Kaempferol Improved Rheumatoid Arthritis by Regulating the Immune Imbalance of Treg/Th17.

The objective of this study was to explore the therapeutic effects of kaempferol (Kae) on rheumatoid arthritis (RA) and to elucidate the underlying mechanisms. The collagen-induced arthritis (CIA) model was established using collagen II to induce RA. Mice were treated with Kae at a dose of 25 or 50 mg/kg/day via gavage. Pathological changes in the ankle joint were analyzed. Enzyme-linked immunosorbent assay (ELISA) was employed to measure the levels of inflammatory factors. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to assess the expression of genes associated with the balance of regulatory T (Treg)/T helper 17 (Th17) cells. Flow cytometry was utilized to determine the Treg/Th17 ratio. Furthermore, these techniques were employed to evaluate the impact of miR-34a and Foxp3 dysregulation on cellular functions in RA under the influence of Kae. Dual luciferase reporter assay was conducted to analyze the binding of miR-34a to Foxp3. Treatment with Kae led to a downregulation of receptor-related orphan receptor gamma t (RORγt) and IL-17 expression, and an upregulation of Foxp3, IL-10, and TGF-β expression in CIA mice. Kae intervention inhibited the production of proinflammatory cytokines and increased the production of anti-inflammatory cytokines. Furthermore, Kae treatment suppressed the expression of miR-34a, which was identified as a target of miR-34a. Finally, Kae regulated Treg/ Th17 balance-related genes and cellular inflammation through the miR-34a/Foxp3 axis. The study demonstrated that Kae effectively ameliorates CIA in mice by modulating the Treg/Th17 balance and related genes via the miR-34a/Foxp3 axis. These findings suggest that Kae may serve as a promising therapeutic agent for the treatment of RA and for restoring immune homeostasis.

Li N ，Yi YK ，Zhao J ，Wang Q ，Yu JY ，You YT ，Zhu YY ，Liu YY ，Zhao XS ，Pan DM ... -  《-》

Kunduan Yimu Decoction affected Th17/Treg balance through microRNA-124 to improve rheumatoid arthritis pathology.

Rheumatoid arthritis (RA) is an autoimmune condition characterized by inflammation and the deterioration of joints. Current treatments often have side effects, highlighting the need for safer options. This study investigates the therapeutic effects of Kunduan Yimu Decoction (KDYMD) on RA, focusing on the role of miR-124 in regulating Th17/Treg differentiation. PBMCs from RA patients were analyzed before and after KDYMD treatment. RT-qPCR was used to measure the miR-124 expressions. Flow cytometry was used to assess the ratios of Th17 to Treg cells. ELISA was used to quantify the cytokine concentrations. The effects of KDYMD on JAK2/STAT3 signaling were evaluated by western blot analysis. A CIA mouse model was used to validate the in vivo effects of KDYMD. MiR-124 expression was significantly upregulated in PBMCs of RA patients after KDYMD treatment. This upregulation was associated with increased Tip60 and Foxp3 expression and decreased RORγt expression. In the cytokine analysis, IL-1, IL-6, and IL-17A were decreased, and IL-10 and TGF- were increased after treatment. Flow cytometry showed a restoration of the Th17/Treg balance, with a decrease in Th17 and an increase in Treg cells. In vivo, KDYMD treatment ameliorated ankle swelling and arthritis index in CIA mice, comparable to methotrexate (MTX). In addition, KDYMD modulated JAK2/STAT3 signaling and enhanced anti-inflammatory responses. KDYMD exerts significant anti-inflammatory effects in RA by upregulating miR-124, which in turn regulates Th17/Treg differentiation and modulates JAK2/STAT3 signaling. A novel mechanism involving miR-124 and immune cell balance suggests KDYMD could be a promising therapeutic agent for RA.

Xu Q ，Shi MF ，Han YF ，Liu MY ，Liu XB ，Ma XN ，Feng W ，Lin CS ，Liu QP ... -  《-》

Bergapten attenuates sepsis-induced acute lung injury in mice by regulating Th17/Treg balance.

Shi S ，Deng R ，Huang R ，Zhou S ... -  《-》

IL-17 Producing T to Foxp3(+)CD4(+) Regulatory T Cell Ratio as a Diagnostic and Prognostic Marker in Women With Recurrent Pregnancy Loss and Its Implications for Intravenous Immunoglobulin Therapy.

