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Objective To investigate the serum expressions of vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGF-β1) and C1q/tumor necrosis factor-related protein 3 (CTRP3) in type II diabetic rats with atherosclerosis and to undermine the interventional mechanism of simvastatin. Methods SD rats were randomly divided into normal diet (NC) group (n=8), high-fat diet (HFD) group (n=8), high-fat diet intervention (HFD+S) group (n=8), model (M) group (n=18) and model intervention (M+S) group (n=16). The diabetic atherosclerosis model was established by streptozotocin (STZ)+ Vitamin D3 (VitD3)+High-fat diet. The group HFD+S and group M+S rats were administrated with simvastatin at 20 mg/(kg⋅d)intragastrically as intervention while distilled water [20 mL/(kg⋅d)] were given to other groups. Serum levels of fasting plasma glucose (FPG), blood lipid, fasting insulin (FINS), VEGF, TGF-β1 and CTRP3 were compared between each groups. Results Characteristics of atheromatous plaque were seen in group M and group M + S whose pathological change were markedly attenuated compared to group M. Serum levels of VEGF, TGF-β1 and CTRP3 were significantly higher in rats from Group HFD than those in rats from group NC. Serum levels of VEGF and TGF-β1 were significantly higher in rats from Group M than those in rats from group NC. Serum level of VEGF was significantly higher in rats from Group M than it in rats from group HFD. Serum level of CTRP3 was significantly lower in rats from Group M than it in rats from group HFD. Moreover, serum levels of TGF-β1 and CTRP3 were significantly higher in rats from Group HFD+S than those in rats from group HFD after the intervention with simvastatin. Serum level of VEGF was significantly lower in rats from Group M+S than it in rats from group M, and serum levels of TGF-β1 and CTRP3 were significantly higher in rats from group M+S than those in rats from group M after the intervention with simvastatin. Conclusion VEGF, TGF-β1 and CTRP3 may participate in development of diabetic atherosclerosis. In addition to its hypolipidemic role, Simvastatin can also down regulate serum level of VEGF and up regulate serum levels of TGF-β1 and CTRP3 to exert a significant protective effect on diabetic atherosclerosis. [ABSTRACT FROM AUTHOR]

Soft tissue sarcomas (STSs) are a rare and fascinating group of diseases that can be subdivided into specific reciprocal translocations in STSs (SRTSs) and nonspecific reciprocal translocations in STSs (NRTSs). PTEN mutations are rare in STSs, suggesting that PTEN expression may be lost by alternative mechanisms such as methylation. In order to reveal whether aberrant PTEN methylation occurs in STSs, MassARRAY Spectrometry was carried to detect methylation patterns of PTEN in STSs. We evaluated methylation levels in 41 CpG sites from −2,515 to −2,186 bp (amplicon A) and −1,786 to −1,416 bp (amplicon B) relative to the translation initiation site in 110 different cases (46 cases of SRTSs, 40 cases of NRTSs, and 24 cases of normal controls). In addition, immunohistochemistry (IHC) was used to detect the loss of PTEN to determine whether PTEN alterations were responsible for decreased PTEN expression. Our data showed that expression of PTEN was diminished in 49 (57%) STSs, whereas the remaining cases (43%) were classified as high expression. Our previous results found that only 2 of 86 cases (2.3%) had a PTEN mutation suggesting that PTEN may be mainly downregulated in STSs by methylation, but not by mutation of PTEN itself. We observed that amplicon A was hypermethylated in STSs with low PTEN expression, whereas normal controls had low methylation levels (P<0.0001), which was not present in amplicon B (P>0.05), nor were there significant differences in the methylation levels in PTEN between SRTS and NRTS cases. The majority of individual CpG units within two amplicons was demonstrated to be hypermethylated. These findings indicate that PTEN hypermethylation is a common event in STSs suggesting that the inactivation of PTEN may be due to hypermethylation in the promoter of PTEN. The aberrant methylation of the CpG sites within PTEN promoter may serve as a potential candidate biomarker for STSs. [ABSTRACT FROM AUTHOR]

The article presents a study on the enhanced green fluorescent protein (EGFP) expression in transgenic chickens. The ability of the 2-(kilobyte) kb promoter fragment of the chicken ovalbumin gene to elicit tissue-specific expression of a foreign EGFP gene in chickens. The study projected potential of chicken ovalbumin promoter for the production of biologically active proteins in egg whites.

Abstract\nSIGNIFICANCE STATEMENTKeratinocyte and fibroblast dysfunctions contribute to delayed healing of diabetic wounds. Small extracellular vesicles (sEV) are key mediators of intercellular communication and are involved in the pathogenesis of several diseases. Recent findings suggest that sEV derived from high-glucose-treated keratinocyte (HaCaT-HG-sEV) can transport LINC01435 to inhibit tube formation and migration of HUVECs, thereby delaying wound healing. This study aimed to elucidate sEV-related communication mechanisms between keratinocytes and fibroblasts during diabetic wound healing. HaCaT-HG-sEV treatment and LINC01435 overexpression significantly decreased fibroblast collagen level and migration ability but significantly increased fibroblast autophagy. However, treatment with an autophagy inhibitor suppressed LINC01435 overexpression-induced decrease in collagen levels in fibroblasts. In diabetic mice, HaCaT-HG-sEV treatment decreased collagen levels and increased the expression of the autophagy-related proteins Beclin-1 and LC3 at the wound site, thereby delaying wound healing. Conclusively, LINC01435 in keratinocyte-derived sEV activates fibroblast autophagy and reduces fibroblast collagen synthesis, leading to impaired diabetic wound healing.Diabetic foot ulcers are a serious complication of diabetes and can lead to amputation and death. Therefore, it is crucial to comprehensively elucidate the mechanisms of delayed diabetic wound healing, with emphasis on the role of keratinocyte-derived small extracellular vesicles. In vivo and in vitro experiments showed that keratinocyte-derived small extracellular vesicles suppressed diabetic wound healing, which is partly attributed to the effects of their content (LINC01435) in fibroblasts. This study suggests that LINC01435 could be targeted to regulate diabetic wound healing. [ABSTRACT FROM AUTHOR]

The thermoresponsive double-hydrophilic glycopolymer (DHG), Poly (6- O -vinyl-nonanedioyl- d -galactose- co - N -vinylcaprolactam) (P(OVNG- co -NVCL)) was synthesized via a chemo-enzymatic process and a free radical copolymerization and the resulting nanofibers were fabricated using an electrospinning process. The desired lower critical solution temperature (LCST) between 32 and 40 °C of the DHG polymers was achieved by adjusting the molar fraction of galactose monomer in the copolymers during the synthesis. The thermoresponsive DHG polymers were found to have good cytocompatibility with Hela cells as determined by the MTT assay, and special recognition of the protein peanut agglutinin (PNA). The drug release properties of these newly designed thermoresponsive DHG P(OVNG- co -NVCL) nanofibers are temperature regulated, can target specific proteins and have the potential application in the field of sustained drug release. [ABSTRACT FROM AUTHOR]

