The Role of the Gut-Joint Axis in the Care of Psoriatic Arthritis: A Two-Sample Bidirectional Mendelian Randomization Study.

INTRODUCTION: Observational studies and clinical trials have supported the association between gut microbiota and psoriatic arthritis. However, the causal link between gut microbiota and psoriatic arthritis is still unclear. METHODS: A two-sample bi-directional Mendelian randomization analysis was performed using the summary statistics of gut microbiota from the largest available genome-wide association study meta-analysis (n = 13,266) conducted by the MiBioGen consortium. The summary statistics of psoriatic arthritis were extracted directly from the FinnGen consortium, which consists of 3186 psoriatic arthritis patients and 24,086 controls. Sensitivity analyses were conducted to assess the validity of our findings. Enrichment analyses were used to investigate the biofunction and pathways. RESULTS: Inverse variance weighted (IVW) estimates suggested that family Rikenellaceae (P = 0.032) and genus Ruminococcaceae UCG011 (P = 0.014) had a detrimental effect on psoriatic arthritis. We also noticed the negative association between the class Methanobacteria (P = 0.032), order Methanobacteriales (P = 0.032), family Methanobacteriaceae (P = 0.032), genus Eubacterium fissicatena group (P = 0.010), genus Methanobrevibacter (P = 0.031), and genus Butyricicoccus (P = 0.041) with psoriatic arthritis. Sensitivity analyses showed that genus Butyricicoccus had pleiotropy and heterogeneity. According to the results of reverse MR analysis, the causal effect of psoriatic arthritis was found on six taxa, respectivelyc family Clostridiaceae1, family Defluviitaleaceae, genus Butyrivibrio, genus Defluviitaleaceae UCG011, genus Clostridium sensu stricto1, and genus Ruminococcaceae UCG011. CONCLUSION: This two-sample bidirectional Mendelian randomization analysis suggested that the gut microbiota had a causal effect on psoriatic arthritis and implied the potential role of probiotics in the management and prevention of psoriatic arthritis.

Dietary intake and incidence risk of idiopathic pulmonary fibrosis: a Mendelian randomization study.

BACKGROUND: Dietary intake has been shown to have a causal relationship with various lung diseases, such as lung cancer and asthma. However, the causal relationship between dietary intake and idiopathic pulmonary fibrosis (IPF) remains unclear. We conducted a two-sample Mendelian Randomization (MR) study to investigate the causal relationship between dietary intake and IPF. METHODS: The exposure datasets included meat, fruit, vegetable, and beverage intake from the UK Biobank. IPF data came from the EBI database of 451,025 individuals. All data in this study were obtained from the IEU Open GWAS Project. The inverse variance weighted (IVW), MR-Egger, and weighted median methods were used as the primary methods. Sensitivity analyses were performed to ensure the validity of the results. RESULTS: Oily fish intake [odds ratio (OR):0.995; 95% confidence interval (CI): 0.993-0.998; p = 6.458E-05] and Dried fruit intake (OR:0.995;95%CI:0.991-0.998; p = 0.001) were discovered as protective factors. There was also a suggestive correlation between Beef intake (OR:1.006;95%Cl:1.001-1.012; p = 0.023) and IPF. Sensitivity analysis did not reveal any contradictory results. No causal relationship was found between IPF and the rest of the dietary exposures. CONCLUSIONS: Our study found that Oily fish and Dried fruit intake were associated with the risk of IPF, while Beef intake was suggestively associated with the risk of IPF. Other studies are still needed to confirm the results in the future.

