Meng Ren

Impaired adipogenesis contributes to obesity-associated metabolic disorders, in which mitochondrial dysfunction plays an important role. Emerging evidence suggests that mitochondria-localized circular RNAs (circRNAs) influence mitochondrial function; however, whether they regulate adipogenesis and systemic metabolism is unclear. By profiling circRNAs in mitochondria isolated from the white adipose tissue (WAT) of obese male mice, we observe an upregulation of Birc6 -circRNA Repressing Adipogenesis and Krebs-cycle Energy (BRAKE) in mitochondria. In vivo, adipocyte-specific circRNA BRAKE knockdown in male mice reduces body weight, restricts fat expansion, and improves insulin sensitivity. In vitro studies show that circRNA BRAKE inhibits adipogenesis. Mechanistically, circRNA BRAKE binds ATP5A and disrupts ATP synthase assembly, thereby reducing ATP production and mTORC1 signaling and suppressing adipogenesis. In omental WAT (oWAT) of patients with obesity, mitochondrial circRNA BRAKE levels are elevated and inversely correlated with mitochondrial bioenergetic function. Collectively, our data identify a mitochondria-localized circRNA that regulates energy metabolism and adipogenesis, suggesting that circRNA BRAKE may represent a potential therapeutic target for obesity-related metabolic diseases.

Background: Cardiometabolic multimorbidity (CMM) burdens aging populations. Obesity drives CMM via insulin resistance and inflammation, but their nonlinear and combined effects remain unclear. We elucidated how these factors contribute to CMM incidence. Methods: From CHARLS 2011 to 2018, 6,510 participants were enrolled. CMM was defined as ≥ 2 of diabetes, heart disease, and stroke. Cox regression, Kaplan-Meier, and Fine-Gray models were used. Restricted cubic splines (RCS) evaluated nonlinear relationships. Multiplicative and additive interactions were assessed, and mediation analysis with 1,000 bootstraps estimated indirect effects. K-means clustering based on eight standardized variables, including age, body mass index (BMI), waist circumference (WC), triglyceride-glucose (TyG), high-sensitivity C-reactive protein (hs-CRP), systolic blood pressure (SBP), high-density lipoprotein cholesterol (HDL-C), and fasting plasma glucose (FPG), identified metabolic phenotypes carried high CMM risk. Results: Over 7 years, 212 (3.26%) developed CMM. RCS revealed a J-shaped association between WC and CMM. Optimal cut-offs were 60 years for age, 25.6 kg/m² for BMI, 90.6 cm for WC, 8.7 for the TyG index, 154.3 mg/dL for LDL-C, and 0.86 mg/L for hs-CRP. All six parameters independently predicted CMM. No significant additive interactions were found, but dual elevation markedly increased risk. The TyG index mediated 14.6% of the BMI effect and 10.0% of the WC effect on CMM. Clustering identified insulin-resistant and obese-insulin-resistant phenotypes. Conclusion: Optimal cut-offs offer practical screening tools. Dual elevation markedly increases CMM risk and insulin resistance mediates adiposity effects. Clustering identified insulin-resistant and obese-insulin-resistant phenotypes, supporting phenotype-based prevention.

Background: Child undernutrition is a serious public health problem that is associated with various infectious diseases (diarrheal diseases, malaria, measles, respiratory infections and tuberculosis). However, an assessment of the global burden of common infectious diseases in children with growth failure is still needed. Objective: This study aims to quantify the global burden of common infectious diseases in children with growth failure and to project future trends to 2050 to contribute to public health interventions. Methods: By analyzing the Global Burden of Disease Study 2021 (GBD 2021), we assessed the correlation and trend of common infectious diseases in malnourished children, stratified by age, country, and territory. In addition, Bayesian age–period–cohort (BAPC) models were used to predict future patterns until 2050. Results: We found that undernutrition among children is closely associated with common infectious diseases. The rate of deaths and disability-adjusted life years among children with diarrheal diseases, malaria, and respiratory infections and tuberculosis was negatively correlated with age. The prevalence of measles was highest in 1–2-year-olds. Diarrheal diseases and malaria are prevalent in Nigeria, measles is endemic in Somalia, and respiratory infections and tuberculosis are widespread in Nigeria and India. The BAPC results show that the malaria burden may increase in the future. Conclusion: This study emphasizes the burden of common infectious diseases in children with growth failure and facilitates international aid and WHO decision-making targeting countries and age groups.