Objectives There have been no previous reports concerning functions of miR-103a in gastric cancer ( GC) cells. Thus the aim of the study was to investigate its expression and role in development of this tumour. Materials and methods Real-time RT- PCR was performed to detect expression of miR-103a in GC cell lines and clinical cancer specimens. To further understand its role, we restored expression of miR-103a in MGC-803 cell line by transfection with miR-103a mimics or inhibitors. Effects of miR-103a on cell proliferation, migration and invasion on targets were also determined. Results miR-103a was down-regulated in both GC cell lines and clinical cancer specimens. Meanwhile, its level was closely associated with pM or pTNM stage of GC. Overexpression of miR-103a markedly suppressed proliferation, migration, and invasion of GC cells, while its inhibition significantly accelerated cell proliferation, migration and invasion. Moreover, c-Myb was identified to be a functional downstream target of miR-103a, ectopic expression of which partially reversed suppression of cell proliferation and invasion. Conclusions Thus our observations suggest that miR-103a functioned as a tumour suppressor by targeting c-Myb. These findings indicate that miR-103a might play a significant role in pathogenesis of GC. [ABSTRACT FROM AUTHOR]

Background: Concerns regarding the use of selected bone marrow stem cells (BMSCs) in the field of cardiac repair after acute ischemic events have been raised. The current meta-analysis aimed to assess the efficacy and safety of selected BMSC transplantation in patients with acute myocardial infarction (AMI) based on published randomized controlled trials (RCTs). Methods: A systematic literature search of PubMed, Ovid LWW, BIOSIS Previews, and the Cochrane library from 1990 to 2014 was conducted. Results from RCTs involving subjects with AMI receiving selected BMSC therapy and followed up for at least 6 months were pooled. Results: Eight trials with a total of 262 participants were included. Data were analyzed using a random effects model. Overall, selected BMSC therapy improved left ventricular ejection fraction (LVEF) by 3.17% (95% confidence interval [CI] 0.57–5.76, P = 0.02), compared with the controls. There were trends toward reduced left ventricular end-systolic volume (LVESV) and fewer major adverse cardiac events (MACEs). Subgroup analysis revealed a significant difference in LVEF in favor of selected BMSC therapy with bone marrow mesenchymal stem cells (BMMSCs) as the cell type. Conclusions: Transplantation of selected BMSCs for patients with AMI is safe and induces a significant increase in LVEF with a limited impact on left ventricular remodeling. [ABSTRACT FROM AUTHOR]

Background: Research has shown that gonadal hormones are involved in metabolic pathways relevant to metabolic syndrome (MetS). Nevertheless, no longitudinal study has been conducted on the association between SHBG and MetS in Chinese. The objective of our study was to determine whether there is any association between middle-aged and elderly males in China., Methods: A total of 531 eligible male subjects, aged above 40 years or older, without MetS at baseline, were recruited. Sex hormone binding globulin (SHBG), total testosterone (TT), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were measured. A harmonized definition and recommended thresholds for the Chinese population were used to determine metabolic syndrome., Results: During 3.2 years of follow-up, 20.7% of subjects had developed MetS. Compared with the non-MetS group, subjects in the new-onset MetS group had significantly lower SHBG (43.5 nmol/L [28.8, 74.9] vs 53.7nmol/L [33.8, 115.0], P=0.0018), TT (18.1nmol/L [13.6-21.7] vs 19.5nmol/L[15.0-23.6], P=0.0204), and LH (5.13mIU/L [3.63-7.29] vs 5.87mIU/L [4.05-8.36]) at baseline. The incidence of MetS was decreased according to elevated SHBG quartiles (Q1:26.9%, Q2:22.7%, Q3:21.1%, Q4:12.1%, P for trend =0.0035), TT (Q1: 25.2%, Q2:23.7%, Q3: 17.3%, Q4: 16.7%, P for trend=0.0425), and LH (Q1:25.0%, Q2:21.8%, Q3: 21.8%, Q4: 14.3%, P for trend=0.0411). Compared with those in quartile 4, the OR[CI] of incident MetS for participants in Quartile 1 was 2.33[1.13-4.79] after multiple adjustments. But associations between incident MetS and different quartiles of LH, TT, and FSH were not observed after multiple adjustments. In the subgroup analyses, the significant association between SHBG level and Mets was detected in subjects over 60 years or older, with normal BMI, without insulin resistance, and with eGFR ≥90 mL/min per 1.73m2., Conclusion: Compared with TT, LH, and FSH, a lower level of SHBG is significantly related to the incidence of MetS among middle-aged and elderly males in China., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Chen, Li, Huang, Lin, Wang, Wang, You, Li, Li, Liang, Xiao, Yan, Lao and Sun.)

