Withdrawn: 'Downregulation of circPPFIA1 elevates radiosensitivity via miR-1299-mediated TXNRD1 inhibition in oesophageal squamous cell carcinoma', Weihui Yu, Ke Ning, Jincheng Xiao, Qiwen Bai and Chenyang Guo. (https://onlinelibrary.wiley.com/doi/10.1111/1440-1681.13751).

The above article, published online on 16 February 2023 in Wiley Online Library (wileyonlinelibrary.com), has been withdrawn by agreement between the journal Editor in Chief, Yang Yang, and John Wiley & Sons Ltd. The withdrawal has been agreed following no response from the authors to requests to sign the journal's publishing license agreement.

Brachial-Ankle Pulse Wave Velocity Mediates the Association between Increased Age and Risk of Sarcopenia among Chinese Patients with Type 2 Diabetes Mellitus.

Background and Aims: Arterial stiffness and sarcopenia are commonly seen in patients with type 2 diabetes mellitus (T2DM), and both are age-related diseases. However, few studies have addressed the causal relationship between age, arterial stiffness, and sarcopenia, especially in patients with T2DM. This study is aimed at investigating the relationship among age, arterial stiffness, and sarcopenia in patients with T2DM. Methods and Results: This cross-sectional study enrolled 557 inpatients with diabetes at the First Affiliated Hospital of Wenzhou Medical University, China, between June 2020 and July 2021. Patients who were diagnosed with T2DM and underwent examination of dual-energy X-ray absorptiometry, handgrip strength, 6-meter walk speed, and brachial-ankle pulse wave velocity (baPWV, a recognized indicator of arterial stiffness) were enrolled. A total of 447 patients were included. A dose-dependent relationship was found between age and sarcopenia. We also found a dose-dependent relationship between age and baPWV. Similarly, significant dose-dependent relationships were found across baPWV tertiles with higher prevalence of sarcopenia. Then, a mediation analysis was performed to explore the mediation effect of arterial stiffness on age-associated sarcopenia. We found that the prevalence of sarcopenia increased by 0.0115 (95% CI, 0.0028-0.0239) per 1 year increase in age by the mediation effect of baPWV and that the direct effect of aging on sarcopenia was 0.0441 (95% CI, 0.0101-0.0909) per 1 year older. baPWV mediated 20.5% of the positive relationship between increased age and the prevalence of sarcopenia. Conclusions: Elevated baPWV partially mediates the association of age and sarcopenia among patients with T2DM.

Circ_0001686 knockdown suppresses tumorigenesis and enhances radiosensitivity in esophagus cancer through regulating miR-876-5p/SPIN1 axis.

BACKGROUND: Abnormal expression of circular RNAs (circRNAs) plays an important role in tumorigenesis and radiosensitivity of many cancers. Nevertheless, it is not clear whether circ_0001686 is associated with the development and radiosensitivity of esophagus cancer. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression levels of circ_0001686, microRNA-876-5p (miR-876-5p) and spindlin 1 (SPIN1). Counting Kit-8 (CCK-8) assay, EdU assay, flow cytometry and transwell assay were applied to evaluate cell viability, cell proliferation, cell apoptosis and cell invasion capacities. Radiosensitivity was monitored by colony formation assay. The target relationship between miR-876-5p and circ_0001686 or SPIN1 was identified by dual-luciferase reporter assay. The protein level of SPIN1 was measured by western blot assay. Xenograft tumor models were used to analyze the influence of circ_0001686 on radiosensitivity and tumor growth in vivo. RESULTS: The expression levels of circ_0001686 and SPIN1 were increased, while miR-876-5p was decreased in esophagus cancer tissues and cells. Interference of circ_0001686 constrained cell proliferation and invasion, but promoted cell apoptosis and radiosensitivity. Additionally, miR-876-5p was the target of circ_0001686 and miR-876-5p inhibition effectively ameliorated the impacts of circ_0001686 deficiency on tumorigenesis and radiosensitivity. Moreover, SPIN1 was a direct target of miR-876-5p and SPIN1 overexpression partially overturned the effects of miR-876-5p transfection on tumor progression and radiosensitivity. Importantly, circ_0001686 could sponge miR-876-5p to regulate SPIN1 expression. In addition, circ_0001686 silencing also constrained tumor growth and increased radiosensitivity in vivo. CONCLUSION: Circ_0001686 contributed to the progression and radioresistance of esophagus cancer cells via regulating SPIN1 expression by targeting miR-876-5p, providing a new therapeutic target for improving the prognosis of esophagus cancer patients.

