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.

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.

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.

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.

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.].

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.

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.

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.

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.

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.

Non-alcoholic Fatty Liver Disease Is Associated With Aortic Calcification: A Cohort Study With Propensity Score Matching.

Objectives: Non-alcoholic fatty liver disease (NAFLD) greatly affects cardiovascular disease, but evidence on the associations between NAFLD and markers of aortic calcification is limited. We aim to evaluate the association between NAFLD and aortic calcification in a cohort of Chinese adults using propensity score-matching (PSM) analysis. Methods: This prospective cohort study involved adults who underwent health-screening examinations from 2009 to 2016. NAFLD was diagnosed by abdominal ultrasonography at baseline, and aortic calcification was identified using a VCT LightSpeed 64 scanner. Analyses included Cox proportional-hazards regression analysis and PSM with predefined covariates (age, gender, marital and smoking status, and use of lipid-lowering drugs) to achieve a 1:1 balanced cohort. Results: Of the 6,047 eligible participants, 2,729 (45.13%) were diagnosed with NAFLD at baseline, with a median age of 49.0 years [interquartile range, 44.0-55.0]. We selected 2,339 pairs of participants with and without NAFLD at baseline for the PSM subpopulation. Compared with those without NAFLD, patients with NAFLD were at a higher risk of developing aortic calcification during follow-up; significant results were observed before and after matching, with the full-adjusted hazard ratios and corresponding 95% confidence intervals being 1.19 (1.02-1.38) and 1.18 (1.01-1.38), respectively (both p < 0.05). In subgroup analyses, no interaction was detected according to age, gender, smoking status, body mass index, total cholesterol, low-density lipoprotein cholesterol, use of lipid-lowering drugs, hypertension, or type 2 diabetes. Conclusions: NAFLD may be independently associated with aortic calcification. Further studies are warranted to elucidate the possible underlying mechanisms.

The anticardiac fibrosis of total alkaloids of Plumula nelumbinis by regulating circulating lipidomic profile: In vivo study.

Plumula nelumbinis has great medicinal potential as a herbal tea and traditional drug in China. This study was aimed to evaluate the anticardiac fibrosis of the total alkaloids of P. nelumbinis (TAP). TAP at 50 mg/kg/day significantly ameliorated isoproterenol-induced cardiac fibrosis in mice (p < .05). The circulating lipidomics study revealed that TAP improved the lipid metabolism dysfunction in cardiac fibrosis. Meanwhile, TAP suppressed the lipid accumulation, decreased MDA level (p < .01) in heart, and increased FFA level (p < .01). Furthermore, integrating lipidomics, chemical profiles and pharmacology network analysis found that AMPK and PI3K/Akt signaling pathways were the potential targeted pathway by TAP to regulate lipid metabolism dysfunction including glycerophospholipid metabolism. Above all, TAP provided a potential anticardiac fibrosis effect partly through regulation of lipid profiles. PRACTICAL APPLICATIONS: The total alkaloids of Plumula nelumbinis (TAP) suppressed ISO-induced cardiac fibrosis in mice. Network pharmacology analysis and experiments revealed that TAP-regulated AMPK and PI3K/Akt signaling pathway to improve lipid metabolism disorder in cardiac fibrosis. This study provides evidence to the therapeutic potential of TAP in the treatment of ISO-induced cardiac fibrosis and could be a drug candidate for prevention and treatment of cardiac fibrosis.

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.

Association of fasting plasma glucose change trajectory and risk of hypertension: a cohort study in China.

We aimed to assess the association between fasting plasma glucose (FPG) change trajectory and incident hypertension among Chinese population. This cohort study included 11,791 adults aged 18-80 years without hypertension at first entry and who completed at least four follow-ups between 2009 and 2016. Logistic regression was used to estimate odds ratios (ORs) and 95% CIs for the association between FPG change trajectory and probability of hypertension. During a median follow-up of 5.10 years (total person-years 61,887.76), hypertension developed in 2177 participants. After adjusting for baseline potential confounders, the probability of hypertension increased with the increasing FPG change trajectory (adjusted OR (aOR) 1.22, 95% CI 1.07-1.40), bell-shape trajectory (aOR 1.15, 95% CI 1.02-1.30) and other-shape trajectory (aOR 1.13, 95% CI 1.02-1.25) which showed a higher variability of FPG compared to the decreasing group. In addition, the increasing FPG change trajectory was associated with a higher probability of hypertension compared with the decreasing group regardless of age and BMI but was only significant in males and in those with normal FPG at baseline. Our study indicates that the increasing FPG change trajectory determines the highest risk of hypertension, demonstrating the importance of maintaining low and stable levels of FPG, especially in males and in those with normal FPG.

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.

Association of Chinese Visceral Adiposity Index and Its Dynamic Change With Risk of Carotid Plaque in a Large Cohort in China.