Methylene blue (MB) was found to exert neuroprotective effect on different brain diseases, such as ischemic stroke. This study assessed the MB effects on ischemia induced brain edema and its role in the inhibition of aquaporin 4 (AQP4) and metabotropic glutamate receptor 5 (mGluR5) expression. Rats were exposed 1 h transient middle cerebral artery occlusion (tMCAO), and MB was injected intravenously following reperfusion (3 mg/kg). Magnetic resonance imaging (MRI) and 2,3,5-triphenyltetrazolium chloride (TTC) staining was performed 48 h after the onset of tMCAO to evaluate the brain infarction and edema. Brain tissues injuries as well as the glial fibrillary acidic protein (GFAP), AQP4 and mGluR5 expressions were detected. Oxygen and glucose deprivation/reoxygenation (OGD/R) was performed on primary astrocytes (ASTs) to induce cell swelling. MB was administered at the beginning of reoxygenation, and the perimeter of ASTs was measured by GFAP immunofluorescent staining. 3,5-dihydroxyphenylglycine (DHPG) and fenobam were given at 24 h before OGD to examine their effects on MB functions on AST swelling and AQP4 expression. MB remarkably decreased the volumes of T2WI and ADC lesions, as well as the cerebral swelling. Consistently, MB treatment significantly decreased GFAP, mGluR5 and AQP4 expression at 48 h after stroke. In the cultivated primary ASTs, OGD/R and DHPG significantly increased ASTs volume as well as AQP4 expression, which was reversed by MB and fenobam treatment. The obtained results highlight that MB decreases the post-ischemic brain swelling by regulating the activation of AQP4 and mGluR5, suggesting potential applications of MB on clinical ischemic stroke treatment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Although obesity and heart rate (HR) were closely related to the prevalence and development of type 2 diabetes mllitus (T2DM), few studies have shown a co-association effect of them on T2DM. We aimed at assessing the interactive effects of HR and obesity with prevalence of T2DM in Chinese population, providing the exact cutpoint of the risk threshold for blood glucose with high HR., Materials and Methods: In the Risk Evaluation of cAncers in Chinese diabeTic Individuals: a lONgitudinal study (REACTION) cohorts (N = 8398), the relationship between HR and T2DM was explored by linear regression, logistic regression, and restricted cubic spline, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Interaction terms between HR and body mass index (BMI) and HR and waist circumference (WC) were introduced into the logistic regression model., Results: In those with HR > 88.0 beats/min, fasting plasma glucose and oral glucose tolerance tests were significantly correlated with HR, and the prevalence of T2DM was highly correlated with HR (all p < .05). There were interactive associations of HR and obesity in patients with T2DM with HR < 74 beats/min., Conclusion: High HR was in interaction with obesity, associating with prevalence of T2DM. The newly subdivided risk threshold for HR with T2DM might be HR > 88 beats/minute., (© 2024 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: Dipeptidyl peptidase-4 inhibitors (DPP-4i) have become firmly established in treatment algorithms and national guidelines for improving glycemic control in type 2 diabetes mellitus (T2DM).To report the findings from a multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial, which was designed to assess the efficacy and safety of a novel DPP-4 inhibitor fotagliptin in treatment-naive patients with T2DM., Methods: Patients with T2DM were randomized to receive fotagliptin (n = 230), alogliptin (n = 113) or placebo (n = 115) at a 2:1:1 ratio for 24 weeks of double-blind treatment period, followed by an open-label treatment period, making up a total of 52 weeks. The primary efficacy endpoint was to determine the superiority of fotagliptin over placebo in the change of HbA1c from baseline to Week 24. All serious or significant adverse events were recorded., Results: After 24 weeks, mean decreases in HbA1c from baseline were -0.70% for fotagliptin, -0.72% for alogliptin and -0.26% for placebo. Estimated mean treatment differences in HbA1c were -0.44% (95% confidence interval [CI]: -0.62% to -0.27%) for fotagliptin versus placebo, and -0.46% (95% CI: -0.67% to -0.26%) for alogliptin versus placebo, and 0.02% (95%CI: -0.16% to 0.19%; upper limit of 95%CI < margin of 0.4%) for fotagliptin versus alogliptin. So fotagliptin was non-inferior to alogliptin. Compared with subjects with placebo (15.5%), significantly more patients with fotagliptin (37.0%) and alogliptin (35.5%) achieved HbA1c < 7.0% after 24 weeks of treatment. During the whole 52 weeks of treatment, the overall incidence of hypoglycemia was low for both of the fotagliptin and alogliptin groups (1.0% each). No drug-related serious adverse events were observed in any treatment group., Conclusions: In summary, the study demonstrated improvement in glycemic control and a favorable safety profile for fotagliptin in treatment-naive patients with T2DM., Trial Registration: ClinicalTrail.gov NCT05782192., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: Chronic kidney disease (CKD) has become a major global health issue, and abnormalities of glucose metabolism are a risk factor responsible for development of CKD. We aimed to investigate associations between glucose metabolism indices and CKD in a Chinese population and determine which index is superior for predicting incident CKD., Methods: We performed a community-based population on 5232 subjects aged ≥40 years without baseline CKD. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m 2 or urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g. We examined the associations of glucose metabolism indices, including fasting plasma glucose (FPG), 2-hour (2 h) oral glucose tolerance test (OGTT), hemoglobin A1c (HbA1c), fasting insulin level, homeostasis model assessment of insulin resistance (HOMA-IR), and HOMA- β and the development of CKD., Results: With an average follow-up of 3.6 years, 6.4% of the subjects developed CKD. Pearson's correlation analysis revealed that FPG, HbA1c, fasting insulin, and HOMA-IR were all significantly correlated with UACR and eGFR. The association persisted in multivariate linear regression analysis adjusted for age and sex. Compared with other glucose indices, HOMA-IR exhibited the strongest associations with CKD in COX multivariate regression analysis (HR = 1.17, 95% CI: 1.04-1.31)., Conclusion: HOMA-IR is superior to other routine indices of glucose metabolism for predicting the development of CKD in middle-aged Chinese persons. Screening with HOMA-IR may help prevent the development of CKD in the general population., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Lili You et al.)

This cross-sectional study aimed to investigate the association between non-alcoholic fatty liver disease (NAFLD) and atherosclerotic cardiovascular disease (ASCVD), a global public health concern. A total of 9044 out of 10,104 adults from Guangzhou, China, were included in the analysis. We utilized the fatty liver index (FLI), a noninvasive indicator of NAFLD, and the pooled cohort equations (PCE) based on the 2013 ACC/AHA Guideline, the China-PAR model, and the Framingham Risk Score to assess the 10-year ASCVD risk. The results demonstrated a significant association between FLI and 10-year ASCVD risk ( p < 0.001). Adjusted for age, individuals with high FLI (≥60) had an odds ratio of 3.91 (95% CI 2.52-6.08) compared to those with low FLI (<30). These findings persisted after adjusting for metabolic indicators. Notably, this association was consistently observed across all three risk prediction models: the PCE model, the China-PAR model, and the Framingham Risk Score. In conclusion, our study provides evidence supporting FLI as a reliable indicator of increased 10-year ASCVD risk in Chinese NAFLD patients. FLI serves as a valuable marker for early detection of ASCVD, highlighting its potential in clinical practice for risk assessment and prevention strategies.