Hsa_circ_0007380 silencing restrains the growth and enhances radiosensitivity in esophagus cancer by miR-644a/Spindlin 1 axis.

Circular RNAs are frequently dysregulated and show important regulatory function of tumorigenesis in cancers. Hsa_circ_0007380 was found to be elevated in human radioresistant esophageal cancer cells. Here, this study aimed to investigate the action and mechanism of hsa_circ_0007380 in esophageal cancer carcinogenesis and radiosensitivity. Quantitative real-time PCR and western blotting were performed to detect levels of genes and proteins. Functional experiments were conducted using MTT assay, EdU assay, clonogenic survival assay, flow cytometry and murine xenograft model assay, respectively. The binding between miR-644a and hsa_circ_0007380 or spindlin1 (SPIN1) was validated using dual-luciferase activity assay. Hsa_circ_0007380 was highly expressed in esophagus cancer tissues and cells, knockdown of hsa_circ_0007380 suppressed esophagus cancer cell proliferation, induced apoptosis and enhanced radiosensitivity in vitro, and the same effects were also confirmed in nude mice. Mechanistically, hsa_circ_0007380 sequestered miR-644a to release SPIN1 expression, implying the hsa_circ_0007380/miR-644a/SPIN1 competing endogenous RNA network esophagus cancer cells. miR-644a was decreased in esophagus cancer, re-expression of miR-644a restrained cell growth and conferred radiosensitivity in esophagus cancer, which were reversed by SPIN1 overexpression. Besides that, inhibition of miR-644a abolished the promoting action of hsa_circ_0007380 knockdown on esophagus cancer apoptosis and radiosensitivity. Hsa_circ_0007380 silencing impedes cell growth and reinforces radiosensitivity in esophagus cancer by miR-644a/SPIN1 axis, suggesting a promising therapeutic target for esophagus cancer combined treatment.

First-degree family history of diabetes is associated with nonalcoholic fatty liver disease independent of glucose metabolic status.

BACKGROUND: The first-degree relatives of patients with diabetes (FDRs) share a common genetic background with patients with diabetes. Insulin resistance is recognized as a common contributor to diabetes and nonalcoholic fatty liver disease (NAFLD). The present study aimed to investigate the association between a first-degree family history of diabetes (FHD) and NAFLD and the influence of glucose metabolic status. METHODS: The present work analyzed a part of the baseline data of the REACTION study conducted in a community population. A total of 11,162 participants with an average age of 55.57 ± 9.66 years were enrolled, including 9870 non-FDRs and 1292 FDRs. First-degree FHD was defined as at least one patient with diabetes among parents, siblings or children. The fatty liver index (FLI) was calculated to identify NAFLD. RESULTS: The proportions of subjects without NAFLD, with intermediate FLI, and with NAFLD differed significantly between non-FDRs and FDRs (P < 0.001). FLI was one of the metabolic factors independently associated with first-degree FHD (P = 0.006). Multivariate variance analysis revealed positive associations of first-degree FHD and glucose metabolic status (both P < 0.001) with FLI, which were independent of each other (P for interaction = 0.182). Multiple stepwise linear regression analysis identified that first-degree FHD was independently and positively associated with FLI in men, premenopausal women, and postmenopausal women (all P < 0.05). CONCLUSION: A first-degree FHD was an independent risk factor for NAFLD. Regardless of the status of glucose metabolism, FDRs were more susceptible to NAFLD.

Madelung disease: A case report.

