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.

Disordered farnesoid X receptor signaling is associated with liver carcinogenesis in Abcb11-deficient mice.

ABCB11 encodes the bile salt export pump (BSEP), a key regulator in maintaining bile acid (BA) homeostasis. Although inherited ABCB11 mutations have previously been linked to primary liver cancer, whether ABCB11 deficiency leads to liver cancer remains unknown. Here, we analyzed ABCB11 mRNA expression levels in liver tumor specimens [29 with hepatocellular carcinoma (HCC), one with intrahepatic cholangiocarcinoma (ICC), and one with mixed HCC/ICC] with adjacent normal specimens and published human datasets. Liver tissues obtained from Abcb11-deficient (Abcb11-/- ) mice and wild-type mice at different ages were compared by histologic, RNA-sequencing, and BA analyses. ABCB11 was significantly downregulated in human liver tumors compared with normal controls. Abcb11-/- mice demonstrated progressive intrahepatic cholestasis and liver fibrosis, and spontaneously developed HCC and ICC over 12 months of age. Abcb11 deficiency increased BAs in the liver and serum in mice, most of which are farnesoid X receptor (FXR) antagonists/non-agonists. Accordingly, the hepatic expression and transcriptional activity of FXR were downregulated in Abcb11-/- mouse livers. Administration of the FXR agonist obeticholic acid reduced liver injury and tumor incidence in Abcb11-/- mice. In conclusion, ABCB11 is aberrantly downregulated and plays a vital role in liver carcinogenesis. The cholestatic liver injury and liver tumors developed in Abcb11-/- mice are associated with increased FXR antagonist BAs and thereby decreased activation of FXR. FXR activation might be a therapeutic strategy in ABCB11 deficiency diseases. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Metabolically obese phenotype and its dynamic change are associated with increased carotid intima-media thickness: Results from a cohort study.

BACKGROUND AND AIMS: To examine associations between metabolically obese phenotypes or their changes and increased carotid intima-media thickness (CIMT). METHODS AND RESULTS: This prospective cohort included 13,681 Chinese adults aged 20-80 years who completed follow-up health examination with carotid ultrasound and were divided according to metabolic and weight status: metabolically healthy and normal weight (MHNW); metabolically obese but normal weight (MONW); metabolically healthy but obese (MHO); metabolically abnormal and obese (MAO). Cox and logistic regression were used to evaluate the associations of the phenotypes or their changes with increased CIMT. During a mean follow-up of 33 months, 1927 participants developed increased CIMT. After adjusting for age, sex and potential biochemical confounders, MAO was significantly associated with increased CIMT (HR 1.22, 95% CI [1.07, 1.4]); the association remained significant in those 40 years or older. Compared with stable MHNW, increased CIMT risk was higher for stable MAO (OR 1.35 [1.16, 1.57]), transitional MAO from MONW (OR 1.44 [1.04, 1.97]), and transitional MHO from MHNW (OR 1.59 [1.10, 2.26]) in demographic adjusted models; only stable MAO remained significant in the multivariate adjusted model (OR 1.23 [1.05, 1.45]). CONCLUSION: MAO significantly elevated the risk of increased CIMT. Stable MAO and obese transitions also promoted CIMT progression.

The association between Chinese Visceral Adipose Index and coronary heart disease: A cohort study in China.

BACKGROUND AND AIMS: The purpose of this study is to explore the relationship between Chinese visceral adipose index (CVAI) and the risk of coronary heart disease (CHD) in Chinese through a large cohort study. METHODS AND RESULTS: This study included 42,165 adults who were without CHD at baseline and who completed at least one annual follow-up between 2009 and 2016. We used the Cox proportional hazards model to estimate Hazard Ratios (HRs) and 95% Confidence Intervals (CIs) for the association between CVAI and risk of CHD. During the median follow-up of 3.36 years (154,808 person years), 520 participants developed CHD, including 374 males and 146 females. Compared with the first quartile of CVAI, the risk of CHD was significantly increased in the fourth quartile of CVAI in multivariate model (HR [95% CI]: 9.92 [5.45, 18.04], P < 0.001). Sensitivity analysis by excluding incident CHD developed in the first two years of follow-up reinforced our results. Gender stratification analyses showed that the relationship between CVAI and CHD risk was higher in males than that in females. The restricted cubic spline showed a non-linear dose-response relationship between CVAI and CHD risk. In addition, CVAI was associated with CHD risk in the subgroups of participants without T2DM, without hypertension, and without fatty liver. CONCLUSION: CVAI was significantly associated with the risk of CHD. Individuals should keep CVAI at normal level to prevent CHD.