Accurate communication between fibroblasts and keratinocytes is crucial for diabetic wound healing. Extracellular vesicles are being explored as essential mediators of intercellular communication in the skin. However, the mechanisms underlying wound healing mediated by fibroblast-derived extracellular vesicles (Fib-EVs) remain unclear. The present study evaluated the role of long noncoding RNA upregulated in diabetic skin (lnc-URIDS) packed in Fib-EVs in the wound healing of streptozotocin-induced diabetes and the potential mechanisms of the effects. We demonstrated that high glucose induced the enrichment of lnc-URIDS in Fib-EVs, facilitated the transfer of lnc-URIDS to primary rat epidermal keratinocytes, and increased the expression of matrix metalloproteinase-9. Mechanistically, the binding of lnc-URIDS to YTH domain family protein-2 enhanced the degradation of YTH domain family protein-2 in the lysosomes, which increased the translational activity of the messenger RNA of matrix metalloproteinase-9 and ultimately induced the degradation of collagen for wound healing. The results provided an insight into the crosstalk and cooperation between fibroblasts and keratinocytes in collagen homeostasis in diabetic wounds and clarified the mechanism by which lnc-URIDS degrades collagen for diabetic wound healing., (Copyright © 2022 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Background: The relationship between thyroid autoimmunity (TAI) and adverse pregnancy outcomes is disputable, and their dose-dependent association have not been fully clarified., Objective: To investigate the association and dose-dependent effect of TAI with multiple maternal and fetal-neonatal complications., Methods: This study is a multi-center retrospective cohort study based on singleton pregnancies of three medical college hospitals from July 2013 to October 2021. The evolution of thyroid function parameters in TAI and not TAI women were described, throughout pregnancy. The prevalences of maternal and fetal-neonatal complications were compared between the TAI and control group. Logistic regression was performed to study the risk effects and dose-dependent effects of thyroid autoantibodies on pregnancy complications, with adjustment of maternal age, BMI, gravidity, TSH concentrations, FT4 concentrations and history of infertility., Results: A total of 27408 participants were included in final analysis, with 5342 (19.49%) in the TAI group and 22066 (80.51%) in control group. TSH concentrations was higher in TAI women in baseline and remain higher before the third trimester. Positive thyroid autoantibodies were independently associated with higher risk of pregnancy-induced hypertension (OR: 1.215, 95%CI: 1.026-1.439), gestational diabetes mellitus (OR: 1.088, 95%CI: 1.001-1.183), and neonatal admission to NICU (OR: 1.084, 95%CI: 1.004-1.171). Quantitative analysis showed that increasing TPOAb concentration was correlated with higher probability of pregnancy-induced hypertension, and increasing TGAb concentration was positively correlated with pregnancy-induced hypertension, small for gestational age and NICU admission. Both TPOAb and TGAb concentration were negatively associated with neonatal birthweight., Conclusion: Thyroid autoimmunity is independently associated with pregnancy-induced hypertension, gestational diabetes mellitus, neonatal lower birthweight and admission to NICU. Dose-dependent association were found between TPOAb and pregnancy-induced hypertension, and between TGAb and pregnancy-induced hypertension, small for gestational age and NICU admission., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xu, Chen, Ren, Gao, Sun, Wu, Ding, Wang, Li, Liu, Wang and Yan.)

Objectives: Adiponectin is closely related to glucose metabolism and traditional diabetes risk factors (obesity, hypertension and dyslipidaemia). We aimed to explore the association between adiponectin levels and newly diagnosed type 2 diabetes mellitus (T2DM) and pre-diabetes in subgroups classified according to T2DM risk factors., Setting: Sun Yat-sen Memorial Hospital of Sun Yat-sen University., Participants: 3680 individuals (1753 men and 1927 women) aged 18-70 years from Guangzhou and Dongguan, China, were enrolled from December 2018 to October 2019., Primary and Secondary Outcome Measures: T2DM was defined as fasting plasma glucose (FPG)≥7.0 mmol/L or HbA1c≥6.5%, and pre-diabetes was defined as 6.1 mmol/L≤FPG<7.0 mmol/L or 5.7≤HbA1c<6.5%., Results: With the increasing number of T2DM risk factors, the proportion of the population with high-quartile adiponectin levels gradually decreased (p<0.001). A low level of adiponectin was significantly associated with diabetes and pre-diabetes in a population with ≥1 T2DM risk factor, whereas its association was not consistently significant in the population with all three T2DM risk factors. For instance, participants were more likely to have diabetes or prediabetes with low levels of adiponectin when they had ≥ one T2DM risk factor (quartile 2 vs. 1: OR 0.71 [95%CI: 0.56-0.89]; P=0.003; quartile 3 vs. 1: OR 0.57 [95%CIs: 0.44-0.72]; P<0.001; and quartile 4 vs. 1: OR 0.52 [95%CIs: 0.40-0.67]; P<0.001)., Conclusion: Adiponectin was negatively associated with diabetes and pre-diabetes in a population with few T2DM risk factors, while their relationship gradually attenuated with the accumulation of T2DM risk factors, especially in a population with coexisting diseases such as obesity, hypertension and dyslipidaemia., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Epidemiological evidence suggests that lipid parameters are related to the progression of chronic kidney disease (CKD). Nevertheless, prospective studies that comprehensively assess the effect of routinely available lipid measures on the development of CKD are lacking. The aim of this study was to longitudinally assess the influence of lipid metabolism indicators on the presence of CKD in a large community-based population. We conducted a prospective cohort study at Sun Yat-sen Memorial Hospital, China, with 5345 patients of 40 years or older. Cox regression models were conducted, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to assess lipid parameters and their relationship with the incidence of CKD. During the follow-up period, 340 (6.4%) subjects developed CKD. The incidence of CKD increased progressively with quartile values of triglyceride (TG), the ratio of non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol (non-HDL-C/HDL-C) and the ratio of TG to HDL-C, but decreased with HDL-C quartiles (p < 0.0001 for all trends). Pearson’s correlation analysis and multiple regression analyses indicated that these parameters were also associated with various indicators of kidney function. Moreover, we found that among all the lipid parameters, TG/HDL-C emerged as the most effective predictor of CKD. In conclusion, our findings suggest that TG/HDL-C better predicts the incidence of CKD in middle-aged and elderly Chinese individuals than other lipid parameters tested in the study.

Purpose: To investigate the effect of grape seed extract on pathological changes of aorta in rats with chronic periodontitis and arteriosclerosis, and to analyze the possible mechanism., Methods: Fifteen SPF male rats with chronic periodontitis and arteriosclerosis were randomly divided into three groups, i.e., model group(n=5), low dose of grape seed extract group (n=5), high dose of grape seed extract group (n=5) , and control group (n=10). The rats in the low and high dose groups were treated with 40 mg·kg-1·d-1 and 80 mg·kg-1·d-1 for 4 weeks respectively, while the rats in the normal control group and the model group were treated with the same amount of normal saline at the same time. The maximal intima-media thickness(IMT) of abdominal aorta was measured by H-E staining, the activity of SOD and the content of MDA in serum were measured by colorimetry, the content of GSH-px in serum and serum levels of inflammatory factor (TNF-α) and interleukin-6(IL-6) were detected by ELISA. p38 mitogen-activated protein kinase/nuclear transcription factor Kappa B p65(p38 MAPK/NF-κB p65) pathway was detected by Western blotting. SPSS 20.0 software package was used for statistical analysis., Results: In the model group, the intima of abdominal aorta was irregularly thickened, with a lot of inflammatory cell infiltration, and arterial lesions appeared. In the low-and high-dose groups of grape seed extract, the plaque of abdominal aorta intima decreased and inflammatory cells reduced significantly, arterial vascular disease was improved, and the improvement was more obvious in high dose group than in low dose group. Compared with the control group, the levels of IMT, serum MDA, TNF-α, IL-6, p-p38MAPK/p38MAPK, NF-κB p65 and serum SOD and GSH-px in the model group were increased, while those in the model group were decreased(P＜0.05); the levels of IMT, serum MDA, TNF-α, IL-6, p-p38MAPK/p38MAPK, NF-κB p65 and SOD, GSH-px were decreased in the low and high dose groups(P＜0.05)., Conclusions: Grape seed extract can inhibit the oxidative stress level and inflammatory reaction in serum of chronic periodontitis with arteriosclerosis rats, thus improving the intimal lesion of aorta, possibly by inhibiting the activation of p38MAPK/NF-κB p65 pathway.