BACKGROUND: Madelung disease (MD) is a rare disorder of fat metabolism, resulting in diffuse, symmetrical and painless deposition of adipose tissue in subcutaneous superficial fascial space and/or deep fascia space of the head, neck and shoulders, etc. CASE SUMMARY: We report a case of MD accompanied by type 2 diabetes in a 61-year-old Chinese male. The patient presented with progressive fat deposition over the mandible, neck, abdomen and elbows. He had a history of smoking and alcohol abuse. Excessive fat deposition was seen in the mandible, elbows and the abdominal area of the patient by ultrasonic examination. Computed tomography showed diffuse and marked soft masses (fat density) in the subcutaneous superficial fascia space of the neck. The patient was diagnosed with MD. He was advised to abstain from alcohol and was followed up regularly. CONCLUSION: This report discusses the pathogenesis, diagnosis and treatment of MD, and raises the clinician's awareness of this disease.

A Clinical Epidemiological Analysis of Prognostic Nutritional Index Associated with Diabetic Retinopathy.

PURPOSE: Prognostic nutritional index (PNI) is an effective tool to evaluate the nutritional conditions and predict prognosis, but clinical data are limited for the use of PNI in diabetic retinopathy (DR). This study aimed to investigate the relationship of PNI with the prevalence and severity of DR in patients with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: This cross-sectional analysis enrolled 1023 individuals with T2DM hospitalized between 2017-2020. PNI was calculated as 10 × serum albumin (g/l) + 0.005 × total lymphocyte count (cells/mL). DR severity was categorized as no, nonproliferative, and vision-threatened DR (VTDR) according to the modified Airlie House classification. Multivariate-adjusted odds ratio (OR) with 95% confidence interval (CI) for the prevalent DR in the top (Q4) compared with the bottom quartile (Q1) of PNI levels were estimated by using logistic regression analyses. RESULTS: PNI levels were significantly lower in individuals with VTDR than those with no and nonproliferative DR (both P < 0.001), and the proportions of individuals with DR were significantly decreased in the top quartile compared with the bottom quartile of PNI levels (P < 0.001). After adjustments for age, gender, DM duration, obesity-related risk factors and clinical biochemical parameters, the higher levels of PNI were significantly associated with a lower prevalence of DR (Q4 vs Q1: OR = 0.402, 95% CI: 0.250-0.649, P < 0.001), with a 5.9% reduction in the prevalence of DR for a per-unit increment in the levels of PNI (OR = 0.941, 95% CI: 0.911-0.972, P < 0.001). The association of PNI and obesity-related indexes (body mass index and waist circumference) with the severity of DR was independent of each other (P<0.001). CONCLUSION: PNI was inversely and independently associated with the severity and prevalence of DR, which suggested that PNI could likely be used to predict DR prognosis in clinical practice.

Associations of early-life exposure to famine with abdominal fat accumulation are independent of family history of diabetes and physical activity.

The present study aimed to investigate the association of early-life exposure to famine with abdominal fat accumulation and function and further evaluate the influence of first-degree family history of diabetes and physical activity on this association. The present work analysed parts of the REACTION study. A total of 3033 women were enrolled. Central obesity was defined as waist circumferences (W) ≥ 85 cm. Chinese visceral adiposity index (CVAI) was used to evaluate visceral adipose distribution and function. Partial correlation analysis showed BMI, W, glycated Hb and CVAI were associated with early-life exposure to famine (both P < 0·05). Logistic regression showed that the risks of overall overweight/obesity and central obesity in fetal, early-childhood, mid-childhood and late-childhood exposed subgroups were increased significantly (all P < 0·05). Compared with the non-exposed group, the BMI, W and CVAI of fetal, early- to late-childhood exposed subgroups were significantly increased both in those with or without first-degree family history of diabetes and in those classified as physically active or inactive, respectively (all P < 0·05). The associations of BMI, W and CVAI with early-life exposure to famine were independent of their associations with first-degree family history of diabetes (all P < 0·01) or physical activity status (all P < 0·001). Early-life exposure to famine contributed to abdominal fat accumulation and dysfunction, which was independent of the influence of genetic background and exercise habits. Physical activity could serve as a supplementary intervention for women with high risk of central obesity.

Association of Serum Fibroblast Growth Factor 23 Levels with the Presence and Severity of Hepatic Steatosis Is Independent of Sleep Duration in Patients with Diabetes.