Jieduquyuziyin prescription enhances CD11a and CD70 DNA methylation of CD4+ T cells via miR-29b-sp1/DNMT1 pathway in MRL/lpr mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Jieduquyuziyin prescription (JP) is a traditional Chinese medicine utilized to treat systemic lupus erythematosus (SLE). Its efficacy has been confirmed through clinical trials and empirical evidence, leading to its authorized use in Chinese hospitals. The development of JP exemplifies the integration of traditional wisdom and scientific approaches, demonstrating the interdisciplinary essence of ethnopharmacology. These results emphasize the potential value of traditional medicine in addressing autoimmune disorders. AIM OF THE STUDY: This study aims to address the effect of JP in MRL/lpr mice and elucidate the pharmacological mechanism by which JP targets CD11a and CD70 DNA methylation via the miR-29b-sp1/DNMT1 pathway. MATERIALS AND METHODS: MRL/lpr mice were divided into three groups: the model group (received distilled water), the positive group (administered AAV/miR-29b-3p inhibitor), and the JP group (treated with JP decoction). C57BL/6 mice were constituted as a control group. Through ELISA assay, serum and urine samples were assessed for anti-dsDNA, TNF-α, TGF-ß, IL-2, and UP. HE and Masson staining were conducted to reveal renal pathology. Genome DNA was extracted from CD4+ T cells of mice spleens to evaluate methylation level. The methylation of CD11a, CD70, and CD40L promoter regions was analyzed by targeted bisulfate sequencing. Their expression at the mRNA and protein levels was examined using quantitative real-time PCR, western blot analysis, immunohistochemistry, and immunofluorescence staining of kidney tissues. Furthermore, the molecular mechanisms underlying the regulation of the miR-29b-sp1/DNMT1 pathway by JP were explored with Jurkat cells transfected with miR-inhibitors or miR-mimics. RESULTS: Mice treated with JP exhibited a significant decrease in anti-dsDNA, TNF-α, TGF-ß, and UP, accompanied by a significant increase in IL-2. HE staining revealed JP effectively mitigated renal inflammatory response, while Masson staining indicated a reduction in collagen fiber content. In addition, JP exhibited a significant impact on the global hypomethylation of SLE, as evidenced by the induction of high methylation levels of CD11a and CD70 promoter regions, mediated through the miR-29b-sp1/DNMT1 pathway. CONCLUSION: Our findings demonstrate JP exerts a protective effect against spontaneous SLE development, attenuates renal pathological changes, and functions as a miRNA inhibitor to enhance CD11a and CD70 DNA methylation through the modulation of the miR-29b-sp1/DNMT1 pathway.

Fasudil compensates podocyte injury via CaMK4/Rho GTPases signal and actin cytoskeleton-dependent activation of YAP in MRL/lpr mice.

Deposition of immune complexes in the glomerulus leads to irreversible renal damage in lupus nephritis (LN), of which podocyte malfunction arises earlier. Fasudil, the only Rho GTPases inhibitor approved in clinical settings, possesses well-established renoprotective actions; yet, no studies addressed the amelioration derived from fasudil in LN. To clarify, we investigated whether fasudil exerted renal remission in lupus-prone mice. In this study, fasudil (20 mg/kg) was intraperitoneally administered to female MRL/lpr mice for 10 weeks. We report that fasudil administration swept antibodies (anti-dsDNA) and attenuated systemic inflammatory response in MRL/lpr mice, accompanied by preserving podocyte ultrastructure and averting immune complex deposition. Mechanistically, it repressed the expression of CaMK4 in glomerulopathy by preserving nephrin and synaptopodin expression. And fasudil further blocked cytoskeletal breakage in the Rho GTPases-dependent action. Further analyses showed that beneficial actions of fasudil on the podocytes required intra-nuclear YAP activation underlying actin dynamics. In addition, in vitro assays revealed that fasudil normalized the motile imbalance by suppressing intracellular calcium enrichment, thereby contributing to the resistance of apoptosis in podocytes. Altogether, our findings suggest that the precise manners of crosstalks between cytoskeletal assembly and YAP activation underlying the upstream CaMK4/Rho GTPases signal in podocytes is a reliable target for podocytopathies treatment, and fasudil might serve as a promising therapeutic agent to compensate for the podocyte injury in LN.