-326, miR-1908-5p, and miR-3940-3p among total DEMs. The NGS and qRT-PCR expression analysis revealed a significantly higher expression of miR-181c-5p among the top 10 DEMs. Predicted target genes of the DEMs showed enrichment in cancer-associated gene ontology terms and KEGG signaling pathways. Transient up-expression of mir-181c-5p showed a time-dependent decrease in MDA-MB-231 and MDA-MB-453 cell viability. Co-treatment of miR-181c-5p mimic and WA (at varying concentration) down-regulated cell cycle progression markers (CDK4 and Cyclin D1) at mRNA and protein levels. The treatment induced apoptosis in MDA-MB-231 cells by modulating the expression/activity of Bax, Bcl2, Caspase 3, Caspase 8, Caspase 3/7, and PARP at mRNA and protein levels. Confocal microscopy and Annexin PI assays revealed apoptotic induction in miRNA- and steroidal-lactone-treated MDA-MB-231 cells. Results indicate that the Withaferin A and miRNA mimic co-treatment strategy may be utilized as a newer therapeutic strategy to treat triple-negative breast cancer. � 2022 by the authors.
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    Naringin dihydrochalcone potentially binds to catalytic domain of matrix metalloproteinase-2: molecular docking, MM-GBSA, and molecular dynamics simulation approach
    (Taylor and Francis Ltd., 2022-09-01T00:00:00) Singh, Atul Kumar; Kumar, Shashank
    Matrix metalloproteinase-2 (MMP2), an extracellular matrix remodulating protein�s increased activity causes cancer-metastasis. Potential MMP2 inhibitors showed sever side-effects in clinical trials. Present study is focused on identification natural MMP2 inhibitor by applying molecular docking, MM-GBSA binding energy estimation and molecular dynamics (MD) simulations. Commercially available flavonoid compound library was used to screen the molecules potentially binding with catalytic domain of MMP2 protein compared to standard MMP2 inhibitor ARP100. Naringin dihydrochalcone (NDC) showed interaction with the important residues (His120, Leu82 and Val117) present at the MMP2 catalytic domain in comparison to known inhibitor ARP100 (dock score ? ?13 and ?8 kcal/mole respectively). Lower ligand-protein binding energy (-67.31 kcal/mole) obtained in MM-GBSA and the MD simulation trajectory analysis showed significant stable and energetically favourable binding of NDC at the catalytic site of MMP2. In conclusion, anti-metastatic potential of NDC should be validated in in�vitro and in�vivo experiments. � 2022 Informa UK Limited, trading as Taylor & Francis Group.