The imbalance in the Th17/Regulatory T (Treg) cell ratio is associated with recurrent pregnancy loss (RPL). This study aimed to determine a cut-off for the Th17/Treg cell ratio to predict pregnancy outcomes in RPL and evaluate the effectiveness of intravenous immunoglobulin (IVIG) based on this cut-off value. This retrospective cohort study included 49 idiopathic RPL and 75 controls. The subgroups of IL-17+ T cell to Foxp3+ T cell ratios in peripheral blood were measured using flow cytometry. The cut-off values of Th17/Treg cell ratios were determined by the ROC curve to distinguish between RPL and controls. The IVIG treatment effectiveness in pregnancy outcome was compared between high- and low-ratio groups. Pearson correlation assessed the Th17/Treg cell ratio's relationship with NK cell cytotoxicity (NKC), NK cell percentage, and Th1/Th2 cell ratio. Using the ROC curve, we identified six Th17/Treg cell ratio markers with diagnostic value, and the following two, CD3+IL-17+ T cell/CD3+Foxp3high T cell ratio (sensitivity at 97%) and CD4+IL-17+ T cell/CD3+Foxp3high T cell ratio (specificity at 93.61%), showed the highest statistical significance in diagnosing idiopathic RPL. Among the six diagnostic markers, in terms of predicting pregnancy outcomes with IVIG treatment, CD3+IL-17+ T cell/CD4+Foxp3+ T cell ratio was the most valuable prognostic marker. In RPL women with high CD3+IL-17+ T cell/CD4+Foxp3+ T cell ratio (≥ 1.096), the live birth rate (LBR) was improved with IVIG treatment. (IVIG treatment, 78.57% vs. no IVIG, 28.57%, p = 0.026). On the other hand, RPL women with low CD3+IL-17+ T cell/CD4+Foxp3+ T cell ratio did not demonstrate the effectiveness of IVIG (LBRs with IVIG treatment, 50.00% vs. no IVIG, 84.62%, p = 0.219). In a correlation study, the CD3+IL-17+ T cell/CD4+Foxp3+ T cell ratio was an independent prognostic marker, showing no correlation with NKC, NK cell percentage, and Th1/Th2 cell ratio. The CD3+IL-17+ T/CD4+Foxp3+ T cell ratio may serve as a valuable marker for understanding the pathogenesis of RPL, predicting pregnancy outcomes, and selecting candidates for immunotherapy. Our study demonstrates that IVIG treatment can significantly improve LBR in women with a high CD3+IL-17+ T/CD4+Foxp3+ T ratio, offering a promising therapeutic approach for this challenging condition.

Park JS ，Song AY ，Bae JY ，Han JW ，Kim TH ，Kim CJ ，Lee SK ... -  《-》

Human umbilical mesenchymal stem cell-derived exosomes alleviate bone destruction and regulate bone immunity via the aryl hydrocarbon receptor to treat rheumatoid arthritis.

Rheumatoid arthritis (RA) can lead to joint deformity, loss of function, and even disability. Bone erosion is a common cause of disability in individuals with RA; bone resorption by osteoclasts (OCs) and bone immunity by regulatory T cells (Tregs) play key roles in this process. Human umbilical mesenchymal stem cells (HUMSCs) can be used to treat RA; however, the regulation of Tregs and OCs by HUMSCs and their therapeutic effects on RA have not been fully elucidated. This study aimed to reveal the effects of exosomes derived from HUMSCs carrying miRNA-150-5p on Tregs and OCs in individuals with RA and to provide innovative evidence for the ability of HUMSCs to alleviate RA. First, we used collagen-induced arthritis (CIA) model mice to verify the efficacy of miR-150-5pmimic-Exos and explored their effects on bone erosion in mouse joints and on Tregs in the lymph nodes. Subsequently, miR-150-5pmimic-Exos and the aryl hydrocarbon receptor (AhR) inhibitor CH223191 were used in in vitro OCs, Tregs, and OC-Treg coculture systems to determine whether miR-150-5pmimic-Exos regulate bone immune microenvironment homeostasis via AhR. Treatment with miR-150-5pmimic-Exos effectively alleviated bone damage to the ankle and knee joints in CIA model mice, inhibited OC differentiation, activated the immunosuppressive function of Tregs, and regulated bone immunity by increasing the expression of AhR/CYP1A1 signalling pathway genes such as Ahr, Arnt, Ahrr, Cyp1a1/1a2 and Cyp1b1 in OCs and Tregs. By coculturing Tregs and OCs, the ability of the miR-150-5pmimic-Exos to inhibit OC differentiation was further strengthened. This study confirmed that miR-150-5pmimic-Exos can reduce bone destruction in mice with CIA. We first showed that miR-150-5pmimic-Exos acted on a Treg-OC coculture system to alleviate bone erosion and regulate bone immunity. This study is expected to provide new ideas for the treatment of RA.

Wang X ，Shi T ，Jiao Y ，Geng Q ，Zhao H ，Deng T ，Xiao C ... -  《-》