Background: Numerous observational studies have shown that liver enzymes correlated with diabetes mellitus (DM) risk significantly, but limited studies showed whether different obesity subgroups present the same correlation. Our objective was to evaluate the association of liver enzymes with DM risk in different obesity subgroups based on a middle-aged Chinese population., Methods: We conducted a population-based cross-sectional study and surveyed 9,916 people aged 40 years and above. A two-slope linear regression model was used to analyze the cutoff points of obesity in DM risk. Restricted cubic splines were used to analyze the correlation between liver enzymes and DM risk in different obesity categories. The odds ratios and 95% confidence intervals (CIs) were calculated using the logistic regression model., Results: The cutoff points of body mass index (BMI) and waist circumference were 30.55 kg/m 2 and 98.99 cm for DM risk, respectively. The serum gamma-glutamyl transferase (GGT) concentration was positively correlated with DM risk in the subgroups with waist circumference <98.99 cm [OR = 1.04, 95% CI (1.03-1.05)], BMI <30.55 kg/m 2 [OR = 1.04, 95% CI (1.03-1.05)], and BMI ≥30.55 kg/m 2 [OR = 1.18, 95% CI (1.04-1.39)], but not in the subgroup with waist circumference ≥98.99 cm. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations have no significant correlation with the risk of diabetes in all groups., Conclusion: The results showed that serum GGT concentration was correlated with DM risk but not with AST or ALT in the middle-aged population. However, the correlation disappeared when waist circumference was over 98.99 cm, and serum GGT concentration had a limited value for DM risk in waist circumference over 98.99 cm., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zheng, Zhang, You, Li, Lin, Sun, Ren, Yan and Wang.)

Oral squamous cell carcinoma (OSCC) is one of the most frequent malignancies found in head and neck cancers. Dysregulation of lncRNAs has been proposed to be related to the development of OSCC. Here, we investigated the function and probable mechanisms of lncRNA DLEU1 in OSCC. OSCC cell lines and human oral keratinocytes (HOKs) were cultured, while SCC-25 and CAL-27 cells were transfected with the corresponding plasmids. Reverse transcription quantitative PCR (RT-qPCR) and western blot were carried out to measure the RNA and protein levels. Cell proliferation, migration and invasion were evaluated using MTT assays, wound healing and Transwell assays. The StarBase database predicted the interactions between DLEU1 and miR-126-5p, as well as miR-126-5p and GAB1, which were further validated using a dual-luciferase reporter assay. Our results indicated that DLEU1 and GAB1 were upregulated, while miR-126-5p was downregulated in OSCC cells. Silencing DLEU1 reduced OSCC cell proliferation, migration, and invasion, while DLEU1 overexpression had the opposite effects. DLEU1 mediated biological effects in OSCC through binding to miR-126-5p, which directly targeted GAB1. miR-126-5p knockdown rescued the inhibitory function of DLEU1 depletion on proliferation, migration and invasion. Meanwhile, the miR-126-5p mimic exerted suppressive functions in the progression of OSCC, which were neutralized after GAB1 overexpression. In summary, lncRNA DLEU1 targets the miR-126-5p/GAB1 axis to aggravate OSCC progression, providing a novel target for treating OSCC., (© 2022 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

A tool was constructed to assess need of an oral glucose tolerance test (OGTT) in patients whose fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) are normal. Data was collected from the longitudinal REACTION study conducted from June to November 2011 (14,686 subjects, aged ≥ 40 y). In people without a prior history of diabetes, isolated high 2-hour plasma glucose was defined as 2-hour plasma glucose ≥ 11.1 mmol/L, FPG < 7.0 mmol/L, and HbA1c < 6.5%. A predictive nomogram for high 2-hour plasma glucose was developed via stepwise logistic regression. Discrimination and calibration of the nomogram were evaluated by the area under the receiver operating characteristic curve (AUC) and Hosmer-Lemeshow test; performance was externally validated in Northeast China. Parameters in the model included gender, age, drinking status, marriage status, history of hypertension and hyperlipidemia, waist-to-hip ratio, FPG, and HbA1c. All variables were noninvasive, except FPG and HbA1c. The AUC of the nomogram for isolated high 2-hour plasma glucose was 0.759 (0.727-0.791) in the development dataset. The AUCs of the internal and externally validation datasets were 0.781 (0.712-0.833) and 0.803 (0.778-0.829), respectively. Application of the nomogram during the validation study showed good calibration, and the decision curve analysis indicated that the nomogram was clinically useful. This practical nomogram model may be a reliable screening tool to detect isolated high 2-hour plasma glucose for individualized assessment in patients with normal FPG and HbA1c. It should simplify clinical practice, and help clinicians in decision-making., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sun, Xiao, You, Hong, Lin, Liu, Huang, Wang, Li, Sun, Chen, Lu, Qi, Wang, Li, Xu, Ren, Yang, Wang and Yan.)

