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Androgenic alopecia (AGA) is a dermatological disease with psychosocial consequences for those who experience hair loss. AGA is linked to an increase in androgen levels caused by an excess of dihydrotestosterone in blood capillaries produced from testosterone by 5α-reductase type II (5αR2), which is expressed in scalp hair follicles; 5αR2 activity and dihydrotestosterone levels are elevated in balding scalps. The diverse health benefits of flavonoids have been widely reported in epidemiological studies, and research interest continues to increase. In this study, a virtual screening approach was used to identify compounds that interact with active site residues of 5αR2 by screening a library containing 241 flavonoid compounds. Here, we report two potent flavonoid compounds, eriocitrin and silymarin, that interacted strongly with 5αR2, with binding energies of −12.1 and −11.7 kcal/mol, respectively, which were more significant than those of the control, finasteride (−11.2 kcal/mol). Molecular dynamic simulations (200 ns) were used to optimize the interactions between compounds and 5αR2 and revealed that the interaction of eriocitrin and silymarin with 5αR2 was stable. The study shows that eriocitrin and silymarin provide developmental bases for novel 5αR2 inhibitors for the management of AGA. [ABSTRACT FROM AUTHOR]

Myostatin (MSTN), a negative regulator of muscle mass, is reported to be increased in conditions linked with muscle atrophy, sarcopenia, and other muscle-related diseases. Most pharmacologic approaches that treat muscle disorders are ineffective, emphasizing the emergence of MSTN inhibition. In this study, we used computational screening to uncover natural small bioactive inhibitors from the Traditional Chinese Medicine database (~38,000 compounds) for the MSTN protein. Potential ligands were screened, based on binding affinity (150), physicochemical (53) and ADMET properties (17). We found two hits (ZINC85592908 and ZINC85511481) with high binding affinity and specificity, and their binding patterns with MSTN protein. In addition, molecular dynamic simulations were run on each complex to better understand the interaction mechanism of MSTN with the control (curcumin) and the hit compounds (ZINC85592908 and ZINC85511481). We determined that the hits bind to the active pocket site (Helix region) and trigger conformational changes in the MSTN protein. Since the stability of the ZINC85592908 compound was greater than the MSTN control, we believe that ZINC85592908 has therapeutic potential against the MSTN protein and may hinder downstream singling by inhibiting the MSTN protein and increasing myogenesis in the skeletal muscle tissues. [ABSTRACT FROM AUTHOR]

Myostatin (MSTN) is a well-reported negative regulator of muscle growth and a member of the transforming growth factor (TGF) family. MSTN has important functions in skeletal muscle (SM), and its crucial involvement in several disorders has made it an important therapeutic target. Several strategies based on the use of natural compounds to inhibitory peptides are being used to inhibit the activity of MSTN. This review delivers an overview of the current state of knowledge about SM and myogenesis with particular emphasis on the structural characteristics and regulatory functions of MSTN during myogenesis and its involvements in various muscle related disorders. In addition, we review the diverse approaches used to inhibit the activity of MSTN, especially in silico approaches to the screening of natural compounds and the design of novel short peptides derived from proteins that typically interact with MSTN. [ABSTRACT FROM AUTHOR]

Simple Summary: The primary characteristics of cancer cachexia are weakness, weight loss, atrophy, fat reduction, and systemic inflammation. Cachexia is strongly associated with cancers involving the lungs, pancreas, esophagus, stomach, and liver, which account for half of all cancer deaths. TGF-β, MSTN, activin, IGF-1/PI3K/AKT, and JAK-STAT signaling pathways are known to underlie muscle atrophy and cachexia. Anamorelin (appetite stimulation), megestrol acetate, eicosapentaenoic acid, phytocannabinoids, targeting MSTN/activin, and molecules targeting proinflammatory cytokines, such as TNF-α and IL-6, are being tested as treatment options for cancer cachexia. Cancer cachexia is a condition marked by functional, metabolic, and immunological dysfunctions associated with skeletal muscle (SM) atrophy, adipose tissue loss, fat reduction, systemic inflammation, and anorexia. Generally, the condition is caused by a variety of mediators produced by cancer cells and cells in tumor microenvironments. Myostatin and activin signaling, IGF-1/PI3K/AKT signaling, and JAK-STAT signaling are known to play roles in cachexia, and thus, these pathways are considered potential therapeutic targets. This review discusses the current state of knowledge of the molecular mechanisms underlying cachexia and the available therapeutic options and was undertaken to increase understanding of the various factors/pathways/mediators involved and to identify potential treatment options. [ABSTRACT FROM AUTHOR]

