Chronic disease management via modulation of cellular signaling by phytoestrogen Bavachin.

The emergence of chronic diseases, particularly cancers, cardiovascular, and bone disorders, presents a formidable challenge, as currently available synthetic drugs often result in significant side effects and incur higher costs. Phytoestrogen Bavachin, present in the Psoralea corylifolia L. plant, represents structural and functional similarity to mammalian estrogen and has recently attracted researchers for its medicinal properties. This review spotlighted the extraction methods, bioavailability and therapeutic interventions of Bavachin against diseases. Bavachin exerted estrogenic properties, demonstrating the ability to bind to estrogen receptors (ERs), mimicking the actions of human estrogen and initiating estrogen-responsive pathways. Bavachin delivered potent therapeutic ventures in abrogating chronic diseases, including cancer, neuronal, bone, cardiovascular, skin, lung, and liver disorders via targeting signaling transductions, managing calcium signaling, immune regulation, inflammation, apoptosis, and oxidative stress. In-silico analysis, including Gene ontology and pathway enrichment analysis, retrieved molecular targets of Bavachin, majorly cytochrome c oxidase (COX), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3), and ER, hypothesizing Bavachin's cellular mechanism in preventing crucial health ailments. Limitations of Bavachin were also summarized, evidenced by hepatotoxicity at specific dosage levels. In conclusion, Bavachin showed promising therapeutic efficacy in suppressing chronic diseases and can be considered as an adequate replacement for hormone replacement therapy, necessitating further investigations on its effectiveness, safety, and clinical outcomes.

Targeting TNF-α-induced expression of TTR and RAGE in rheumatoid arthritis: Apigenin's mediated therapeutic approach.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease induced by TNF-α, which increases fibroblast-like synoviocytes inflammation, resulting in cartilage destruction. The current work sought to comprehend the pathophysiological importance of TNF-α stimulation on differential protein expression and their regulation by apigenin using in-vitro and in-vivo models of RA. METHODS: The human RA synovial fibroblast cells were stimulated with or without TNF-α (10 ng/ml) and treated with 40 µM apigenin. In-silico, in-vitro and in-vivo studies were performed to confirm the pathophysiological significance of apigenin on pro-inflammatory cytokines and on differential expression of TTR and RAGE proteins. RESULTS: TNF-α induced inflammatory response in synoviocytes revealed higher levels of IL-6, IL-1ß, and TNF-α cytokines and upregulated differential expression of TTR and RAGE. In-silico results demonstrated that apigenin has a binding affinity towards TNF-α, indicating its potential effect in the inflammatory process. Both in-vitro and in-vivo results obtained by Western Blot analysis suggested that apigenin reduced the level of p65 (p = 0.005), TTR (p = 0.002), and RAGE (p = 0.020). CONCLUSION: The findings of this study suggested that TNF-α promotes the differential expression of pro-inflammatory cytokines, TTR, and RAGE via NF-kB pathways activation. Anti-inflammatory effect of apigenin impedes TNF-α mediated dysregulation or expression associated with RA pathogenesis.

Mitochondrial functioning in Rheumatoid arthritis modulated by estrogen: Evidence-based insight into the sex-based influence on mitochondria and disease.

Alteration of immune response and synovium microvasculature in Rheumatoid arthritis (RA) progression has been suggested to be associated with mitochondrial functioning. Mitochondria, with maternally inherited DNA, exhibit differential response to the female hormone estrogen. Various epidemiological evidence has also shown the prominence of RA in the female population, depicting the role of estrogen in modulating the pathogenesis of RA. As estrogen regulates the expression of differential proteins and associated signaling pathways of RA, its influence on mitochondrial functioning seems evident. Thus, in this review, the studies related to mitochondria and their relation with estrogen and Rheumatoid arthritis were retrieved. We analyzed the different mitochondrial activities that are altered in RA and the possibility of their estrogenic control. The study expands to in silico analysis, revealing the differential mitochondrial proteins expressed in RA and examining these proteins as potential estrogenic targets. It was found that ALDH2, CASP3, and SOD2 are the major mitochondrial proteins involved in RA progression and are also potent estradiol targets. The analysis establishes the role of mitochondrial proteins in RA progression, which were found to be direct or indirect targets of estrogen, depicting its potential for regulating mitochondrial functions in RA.

Anti-inflammatory potential of selective small compounds by targeting TNF-α & NF-kB signaling: a comprehensive molecular docking and simulation study.