PURPOSE: Fibroblast growth factor (FGF) 23 is currently recognized to be involved in the occurrence and development of metabolic diseases. The present study aimed to investigate the association between serum FGF23 levels and hepatic steatosis, as well as the influence of sleep duration. PATIENTS AND METHODS: The present study population was selected from patients with diagnosed diabetes hospitalized during February 2018 to April 2019. Serum FGF23 levels were assessed by two-side sandwich enzyme-linked immunosorbent assay. The presence and severity of hepatic steatosis were determined by controlled attenuation parameter (CAP). Hepatic steatosis was determined as CAP≥302 dB/m. RESULTS: Serum FGF23 levels were significantly higher in individuals with hepatic steatosis than in those without hepatic steatosis (P=0.004). The present study population was divided into Q1-Q4 according to serum FGF23 quartiles. The risks of hepatic steatosis were increased more than 3 folds in Q2-Q4 (all P<0.01) compared to Q1. CAP showed an uptrend from Q1 to Q4 (P=0.005), even after adjustment for gender and age (P=0.001). Multivariate variance analyses showed significant differences in CAP among Q1-Q4 (P=0.008) and between individuals with short and long sleep duration (P=0.023), which were independent of each other. Serum FGF23 levels were positively associated with CAP independent of gender, age, total metabolic traits, and sleep duration (P=0.042). CONCLUSION: Serum FGF23 levels were independently and positively associated with the severity of hepatic steatosis. The associations of serum FGF23 levels and sleep duration with hepatic steatosis were independent of each other.

Duration of reproductive years and time since menopause were associated with metabolic syndrome in postmenopausal parous women of Chinese ancestry.

OBJECTIVE: Although duration of reproductive years and time since menopause were previously implicated in the metabolic syndrome, the evidence is more limited. Few of the previous studies were able to take into account related reproductive variables simultaneously. The aim of the present study was to explore the influence of these two reproductive factors on the prevalence of metabolic syndrome in postmenopausal parous women from Southeast China. METHODS: In all, 1,536 postmenopausal parous women were recruited. Self-reported information about reproductive status, including age at menarche, age at menopause, number of children, prepregnancy body weight, and oral contraceptive use, was collected, and duration of reproductive years and time since menopause were calculated. Clinical parameters related with metabolic syndrome were also measured. RESULTS: Longer duration of reproductive years was significantly related with increased presence of the metabolic syndrome (odds ratio [OR] 1.570, 95% confidence interval [CI] 1.091, 2.259 for tertile 2 group; OR 1.850, 95% CI 1.163, 2.944 for tertile 3 group; P for trend = 0.010). Women with more than 20 years since menopause were more likely to experience metabolic syndrome (OR 2.422, 95% CI 1.109, 5.286, P = 0.026) and elevated blood pressure (OR 3.239, 95% CI 1.406, 7.458, P = 0.006) when compared with those with less than 10 years since menopause. CONCLUSIONS: Longer duration of reproductive years and time since menopause were associated with higher prevalence of metabolic syndrome in postmenopausal parous women from Southeast China.

Inhibition of STAT3 in tubular epithelial cells prevents kidney fibrosis and nephropathy in STZ-induced diabetic mice.

Recent evidences indicate that signal transducer and activator of transcription 3 (STAT3) is one of the crucial signaling pathways in the progression of diabetic nephropathy (DN). Here, we investigated the hypothesis that pharmacological blockade of STAT3 limits the progression of DN. Treatment with selective STAT3 inhibitor, S3I-201 for 16 weeks significantly attenuated kidney injuries in streptozotocin (STZ) induced diabetic mice, associated with downregulated expression of TGF-ß1, ACE/AT1, and VEGF in diabetic mouse kidneys. Similar results were confirmed using genetic knockdown of STAT3 in mouse kidneys by injections of AAV2 expressing STAT3 shRNA in diabetic mouse. Further, STAT3 localization in kidney tissue was evaluated using immunofluorescent double-staining analysis, which indicated that STAT3 expression was mainly in the tubular epithelial cells. As expected, in renal tubular epithelial NRK-52E cells, high glucose (HG)-induced overexpression of TGF-ß1, ACE/AT1, and VEGF were abrogated by S3I-201 pretreatment, as well as by genetic knockdown of STAT3 using specific siRNA sequence. This study found that renal tubular epithelial cells contributed to STAT3-mediated progression of DN and provided the first evidence that pharmacological inhibition of STAT3 attenuates DN.