The association between low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio cholesterol ratio and thickened carotid intima-media thickness: A case-control study.

BACKGROUND: It is indicated that Low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio (LDL-C/HDL-C ratio) has greater predictive value for thickened carotid intima-media thickness (CIMT) comparing with classic lipid parameters. However, there have been few reports about their association in general Chinese population. METHOD: We included a total of 1220 CIMT participants and 2440 matched controls, who had ultrasonography of carotid artery during 2009 and 2016. Univariate and multivariate logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for thickened CIMT risk associated with LDL-C/HDL-C ratio. RESULT: In the univariate logistic regression model, there was significant association between LDL-C/HDL-C ratio and thickened CIMT (Q4 vs. Q1, OR = 1.94, 95% CI: 1.60-2.36; ptrend < 0.05). After adjusting for potential covariates, LDL-C/HDL-C ratio remained significantly associated with thickened CIMT (Q4 vs. Q1, OR = 1.81, 95% CI: 1.41-2.34, ptrend < 0.001; ≥3.05 v.s. <3.05, OR = 1.66, 95% CI: 1.37-2.02). In subgroup analyses, the association between LDL-C/HDL-C ratio and thickened CIMT remained significant in the subgroups stratified by sex, impaired fasting glucose (IFG), hypertension, and fatty liver disease but only remained significant in the subgroups of ≥45 years (OR = 2.01, 95% CI: 1.46-2.76; Ptrend<0.05), BMI ≥24 (kg/m2) (OR = 2.22; 95% CI = 1.63-3.03; Ptrend < 0.05) and BMI ≥25 (kg/m2) (OR = 2.50, 95% CI: 1.76-3.54; Ptrend < 0.05), dyslipidemia (OR = 3.28, 95% CI: 1.83-5,85; Ptrend < 0.001), and without periodontitis (OR = 2.08, 95% CI: 1.54-2.81 ; Ptrend < 0.05) comparing Q4 to Q1. Similar results were observed in the subgroup analyses for LDL-C/HDL-C ratio ≥3.05 v.s. <3.05 except for the age stratification. CONCLUSION: High LDL-C/HDL-C ratio could significantly increase the risk of thickened CIMT independent of gender, IFG, hypertension, and fatty liver disease in general Chinese population.

Platelet-Lymphocyte Ratio, Neutrophil-Lymphocyte Ratio and Their Dynamic Changes with Type 2 Diabetes Mellitus: A Cohort Study in China.

BACKGROUND: This study aimed at investigating the relationships between Platelet-Lymphocyte ratio (PLR) and Neutrophil-Lymphocyte ratio (NLR) and their dynamic changes (∆PLR, ∆NLR) with type 2 diabetes mellitus (T2DM) in a Chinese cohort study. METHODS: This study recruited 41,439 individuals who were diagnosed without T2DM at first health examination and completed at least one follow-up. The relationships between NLR, PLR, ∆PLR, ∆NLR and T2DM risk were analyzed using the Cox regression model with corresponding Hazard Ratios (HRs) and 95% Confidence Intervals (CIs). RESULTS: PLR exhibited significant correlation with T2DM risk in a linear reverse dose-response pattern, the corresponding HRs and 95% CIs were 0.81 (0.72, 0.90), 0.71 (0.63, 0.80) and 0.56 (0.49, 0.64) respectively (Ptrend < 0.001) for Q2, Q3 and Q4 vs Q1 after adjusting for age, gender, BMI, TG, TC, HDL-C, FPG, ALT, AST, heart rate, smoking, family history of diabetes, and alcohol consumption at baseline in Model 3. The significance remained in subgroups of women, <45 years, ≥45 years, BMI ≥ 24, with fatty liver disease, without fatty liver disease and normotension. Comparing with the largest decrease group of NLR (∆NLR < -0.32), the risk of T2DM increased for -0.003 ≤ ∆NLR < 0.31 (HR 1.17, 95% CI 1.01-1.36) and ∆NLR ≥ 0.31 (HR 1.23, 95% CI 1.06-1.43). CONCLUSIONS: Higher PLR could reduce the risk of T2DM. Larger increase of NLR could increase T2DM risk.

