Jiedu-Quyu-Ziyin Fang (JQZF) inhibits the proliferation and activation of B cells in MRL/lpr mice via modulating the AKT/mTOR/c-Myc signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Jiedu-Quyu-Ziyin Fang (JQZF) is a new herbal formula improved based on "Sheng Ma Bie Jia Tang" in the Golden Chamber, has been proved to be effective in the treatment of SLE. The ability of JQZF to prevent lymphocyte growth and survival has been demonstrated in earlier investigations. However, the specific mechanism of JQZF on SLE has not been fully investigated. AIM OF THE STUDY: To reveal the potential mechanisms of JQZF inhibiting B cell proliferation and activation in MRL/lpr mice. MATERIALS AND METHODS: MRL/lpr mice were treated with low-dose, high-dose JQZF and normal saline for 6 weeks. The effect of JQZF on disease improvement in MRL/lpr mice was studied using enzyme-linked immunosorbent assay (ELISA), histopathological staining, serum biochemical parameters and urinary protein levels. The changes of B lymphocyte subsets in the spleen were analyzed by flow cytometry. The contents of ATP and PA in B lymphocytes from the spleens of mice were determined by ATP content assay kit and PA assay kit. Raji cells (a B lymphocyte line) were selected as the cell model in vitro. The effects of JQZF on the proliferation and apoptosis of B cells were detected by flow cytometry and CCK8. The effect of JQZF on the AKT/mTOR/c-Myc signaling pathway in B cells were detected via western blot. RESULTS: JQZF, especially at high dose, significantly improved the disease development of MRL/lpr mice. Flow cytometry results showed that JQZF affected the proliferation and activation of B cells. In addition, JQZF inhibited the production of ATP and PA in B lymphocytes. In vitro cell experiments further confirmed that JQZF can inhibit Raji proliferation and promote cell apoptosis through AKT/mTOR/c-Myc signaling pathway. CONCLUSION: JQZF may affect the proliferation and activation of B cells by inhibiting the AKT/mTOR/c-Myc signaling pathway.

Efficacy and safety of tofacitinib combined with methotrexate in the treatment of rheumatoid arthritis: A systematic review and meta-analysis.

Objective: To evaluate the efficacy and safety of tofacitinib in combination with methotrexate (MTX) versus MTX monotherapy in patients with active rheumatoid arthritis (RA). Methods: Trials were identified from four electronic databases: PubMed, Web of science, Cochrane Library and EMBASE from inception to April 2022. Two independent reviewers evaluated each database to scan the title, abstract and keywords of each record retrieved. Full articles were further assessed when the information suggested that the study was a randomized clinical trial (RCT) comparing tofacitinib combined with MTX vs. MTX monotherapy in patients with active RA. Data were extracted from the literature, and the methodological quality of the included literature were evaluated and screened by two reviewers independently. The results were analyzed using RevMan5.3 software. The full text of the studies and extracted data were reviewed independently according to PRISMA guidelines. The outcome indicators were ACR 20, ACR 50, ACR 70, Disease activity score 28 (DAS28), erythrocyte sedimentation Rate (ESR) and adverse events (AEs). Results: Of 1152 studies yielded by the search, 4 were retained, totaling 1782 patients (1345 treated with tofacitinib combined with MTX vs 437 received MTX. In the trial of insufficient response to MTX treatment, tofacitinib combined with MTX had significant advantages compared with MTX monotherapy. Numerically higher ACR20, ACR50 and ACR70 response rates were observed in the tofacitinib combined with MTX groups versus MTX monotherapy. ACR20 (odds ratio (OR), 3.62; 95% CI, 2.84-4.61; P < 0.001), ACR50 (OR, 5.17; 95% CI, 3.62-7.38; P < 0.001), and ACR70 (OR, 8.44; 95% CI, 4.34-16.41; P < 0.001), DAS28 (ESR) < 2.6 (OR, 4.71, 95% CI, 2.06-10.77; P < 0.001). The probability of adverse events of tofacitinib combined with MTX was lower than that of MTX monotherapy (OR, 1.42; 95% CI, 1.08-1.88; P = 0.01). The number of cases discontinued due to lack of efficacy or adverse events was similar in both groups (OR, 0.93; 95% CI, 0.52-1.68). The probability of abnormal liver enzymes in the treatment of tofacitinib combined with MTX was significantly lower than that of MTX monotherapy (OR, 1.86; 95% CI, 1.35-2.56). However, there was no significant difference between the two groups in severe adverse reactions, neutropenia, anemia and cardiovascular disease. Conclusions: In terms of ACR20/50/70 and DAS28 (ESR), tofacitinib combined with MTX demonstrated superiority to MTX monotherapy in the treatment of patients with refractory RA. Considering the hepatoprotective and observably therapeutic efficacy, tofacitinib combined with MTX could be effective in treating refractory RA. However, in terms of hepatoprotective, it requires further large-scale and high-quality clinical trials to confirm.