Association of bone mineral density with a first-degree family history of diabetes in normoglycemic postmenopausal women.

OBJECTIVE: A first-degree family history of diabetes (FHD) contributes to increased risks of metabolic and cardiovascular diseases. Bone is an insulin-resistant site and an organ susceptible to microvascular complications. The goal of the present study was to investigate the association of FHD with bone mineral density (BMD) in postmenopausal women. METHODS: In all, 892 normoglycemic postmenopausal women were divided into subgroups of participants with or without a first-degree FHD. BMD was measured using dual-energy x-ray absorptiometry. Fasting plasma insulin and glucose levels were measured, and insulin resistance was evaluated using the Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) index. RESULTS: The BMD of the lumbar spine and femoral neck were much higher in the participants with a first-degree FHD than in those without an FHD (all P < 0.05). Lumbar spine BMD and femoral neck BMD were both positively associated with HOMA-IR (P = 0.041 and P = 0.005, respectively). Multiple stepwise regression analysis showed that a first-degree FHD was an independent factor that was positively associated with lumbar spine BMD (standardized ß = 0.111, P = 0.001) and femoral neck BMD (standardized ß = 0.078, P = 0.021). A first-degree FHD was associated with increased BMD, insulin resistance, and hyperinsulinemia. CONCLUSIONS: Our study indicated that normoglycemic postmenopausal women with a first-degree FHD exhibit increased BMD with insulin resistance and hyperinsulinemia. A first-degree FHD was an independent factor associated with elevated BMD in Chinese women after menopause.

PREVIOUS DELIVERY OF MACROSOMIA IS ASSOCIATED WITH MATERNAL ADIPOSITY IN LATER LIFE IN CHINESE PAROUS WOMEN WITH NORMAL WEIGHT BEFORE AND/OR AFTER PREGNANCY.

Objective: Obesity has become a major worldwide health challenge. Macrosomic infants are more likely to experience type 2 diabetes mellitus, obesity and hypertension in adulthood. However, whether macrosomia increases the risk of maternal adiposity later in life is still unknown. Methods: One thousand nine hundred eighty-six unrelated parous women of Chinese Han ancestry aged from 40 to 76 years were enrolled. Self-reported information about reproductive status, including age at menarche, number of children, previous delivery of macrosomic infants, and body weight before and after pregnancy were obtained from personal interview by trained interviewers using a standard questionnaire. Macrosomia was defined as birth weight greater than 4,000 g. Adiposity indexes were measured or calculated. Results: Prior delivery of macrosomia was associated with an increased risk of having obesity in parous women with normal weight before pregnancy (odds ratio [OR] = 1.840; 95% confidence interval [CI] 1.028, 3.294; P = .040), as well as a higher risk of overweight/obesity in parous women with normal weight after pregnancy (OR = 1.777; 95% CI 1.131, 2.794; P = .013). In addition, previous delivery of macrosomia was related with 1.919 (95% CI 1.207, 3.050; P = .006) times higher risk of overweight/obesity in parous women with normal weight before and after pregnancy. Conclusion: The present study suggests that prior delivery of macrosomia may be an independent risk factor for adiposity later in life in parous women with normal weight before and/or after pregnancy. Abbreviations: BMI = body mass index; CI = confidence interval; OR = odds ratio; WC = waist circumference; WHR = waist-to-hip ratio; WHtR = waist-to-height ratio.

Genetic Variants Flanking the FGF21 Gene Were Associated with Renal Function in Chinese Patients with Type 2 Diabetes.

