Molecular Mechanisms in the Etiology of Polycystic Ovary Syndrome (PCOS): A Multifaceted Hypothesis Towards the Disease with Potential Therapeutics.

Among the premenopausal women, Polycystic Ovary Syndrome (PCOS) is the most prevalent endocrinopathy affecting the reproductive system and metabolic rhythms leading to disrupted menstrual cycle. Being heterogeneous in nature it is characterized by complex symptomology of oligomennorhoea, excess of androgens triggering masculine phenotypic appearance and/or multiple follicular ovaries. The etiology of this complex disorder remains somewhat doubtful and the researchers hypothesize multisystem links in the pathogenesis of this disease. In this review, we attempt to present several hypotheses that tend to contribute to the etiology of PCOS. Metabolic inflexibility, aberrant pattern of gonadotropin signaling along with the evolutionary, genetic and environmental factors have been discussed. Considered a lifelong endocrinological implication, no universal treatment is available for PCOS so far however; multiple drug therapy is often advised along with simple life style intervention is mainly advised to manage its cardinal symptoms. Here we aimed to present a summarized view of pathophysiological links of PCOS with potential therapeutic strategies.

VDR downregulation and promoter hypermethylation as one of the causes for triggering type 2 diabetes mellitus: Clinical and molecular studies.

Background: Our present study was to investigate the methylation and Gene expression of the vitamin D receptor (VDR) gene in the causing T2DM and to determine the inflammatory biomarkers in exaggerating T2DM in Kashmiri population. Methods: In this study, T2DM cases (n = 100) and controls (n = 100) of Kashmiri population were designed. Blood samples were taken from both groups, and serum vitamin D levels, inflammatory biomarkers (TNF-α, IL-6, IL-10, CRP, Leptin and adiponectin) were estimated by ELISA. By using methylation-specific PCR (MS-PCR) and RT-PCR, respectively, the levels of methylation and expression were measured after the extraction of DNA and RNA. Results: Studies using RT-PCR demonstrated that patients with diabetes had a lower degree of VDR expression than control subjects (P > 0.05). The T2DM was shown to be strongly correlated with hypermethylation (p-value < 0.001, OR 2.9; 95%CI 1.6-5.54). When compared to control groups, T2DM patients' levels of vitamin D in their serum were considerably lower (p < 0.01). Pro-inflammatory mediators like TNF-α, CRP, IL-6, and leptin levels were discovered to be higher, and concentrations of anti-inflammatory mediators like IL-10 and adiponectin were observed to be lower in people with T2DM than in people without the condition (p < 0.05). Conclusions: This study suggests the hypermethylation and down expression of VDR as one of the basis for causing T2DM in kashmiri individuals, exaggerated by enhanced degree of TNF-α, CRP, IL-6 and leptin and diminished concentration of IL-10 and adiponectin in T2DM. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-023-01266-6.

Metabolic and Genetic Association of Vitamin D with Calcium Signaling and Insulin Resistance.

Various evidences have unveiled the significance of Vitamin D in diverse processes which include its action in prevention of immune dysfunction, cancer and cardiometabolic disorders. Studies have confirmed the function of VD in controlling the expression of approximately nine hundred genes including gene expression of insulin. VD insufficiency may be linked with the pathogenesis of diseases that are associated with insulin resistance (IR) including diabetes as well as obesity. Thus, VD lowers IR-related disorders such as inflammation and oxidative stress. This review provides an insight regarding the molecular mechanism manifesting, how insufficiency of VD may be connected with the IR and diabetes. It also discusses the effect of VD in maintaining the Ca2+ levels in beta cells of the pancreas and in the tissues that are responsive to insulin.

Metabolomic and biotechnological approaches to determine therapeutic potential of Withania somnifera (L.) Dunal: A review.

BACKGROUND: Withania somnifera, a high value medicinal plant is a major source of pharmaceutically important active compounds withanolides. Withania somnifera has been used in ayurveda as health restorative and anabolic agent besides having anti-arthritic, antidepressant, anti-microbial, anti-inflammatory, anti-diabetic, anti-stress, neuroprotective and cardio-protective activities. HYPOTHESIS/PURPOSE: The mining of the compound(s) of interest offers opportunity to identify desired attributes in the therapeutic area of interest. Metabolomic has become an important tool in the field of pharmacological and functional genomics of medicinal plants. The analysis supports the information regarding differential outline of the gene expression for increasing important withanolides viz. withanolide A and withaferin A in W. somnifera. STUDY DESIGN: The bioinformatics and biotechnological approaches viz. tissue culture, genetic transformation, genomic, transcriptomic, proteomic, gene mining and metabolomic studies have opened new windows about engineering of withanolide production. METHODS: Target and network analysis for maximum therapeutic potential of Withania somnifera have been determined by employing Genemania software for finding interactions among various human genes that are being affected by active constituents. RESULTS: Some of the major bioactive compounds of Withania somnifera have been discussed on protein-protein, protein-DNA and genetic interactions with respect to gene and protein expression data, protein domains, metabolic profiling, root organ culture, genetic transformation and phenotypic screening profiles CONCLUSION: The implementation of latest bioinformatic tools in combination with biotechnological techniques for breeding platforms are important in conservation of medicinal plant species in danger. The current review is based on molecular and in vitro methodologies employed in W. somnifera for accepting their importance in the improvement of this valuable medicinal species.

Overexpression of Striated Muscle Activator of Rho Signaling (STARS) Increases C2C12 Skeletal Muscle Cell Differentiation.

BACKGROUND: Skeletal muscle growth and regeneration depend on the activation of satellite cells, which leads to myocyte proliferation, differentiation and fusion with existing muscle fibers. Skeletal muscle cell proliferation and differentiation are tightly coordinated by a continuum of molecular signaling pathways. The striated muscle activator of Rho signaling (STARS) is an actin binding protein that regulates the transcription of genes involved in muscle cell growth, structure and function via the stimulation of actin polymerization and activation of serum-response factor (SRF) signaling. STARS mediates cell proliferation in smooth and cardiac muscle models; however, whether STARS overexpression enhances cell proliferation and differentiation has not been investigated in skeletal muscle cells. RESULTS: We demonstrate for the first time that STARS overexpression enhances differentiation but not proliferation in C2C12 mouse skeletal muscle cells. Increased differentiation was associated with an increase in the gene levels of the myogenic differentiation markers Ckm, Ckmt2 and Myh4, the differentiation factor Igf2 and the myogenic regulatory factors (MRFs) Myf5 and Myf6. Exposing C2C12 cells to CCG-1423, a pharmacological inhibitor of SRF preventing the nuclear translocation of its co-factor MRTF-A, had no effect on myotube differentiation rate, suggesting that STARS regulates differentiation via a MRTF-A independent mechanism. CONCLUSION: These findings position STARS as an important regulator of skeletal muscle growth and regeneration.