Background: Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) of the gallbladder are rare malignancies. Here we presented two cases and reviewed the related literature., Case Presentation: Our two patients were postoperatively diagnosed with gallbladder MiNENs, which pathologically consisted of a large cell neuroendocrine carcinoma and papillary adenocarcinoma. After cholecystectomy, one patient had a survival time of 30 months, while the other remained alive through 12 months of follow-up. In the literature, a total of 72 cases of gallbladder MiNENs were identified, and with our two patients included, we calculated a male-to-female ratio of 0.22 and a mean age of 64.5 years for the 74 reported cases. About one-half of these patients were found to have gallstones and presented with abdominal pain or discomfort in a relatively early stage. The preoperative diagnosis of these 74 cases mainly relied on abdominal ultrasound, contrast-enhanced computed tomography (CT) scanning, and magnetic resonance imaging or positron emission tomography/CT. However, the final diagnosis was established based upon the pathological evidence and expression of synaptophysin (Syn) and/or chromogranin A identified by immunohistochemical staining or neurosecretory granules detected by electron microscopy. Fifty-eight patients (78.4%) underwent various operations including simple cholecystectomy (n = 14), en bloc cholecystectomy (n = 9), standard or non-standard radical cholecystectomy (n = 25), or extended radical cholecystectomy (n = 6). The mean size of the resected gallbladder masses was 50.8 ± 36.1 mm (n = 63) with regional lymph node metastasis in 37 patients (52.1%), liver invasion or staging greater than T3 in 33 patients (45.8%), and hepatic metastasis in 26 patients (35.1%). The postoperative median survival time was 36 ± 11.42 months (95% confidence interval, 13.62 to 58.38 months). The log-rank analysis did not find that postoperative adjuvant chemotherapy contributed to a longer survival time relative to that among the patients who did not receive chemotherapy (numbers of patients, 15 versus 43; survival times, 36 months versus 30 months, p > 0.05)., Conclusions: Our two cases and the cases in the literature suggest that MiNENs of the gallbladder predominantly occur in women; are associated with early lymph node metastasis, local hepatic invasion, and hepatic metastasis; and can be managed by various surgeries as well as chemotherapy combined with somatostatin analogs., (© 2022. The Author(s).)

Dysregulation of macroautophagy/autophagy contributes to the delay of wound healing in diabetic skin. N 6 -methyladenosine (m 6 A) RNA modification is known to play a critical role in regulating autophagy. In this study, it was found that SQSTM1/p62 (sequestosome 1), an autophagy receptor, was significantly downregulated in two human keratinocyte cells lines with short-term high-glucose treatment, as well as in the epidermis of diabetic patients and a db/db mouse model with long-term hyperglycemia. Knockdown of SQSTM1 led to the impairment of autophagic flux, which was consistent with the results of high-glucose treatment in keratinocytes. Moreover, the m 6 A reader protein YTHDC1 (YTH domain containing 1), which interacted with SQSTM1 mRNA, was downregulated in keratinocytes under both the acute and chronic effects of hyperglycemia. Knockdown of YTHDC1 affected biological functions of keratinocytes, which included increased apoptosis rates and impaired wound-healing capacity. In addition, knockdown of endogenous YTHDC1 resulted in a blockade of autophagic flux in keratinocytes, while overexpression of YTHDC1 rescued the blockade of autophagic flux induced by high glucose. In vivo , knockdown of endogenous Ythdc1 or Sqstm1 inhibited autophagy in the epidermis and delayed wound healing. Interestingly, we found that a decrease of YTHDC1 drove SQSTM1 mRNA degradation in the nucleus. Furthermore, the results revealed that YTHDC1 interacted and cooperated with ELAVL1/HuR (ELAV like RNA binding protein 1) in modulating the expression of SQSTM1 . Collectively, this study uncovered a previously unrecognized function for YTHDC1 in modulating autophagy via regulating the stability of SQSTM1 nuclear mRNA in diabetic keratinocytes. Abbreviations: ACTB: actin beta; AGEs: glycation end products; AL: autolysosome; AP: autophagosome; ATG: autophagy related; AKT: AKT serine/threonine kinase; ANOVA: analysis of variance; BECN1: beclin 1; Co-IP: co-immunoprecipitation; DEGs: differentially expressed genes; DM: diabetes mellitus; ELAVL1: ELAV like RNA binding protein 1; FTO: FTO alpha-ketoglutarate dependent dioxygenase; G: glucose; HaCaT: human keratinocyte; GO: Gene Ontology; GSEA: Gene Set Enrichment Analysis; HE: hematoxylin-eosin; IHC: immunohistochemical; IRS: immunoreactive score; KEAP1: kelch like ECH associated protein 1; KEGG: Kyoto Encyclopedia of Genes and Genomes; m 6 A: N 6 -methyladenosine; M: mannitol; MANOVA: multivariate analysis of variance; MAP1LC3: microtubule associated protein 1 light chain 3; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MeRIP: methylated RNA immunoprecipitation; METTL3: methyltransferase 3, N6-adenosine-methytransferase complex catalytic subunit; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin complex 1; NBR1: NBR1 autophagy cargo receptor; NFE2L2: nuclear factor, erythroid 2 like 2; NG: normal glucose; NHEK: normal human epithelial keratinocyte; OE: overexpressing; p-: phospho-; PI: propidium iodide; PPIN: Protein-Protein Interaction Network; RBPs: RNA binding proteins; RIP: RNA immunoprecipitation; RNA-seq: RNA-sequence; RNU6-1 : RNA, U6 small nuclear 1; ROS: reactive oxygen species; siRNAs: small interfering RNAs; SQSTM1: sequestosome 1; SRSF: serine and arginine rich splicing factor; T2DM: type 2 diabetes mellitus; TEM: transmission electron microscopy; TUBB: tubulin beta class I; WT: wild-type; YTHDC1: YTH domain containing 1.

The present study explored the mechanism of Qingwei Powder(QP) in the treatment of periodontitis based on chromatography-mass spectrometry and network pharmacology-molecular docking techniques. UPLC-Q-TOF-MS and GC-MS were used to identify the chemical constituents of QP. The active components and targets were screened out through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), and their targets were predicted using SwissTargetPrediction. Targets related to periodontitis were obtained from GeneCards, OMIM, and DisGeNET. Venn diagram was constructed using Venny 2.1 to obtain the intersection targets. Cytoscape 3.7.2 was used to construct the &quot;chemical component-target-disease&quot; network. The targets were analyzed for Gene Ontology(GO) function and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment by clusterProfiler R, and the &quot;chemical component-target-pathway&quot; network was constructed. The binding activity of the active components to the target proteins was verified by molecular docking. A total of 189 chemical components were obtained by UPLC-Q-TOF-MS and GC-MS, including 39 active components with 180 potential targets related to periodontitis. Target enrichment analysis of the active components yielded 92 KEGG pathways. Twenty KEGG pathways, 34 active components, and 99 targets were involved in the &quot;chemical component-target-pathway&quot; network. Molecular docking verified a good binding ability of the key targets to the key compounds. This study preliminarily indicates that QP is effective in treating periodontitis through multiple components, multiple targets, and multiple pathways, which reflects the complex system of Chinese medicine. This study provides the theoretical foundation for the subsequent research on the material basis and key quality attributes of QP.

