Global Epidemiology of Gallstones in the 21st Century: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Gallstones are common and associated with substantial health and economic burden. We aimed to comprehensively evaluate the prevalence and incidence of gallstones in the 21st century. METHODS: We systematically searched PubMed and Embase to identify studies reporting the prevalence and/or incidence of gallstones between January 1, 2000, and November 18, 2023. Pooled prevalence and incidence were calculated using DerSimonian and Laird's random-effects model. We performed subgroup analyses and meta-regression based on age, sex, geographic location, population setting, and modality of detection to examine sources of heterogeneity. RESULTS: Based on 115 studies with 32,610,568 participants, the pooled prevalence of gallstones was 6.1% (95% CI, 5.6-6.5). Prevalence was higher in females vs males (7.6% vs 5.4%), in South America vs Asia (11.2% vs 5.1%), in upper-middle-income countries vs high-income countries (8.9% vs 4.0%), and with advancing age. On sensitivity analysis of population-based studies, the prevalence of gallstones was 5.5% (95% CI, 4.1-7.4; n = 44 studies), and when limiting subgroup analysis to imaging-based detection modalities, the prevalence was 6.7% (95% CI, 6.1-7.3; n = 101 studies). Prevalence has been stable over the past 20 years. Based on 12 studies, the incidence of gallstones was 0.47 per 100 person-years (95% CI, 0.37-0.51), without differences between males and females, and with increasing incidence in more recent studies. CONCLUSIONS: Globally, 6% of the population have gallstones, with higher rates in females and in South America. The incidence of gallstones may be increasing. Our findings call for prioritizing research on the prevention of gallstones.

Association between serum albumin concentration change trajectory and risk of hypertension: a cohort study in China.

Background: We sought to assess the risk of hypertension based on the trajectory of changes in serum albumin concentrations. Methods: A total of 11,946 nonhypertension adults aged 30-60 years who underwent at least 3 medical examinations between 2009 and 2016 were included in this study. Group-based trajectory models were obtained for 4 category groups, and logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for each category group of serum albumin concentration and the risk of hypertension. Results: During a mean follow-up period of 4.30 years, 1,537 hypertension events occurred in 11,946 subjects without hypertension. A high stable trajectory of serum albumin concentrations (OR, 0.70, 95% CI, 0.51-0.96) was associated with a significantly lower risk of developing hypertension. The results of the sensitivity analysis of the high stable trajectory (OR, 0.64, 95% CI, 0.43-0.96) remained statistically significant. Subjects with normal weight and those ≥45 years of age had a significantly lower risk of hypertension at moderate increase (P = 0.053 or 0.026) and high stable trajectories (P = 0.011 or 0.016). In males and overweight subjects, the risk of hypertension was significantly lower in the high stable trajectory (P = 0.038 or 0.044). Conclusion: In this study, we found that moderate increase in serum albumin concentrations and a high stable trajectory were significantly associated with a reduced risk of hypertension in subjects aged ≥45 years and those with normal weight and that high stable serum albumin concentrations were significantly associated with a reduced risk of hypertension in males and overweight subjects.