AIMS: Fibroblast growth factor 21 (FGF21) is closely linked with metabolic disorders including diabetes. Evidences suggested that FGF21 may play a protective role against diabetic kidney disease (DKD). However, the relationship between genetic variants in the FGF21 gene region and DKD remains unknown. In our study, we aimed to investigate the association of genetic variations in this gene region with DKD and DKD-related clinical traits. MATERIALS AND METHODS: We recruited 1340 Han Chinese participants with type 2 diabetes, including 596 DKD patients and 744 patients who was diagnosed with diabetes for more than 5 years but did not progress to DKD. Three single-nucleotide polymorphisms were selected (rs2071699, rs838136, and rs499765) and genotyped. The association between these SNPs and DKD as well as DKD-related quantitative traits was analyzed. RESULTS: We did not find any significant association between these SNPs and susceptibility to DKD in the present study. However, a significant association with estimated glomerular filtration rate (eGFR) was detected: in the non-DKD group, rs838136 was significantly associated with eGFR under an additive model (ß = 0.013 ± 0.006, P = 0.0295, ß was calculated for log10eGFR) as well as a recessive model (P = 0.0385) and rs499765 was associated with eGFR under a dominant model (P = 0.0411) and in the DKD group, rs499765 showed a trend toward association with eGFR under an additive model (ß = -0.022 ± 0.012, P = 0.0820, ß was calculated for log10eGFR) and showed a significant association with eGFR under a dominant model (P = 0.0182). CONCLUSIONS: Our findings indicated that genetic variations adjacent to FGF21 were associated with eGFR in Chinese diabetic patients.

MD2 blockade prevents oxLDL-induced renal epithelial cell injury and protects against high-fat-diet-induced kidney dysfunction.

There is a strong epidemiological link between obesity, a growing worldwide concern, and kidney disease. Emerging evidence indicates that the pathogenic basis of obesity-related kidney disease may be attributed to Toll-like receptor 4 (TLR4) of the innate immune system. We hypothesized that renal epithelial cell injury in response to oxidized low-density lipoprotein (oxLDL) requires myeloid differentiation factor 2 (MD2), a co-receptor of TLR4. Moreover, we also hypothesized that renal dysfunction is MD2-dependent in the high-fat diet (HFD) mouse model. Results indicated that the MD2 selective inhibitor (L6H21) abrogated the oxLDL-induced formation of MD2-TLR4 dimerization in the renal proximal tubular epithelial cell line NRK-52E. Further, MD2 blockade in NRK-52E cells using siRNA target sequences or L6H21 prevented oxLDL-induced cell injury as indicated by expression of profibrotic molecules, autophagic activity and apoptosis. Similarly, TLR4 knockdown in NRK-52E cells using siRNA target sequences prevented oxLDL-induced cell injury. In the HFD mouse model, MD2 knockout protected against development of kidney dysfunction and renal tissue injury, corroborating the observations observed in NRK-52E cells. Thus, the oxLDL-induced renal tubular epithelial cell profibrotic responses, autophagy and apoptosis were dependent on MD2, as were the renal dysfunction and tissue impairment in HFD mice. These are new findings indicating that the MD2-TLR4 immune signaling complex is a critical pathogenic factor in the development of kidney disease related to obesity or metabolic syndrome.

Blockade of myeloid differentiation 2 attenuates diabetic nephropathy by reducing activation of the renin-angiotensin system in mouse kidneys.

BACKGROUND AND PURPOSE: Both innate immunity and the renin-angiotensin system (RAS) play important roles in the pathogenesis of diabetic nephropathy (DN). Myeloid differentiation factor 2 (MD2) is a co-receptor of toll-like receptor 4 (TLR4) in innate immunity. While TLR4 is involved in the development of DN, the role of MD2 in DN has not been characterized. It also remains unclear whether the MD2/TLR4 signalling pathway is associated with RAS activation in diabetes. EXPERIMENTAL APPROACH: MD2 was blocked using siRNA or the low MW inhibitor, L6H9, in renal proximal tubular cells (NRK-52E cells) exposed to high concentrations of glucose (HG). In vivo, C57BL/6 and MD2-/- mice were injected with streptozotocin to induce Type 1 diabetes and nephropathy. KEY RESULTS: Inhibition of MD2 by genetic knockdown or the inhibitor L6H9 suppressed HG-induced expression of ACE and angiotensin receptors and production of angiotensin II in NRK-52E cells, along with decreased fibrosis markers (TGF-ß and collagen IV). Inhibition of the MD2/TLR4-MAPKs pathway did not affect HG-induced renin overproduction. In vivo, using the streptozotocin-induced diabetic mice, MD2 was overexpressed in diabetic kidney. MD2 gene knockout or L6H9 attenuated renal fibrosis and dysfunction by suppressing local RAS activation and inflammation. CONCLUSIONS AND IMPLICATIONS: Hyperglycaemia activated the MD2/TLR4-MAPKs signalling cascade to induce renal RAS activation, leading to renal fibrosis and dysfunction. Pharmacological inhibition of MD2 may be considered as a therapeutic approach to mitigate DN and the low MW inhibitor L6H9 could be a candidate for such therapy.