Excess iodine intake due to iodinated contrast media (ICM) infusion during medical examinations is considered as a potential cause of thyroid abnormalities. However, the short-term effects of ICM exposure on patients in a Chinese population are not well elucidated. In total, 200 patients who received intravenous ICM were enrolled, and their thyroid function was determined before ICM exposure (baseline) as well as 1 week and 1 month after the ICM infusion. The relationship between the peak urinary iodine concentration (UIC) and the contrast agent (CA) dose was then investigated. Three months after ICM exposure, the patients who developed thyroid dysfunction within 1 month of ICM exposure were followed up. This study included 125 males and 75 females, with a mean age of 56.56 ± 13.89 years old and an average CA dose of 26.93 ± 8.35 g. Patients with thyroid nodules had an increased risk of subclinical hyperthyroidism (OR = 2.1491, 95% CI: 1.0335-71.1880, p = 0.0465). Additionally, the urinary iodine level (1658.37 ± 527.47 μg/L) peaked at 1 week after ICM exposure, and the peak level was weakly positively correlated with free thyroxine (FT4) level (r = 0.1531, p = 0.0317). Meanwhile, CA dose weakly negatively correlated with anti-thyroid peroxidase antibody (TPOAb) (r=-0.2077, p = 0.0035). The follow-up results at 3 months after ICM exposure showed that the newly developed abnormal thyroid function within 1 month of ICM exposure had mostly returned to normal. Patients with thyroid nodules had an increased risk of subclinical hyperthyroidism 1 month after iodine contrast imaging. The effect was transient, and most patients self-recovered without any intervention.

Background Prediabetes is associated with higher risk of chronic kidney disease (CKD), however studies investigating the prognostic index for incident CKD in patients with prediabetes are lacking. Thus, the present study aims to find the risk factors for CKD in prediabetic population. Methods We included 1220 prediabetic participants without CKD in the REACTION study and examined the associations of clinical indicators with CKD incidence with 3.6 years of follow-up using logistic regression analyses. To explore the nonlinear relationship between the Urine Albumin-To-Creatinine Ratio (UACR) and the hazard ratio (HR) of CKD, a Restricted Cubic Spline (RCS) analysis was conducted. Logistic regression analysis was employed to assess the association between UACR categories and the risk of CKD incidence. Results There were 78 (6.4%) individuals developed CKD, and elevated UACR was observed in patients who developed CKD. UACR was an independent risk factor of CKD after adjusting for covariates and RCS presented an association between elevated UACR and higher risk of CKD incidence. UACR cutoff points of 7.54 mg/g overall was associated with the risk of CKD progression. In comparison to a UACR range of 0-7.54 mg/g (B1), those who falling within the ranges of 7.54–14.95 (B2), 14.95–22.36 (B3), and 22.36-30 (B4), exhibited a significantly increased risk of CKD development. eGFR below the threshold of 81.64 mL/min/1.73m² was significantly associated with an increased risk of CKD characterized by impaired glomerular filtration. Conclusion In conclusion, the novel UACR cutoff of 7.54 mg/g serves as an effective tool to identify individuals at high risk of developing CKD-ACR during the prediabetes stage.

Delayed diabetic wound healing is a global health issue with unclear pathogenesis. Ferroptosis, a form of cell death involving iron and lipid peroxidation, may contribute to delayed diabetic wound. This study investigates the role of ferroptosis in diabetic wound keratinocytes. We measured lipid peroxidation products (MDA, 4-HNE), ACSL4, and GPX4 protein levels in diabetic keratinocytes and assessed mitochondrial morphology. Ferrostatin-1 (Fer-1) was used to inhibit ferroptosis in diabetic rat wounds, and its effects on healing and expression levels were evaluated. Pull-down assays, silver staining, and mass spectrometry were employed to study ACSL4 mRNA regulation. A YTHDF2 knockdown adenovirus was used to manipulate YTHDF2 expression in rat wounds. Ferroptosis was detected in diabetic keratinocytes, hindering wound healing, a process reversible with Fer-1. High glucose induced ACSL4 expression, driving keratinocyte ferroptosis and delayed healing. YTHDF2 interacts with N6-methyladenosine-modified ACSL4 mRNA, affecting its stability and expression. YTHDF2 knockdown increased ACSL4, promoting ferroptosis and impairing healing. Our findings illustrate the significant involvement of ferroptosis in the dysfunction of diabetic keratinocytes, suggesting that targeting ferroptosis may offer a viable therapeutic approach for improving diabetic wound healing.