Dose-response association of the ZJU index and fatty liver disease risk: A large cohort in China.

AIM: The aim of this study is to investigate the sex-specific association between the ZJU index and risk of fatty liver disease in a large Chinese cohort. METHODS: A total of 28 729 adults without fatty liver disease at baseline and who completed at least one follow-up of annual examinations between 2009 and 2016 were included in this study. The Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for fatty liver disease risk associated with the ZJU index. RESULTS: During a median follow-up of 3.01 years, 7373 developed fatty liver disease. There were significant associations between the ZJU index and fatty liver disease for women and men with increasing HRs as the quartiles increase across Q2-Q4, corresponding HRs (95% CIs) in M3 were 2.28 (1.98-2.64), 3.52 (3.07-4.04), and 4.87 (4.24-5.59) for women and 2.44 (2.17-2.75), 4.18 (3.73-4.68), and 6.23 (5.56-6.98) for men. The association between the ZJU index and fatty liver disease risk remained significant in all the subgroups except that of T2DM and abdominal obesity subgroups for men. However, the association became nonsignificant when comparing Q3 and Q2 of the ZJU index with reference in the subgroups of T2DM for men, and nonsignificant when comparing Q3 of the ZJU index with reference in the subgroups of participants with T2DM and abdominal obesity for women. CONCLUSION: The ZJU index was significantly associated with the risk of fatty liver disease in Chinese population. It will be better to keep body mass index, alanine aminotransferase, aspartate aminotransferase, triglyceride, and fasting plasma glucose at a normal level for preventing fatty liver disease.

Association between blood urea nitrogen and incidence of type 2 diabetes mellitus in a Chinese population: a cohort study.

To examine the association between blood urea nitrogen (BUN) and risk of type 2 diabetes (T2DM) among Chinese adults, we performed an ongoing cohort study of 38578 Chinese adults (56.3% males; average age, 41.6 y) who underwent repeated health check-up examinations between 2009 and 2016 and without T2DM at baseline. During follow-up, incident T2DM cases were identified based on self-report, medication use, measurements of fasting plasma glucose, 2 h post oral glucose, or haemoglobinA1c. 2009 (5.2%) cases confirmed with incident T2DM were identified during median follow-up of 3.1 years. With increasing quartiles of BUN levels, the incidences of T2DM gradually increased with 0.69%, 1.11%, 1.53%, and 1.87% for quartile 1 to quartile 4 (p trend <0.001). Compared with quartile 1, the multivariate-adjusted hazard ratios (HRs) and its 95% confidence intervals (95% CIs) for T2DM risk were 1.16 (0.97-1.38) for quartile 2, 1.28 (1.07-1.51) for quartile 3, and 1.28 (1.08-1.52) for quartile 4 (p trend = 0.005). HR for per each standard deviation increase in BUN level was 1.10 (1.04-1.16) (p trend <0.001). This association tended to be more pronounced in those with a lower body mass index at baseline (p-interaction <0.001). Our results suggested that BUN levels were positively associated with incident T2DM risk among Chinese adults. Future prospective investigations in other populations are necessary to confirm our findings.

Baseline serum albumin and its dynamic change is associated with type 2 diabetes risk: A large cohort study in China.

