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The activated Gα protein subunit (Gαs) and the inhibitory Gα protein subunit (Gαi) are involved in the signal transduction of G protein coupled receptors (GPCRs). Moreover, the conversion of Gαi/Gαs can couple with sphingosine-1-phosphate receptors (S1PRs) and have a critical role in rheumatoid arthritis (RA). Through binding to S1PRs, sphingosine-1-phosphate (S1P) leads to activation of the pro-inflammatory signaling in rheumatoid arthritis synovial fibroblasts (RASFs). Geniposide (GE) can alleviate RASFs dysfunctions to against RA. However, its underlying mechanism of action in RA has not been elucidated so far. This study aimed to investigate whether GE could regulate the biological functions of MH7A cells by inhibiting S1PR1/3 coupling Gαi/Gαs conversion. We use RASFs cell line, namely MH7A cells, which were obtained from the patient with RA and considered to be the main effector cells in RA. The cells were stimulated with S1P (5 μmol/L) and then were treated with or without different inhibitors: Gαi inhibitor pertussis toxin (0.1 μg/mL), S1PR1/3 inhibitor VPC 23019 (5 μmol/L), Gαs activator cholera toxin (1 μg/mL) and GE (25, 50, and 100 μmol/L) for 24 h. The results showed that GE may inhibit the abnormal proliferation, migration and invasion by inhibiting the S1P-S1PR1/3 signaling pathway and activating Gαs or inhibiting Gαi protein in MH7A cells. Additionally, GE could inhibit the release of inflammatory factors and suppress the expression of cAMP, which is the key factor of the conversion of Gαi and Gαs. GE could also restore the dynamic balance of Gαi and Gαs by suppressing S1PR1/3 and inhibiting Gαi/Gαs conversion, in a manner, we demonstrated that GE inhibited the activation of Gα downstream ERK protein as well. Taken together, our results indicated that down-regulation of S1PR1/3-Gαi/Gαs conversion may play a critical role in the effects of GE on RA and GE could be an effective therapeutic agent for RA.

Background: To investigate the causal role of lipid in sepsis and determine the effect of lipid-lowering interventions on the disease. Methods: Two-sample Mendelian randomization analyses were conducted to evaluate the associations of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein B and apolipoprotein A-I levels with risks for sepsis, and those of low-density lipoprotein cholesterol (HMGCR, PCSK9, NPC1L1), triglycerides (LPL, ANGPTL3, APOC3) and high-density lipoprotein cholesterol (CETP), apolipoprotein A-I (CETP), apolipoprotein B (HMGCR, PCSK9, NPC1L1, LPL, APOC3) with sepsis. Results: HMGCR-mediated low-density lipoprotein cholesterol and apolipoprotein B were associated with an increased risk of sepsis, with an odds ratio value of 1.4 (95% confidence interval (CI): 1.06-1.84, P = 0.017) and 1.41 (95% CI: 1.01-1.98, P = 0.046). CETP-mediated high-density lipoprotein cholesterol and apolipoprotein A-I were associated with a reduced risk of sepsis, with an odds ratio of 0.87 (95% CI: 0.82-0.92, P < 0.01) respectively and 0.84 (95% CI: 0.78-0.9, P < 0.01). Sensitivity analysis showed that the results were robust. Conclusion: HMG-CoA reductase inhibitors and CETP inhibitors may contribute to the prevention and treatment of sepsis. [ABSTRACT FROM AUTHOR]

Background: This study utilizes the two-sample Mendelian randomization method to examine the correlations between 196 variants of gut microbiota and sepsis. Methods: This study leveraged summary statistics data from the genome-wide association studies on gut microbiota and sepsis, obtained from MiBioGen (n = 18340) and the UK Biobank (n = 462918). Following pre-determined P-value and clumping thresholds, independently significant SNPs associated with the abundance of 196 gut microbiota were selected as instrumental variables. The primary methodology for the Mendelian randomization study involved the inverse-variance weighting method, with results being assessed based on the odds ratio and a 95% confidence interval. To assure the solidity of our findings, we executed an array of sensitivity analyses, encompassing the Mendelian randomization-Egger intercept test, Mendelian randomization pleiotropy residual sum and outlier test, Cochran's Q test, and the leave-one-out test. Results: An elevated presence of Bifidobacterium may diminish sepsis risk (odds ratio = 0.79; 95% confidence interval 0.72-0.86; P = 5.19e-07). No signs of heterogeneity or pleiotropy were exhibited in the sensitivity analysis. Conclusion: Bifidobacterium may be instrumental in reducing sepsis risk. [ABSTRACT FROM AUTHOR]

This paper studies the nonlinear vibration of a cable with multiple intra-span elastic supports under primary resonance excitation. The elastic supports are treated as linear springs in the analysis. Lagrange's equation and modal superposition approach are employed to derive the dynamic equilibrium equations of the cable based on the energy of system. The nonlinear dynamic behaviour of a cable is analysed in this work, and 3:1 internal resonance is investigated, with coupled in-plane and out-of-plane motions discussed as well. A cable with both two edges simply supported subjected to harmonic excitation is studied by using homotopy analysis method. The amplitude-frequency response and the first approximation solutions of the double-modal motion are obtained. Through comparison with four-order Runge-kutta approach, it demonstrates this method is accurate. Finally, numerical analysis is performed to study how the pretensions, the damping coefficients and the linear stiffness coefficients of the elastic supports influence the amplitude-frequency and amplitude-excitation curves. A range of nonlinear dynamic properties of a cable are acquired, especially the internal resonance issue, which requires the cables stay beyond the region of resonance prior to perform structural design. [ABSTRACT FROM AUTHOR]