Department Of Biochemistry And Microbial Sciences

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    A review of chromium (Cr) epigenetic toxicity and health hazards
    (Elsevier B.V., 2023-04-17T00:00:00) Iyer, Mahalaxmi; Anand, Uttpal; Thiruvenkataswamy, Saranya; Babu, Harysh Winster Suresh; Narayanasamy, Arul; Prajapati, Vijay Kumar; Tiwari, Chandan Kumar; Gopalakrishnan, Abilash Valsala; Bontempi, Elza; Sonne, Christian; Barcel�, Dami�; Vellingiri, Balachandar
    Carcinogenic metals affect a variety of cellular processes, causing oxidative stress and cancer. The widespread distribution of these metals caused by industrial, residential, agricultural, medical, and technical activities raises concern for adverse environmental and human health effects. Of these metals, chromium (Cr) and its derivatives, including Cr(VI)-induced, are of a public health concern as they cause DNA epigenetic alterations resulting in heritable changes in gene expression. Here, we review and discuss the role of Cr(VI) in epigenetic changes, including DNA methylation, histone modifications, micro-RNA changes, biomarkers of exposure and toxicity, and highlight prevention and intervention strategies to protect susceptible populations from exposure and adverse occupational health effects. Cr(VI) is a ubiquitous toxin linked to cardiovascular, developmental, neurological, and endocrine diseases as well as immunologic disorders and a high number of cancer types in humans following inhalation and skin contact. Cr alters DNA methylation levels as well as global and gene-specific histone posttranslational modifications, emphasizing the importance of considering epigenetics as a possible mechanism underlying Cr(VI) toxicity and cell-transforming ability. Our review shows that determining the levels of Cr(VI) in occupational workers is a crucial first step in shielding health problems, including cancer and other disorders. More clinical and preventative measures are therefore needed to better understand the toxicity and safeguard employees against cancer. � 2023
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    The Epigenetics of Noncoding RNA
    (Elsevier, 2022-09-16T00:00:00) Chhabra, Ravindresh
    DNA, RNA, and the proteins are the major players in the flow of genetic information. Out of these, RNA is the most versatile biomolecule as it exists in multiple forms and each form carries out specified functions in the cell. RNA can be classified into coding and noncoding RNA (ncRNA). The noncoding RNA is further subdivided into long noncoding RNA (>200 nucleotides) and small noncoding RNA (<200 nucleotides). The coding RNA is the one which gets translated into proteins; whereas, the ncRNA is usually responsible for the regulation of gene expression. The ncRNA has been implicated in a number of pathological conditions including cancer, diabetes, neurological disorders and developmental defects. The interplay between ncRNAs and epigenetics often plays a significant role in the onset and progression of some of the aforementioned diseases. This chapter elaborates on the different ways in which epigenetic phenomenon is regulated by ncRNA and the effect of epigenetic modification on the expression of ncRNA. � 2023 Elsevier Inc. All rights reserved.
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    Withaferin A mediated changes of miRNA expression in breast cancer-derived mammospheres
    (John Wiley and Sons Inc, 2022-06-30T00:00:00) Prajapati, Kumari Sunita; Shuaib, Mohd.; Gupta, Sanjay; Kumar, Shashank
    Breast cancer is a heterogeneous disease consisting of atypical cell populations that share stem cell-like characteristics associated with therapeutic resistance, disease relapse, and poor clinical outcome. MicroRNAs (miRNA),�and small noncoding RNA, are pivotal in the regulation of self-renewal, stemness, and cellular differentiation. Withaferin A (WA), a steroidal lactone, is a major bioactive constituent of Withania somnifera (Solanaceae) known for its anticancer properties. In this study, the effect of WA on modulation of miRNA expression in breast cancer-derived mammosphere was assessed utilizing small RNA sequencing. Treatment with WA inhibited MCF-7 and T47D cells derived mammosphere formation with a significant decrease in CD44, EpCAM, Nanog, OCT4, and SOX2 as markers of self-renewal and stemness. Small RNA sequencing demonstrated a total of 395 differentially expressed miRNAs (DEMs) including 194 upregulated and 201 downregulated miRNAs in WA-treated�MCF-7 mammospheres. Bioinformatics analysis utilizing the�KEGG pathway, Gene Ontology enrichment, protein?protein, and miRNA-mRNA interaction network identified altered expression in a few hub genes viz.�AKT1, PTEN, MYC, CCND1,�VEGFA,�NOTCH1, and�IGFR1�associated with DEMs in WA-treated�mammospheres. Further quantitative�RT-PCR analysis validated the expression of DEMs including miR-549a-5p, miR-1247-5p, miR-124-5p, miR-137-5p, miR-34a-5p, miR-146a-5p, miR-99a-5p, miR-181a-5p, let-7c-5p, and let-7a-5p. In particular, let-7c-5p is designated as a tumor suppressor in breast cancer. An increase in miR-let-7c-5p expression was noted after WA treatment, with a simultaneous decrease in CCND1 and c-MYC at mRNA and protein levels. Taken together, our study demonstrated WA-mediated miRNA expression, in particular, upregulation of miR-let-7c-5p, leads to the inhibition of breast cancer cells derived mammospheres. � 2022 Wiley Periodicals LLC.