BACKGROUND: The study aimed to investigate the associations of baseline serum albumin level and its dynamic change with type 2 diabetes mellitus (T2DM) risk in a large Chinese cohort study. METHODS: This cohort study included 30 442 adults without T2DM at first entry, who completed at least one follow-up of annual examinations between 2009 and 2016. Serum albumin level was measured at baseline and at every annual check-up. The dynamic change in serum albumin level (∆ALB) was calculated by subtracting serum albumin level at baseline from that at the last follow-up. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Cox regression models. RESULTS: During 7 years of follow-up, we identified 1634 T2DM events. From the lowest to the highest quartile of serum albumin level, adjusted HRs (95% CI) were 1.00 (reference), 0.96 (0.94, 1.01), 0.98 (0.95, 1.02) and 0.88 (0.85, 0.98), respectively. As compared with stable change in serum albumin (-0.2 ≤ ∆ALB <1.0 g/L), the risk of T2DM increased for ∆ALB < -2.0 g/L (HR 1.44, 95% CI 1.24-1.68) and decreased for ∆ALB ≥3.0 g/L (0.81, 0.68-0.97) after adjusting for potential confounding factors. Restricted cubic splines showed a linear dose-response association between baseline serum albumin level and T2DM risk (Pnonlinearity 0.715) and a nonlinear dose-response association between ∆ALB and T2DM risk (Pnonlinearity 0.011). CONCLUSIONS: Baseline serum albumin level appears to be inversely associated with T2DM risk. Adults with reduced serum albumin level could be early identified for diabetes risk in clinical practice.

LDL-cholesterol to HDL-cholesterol ratio discordance with lipid parameters and carotid intima-media thickness: a cohort study in China.

BACKGROUND: The discordance of the low-density lipoprotein cholesterol-to-high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio with alterative lipid parameters may explain the inconsistent association of CIMT with the LDL-C/HDL-C ratio. Therefore, this study aimed to explore the associations between LDL-C/HDL-C ratio discordance with alternative lipid parameters and elevated carotid intima-media thickness (CIMT) risk in a large cohort in Beijing, China. METHODS: In total, 13,612 adults who didn't have elevated CIMT at baseline and who participated in at least one follow-up of annual examination between 2009 and 2016 were included in this cohort study. A multivariable Cox regression model was utilized to evaluate the associations of discordance of the LDL-C/HDL-C ratio with TC, TGs, LDL-C and HDL-C with elevated CIMT risk. RESULTS: During 37,999 person-years of follow-up, 2004 individuals (1274 men and 730 women) developed elevated CIMT. Among individuals with normal TC and TGs, 16.6 and 15.2% individuals had a discordantly high LDL-C/HDL-C ratio, respectively, and the risk of elevated CIMT increased by 1.54 (95% CI 1.33, 1.77) and 1.53 (95% CI 1.33, 1.76), respectively, comparing to individuals with a concordantly low LDL-C/HDL-C ratio. A high LDL-C/HDL-C ratio could significantly increase elevated CIMT risk regardless of discordance/concordance with LDL-C and HDL-C (P < 0.001). A low LDL-C/HDL-C ratio with discordantly normal HDL-C and high LDL-C (13.2% of individuals) had a 32% (HR = 1.32, 95% CI 1.11, 1.57) higher risk of elevated CIMT than concordantly low LDL-C and normal HDL-C. Sensitivity analysis by excluding CIMT developed in the first 2 years follow-up further confirmed the above results. CONCLUSIONS: A high LDL-C/HDL-C ratio could significantly increase elevated CIMT risk regardless of discordance/concordance with TC, TGs, LDL-C and HDL-C Even a low LDL-C/HDL-C ratio with discordantly high LDL-C and normal HDL-C could also significantly increase CIMT risk. Individuals should maintain both the LDL-C/HDL-C ratio and LDL-C at normal levels to prevent elevated CIMT.

A Systematic Review of Phytochemistry, Pharmacology and Pharmacokinetics on Astragali Radix: Implications for Astragali Radix as a Personalized Medicine.