Formononetin, a bioactive isoflavonoid constituent from Astragalus membranaceus (Fisch.) Bunge, ameliorates type 1 diabetes mellitus via activation of Keap1/Nrf2 signaling pathway: An integrated study supported by network pharmacology and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Type 1 diabetes mellitus (T1DM) results from insulin deficiency due to the destruction of pancreatic ß-cells. Previously, our studies showed that inhibition of Keap1/Nrf2 signaling pathway promoted the onset of T1DM, which suggests that finding drugs that can activate the Keap1/Nrf2 signaling may be a promising therapeutic strategy for the T1DM treatment. Astragalus membranaceus (Fisch.) Bunge is a common traditional Chinese medicine that has been frequently applied in Chinese clinics for the treatment of diabetes and other diseases. Formononetin (FMNT), one of the major isoflavonoid constituents isolated from this herbal medicine, possesses diverse pharmacological benefits and T1DM therapeutic potential. However, the exact molecular mechanisms underlying the action of FMNT in ameliorating T1DM have yet to be fully elucidated. AIMS OF THE STUDY: This study is to investigate the regulation of FMNT on the Keap1/Nrf2 signaling pathway to ameliorate T1DM based on network pharmacology approach combined with experimental validation. MATERIALS AND METHODS: A mouse-derived pancreatic islet ß-cell line (MIN6) was used for the in vitro studies. An alloxan (ALX)-induced T1DM model in wild-type and Nrf2 knockout (Nrf2-/-) C57BL/6J mice were established for the in vivo experiments. The protective effects of FMNT against ALX-stimulated MIN6 cell injury were evaluated using MTT, EdU, apoptosis and comet assays. The levels of blood glucose in mice were measured by using a blood monitor and test strips. The protein expression was detected by Western blot analysis. Furthermore, the binding affinity of FMNT to Keap1 was evaluated using cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) assay, and solvent-induced protein precipitation (SIP) assay. The interaction pattern between FMNT and Keap1 was assessed by molecular docking and molecular dynamics simulation techniques. RESULTS: Network pharmacology analysis revealed that FMNT exerted its therapeutic effect against T1DM by mainly regulating oxidative stress response-associated signaling molecules and pathways, such as Nrf2 regulating anti-oxidant/detoxification enzymes and Keap1-Nrf2 signaling pathway. The in vivo results showed that FMNT significantly deceased the ALX-induced high blood glucose levels and conversely increased the ALX-induced low insulin contents. In vitro, FMNT markedly protected MIN6 cells from ALX-induced cytotoxicity, proliferation inhibition and DNA damage and reduced the ALX-stimulated cell apoptosis. FMNT also inhibited ALX-induced overproduction of intracellular ROS to alleviate oxidative stress. In addition, FMNT could bind to Keap1 to notably activate the Keap1/Nrf2 signaling to upregulate Nrf2 expression and promote the Nrf2 translocation from the cytoplasm to the nucleus, resulting in enhancing the expression of antioxidant proteins HO-1 and NQO1. Inhibition of Keap1/Nrf2 signaling by ALX was also markedly abolished in the cells and mice exposed to FMNT. Moreover, these effects of FMNT in ameliorating T1DM were not observed in Nrf2-/- mice. CONCLUSIONS: This study demonstrates that FMNT could bind to Keap1 to activate the Keap1/Nrf2 signaling to prevent intracellular ROS overproduction, thereby attenuating ALX-induced MIN6 cell injury and ameliorating ALX-stimulated T1DM. Results from this study might provide evidence and new insight into the therapeutic effect of FMNT and indicate that FMNT is a promising candidate agent for the treatment of T1DM in clinics.

Association between hyperuricemia and hypertension and the mediatory role of obesity: a large cohort study in China

SUMMARY OBJECTIVE: This study aimed to investigate the sex-specific association between hyperuricemia and the risk of hypertension and whether obesity mediates this association. METHODS: This study included 31,395 (47.0% women) adults without hypertension, cardiovascular disease, or cancer at baseline who completed at least one follow-up annual examination between 2009 and 2016. Cox regression models were performed to calculate hazard ratios and 95% confidence intervals. Mediation analysis was conducted to estimate the effect of body mass index on the association between hyperuricemia and hypertension. RESULTS: During a median 2.9-year follow-up, hyperuricemia was significantly associated with a higher risk of hypertension (HR 1.15, 95%CI 1.07-1.24 for all participants; HR 1.12, 95%CI 1.03-1.22 for men; and HR 1.23, 95%CI 1.02-1.48 for women) after adjustment for potential confounders. Additional adjustment for body mass index attenuated this association (HR 1.09, 95%CI 1.08-1.10 for all participants; HR 1.07; 95%CI 0.98-1.16 for men; HR 1.18; 95%CI 0.96-1.44 for women). Mediation analysis showed that BMI partially mediated the relationship between hyperuricemia and incident hypertension (indirect effect HR 1.09, 95%CI 1.08-1.10; direct effect: HR 1.08, 95%CI 1.02-1.15). The percentage of the mediation effect was 53.2% (95%CI 37.9-84.5). CONCLUSION: Hyperuricemia is associated with a risk of hypertension in both sexes, and BMI partially mediates hyperuricemia-related incident hypertension.