Triptolide in the treatment of systemic lupus erythematosus - regulatory effects on miR-146a in B cell TLR7 signaling pathway in mice.

Objective: To clarify the mechanism of triptolide (TP) in alleviating the conditions underlying SLE. Methods: Eight-week-old MRL/lpr mice were randomly divided into a model group (n = 5), low-dose TP (TP-L) group (n = 5), and high-dose TP (TP-H) group (n = 5). Mice in these groups were gavaged with normal saline, low-dose TP solution, and high-dose TP solution for 8 weeks, respectively. The expression levels of anti-dsDNA, IgG, IgM, IgA, C3, C4, and CREA, BUN, ALT, AST, ALB, and ALP indexes in the serum of mice were detected. The proportion of CD19+CD138+B220- cells in the spleen and the pathological changes of kidney tissue in the mice were also evaluated. The possible signaling pathways and microRNA (miRNA) targets of TP in the treatment of SLE were analyzed using network pharmacology. The expressions of TLR7 mRNA and miR-146a in Raji cells (a B lymphocyte line) were detected using qPCR before and after intervention with a miR-146a inhibitor. The protein expression levels of TLR7, MyD88, p-IRAK1, and p-NF-κBp65 were detected using western blot analysis. Results: TP could significantly decrease the levels of ds-DNA and IgG, alleviate pathological injury in renal tissue, and upregulate miR-146a expression in the B cells of MRL/lpr mice without obvious liver and kidney toxicity. Network pharmacology analysis showed that TP could mainly regulate the Toll-like receptor signaling pathway, and NF-κB signaling pathway, among others. miRNA target prediction suggested that TP could regulate miRNAs such as miR-146a. In vitro cell experiments further confirmed that TP could significantly upregulate miR-146a expression and downregulate the expression of TLR7 mRNA and protein levels TLR7, MyD88, p-IRAK1, and p-NF-κBp65. After intervention with a miR-146a inhibitor, TP had no obvious inhibitory effects on TLR7, MyD88, p-IRAK1, and p-NF-κBp65 expression. Conclusion: TP may exert therapeutic effects on SLE by regulating miR-146a expression, inhibiting the TLR7/NF-κB signaling pathway, and affecting B cell activation.

Guidelines on the treatment with integrated traditional Chinese medicine and western medicine for severe coronavirus disease 2019.

Severe Coronavirus Disease 2019 (COVID-19) is characterized by numerous complications, complex disease, and high mortality, making its treatment a top priority in the treatment of COVID-19. Integrated traditional Chinese medicine (TCM) and western medicine played an important role in the prevention, treatment, and rehabilitation of COVID-19 during the epidemic. However, currently there are no evidence-based guidelines for the integrated treatment of severe COVID-19 with TCM and western medicine. Therefore, it is important to develop an evidence-based guideline on the treatment of severe COVID-19 with integrated TCM and western medicine, in order to provide clinical guidance and decision basis for healthcare professionals, public health personnel, and scientific researchers involved in the diagnosis, treatment, and care of COVID-19 patients. We developed and completed the guideline by referring to the standardization process of the "WHO handbook for guideline development", the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, and the Reporting Items for Practice Guidelines in Healthcare (RIGHT).