School Of Basic And Applied Sciences
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Item Onco-Pathogen Mediated Cancer Progression and Associated Signaling Pathways in Cancer Development(MDPI, 2023-05-28T00:00:00) Kannampuzha, Sandra; Gopalakrishnan, Abilash Valsala; Padinharayil, Hafiza; Alappat, Reema Rose; Anilkumar, Kavya V.; George, Alex; Dey, Abhijit; Vellingiri, Balachandar; Madhyastha, Harishkumar; Ganesan, Raja; Ramesh, Thiyagarajan; Jayaraj, Rama; Prabakaran, D.S.Infection with viruses, bacteria, and parasites are thought to be the underlying cause of about 8�17% of the world�s cancer burden, i.e., approximately one in every five malignancies globally is caused by an infectious pathogen. Oncogenesis is thought to be aided by eleven major pathogens. It is crucial to identify microorganisms that potentially act as human carcinogens and to understand how exposure to such pathogens occur as well as the following carcinogenic pathways they induce. Gaining knowledge in this field will give important suggestions for effective pathogen-driven cancer care, control, and, ultimately, prevention. This review will mainly focus on the major onco-pathogens and the types of cancer caused by them. It will also discuss the major pathways which, when altered, lead to the progression of these cancers. � 2023 by the authors.Item Impact of noncoding RNAs on cancer directed immune therapies: Now then and forever(John Wiley and Sons Inc, 2022-04-30T00:00:00) Roy, Roshan Kumar; Yadav, Rakhi; Sharma, Uttam; Wasson, Mishi Kaushal; Sharma, Ashok; Tanwar, Pranay; Jain, Aklank; Prakash, HridayeshAccumulating evidence demonstrates that the host genome's epigenetic modifications are essential for living organisms to adapt to extreme conditions. DNA methylation, covalent modifications of histone and interassociation of noncoding RNAs facilitate the cellular manifestation of epigenetic changes in the genome. Out of various factors involved in the epigenetic programming of the host, noncoding RNAs (ncRNAs) such as microRNA (miRNA), long noncoding RNA (lncRNA), circular RNA, snoRNA and piRNA are new generation noncoding molecules that influence a variety of cellular processes like immunity, cellular differentiation and tumor development. During tumor development, temporal changes in miRNA/lncRNA rheostat influence sterile inflammatory responses accompanied by the changes in the carcinogenic signaling in the host. At the cellular level, this is manifested by the upregulation of inflammasome and inflammatory pathways, which promotes cancer-related inflammation. Given this, we discuss the potential of lncRNAs, miRNAs, circular RNA, snoRNA and piRNA in regulating inflammation and tumor development in the host. � 2022 UICC.Item Circulating miR-320a Acts as a Tumor Suppressor and Prognostic Factor in Non-small Cell Lung Cancer(Frontiers Media S.A., 2021-03-23T00:00:00) Khandelwal, Akanksha; Sharma, Uttam; Barwal, Tushar Singh; Seam, Rajeev Kumar; Gupta, Manish; Rana, Manjit Kaur; Vasquez, Karen M.; Jain, AklankDysregulated expression profiles of microRNAs (miRNAs) have been observed in several types of cancer, including non-small cell lung cancer (NSCLC); however, the diagnostic and prognostic potential of circulating miRNAs in NSCLC remains largely undefined. Here we found that circulating miR-320a was significantly down-regulated (~5.87-fold; p < 0.0001) in NSCLC patients (n = 80) compared to matched control plasma samples from healthy subjects (n = 80). Kaplan-Meier survival analysis revealed that NSCLC patients with lower levels of circulating miR-320a had overall poorer prognosis and survival rates compared to patients with higher levels (p < 0.0001). Moreover, the diagnostic and prognostic potential of miR-320a correlated with clinicopathological characteristics such as tumor size, tumor node metastasis (TNM) stage, and lymph node metastasis. Functionally, depletion of miR-320a in human A549 lung adenocarcinoma cells induced their metastatic potential and reduced apoptosis, which was reversed by exogenous re-expression of miR-320a mimics, indicating that miR-320a has a tumor-suppressive role in NSCLC. These results were further supported by high levels of epithelial-mesenchymal transition (EMT) marker proteins (e.g., Beta-catenin, MMP9, and E-cadherin) in lung cancer cells and tissues via immunoblot and immunohistochemistry experiments. Moreover, through bioinformatics and dual-luciferase reporter assays, we demonstrated that AKT3 was a direct target of miR-320a. In addition, AKT3-associated PI3K/AKT/mTOR protein-signaling pathways were elevated with down-regulated miR-320a levels in NSCLC. These composite data indicate that circulating miR-320a may function as a tumor-suppressor miRNA with potential as a prognostic marker for NSCLC patients. � Copyright � 2021 Khandelwal, Sharma, Barwal, Seam, Gupta, Rana, Vasquez and Jain.Item Recent Advancements in the Discovery of MDM2/MDM2-p53 Interaction Inhibitors for the Treatment of Cancer(Bentham Science Publishers, 2022-11-16T00:00:00) Bhatia, Neha; Khator, Rakesh; Kulkarni, Swanand; Singh, Yogesh; Kumar, Pradeep; Thareja, SureshDiscovery of MDM2 and MDM2-p53 interaction inhibitors changed the direction of anticancer research as it is involved in about 50% of cancer cases globally. Not on-ly the inhibition of MDM2 but also its interaction with p53 proved to be an effective strategy in anticancer drug design and development. Various molecules of natural as well as synthetic origin have been reported to possess excellent MDM2 inhibitory potential. The present review discusses the pathophysiology of the MDM2-p53 interaction loop and MDM2/MDM2-p53 interaction inhibitors from literature covering recent patents. Focus has