Background We aimed to evaluate the association between the Chinese visceral adiposity index (CVAI) and its dynamic change and risk of carotid plaque based on a large Chinese cohort. Methods and Results This cohort included 23 522 participants aged 20 to 80 years without elevated carotid intima-media thickness and carotid plaque at baseline and who received at least 2 health checkups. CVAI was calculated at baseline and at every checkup. The dynamic change in CVAI was calculated by subtracting CVAI at baseline from that at the last follow-up. Cox proportional hazard regression model was used to estimate hazard ratios (HRs) and 95% CIs. The restricted cubic spline was applied to model the dose-response association between CVAI and carotid plaque risk. During the 82 621 person-years of follow-up, 5987 cases of carotid plaque developed (7.25/100 person-years). We observed a significant positive correlation between CVAI and carotid plaque risk (HR, 1.53; 95% CI, 1.48-1.59 [P<0.001]) in a nonlinear dose-response pattern (Pnonlinearity<0.001). The sensitivity analyses further confirmed the robustness of the results. The association was significant in all subgroup analyses stratified by sex, hypertension, and fatty liver disease except for the diabetes subgroup. The association between CVAI and carotid plaque risk was much higher in men than in women. No significant association was identified between change in CVAI and carotid plaque risk. Conclusions CVAI was positively associated with carotid plaque risk in a nonlinear dose-response pattern in this study. Individuals should keep their CVAI within a normal level to prevent the development of carotid plaque.

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.

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.

Association between serum prostate-specific antigen concentrations and the risk of developing type 2 diabetes mellitus in Chinese men: A cohort study.

AIMS/INTRODUCTION: The current literature suggests that men with diabetes have a lower prostate-specific antigen concentration than men without diabetes, but the causal association remains unclear. We aimed to investigate the association between serum prostate-specific antigen concentrations and the risk of type 2 diabetes mellitus in a cohort study of a Chinese population. MATERIALS AND METHODS: We designed a cohort study that comprised 16,811 initially non-diabetic Chinese men who received annual health checkups between 2009 and 2016. The outcome of this study was type 2 diabetes mellitus, identified by medical diagnosis, self-reportage, medication use, fasting glucose, 2-h post oral glucose or glycated hemoglobin measurements. Cox proportional hazards models were carried out to evaluate the association. RESULTS: During a median follow-up period of 3.8 years (interquartile range 1.91-5.73 years), 1,260 participants developed incident type 2 diabetes mellitus. The multivariable model, adjusted for various potential confounders, showed that serum prostate-specific antigen concentrations were inversely related to type 2 diabetes mellitus risk (P for trend = 0.014). Compared with the lowest quartile of serum prostate-specific antigen, the hazard ratio and 95% confidence intervals of type 2 diabetes mellitus risk for quartile 2-4 were 0.84 (0.66-1.07), 0.75 (0.59-0.94) and 0.77 (0.62-0.96), respectively. Subgroup analyses suggested the inverse relationship was more prominent in overweight or obese participants (P for interaction = 0.013). CONCLUSIONS: High serum prostate-specific antigen concentration was associated with a low risk of type 2 diabetes mellitus in Chinese men. Future studies are required to confirm these findings and investigate underlying mechanisms.

Inhibition of the Keap1/Nrf2 Signaling Pathway Significantly Promotes the Progression of Type 1 Diabetes Mellitus.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by insulin deficiency due to pancreatic ß-cell damage and leads to hyperglycemia. The precise molecular mechanisms of the etiology of T1DM are not completely understood. Oxidative stress and the antioxidant status of pancreatic ß-cells play a vital role in the pathogenesis and progression of T1DM. The Keap1/Nrf2 signaling pathway plays a critical role in cellular resistance to oxidative stress. This study is aimed at investigating the role of the Keap1/Nrf2 signaling pathway in the progression of T1DM. An alloxan- (ALX-) stimulated T1DM animal model in wild-type (WT) and Nrf2 knockout (Nrf2-/-) C57BL/6J mice and a mouse pancreatic ß-cell line (MIN6) were established. Compared with the tolerant (ALX exposure, nondiabetic) WT mice, the sensitive (ALX exposure, diabetic) WT mice exhibited higher blood glucose levels and lower plasma insulin levels. The Keap1/Nrf2 signaling pathway was significantly inhibited in the sensitive WT mice, which was reflected by overexpression of Keap1 and low expression of Nrf2, accompanied by a marked decrease in the expression of the antioxidative enzymes. Compared with WT mice, the Nrf2-/- mice had an increased incidence of T1DM and exhibited more severe pancreatic ß-cell damage. The results of in vitro experiments showed that ALX significantly inhibited the viability and proliferation and promoted the apoptosis of MIN6 cells. ALX also markedly increased intracellular ROS production and caused DNA damage in MIN6 cells. In addition, the Keap1/Nrf2 signaling pathway was significantly inhibited in the damaged MIN6 cells. Moreover, Nrf2 silencing by transfection with Nrf2 siRNA markedly exacerbated ALX-induced MIN6 cell injury. Conclusively, this study demonstrates that inhibition of the Keap1/Nrf2 signaling pathway could significantly promote the incidence of T1DM. This study indicates that activation of Keap1/Nrf2 signaling in pancreatic ß-cells may be a useful pharmacological strategy for the clinical prevention and treatment of T1DM.