Background: Education attainment can improve life expectancy and guide healthy behaviours throughout an entire lifetime. A nationwide longitudinal study of the association of education status with the risk of hypertension and its control in China is lacking., Methods: The China Cardiometabolic Disease and Cancer Cohort Study is a multicentre, population-based, prospective cohort study. We performed the baseline survey from 2011 to 2012. A follow-up visit was conducted during 2014-2016. 101 959 subjects were included in the final data analyses. Cox proportional hazards regression was used to examine the associations of education levels with the risk of hypertension and uncontrolled hypertension., Results: During follow-up, 11 189 (19.9%) participants had developed hypertension among subjects without hypertension at baseline. Among the participants with hypertension at baseline, only 40.6% had controlled hypertension. Compared with the participants' education level at elementary school and below, the multivariable-adjusted HR for incident hypertension was 0.76 (95% CI, 0.72 to 0.80) in those with a middle school education level and 0.67 (95% CI, 0.63 to 0.70) in those with a high school degree or above. Correspondingly, multivariable-adjusted HRs associated with uncontrolled hypertension were 0.90 (95% CI, 0.87 to 0.92) in participants with a middle school education level and 0.85 (95% CI, 0.82 to 0.88) in participants with a high school degree or above level., Conclusion: Participants with education attainment at elementary school and below exhibited excess risks of newly diagnosed hypertension and worse blood pressure control compared with individuals with education attainment at middle school or above., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Identifying the metabolite profile of individuals with prediabetes who turned to type 2 diabetes (T2D) may give novel insights into early T2D interception. The purpose of this study was to identify metabolic markers that predict the development of T2D from prediabetes in a Chinese population., Methods: We used an untargeted metabolomics approach to investigate the associations between serum metabolites and risk of prediabetes who turned to overt T2D (n=153, mean follow up 5 years) in a Chinese population (REACTION study). Results were compared with matched controls who had prediabetes at baseline [age: 56 ± 7 years old, body mass index (BMI): 24.2 ± 2.8 kg/m2] and at a 5-year follow-up [age: 61 ± 7 years old, BMI: 24.5 ± 3.1 kg/m2]. Confounding factors were adjusted and the associations between metabolites and diabetes risk were evaluated with multivariate logistic regression analysis. A 10-fold cross-validation random forest classification (RFC) model was used to select the optimal metabolites panels for predicting the development of diabetes, and to internally validate the discriminatory capability of the selected metabolites beyond conventional clinical risk factors., Findings: Metabolic alterations, including those associated with amino acid and lipid metabolism, were associated with an increased risk of prediabetes progressing to diabetes. The most important metabolites were inosine [odds ratio (OR) = 19.00; 95% confidence interval (CI): 4.23-85.37] and carvacrol (OR = 17.63; 95% CI: 4.98-62.34). Thirteen metabolites were found to improve T2D risk prediction beyond eight conventional T2D risk factors [area under the curve (AUC) was 0.98 for risk factors + metabolites vs 0.72 for risk factors, P < 0.05]., Interpretations: Use of the metabolites identified in this study may help determine patients with prediabetes who are at highest risk of progressing to diabetes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ren, Lin, Liu, Sun, Wang, Lao, Fan, Wang, Liu, Du, Zhu, Wang and Yan.)

Objective: Adiponectin is an adipocyte-derived hormone with an important role in glucose metabolism. The present study explored the effect of adiponectin in diverse population groups on pre-diabetes and newly diagnosed diabetes., Methods: A total of 3300 individuals were enrolled and their data were collected in the analyses dataset from December 2018 to October 2019. Cluster analysis was conducted based on age, BMI, waistline, body fat, systolic blood pressure, triglycerides, and glycosylated hemoglobin 1c. Cluster analysis divided the participants into four groups: a young-healthy group, an elderly-hypertension group, a high glucose-lipid group, and an obese group. Odds ratio (OR) and 95% CIs were calculated using multivariate logistic regression analysis., Results: Compared with the first quartile of adiponectin, the risk of pre-diabetes of fourth quartile was decreased 61% (aOR = 0.39, 95% CI (0.20-0.73)) in the young-healthy group; and the risk of diabetes of fourth quartile was decreased 85% (aOR = 0.15, 95% CI (0.02-0.67)) in the obese group. There were no significant correlations between the adiponectin level and diabetes/pre-diabetes in the other two groups. Additionally, receiver operating characteristic curve analysis indicated that adiponectin could significantly improve the diagnosis based on models in the young-healthy group (from 0.640 to 0.675) and the obese group (from 0.714 to 0.761)., Conclusions: Increased adiponectin levels were associated with decreased risk of pre-diabetes in the young-healthy population, and with a decreased the risk of diabetes in the obese population. An increased adiponectin level is an independent protective factor for pre-diabetes and diabetes in a specific population in south China.

Purpose: We elucidate the effect of Growth differentiation factor-15(GDF-15)/adiponectin ratio in improving the assessment value for odds of type 2 diabetes., Methods: Cross-sectional design. A total of 405 participants (135 patients with newly diagnosed type 2 diabetes, 135 age- and sex-matched participants with prediabetes, and 135 healthy controls) were collected from Guangzhou and Dongguan, China. The serum GDF-15 and adiponectin levels were measured by ELISA and latex-enhanced immunoturbidimetry. Logistic regression analysis and restricted cubic splines were used to evaluate the associations between diabetes and the indicators., Results: The low level of adiponectin and high GDF-15/adiponectin ratio were significantly associated with increased odds of type 2 diabetes, but not for GDF-15. Three clusters were identified based on the K-means clustering analysis. Compared to the lowest quartiles of adiponectin, the OR and 95% CI of the highest adiponectin with type 2 diabetes was 0.24 (0.07-0.74, p trend = 0.004) after adjusting for sex, age, BMI, and DBP only in cluster 1. After adjusting for confounding factors, subjects with the highest GDF-15/adiponectin ratio quartiles had 3.9 times (OR = 3.85, 95% CI = 0.76-24.25) and 3.8 times (OR = 3.80, 95% CI = 1.02-14.68) higher odds of type 2 diabetes in cluster 2 and cluster 3, respectively. The association between the GDF-15/adiponectin ratio and type 2 diabetes was attenuated, but still remarkable (OR = 3.18, 95% CI = 1.11-10.18), in cluster 1., Conclusions: Higher GDF-15/adiponectin ratio is independently associated with increased odds of type 2 diabetes for all study populations, suggesting that the GDF-15/adiponectin ratio may be a better indicator of type 2 diabetes.