Astragali radix (AR) is one of the most widely used traditional Chinese herbal medicines. Modern pharmacological studies and clinical practices indicate that AR possesses various biological functions, including potent immunomodulation, antioxidant, anti-inflammation and antitumor activities. To date, more than 200 chemical constituents have been isolated and identified from AR. Among them, isoflavonoids, saponins and polysaccharides are the three main types of beneficial compounds responsible for its pharmacological activities and therapeutic efficacy. After ingestion of AR, the metabolism and biotransformation of the bioactive compounds were extensive in vivo. The isoflavonoids and saponins and their metabolites are the major type of constituents absorbed in plasma. The bioavailability barrier (BB), which is mainly composed of efflux transporters and conjugating enzymes, is expected to have a significant impact on the bioavailability of AR. This review summarizes studies on the phytochemistry, pharmacology and pharmacokinetics on AR. Additionally, the use of AR as a personalized medicine based on the BB is also discussed, which may provide beneficial information to achieve a better and more accurate therapeutic response of AR in clinical practice.

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.

Reprogramming macrophage metabolism following myocardial infarction: A neglected piece of a therapeutic opportunity.

Given the global prevalence of myocardial infarction (MI) as the leading cause of mortality, there is an urgent need to devise novel strategies that target reducing infarct size, accelerating cardiac tissue repair, and preventing detrimental left ventricular (LV) remodeling. Macrophages, as a predominant type of innate immune cells, undergo metabolic reprogramming following MI, resulting in alterations in function and phenotype that significantly impact the progression of MI size and LV remodeling. This article aimed to delineate the characteristics of macrophage metabolites during reprogramming in MI and elucidate their targets and functions in cardioprotection. Furthermore, we summarize the currently proposed regulatory mechanisms of macrophage metabolic reprogramming and identify the regulators derived from endogenous products and natural small molecules. Finally, we discussed the challenges of macrophage metabolic reprogramming in the treatment of MI, with the goal of inspiring further fundamental and clinical research into reprogramming macrophage metabolism and validating its potential therapeutic targets for MI.

Pharmacological upregulation of macrophage-derived itaconic acid by pubescenoside C attenuated myocardial ischemia-reperfusion injury.

INTRODUCTION: Myocardial ischemia-reperfusion injury (MIRI) remains a prevalent clinical challenge globally, lacking an ideal therapeutic strategy. Macrophages play a pivotal role in MIRI pathophysiology, exhibiting dynamic inflammatory and resolutive functions. Macrophage polarization and metabolism are intricately linked to MIRI, presenting potential therapeutic targets. Pubescenoside C (PBC) from Ilex pubescens showed significantly anti-inflammatory effects, however, the effect of PBC on MIRI is unknown. OBJECTIVES: This study aimed to assess the cardioprotective effects of PBC against MIRI and elucidate the underlying mechanisms. METHODS: Sprague-Dawley rats, H9c2 and RAW264.7 macrophages were used to establish the in vitro and in vivo models of MIRI. TTC/Evans blue staining, immunohistochemical staining, metabonomics analysis, chemical probe, surface plasmon resonance (SPR), co-immunoprecipitation (CO-IP) assays were used for pharmacodynamic and mechanism study. RESULTS: PBC administration effectively reduced myocardial infarct size, decreased ST-segment elevation, and lowered CK-MB levels, concurrently promoting macrophage M2 polarization in MIRI. Furthermore, PBC-treated macrophages and their conditioned culture medium attenuated the apoptosis of H9c2 cells induced by oxygen-glucose deprivation/reoxygenation (OGD/R). Metabonomics analysis revealed that PBC increased the production of itaconic acid (ITA) and malic acid (MA) in macrophages, which conferred protection against OGD/R injury in H9c2 cells. Mechanistic investigations indicated that ITA exerted its effects by covalently modifying pyruvate kinase M2 (PKM2) at Cys474, Cys424, and Lys151, thereby facilitating PKM2's mitochondrial translocation and enhancing the PKM2/Bcl2 interaction, subsequently leading to decreased degradation of Bcl2. SPR assays further revealed that PBC bound to HSP90, facilitating the interaction between HSP90 and GSK3ß and resulting in the inactivation of GSK3ß activity and upregulation of key metabolic enzymes for ITA and MA production (Acod1 and Mdh2). CONCLUSION: PBC alleviates MIRI-induced cardiomyocyte apoptosis by modulating the HSP90/ITA/PKM2 axis. Furthermore, pharmacological upregulation of ITA emerges as a promising therapeutic approach for MIRI, hinting at PBC's potential as a candidate drug for MIRI therapy.