Inverse association between physical activity and blood glucose is independent of sex, menopause status and first-degree family history of diabetes.

AIMS/INTRODUCTION: Exercise training is a recognized strategy central to the prevention, treatment, and management of diabetes and prediabetes. The aim of the present study was to investigate the association between physical activity and blood glucose, as well as the influence of sex, menopause status and family history of diabetes. MATERIALS AND METHODS: Participants with normal weight were selected from Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal Study, and divided into inactive (moderate-to-vigorous-intensity physical activity [MVPA] <30 min/week), low-degree (MVPA ≥30 and ≤420 min/week) and high-degree (MVPA >420 min/week) activity groups. RESULTS: A total of 2,601 individuals with an average age of 57.85 ± 8.39 years were enrolled. Multivariate anova uncovered that after adjustment for sex and menopause status, and family history of diabetes, respectively, fasting plasma glucose, 2-h plasma glucose and glycated hemoglobin A1c decreased through inactive, low-degree and high-degree activity groups (all P for trend <0.05). The association of blood glucose indexes with physical activity was independent of this association with sex and menopause status, and first-degree family history of diabetes, respectively. Multivariate linear regression analyses showed that MVPA was an independent factor associated negatively with fasting plasma glucose, 2-h plasma glucose and glycated hemoglobin A1c, respectively (all P < 0.01). CONCLUSIONS: A higher degree of physical activity was associated with lower blood glucose regardless of sex, menopause status and first-degree family history of diabetes. MVPA is a negative factor associated with blood glucose independently. Physical activity of adequate duration and intensity is strongly recommended to individuals with susceptibility to diabetes as a result of sex and family history, but without overweight/obesity.

Inhibition of STAT3 activation mediated by toll-like receptor 4 attenuates angiotensin II-induced renal fibrosis and dysfunction.

BACKGROUND AND PURPOSE: Hypertension adversely affects the kidney and is the second leading cause of kidney failure. Overproduction of angiotensin II greatly contributes to the progression of hypertensive kidney disease. Angiotensin II has recently been shown to activate STAT3 in cardiovascular cells. However, the underlying mechanisms of STAT3 activation by angiotensin II and downstream functional consequences in the kidneys are not fully understood. EXPERIMENTAL APPROACH: C57BL/6 mice were treated with angiotensin II by subcutaneous infusion for 1 month to develop nephropathy. Mice were treated with either adeno-associated virus expressing STAT3 shRNA or STAT3 inhibitor, S3I-201. Human archival kidney samples from five patients with hypertension and five individuals without hypertension were also examined. In vitro, STAT3 was blocked using siRNA or STAT3 inhibitor S3I-201 in the renal proximal tubular cell line, NRK52E, after exposure to angiotensin II. KEY RESULTS: Angiotensin II activated STAT3 in kidney epithelial cells through engaging toll-like receptor 4 (TLR4) and JAK2, which was independent of IL-6/gp130 and angiotensin AT1 receptors. Angiotensin II-mediated STAT3 activation increased fibrotic proteins and resulted in renal dysfunction. Both STAT3 inhibition by the low MW compound S3I-201 and TLR4 deficiency normalized renal fibrosis and dysfunction caused by Ang II in mice, without affecting hypertension. CONCLUSIONS AND IMPLICATIONS: Our study reveals a novel mechanism of STAT3 activation, induced by angiotensin II, in kidney tissues and highlights a translational significance of a STAT3 inhibitor as potential therapeutic agent for hypertensive kidney disease.