Epigenetic dysregulation in cancers by isocitrate dehydrogenase 2 (IDH2).

Recent advances in genome-wide studies have revealed numerous epigenetic regulations brought about by genes involved in cellular metabolism. Isocitrate dehydrogenase (IDH), an essential enzyme, that converts isocitrate into -ketoglutarate (KG) predominantly in the tricarboxylic acid (TCA) cycle, has gained particular importance due to its cardinal role in the metabolic pathway in cells. IDH1, IDH2, and IDH3 are the three isomeric IDH enzymes that have been shown to regulate cellular metabolism. Of particular importance, IDH2 genes are associated with several cancers, including gliomas, oligodendroglioma, and astrocytomas. These mutations lead to the production of oncometabolite D-2-hydroxyglutarate (D-2-HG), which accumulates in cells promoting tumor growth. The enhanced levels of D-2-HG competitively inhibit α-KG dependent enzymes, inhibiting cell TCA cycle, upregulating the cell growth and survival relevant HIF-1α pathway, promoting DNA hypermethylation related epigenetic activity, all of which synergistically contribute to carcinogenesis. The present review discusses epigenetic mechanisms inIDH2 regulation in cells and further its clinical implications.

Potential inhibitors of VEGFR1, VEGFR2, and VEGFR3 developed through Deep Learning for the treatment of Cervical Cancer.

Cervical cancer stands as a prevalent gynaecologic malignancy affecting women globally, often linked to persistent human papillomavirus infection. Biomarkers associated with cervical cancer, including VEGF-A, VEGF-B, VEGF-C, VEGF-D, and VEGF-E, show upregulation and are linked to angiogenesis and lymphangiogenesis. This research aims to employ in-silico methods to target tyrosine kinase receptor proteins-VEGFR-1, VEGFR-2, and VEGFR-3, and identify novel inhibitors for Vascular Endothelial Growth Factors receptors (VEGFRs). A comprehensive literary study was conducted which identified 26 established inhibitors for VEGFR-1, VEGFR-2, and VEGFR-3 receptor proteins. Compounds with high-affinity scores, including PubChem ID-25102847, 369976, and 208908 were chosen from pre-existing compounds for creating Deep Learning-based models. RD-Kit, a Deep learning algorithm, was used to generate 43 million compounds for VEGFR-1, VEGFR-2, and VEGFR-3 targets. Molecular docking studies were conducted on the top 10 molecules for each target to validate the receptor-ligand binding affinity. The results of Molecular Docking indicated that PubChem IDs-71465,645 and 11152946 exhibited strong affinity, designating them as the most efficient molecules. To further investigate their potential, a Molecular Dynamics Simulation was performed to assess conformational stability, and a pharmacophore analysis was also conducted for indoctrinating interactions.

The role of kisspeptin in the pathogenesis of a polycystic ovary syndrome.

Hypothalamic-pituitary gonadal (HPG) axis is responsible for the development and regulation of the female reproductive system. In polycystic ovary syndrome (PCOS), there is a disturbance in the HPG axis. Kisspeptin, a neuropeptide produced by the KISS1 gene, plays a vital role in the regulation of HPG axis by binding with its receptors KISS1R/GPR54, and stimulates gonadotropin secretion from the hypothalamus into pituitary to release luteinizing hormone (LH) and follicle stimulating hormone (FSH). Polymorphisms or mutations in the KISS1 gene can cause disturbance in the kisspeptin signaling pathway and is thought to disrupt HPG axis. Altered signaling of kisspeptin can cause abnormal secretion of GnRH pulse, which leads to increased LH/FSH ratio, thereby affecting androgen levels and ovulation. The increased levels of androgen worsen the symptoms of PCOS. In the present article, we review the molecular physiology and pathology of kisspeptin and how it is responsible for the development of PCOS. The goal of this review article is to provide an overview and metabolic profile of kisspeptin in PCOS patients and the expression of kisspeptin in PCOS animal models. In the present article, we also review the molecular physiology and pathology of kisspeptin and how it is responsible for the development of PCOS.

Unveiling the ESR1 Conformational Stability and Screening Potent Inhibitors for Breast Cancer Treatment

BACKGROUND: The current study recognizes the significance of estrogen receptor alpha (ERα) as a member of the nuclear receptor protein family, which holds a central role in the pathophysiology of breast cancer. ERα serves as a valuable prognostic marker, with its established relevance in predicting disease outcomes and treatment responses. METHOD: In this study, computational methods are utilized to search for suitable drug-like compounds that demonstrate analogous ligand binding kinetics to ERα. RESULTS: Docking-based simulation screened out the top 5 compounds - ZINC13377936, NCI35753, ZINC35465238, ZINC14726791, and NCI663569 against the targeted protein. Further, their dynamics studies reveal that the compounds ZINC13377936 and NCI35753 exhibit the highest binding stability and affinity. CONCLUSION: Anticipating the competitive inhibition of ERα protein expression in breast cancer, we envision that both ZINC13377936 and NCI35753 compounds hold substantial promise as potential therapeutic agents. These candidates warrant thorough consideration for rigorous In vitro and In vivo evaluations within the context of clinical trials. The findings from this current investigation carry significant implications for the advancement of future diagnostic and therapeutic approaches for breast cancer.