Tumor necrosis factor alpha (TNF-α) is the major cause of inflammation in autoimmune diseases like rheumatoid arthritis (RA). It's mechanisms of signal transduction through nuclear factor kappa B (NF-kB) pathway via small molecules such as metabolite crosstalk are still elusive. In this study, we have targeted TNF-α and NF-kB through metabolites of RA, to inhibit TNF-α activity and deter NF-kB signaling pathways, thereby mitigating the disease severity of RA. TNF-α and NF-kB structure was obtained from PDB database and metabolites of RA were selected from literature survey. In-silico studies were carried out by molecular docking using AutoDock Vina software and further, known TNF-α and NF-kB inhibitors were compared and revealed metabolite's capacity to targets the respective proteins. Most suitable metabolite was then validated by MD simulation to verify its efficiency against TNF-α. Total 56 known differential metabolites of RA were docked with TNF-α and NF-kB compared to their corresponding inhibitor compounds. Four metabolites such as Chenodeoxycholic acid, 2-Hydroxyestrone, 2-Hydroxyestradiol (2-OHE2), and 16-Hydroxyestradiol were identified as a common TNF-α inhibitor's having binding energies ranging from -8.3 to -8.6 kcal/mol, followed by docking with NF-kB. Further, 2-OHE2 was selected because of having binding energy -8.5 kcal/mol, found to inhibit inflammation and the effectiveness was validated by root mean square fluctuation, radius of gyration and molecular mechanics with generalized born and surface area solvation against TNF-α. Thus 2-OHE2, an estrogen metabolite was identified as the potential inhibitor, attenuated inflammatory activation and can be utilized as a therapeutic target to disseminate severity of RA.

Estrogen-mediated differential protein regulation and signal transduction in rheumatoid arthritis.

Exploration of the dual and opposing facets of estrogen necessitates a clear understanding to diminish the controversy of estrogen regulation in averting the systemic, autoimmune, joint degrading disorder, and rheumatoid arthritis (RA). Experimental evidences consider estrogen as a pivotal enzyme to modulate the disease progression via managing several cellular mechanisms targeting inflammatory markers such as TNF, ILs, nuclear factor kappa B, and other regulatory proteins like matrix metalloproteinases impeding joint erosion and cartilage degradation. Estrogen modulates cellular signaling associated with inflammation, oxidative stress, related cardiovascular risk, and miRNA regulation during RA progression. Studies determining estrogen regulation in RA complicate the resemblance of the outcome as they represent both hyper and hypo level of estrogen is linked to the disease. Although some reports deliver estrogen as malign, there is now increasing evidence of rendering protection dose dependently. Variation in estrogen level causes differential expression of certain proteins and their related signaling which is directly or indirectly linked to RA pathogenesis. This review summarizes the variations in protein expression levels by focusing on the in vitro, in vivo,and clinical studies of estrogen deficiency and treatment. Construction of protein-protein interaction network, GO, and KEGG pathway enrichment analysis of the differentially expressed proteins assist in hypothesizing a potential molecular mechanism of estrogen in RA via in silico studies. Targeting these differential proteins can emerge a new path for developing advanced therapeutic strategies.

Anti-inflammatory activity of nicotine isolated from Brassica oleracea in rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis (RA) is an autoimmune disease, associated with chronic inflammation of synoviocytes. Tumor necrosis factor α (TNF-α) plays a crucial role in the pathogenesis of RA through pro-inflammatory cytokines. Nicotine, an alkaloid used as herbal medicine, often worked as an anti-inflammatory agent. In the present study, we tried to uncover the anti-inflammatory impact of nicotine against RA. MATERIALS AND METHODS: Nicotine was isolated from Brassica oleracea, purified by high profile/phase liquid chromatography (HPLC). In-silico docking was carried out using bioinformatics tools SwissADME (absorption, distribution, metabolism and excretion), PASS, and Drug-induced Gene Expression Profile (DIGEP)-Pred to determine drug likeliness of nicotine. The in-vitro study was performed in TNFα-induced SW982 synoviocytes by qPCR. mRNA expression of pro-inflammatory cytokines (TNF, IL6, IL1ß) and proteins (TRAF2, P50, P65) were analyzed followed by validation of P65 (RELA), pP65, IkBα by Western blot analysis. RESULTS: Nicotine compound was extracted from Brassica oleracea and purified by HPLC method (Rt values at 2.67 min). The physicochemical, pharmacokinetic properties and drug-likeliness of nicotine were studied by in-silico analysis. In-vitro studies revealed that nicotine lowers the expression of inflammatory cytokines (TNF, IL6, IL1ß) and proteins (TNF receptor-associated factor 2 (TRAF2), P50, P65) at 1 µg/ml in TNFα-induced SW982 cells. CONCLUSION: Nicotine from natural sources (Brassica oleracea) has been found to be an effective anti- inflammatory compound at a low dosage; thus, identifying the role of nicotine present in the natural sources as a therapeutic option for RA, may be recommended as remedial drug instead of synthetic drug.