also been put on characteristic features of the active site of the target and its desired interactions with the currently FDA-approved inhibitor. The designing approach of previ-ously reported MDM2/MDM2-p53 interaction inhibitors, their SAR studies, in silico studies, and the biological efficacy of various inhibitors from natural as well as synthetic origins are also elaborated. An attempt is made to cover recently patented MDM2/MD-M2-p53 interaction inhibitors. � 2023 Bentham Science Publishers.Item An Insight to Heat Shock Protein 90: A Remedy for Multiple Problems(Bentham Science Publishers, 2022-08-30T00:00:00) Yadav, Megha; Singh, Ankit Kumar; Kumar, Adarsh; Thareja, Suresh; Kumar, PradeepHeat shock protein 90 (Hsp90) is a chaperone protein that prevents many other proteins from aggre-gating by folding them in a certain way. Hsp90 consists of three structural domains: N-terminal, middle and C-terminal domains. Hsp90 has many activities in numerous proteins and signaling pathways like chimeric fusion proteins, steroid hormone receptors, tumor suppressor genes, and cell cycle regulatory proteins. The role of Hsp90 is not only in cancer but also in other diseases like COVID-19, leishmaniasis, diabetes, flavi virus, systemic sclerosis, grass carp reovirus, psoriasis, malaria, cardiac fibrosis, and alcohol-related liver diseases. This review is a compilation of the pharmacological profile of Hsp90 inhibitors, problems associated with them, and suggested remedies for the same. � 2022 Bentham Science Publishers.Item Multifarious Effects of Arsenic on Plants and Strategies for Mitigation(MDPI, 2023-02-09T00:00:00) Beniwal, Rahul; Yadav, Radheshyam; Ramakrishna, WusirikaArsenic contamination in soil and water is a major problem worldwide. Inorganic arsenic is widely present as arsenate and arsenite. Arsenic is transferred to crops through the soil and irrigation water. It is reported to reduce crop production in plants and can cause a wide array of diseases in humans, including different types of cancers, premature delivery, stillbirth, and spontaneous abortion. Arsenic methyltransferase (AS3MT) in the human body converts inorganic arsenic into monomethylarsonic acid and dimethylarsinic acid, which are later excreted from the body. Arsenic transfer from the soil to grains of rice involves different transporters such as Lsi1, Lsi2, and Lsi6. These transporters are also required for the transfer of silicate, which makes them important for the plant. Different mitigation strategies have been used to mitigate arsenic from crops, such as plant growth-promoting bacteria, fungi, and nanoparticles, as well as using different plant genotypes and plant extracts. Different factors such as nitric oxide, Fe, and jasmonate also affect the response of a plant to the oxidative stress caused by arsenic. This review highlights the various effects of arsenic on plants with respect to their biochemical, molecular, and physiological aspects and the employment of classical and innovative methods for their mitigation. The current review is expected to initiate further research to improve As remediation to mitigate the effect of heavy metal pollution on the environment. � 2023 by the authors.Item 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, ShashankApoptosis 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.Item 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, ShashankMatrix 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.Item DNA barcode-based identification and comparative anti-cancer effects of different species of brown seaweed Sargassum C. Agardh of Indian coasts(Central University of Punjab, 2018) Bhushan, Satej; Bast, Felix & Singh, SandeepSargassum C. Agardh is a ubiquitous, multicellular brown seaweed that represents the most species-rich genus of the brown algal order Fucales, with more than 500 species reported worldwide. The present study aimed to identify different Sargassum isolates from India by DNA barcoding of mitochondrial (cox3), chloroplast (rbcL), and nuclear (18S) regions and further phylogenetic analyses. Total of 17 geographical isolates were collected across Indian coasts. Phylogeny reconstruction using Bayesian Inference was done which suggested congruency with known taxonomic hierarchy of Sargassum. Total of five different species were identified (S. portierianum, S. cymosum, S.aquifolium, S. ilicifolium, S. polycystum). In addition, comparative evaluation of anti-cancer potential of all the isolates was carried out and putative relationship between phylogeny and anticancer potential was established. MTT assay with 3 different cell lines showed cytotoxicity with IC50 as low as 0.167 ± 0.01, 0.243 ± 0.007, 0.25 ± 0.03 µg/µL in MDA-MB-231 (Breast Cancer), T-47D (Breast Cancer), H1299 (Lung Cancer) cells respectively, while no toxicity was observed with human peripheral blood mononuclear cells (hPBMCs). I was also able to isolate one lead aliphatic compound (SA1) whch was identified to be a polysaccharide using NMR spectroscopy. Similar to the extract, purified compound SA1 also showed anticancer activity. Further evaluations revealed that SA1 as well as the extracts interfere with the antioxidant defence components of cancer cells (SOD, Catalase, and GR) which results in the induction of mitochondrial death pathway at G1 phase (for extracts) as well as at G2M phase (for SA1). Extracts as well as SA1 were also able to inhibit cancer cell migration at sub IC50 doses. In addition, sub IC50 treatments lead to decreased colony formation compared to the control. Overall, our results show that these extracts as well as SA1 are able to target multiple properties of cancerItem 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.