Natural products from plant sources, embracing inherently ample structural diversity than synthetic ones are the major sources of anticancer agents and will constantly play as protagonists for discovering new drugs. Polo-like kinases (PLKs) play a leading role in the ordered execution of mitotic events and 4 mammalian PLK family members have been identified. PLK1 is an attractive target for anticancer drugs in mammalian cells, among the four members of PLKs. The present study expresses the molecular interaction of compounds (1,2-Benzenedicarboxylic acid bis (2 ethylhexyl) ester, squalene, 3,5-bis (1,1-dimethylethyl) phenol, Pentamethyl tetrahydro-5H-chromene, (1,4-Cyclohexylphenyl) ethanone and 6-Vinyl-7-methoxy-2,2-dimethylchromene) isolated from methanolic extract of leaves of Ageratum houstonianum with PLK1 enzyme. Docking between PLK1 and each of these compounds (separately) was performed using "Auto dock 4.2." (1,4-Cyclohexylphenyl) ethanone showed the maximum potential as a promising inhibitor of PLK1 enzyme with reference to ΔG (-6.84 kcal/mol) and Ki (9.77 μM) values. This was sequentially followed by Pentamethyl tetrahydro-5H-chromene (ΔG = -6.60 kcal/mol; Ki = 14.58 μM), squalene (ΔG = -6.17 kcal/mol; Ki = 30.12 μM), 6-Vinyl-7-methoxy-2,2-dimethylchromene (ΔG = -5.91 kcal/mol; Ki = 46.68 μM), 3, 5-bis (1,1-dimethylethyl) phenol (ΔG = -5.70 kcal/mol; Ki = 66.68 μM) and 1,2-Benzenedicarboxylic acid bis (2 ethylhexyl) ester (ΔG = -5.58 kcal/mol; Ki = 80.80 μM). These results suggest that (1,4-Cyclohexylphenyl) ethanone might be a potent PLK1 inhibitor. Further, in vitro and in vivo rumination are warranted to validate the anticancer potential of (1,4-Cyclohexylphenyl) ethanone. [ABSTRACT FROM AUTHOR]

The skeletal muscle (SM) is the largest organ in the body and has tremendous regenerative power due to its myogenic stem cell population. Myostatin (MSTN), a protein produced by SM, is released into the bloodstream and is responsible for age-related reduced muscle fiber development. The objective of this study was to identify the natural compounds that inhibit MSTN with therapeutic potential for the management of age-related disorders, specifically muscle atrophy and sarcopenia. Sequential screening of 2000 natural compounds was performed, and dithymoquinone (DTQ) was found to inhibit MSTN with a binding free energy of −7.40 kcal/mol. Furthermore, the docking results showed that DTQ reduced the binding interaction between MSTN and its receptor, activin receptor type-2B (ActR2B). The global energy of MSTN-ActR2B was found to be reduced from −47.75 to −40.45 by DTQ. The stability of the DTQ–MSTN complex was subjected to a molecular dynamics analysis for up to 100 ns to check the stability of the complex using RMSD, RMSF, Rg, SASA, and H-bond number. The complex was found to be stable after 10 ns to the end of the simulation. These results suggest that DTQ blocks MSTN signaling through ActR2B and that it has potential use as a muscle growth-promoting agent during the aging process. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is an increasing global public health problem, and its prevalence is expected to rise in coming decades. Dipeptidyl peptidase-4 (DPP-4) is a therapeutic target for the management of T2DM, and its inhibitors prevent the degradation of glucose-dependent insulinotropic peptide and glucagon-like peptide 1, and thus, maintain their endogenous levels and lower blood glucose levels. Various medicinal plant extracts and isolated bioactive compounds exhibit DPP-4 inhibitory activity. In this review, we discussed different natural sources that have been shown to have anti-diabetic efficacy with a particular emphasis on DPP-4 inhibition. Furthermore, the effect of DPP-4 inhibition on pancreatic beta cell function, skeletal muscle function, and the glucose-lowering mechanisms were also discussed. We believe that scientists looking for novel compounds with therapeutic promise against T2DM will be able to develop antidiabetic drugs using these natural sources. [ABSTRACT FROM AUTHOR]