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.

Liver Function-Related Indicators and Risk of Gallstone Diseases-A Multicenter Study and a Systematic Review and Meta-Analysis.

Purpose of the study: We aim to examine the association between liver function-related indicators and gallstone disease (GSD) risk. Study design: The subjects who participated in the China Multicenter Physical Examination Cohort (CMPEC) were enrolled. Relative odds ratios (ORs) with 95% CIs and standardized mean differences (SMDs) were applied to investigate the effect of liver function-related indicators and GSD risk. Moreover, a systematic review and meta-analysis were conducted until July 2021. Additionally, the results in the CMPEC and the systematic review and meta-analysis were combined by meta-analysis. Finally, the results were validated by a cohort study of the UK Biobank (UKB). Results and conclusions: Totally, 369,931 subjects in CMPEC were included in the study. A total of 28 publications were incorporated into the systematic review and meta-analysis. The pooled analysis suggested that aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total protein (TP), and low albumin (ALB) were positively associated with the risk of GSD. Meanwhile, GSD present to have higher AST, ALT, gamma-glutamyl transferase (GGT), total bilirubin (TBil), globulin (G), and ALP levels and relatively lower TP and ALB levels than the healthy participants. These results were consistent when stratified by the study design, geographic background, and study quality. Only the association between ALP and GSD risk was validated in the UKB cohort. This study suggests liver function indicators were associated with GSD risk. The results may provide the basis for exploring the etiology of GSD and may help clinicians identify high-risk subjects. Trial Registration: PROSPERO (CRD42020179076).

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

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.

Predicting the Risk of Type 2 Diabetes Mellitus with the New Chinese Diabetes Risk Score in a Cohort Study.

Objectives: The New Chinese Diabetes Risk Score (NCDRS) is a noninvasive tool to assess the risk of type 2 diabetes mellitus (T2DM) in the Chinese population. Our study aimed to evaluate the performance of the NCDRS in predicting T2DM risk with a large cohort. Methods: The NCDRS was calculated, and participants were categorized into groups by optimal cutoff or quartiles. Hazard ratios (HRs) and 95% confidential intervals (CIs) in Cox proportional hazards models were used to estimate the association between the baseline NCDRS and the risk of T2DM. The performance of the NCDRS was assessed by the area under the curve (AUC). Results: The T2DM risk was significantly increased in participants with NCDRS ≥25 (HR = 2.12, 95% CI 1.88-2.39) compared with NCDRS <25 after adjusting for potential confounders. T2DM risk also showed a significant increasing trend from the lowest to the highest quartile of NCDRS. The AUC was 0.777 (95% CI 0.640-0.786) with a cutoff of 25.50. Conclusion: The NCDRS had a significant positive association with T2DM risk, and the NCDRS is valid for T2DM screening in China.

Corrigendum: Non-alcoholic fatty liver disease is associated with aortic calcification: a cohort study with propensity score matching.

[This corrects the article DOI: 10.3389/fendo.2022.880683.].

Association between Periodontitis and Aortic Calcification: A Cohort Study.

The present study investigated the association between the presence of periodontitis and aortic calcification (AC) risk among Chinese adults. A total of 6059 individuals who underwent regular health check-ups and received a diagnosis of periodontitis between 2009 and 2016 were included. The outcome was AC, assessed by a chest low-dose spiral CT scan. Cox proportional hazards regression analysis was used to assess the association between periodontitis and AC risk after adjusting for several confounders. After a median follow-up period of 2.3 years (interquartile range: 1.03-4.97 years), 843 cases of AC were identified, with 532 (12.13%) and 311 (18.59%) patients in the non-periodontitis group and periodontitis group, respectively. Multivariate analyses demonstrated that, compared with those without periodontitis, the hazard ratio and 95% confidence interval for AC risk in participants with periodontitis was 1.18 (1.02-1.36) (P = .025) in the fully adjusted model. Stratified analyses showed that the positive relationship between periodontitis and AC was more evident in males and participants <65 years of age (pinteraction = .005 and .004, respectively). Our results show that the presence of periodontitis was positively associated with AC among Chinese adults, especially among males and younger participants.