STA-21 regulates Th-17/Treg balance and synovial fibroblasts functions in rheumatoid arthritis.

JAK/STAT signaling pathway plays a significant role in cytokines and growth factors signaling involved in the pathogenesis of rheumatoid arthritis (RA). STAT3 is a major downstream signaling mediator of important pro-inflammatory cytokines involved in Th-17 cell differentiation playing a significant role in regulating Th-17/ Treg balance and the development of autoimmune diseases, especially RA. Studies also have reported the role of the STAT3 pathway in inflammatory and destructive functions of synovial fibroblasts (SFs) in RA. STA-21 is a small molecule inhibitor that can inhibit STAT3 activation impairing the expression of STAT3 target genes. In this study, we tested whether a STAT3 inhibitor, STA-21, can alter Th-17/Treg balance and SF functions in RA. Peripheral blood mononuclear cells (PBMC) and SFs were isolated from 34 RA patients undergoing orthopedic surgery and 15 healthy controls to investigate in vitro effects of STA-21. The main assays were MTT assay, PI staining, reverse transcription-PCR (RT-PCR), flow cytometric analysis, and ELISA. Results showed that STA-21 reduced the proportion of Th-17 cells and the expression of STAT3 target genes, RORγt, IL-21, and IL-23R involved in Th-17 cells differentiation while it conversely increased the proportion of Treg cells, which theoretically may result in suppression of inflammation. We found that STAT3 activation and its target gene expression increased in RA-SFs. In addition, results showed that STA-21 can reduce the expression of STAT3 target genes related to cell proliferation, apoptosis, and inflammation leading to a decrease in proliferation and conversely increase in apoptosis of RA-SFs. Overall, our findings provide evidence that STA-21 can reduce inflammatory immune processes conducted by T cells and RA-SFs in RA, suggesting that this compound is a suitable option for clinical studies in RA.

Green Synthesis of Silver Nanoparticles from Aqueous Extract of Tinospora crispa Stems Accelerate Wound Healing in Rats.

GRAPHICAL ABSTRACT: [Formula: see text].

A novel hypothesis for COVID-19 pathogenesis: Retinol depletion and retinoid signaling disorder.

The SARS-CoV-2 virus has caused a worldwide COVID-19 pandemic. In less than a year and a half, more than 200 million people have been infected and more than four million have died. Despite some improvement in the treatment strategies, no definitive treatment protocol has been developed. The pathogenesis of the disease has not been clearly elucidated yet. A clear understanding of its pathogenesis will help develop effective vaccines and drugs. The immunopathogenesis of COVID-19 is characteristic with acute respiratory distress syndrome and multiorgan involvement with impaired Type I interferon response and hyperinflammation. The destructive systemic effects of COVID-19 cannot be explained simply by the viral tropism through the ACE2 and TMPRSS2 receptors. In addition, the recently identified mutations cannot fully explain the defect in all cases of Type I interferon synthesis. We hypothesize that retinol depletion and resulting impaired retinoid signaling play a central role in the COVID-19 pathogenesis that is characteristic for dysregulated immune system, defect in Type I interferon synthesis, severe inflammatory process, and destructive systemic multiorgan involvement. Viral RNA recognition mechanism through RIG-I receptors can quickly consume a large amount of the body's retinoid reserve, which causes the retinol levels to fall below the normal serum levels. This causes retinoid insufficiency and impaired retinoid signaling, which leads to interruption in Type I interferon synthesis and an excessive inflammation. Therefore, reconstitution of the retinoid signaling may prove to be a valid strategy for management of COVID-19 as well for some other chronic, degenerative, inflammatory, and autoimmune diseases.