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    Identification of cancer stemness related miRNA(s) using integrated bioinformatics analysis and in vitro validation
    (Springer Science and Business Media Deutschland GmbH, 2021-09-23T00:00:00) Prajapati, Kumari Sunita; Shuaib, Mohd; Kushwaha, Prem Prakash; Singh, Atul Kumar; Kumar, Shsahank
    The stemness property of cells allows them to sustain their lineage, differentiation, proliferation, and regeneration. MicroRNAs are small non-coding RNAs known to regulate the stemness property of cells by regulating the expression of stem cell signaling pathway proteins at mRNA level. Dysregulated miRNA expression and associated stem cell signaling pathways in normal stem cells give rise to cancer stem cells. Thus, the present study was aimed to identify the miRNAs involved in the regulation of major stem cell signaling pathways. The proteins (n = 36) involved in the signaling pathways viz., Notch, Wnt, JAK-STAT, and Hedgehog which is associated with the stemness property was taken into the consideration. The miRNAs, having binding sites for the targeted protein-encoding gene were predicted using an online tool (TargetScan) and the common miRNA among the test pathways were identified using Venn diagram analysis. A total of 22 common miRNAs (including 8 non-studied miRNAs) were identified which were subjected to target predictions, KEGG pathway, and gene ontology (GO) analysis to study their potential involvement in the stemness process. Further, we studied the clinical relevance of the non-studied miRNAs by performing the survival analysis and their expression levels in clinical breast cancer patients using the TCGA database. The identified miRNAs showed overall poor survival in breast cancer patients. The miR-6844 showed significantly high expression in various clinical subgroups of invasive breast cancer patients compared with the normal samples. The expression levels of identified miRNA(s) were validated in breast normal, luminal A, triple-negative, and stem cells in vitro models using qRT-PCR analysis. Further treatment with the phytochemical showed excellent down regulation of the lead miRNA. Overall the study first time reports the association of four miRNAs (miR-6791, miR-4419a, miR-4251 and miR-6844) with breast cancer stemness. � 2021, King Abdulaziz City for Science and Technology.
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    Obesity and Cancer
    (Springer Singapore, 2021-07-18T00:00:00) Kumar, Shashank; Gupta, Sanjay
    This book highlights the concordance between signaling pathways that are involved in obesity and cancer cross-talks. It describes the role of cytokines, chemokines, growth factors, insulin, and adipokines in the development of obesity-associated cancers. The book reviews the role of inflammatory signaling pathways such as estrogen-mediated signaling, mTOR and AMP-activated protein kinase pathway and the involvement of adaptive and innate immunity, oxidative stress, gene polymorphism, dietary phytochemicals, and miRNAs in obesity and cancer. In addition, it covers the latest research on the drugs and natural therapeutic agents that target obesity-induced cancers and discusses various in vivo models for studying obesity and obesity-associated cancer. Lastly, it analyses the role of genetic polymorphisms in the obesity-related genes that influence cancer development. The book is a useful resource for researchers in the field of cancer, pharmacology, food chemistry, and clinical biochemistry. � The Editor(s) (if applicable) and The Author(s), under exclusive license to Taylor and Francis Pte Ltd. 2021.
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    The journey of noncoding RNA from bench to clinic
    (Elsevier, 2021-01-30T00:00:00) Chhabra, Ravindresh
    The discovery of noncoding RNA (ncRNA) in the 90s completely changed our understanding of gene regulation. The ncRNAs specialize in regulating the gene expression, which enables them to induce a remarkable change in cellular pathways. The ncRNAs are categorized as small (<200 nucleotides) and long ncRNA (>200 nucleotides). The small ncRNAs are further classified as miRNAs, piwi-interacting RNAs (piRNAs), small interfering RNAs (siRNAs), and small nucleolar RNAs (snoRNAs). Both miRNAs and siRNAs silence gene expression by binding to their target mRNA but follow different mechanisms. piRNAs are responsible for bringing about transposon repression, and snoRNAs are mainly involved in the modification of rRNAs. The lncRNAs have diverse functions that range from chromatin modification to acting as a precursor of miRNAs to binding to mRNAs and blocking their translation. With such important functions in their repertoire, tightly regulated tissue-specific expression and differential expression in diseased conditions, the potential of ncRNAs as therapeutic targets and biomarkers is waiting to be exploited. As per the ClinicalTrials database of NLM, the number of clinical trial studies recorded for miRNAs, siRNAs, and lncRNAs are 861, 67, and 39, respectively. The siRNA therapeutic, Patisiran, became the first ncRNA to receive FDA approval for the treatment of a rare polyneuropathy in 2018. Miravirsen, an inhibitor of miR-122 is the first miRNA therapeutic drug, which is currently in multiple phase 2 clinical trials for the treatment of Hepatitis C. The lncRNA PCA3 was approved as a biomarker for prostate cancer in 2012. This chapter discusses the journey of ncRNA from bench to clinic with a few specific examples elaborating on the basic research involved in identifying them as biomarkers or therapeutic targets and bottlenecks in their clinical use. � 2021 Elsevier Inc. All rights reserved.
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    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.