Diabetic foot ulcers are severe diabetic complications, and promoting impaired angiogenesis is essential for wound healing. Pro-angiogenic galectin-3 is elevated in diabetic serum and promotes systemic insulin resistance that may impair wound healing. However, the exact role of galectin-3 in the regulation of diabetic wound healing remains unclear. Here, we demonstrate that galectin-3 promotes skin wound healing and angiogenesis via binding to its receptor integrin α5β1, and enhances downstream focal adhesion kinase phosphorylation by forming a liquid-liquid phase separation with integrin α5β1. Under diabetic conditions, aberrant accumulated advanced glycation end-products bind to galectin-3, blocking its interaction with integrin α5β1 and impairing angiogenesis. Topical treatment of recombinant galectin-3 in hydrogels promotes diabetic wound healing in rodents without causing systemic insulin resistance and synergizes with insulin. This study clarifies the binding of galectin-3 to integrin α5β1, instead of advanced glycation end-products, forming phase separation to promote angiogenesis and diabetic wound healing, laying the foundation for local galectin-3 therapy to treat diabetic foot ulcers.

Background: There is a correlation between dyslipidemia and elevated blood pressure, but the relationship between different lipid parameters and elevated blood pressure is inconsistent. Therefore, understanding the impact of dyslipidemia on blood pressure is significant for the prevention and control of ASCVD. Our study is aimed at assessing longitudinally the correlation between lipid parameters and the incidence of stage 1 hypertension in a large Chinese community population. Methods: This community-based cohort study conducted from 2011 to 2014–2016 included 2,843 eligible individuals aged 40 years or older. The diagnosis of stage 1 hypertension was systolic blood pressure (SBP) 130~139 mmHg and/or diastolic blood pressure (DBP) 80~89 mmHg. We collect data through standardized questionnaires and clinical and biochemical measurements conducted in unified institutions. The relationship between lipid parameters and risk of stage 1 hypertension were estimated using multiple Cox regression analysis. Results: During the follow-up period, 388 subjects (13.7%) developed stage 1 hypertension. Incidence of stage 1 hypertension gradually increased with the quartiles of triglycerides (TG) and the ratio of TG to high-density lipoprotein cholesterol (TG/HDL-C, all P < 0.0001). Multiple Cox regression analyses indicated that, compared to the quartile 1 of TG/HDL-C, quartile 4 was associated with higher risk of incident stage 1 hypertension (model 1: HR = 2.06, 95% CI 1.49–2.84; model 2: HR = 1.95, 95% CI 1.41–2.70; model 3: HR = 1.48, 95% CI 1.05–2.09). Conclusions: Our study findings suggest that TG/HDL-C is independently associated with the incidence of stage 1 hypertension in the Chinese middle-aged and elderly population.

Objectives: The relationships between the triglyceride-glucose (TyG) index, TyG-related parameters of different obesity phenotypes and the risk of type 2 diabetes (T2D) remain unclear. We aimed to determine associations between TyG index, obesity-related TyG parameters and T2D risk in Chinese adults.Methods: This cross-sectional study included 9489 participants aged ≥40 years from a large scale, community-based cohort study. Multivariable logistic regression was performed to estimate odds ratios (ORs) and 95% confidence intervals (CIs). The receiver operating characteristic (ROC) curve was employed to test and compare the predictive power of obesity-related TyG parameters across different phenotypes for the risk of T2D.Results: A total of 2081 (21.9%) participants with T2D were identified. When comparing with participants in the bottom quartile of TyG index, a heightened risk of T2D was observed among the highest quartile group, with an adjusted OR of 5.89 (95% CI: 4.98–6.98). Comparable relationships were found between obesity-related TyG indices and T2D, including TyG-waist circumference (TyG-WC), TyG-waist-to-height ratio (TyG-WHtR), TyG-body mass index (TyG-BMI) and TyG-body fat percentage (TyG-BFP). Abdominal obesity-related TyG indices had the highest predictive capability for T2D, with the area under the curve (AUC) was 0.711 (0.697–0.724) for TyG-WHtR and 0.705 (0.691–0.719) for TyG-WC, which was superior to the general obesity-related TyG indices, with the AUC were 0.683 (0.669–0.698) and 0.631 (0.616–0.646) for TyG-BMI and TyG-BFP, respectively.Conclusions: Our findings demonstrate a positive associations between TyG index, obesity-related TyG indices and risk of T2D. Abdominal obesity-related TyG indices had a better predictive value to diabetes than general obesity-related TyG indices.