Association between the initial dose urate-lowering drugs and gout flares in adult males with gout.

OBJECTIVES: Frequent gout attacks in the initial introduction of urate-lowering therapy (ULT) are significant causes of poor drug adherence and ULT discontinuation. Initial low-dose urate-lowering drugs may be effective in reducing gout flares, however, robust evidence is sparse. The aim of this study was therefore to assess the association of initial dose urate-lowering drugs with gout flares in adult males with gout during the initial introduction of ULT. METHODS: This cohort study obtained data on consecutive gout patients from a single-center gout cohort study from August 2017 to October 2020. A standard questionnaire was applied to collect demographic and clinical information, and biochemical parameters were tested on the same day. The primary end point was to estimate the association of initial dose febuxostat with gout flares, using cox hazard models with inverse probability of treatment weighting (IPTW). RESULTS: A total of 582 gout patients were included in this study. During 6-week follow-up, 71 (12.2%) patients suffered gout flares. In the main analysis using cox hazard models with IPTW, compared with colchicine prophylaxis, initial low-dose febuxostat alone had no statistical significance with the increased risk of gout flares [hazard ratio (HR), 1.26; 95% CI, 0.58-2.72], while initial high-dose febuxostat was associated with an increased risk of gout flares (HR, 3.08; 95% CI, 1.34-7.07). CONCLUSIONS: This observational study demonstrated that initial low-dose febuxostat was equally effective in preventing gout flares as colchicine prophylaxis, while initial high-dose febuxostat alone was associated with an increased risk of gout flares.

Lariciresinol protects rats from complete Freund's adjuvant induced arthritis in rats via modulation of transforming growth factor-ß and nuclear factor kappa B pathway: An in vivo and in silico study.

Rheumatoid arthritis (RA) is a severe inflammatory auto-immune disorder affecting millions of people across the globe. The current therapeutic options are not adequate to address the complications of RA. Therefore, the present study was conducted to elucidate the protective effect of lariciresinol, a lignan, against Complete Freund's adjuvant (CFA)-induced arthritis in rats. The results of the study showed that lariciresinol improves paw swelling and arthritic scores in rats as compared to CFA rats. Lariciresinol also showed a significant reduction in rheumatoid factor, C-reactive protein, tumor necrosis factor-α, interleukin (IL)-17, and tissue inhibitor of metalloproteinases-3 level with a simultaneous increase in IL-4 level. The burden of oxidative stress was also reduced in CFA rats, as shown by reduced MDA levels and increased SOD and GPx after the administration of lariciresinol. In a Western blot analysis, lariciresinol showed a significant reduction of transforming growth factor-ß and nuclear factor-κB (NF-κB) protein levels in CFA rats. To understand the binding characteristic of lariciresinol with NF-κB, molecular docking analysis was conducted, which showed Larciresinol interacted with the active site of NF-κB. Our study demonstrated the significant protective effect of lariciresinol against RA via multi-target action.

Poplar's Waterlogging Resistance Modeling and Evaluating: Exploring and Perfecting the Feasibility of Machine Learning Methods in Plant Science.

Floods, as one of the most common disasters in the natural environment, have caused huge losses to human life and property. Predicting the flood resistance of poplar can effectively help researchers select seedlings scientifically and resist floods precisely. Using machine learning algorithms, models of poplar's waterlogging tolerance were established and evaluated. First of all, the evaluation indexes of poplar's waterlogging tolerance were analyzed and determined. Then, significance testing, correlation analysis, and three feature selection algorithms (Hierarchical clustering, Lasso, and Stepwise regression) were used to screen photosynthesis, chlorophyll fluorescence, and environmental parameters. Based on this, four machine learning methods, BP neural network regression (BPR), extreme learning machine regression (ELMR), support vector regression (SVR), and random forest regression (RFR) were used to predict the flood resistance of poplar. The results show that random forest regression (RFR) and support vector regression (SVR) have high precision. On the test set, the coefficient of determination (R2) is 0.8351 and 0.6864, the root mean square error (RMSE) is 0.2016 and 0.2780, and the mean absolute error (MAE) is 0.1782 and 0.2031, respectively. Therefore, random forest regression (RFR) and support vector regression (SVR) can be given priority to predict poplar flood resistance.

Vasoactive intestinal peptide-induced tolerogenic dendritic cells attenuated arthritis in experimental collagen-induced arthritic mice.

AIM: Cumulative evidence has revealed that tolerogenic dendritic cells (tolDC) could relieve inflammation reactions in various autoimmune diseases. This study investigated the potential therapeutic application of vasoactive intestinal peptide (VIP)-induced tolDC (VIP-DC) on arthritis using collagen-induced arthritis (CIA) mice. METHODS: Bone marrow cells were differentiated into dendritic cells (DC) using granulocyte macrophage colony-stimulating factor and interleukin (IL)-4. tolDC were induced by either VIP or Bay 11-7082 in vitro. Immunophenotypes and cytokine production of VIP-DC and Bay-DC were detected by fluorescence-activated cell sorting and enzyme-linked immunosorbent assay, respectively. Bay-DC, VIP-DC and untreated DC were ip administrated to CIA mice on day 40 when arthritis was onset. The treatment effects on arthritic and pathological changes, including synovial hyperplasia, pannus formation, inflammation and bone erosion, were assessed. RESULTS: VIP-DC (40 ng/mL) and Bay-DC (0.5 µg/mL) had a lower level of major histocompatibility complex II, CD40 and CD86 expression, reduced γ-interferon and increased IL-4 production (P < 0.05 or 0.01), compared with untreated DC. The administration of VIP-DC and Bay-DC decreased the arthritis score clinically at the end of the therapy. Pathological assessments showed that bone erosion and inflammation were alleviated in the VIP-DC group compared with those in the untreated DC group (P < 0.05 and P < 0.01, respectively). CONCLUSION: VIP-DC showed reduced immunogenicity and enhanced anti-inflammatory cytokine production. Both VIP-DC and Bay-DC could ameliorate arthritis in CIA mice clinically. VIP-DC were not inferior to Bay 11-7082-induced tolDC but may exert a better preventive effect on bone destruction.

IL-1ß functionally attenuates ABCG2 and PDZK1 expression in HK-2 cells partially through NF-ĸB activation.

Long-standing untreated hyperuricemia could lead to gout. Several recent studies have demonstrated a significant decrease of serum urate during acute gout attack, which is an aseptic inflammation process focusing on IL-1ß. However, how IL-1ß, by itself, alters the expression and the functional activity of urate transporters in renal tubular epithelial cells is still unclear. Herein, we revealed that IL-1ß could attenuate the mRNA and protein levels of ABCG2, a major urate efflux pump, in HK-2 cells by real-time PCR and Western-blot assays. Moreover, using an ABCG2 specific inhibitor and a new sensitive and specific detection system, it was found that IL-1ß also reduced the ABCG2 transporter activities. Incubation with specific inhibitors of the NF-κB pathway partly dampened the inhibitory effect of IL-1ß on ABCG2, indicating that IL-1ß reduced the ABCG2 expression partially through the NF-ĸB pathway. Furthermore, the decreased expression of PDZK1 induced by IL-1ß, which is dependent on the NF-κB pathway, could account for the imbalance between the functions and expressions of ABCG2 on this status. These findings demonstrated a new role for IL-1ß, whereby it leads to the inhibition of ABCG2 in renal tubular epithelial cells; this new role probably does not encompass its involvement in the process of renal urate excretion mediated by inflammation. Therefore, other regulation mechanisms of urate reabsorption in renal tubular epithelial cells deserve to be examined in further studies.