Slips, trips, and falls (STFs) pose a significant financial burden to employers and account for over 33% of the total nonfatal workers' compensation cost in the United States. Previous analyses documenting the burden of STF incidents in the mining industry have focused on occupational fatalities or STFs during equipment ingress, egress. There is limited information on the burden of nonfatal STF incidents in the mining industry and most of it is outdated. Hence, to increase awareness and highlight the importance of STFs in the mining industry, this analysis documents the burden associated with nonfatal STF incidents at surface stone, sand, and gravel (SSG) mines from 2008 through 2017. In this time frame, nonfatal STF incidents occurred at a rate of 62 per 10,000 full-time equivalent (FTE) employees per year. Pits had a higher prevalence of injuries, but plants had a higher incidence rate. In addition, nonfatal STF incidents at surface SSG mines led to approximately 23,800 total days lost per year with an estimated cost to the mining industry of $17.5 million per year. Assessed violations that are not related to reported injuries but are related to STF hazards identified during Mine Safety and Health Administration (MSHA) inspections cost the mining industry approximately $3 million per year from 2013 through 2017. Based on the data analyzed in this study, falls to the lower level pose a higher burden in terms of cost; however, falls to the same level have a higher number of incidents and incidence rate.

Wound healing in diabetic skin is impaired by excessive activation of matrix metalloproteinase-9 (MMP-9). MMP-9 transcription is activated by Ten-eleven translocation 2 (TET2), a well-known DNA demethylation protein that induces MMP-9 promoter demethylation in diabetic skin tissues. However, how TET2 is targeted to specific loci in the MMP-9 promoter is unknown. Here, we identified a TET2-interacting long noncoding RNA (TETILA) that is upregulated in human diabetic skin tissues. TETILA regulates TET2 subcellular localization and enzymatic activity, indirectly activating MMP-9 promoter demethylation. TETILA also recruits thymine-DNA glycosylase (TDG), which simultaneously interacts with TET2, for base excision repair-mediated MMP-9 promoter demethylation. Together, our results suggest that the TETILA serves as a genomic homing signal for TET2-mediated demethylation specific loci in MMP-9 promoter, thereby disrupting the process of diabetic skin wound healing.

Apoptosis is a mechanism to remove unwanted cells in the tissue. In diabetic wound, which is characterized by delayed healing process, excessive apoptosis is documented and plays a crucial role. Matrix metalloproteinase 9 (MMP9), which is elevated in non-healed diabetic wound, is necessary for healing process but its abnormality resulted in a delayed healing. The classical function of MMP9 is the degradation of extracellular matrix (ECM). However, there is some literature evidence that MMP9 triggers cell apoptosis. Whether the excessive MMP9 contributes to epidermis cell apoptosis in delayed healing diabetic wound and the underlying mechanisms is not clear. In this study, we aimed to explore whether MMP9 induced keratinocyte apoptosis and investigate the plausible mechanisms. Our in vitro study showed that advanced glycation end products (AGEs) induced keratinocyte apoptosis and enhanced MMP9 level. Besides, MMP9, both intra-cellular expressions and extra-cellular supplement, promoted cell apoptosis. Further, MMP9 resulted in an increased expression of FasL, other than Fas and p53. These findings identified a novel effect that MMP9 exerted in delayed diabetic wound healing, owing to a pro-apoptotic effect on keratinocyte, which was mediated by an increase of FasL expression. This study increases understanding of elevated MMP9 which is involved in diabetic wound repair and offers some insights into novel future therapies.

Background: Rational measures in estimating adiposity distribution in diabetic patients has yet to be validated. This study aims to provide insight about the possible links between routinely available body adiposity parameters and the development of both diabetes and insulin resistance., Methods: We performed a population-based cross-sectional study in 9496 subjects aged 40 years or older. All of the body adiposity measures including body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), waist-height ratio (WHtR), visceral adiposity index (VAI), body adiposity index (BAI) and lipid accumulation product index (LAP) were separately evaluated according to standard measurement methods. Diabetes was diagnosed according to the American Diabetes Association 2010 criteria., Results: All tested body adiposity measurements were significantly associated with fasting plasma glucose (FPG), oral glucose tolerance test (OGTT) 2 h glucose, HbA1c and fasting insulin. Compared with other adiposity phenotypes, LAP have shown the relatively strongest while BAI have shown the relatively weakest association with increased odds of both diabetes and insulin resistance across all logistic regression models. Additionally, LAP provided the best discrimination accuracy for diabetes [area under the curve (AUC): 0.658 95% confidence intervals (CI) 0.645-0.671] and insulin resistance (AUC: 0.781 95% CI 0.771-0.792) when compared with other body adiposity parameters., Conclusions: The LAP index seems to be a better indicator than other adiposity measures tested in the study to evaluate the association of visceral fat mass with diabetes and insulin resistance, which should be given more consideration in the clinical practice., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Objectives: This study utilized personal noise measurements and fit-testing to evaluate the association between noise exposures and personal attenuation rating (PAR) values among participating workers, and second, to compare the attenuated exposure levels received by the workers and the British Standards Institute's recommended noise exposure range of 70 to 80 dBA., Design: We measured hearing protection device (HPD) attenuation among a sample of 91 workers at 2 US metal manufacturing facilities, through performance of personal noise dosimetry measurements and HPD fit-testing over multiple work shifts. We compared this testing with participant questionnaires and annual audiometric hearing threshold results., Results: The average 8-hr time-weighted average noise exposures for study participants was 79.8 dBA (SD = 7.0 dBA), and the average PAR from fit-testing was 20.1 dB (±6.7 dB). While differences existed between sites, 84% of the 251 PAR measurements resulted in effective protection levels below the recommended 70 dBA (indicating overprotection), while workers were underprotected (i.e., effective exposures >80 dBA) during <1% of monitored shifts. Our results also demonstrated a significant positive relationship between measured noise exposure and PAR among non-custom-molded plug users (p = 0.04). Non-custom-molded plug wearers also showed a significant increase in PAR by sequential fit-test interaction (p = 0.01), where on average, subsequent fit-testing resulted in increasingly higher HPD attenuation. Workers at site 1 showed higher PARs. PARs were significantly related to race, even when adjusting for site location. While age, hearing threshold level, task, and self-reported tinnitus showed no significant effect on individual PAR in an unadjusted model, site, race, and sand- or water-blasting activities were significant predictors in adjusted models. Within-worker variability in time-weighted averages and PARs across repeated measurements was substantially lower than variability between workers., Conclusions: Careful selection of HPDs is necessary to minimize instances of overprotection to workers in low and moderate occupational noise environments. The use of fit-testing in hearing conservation programs to evaluate PAR is recommended to avoid overprotection from noise exposure while also minimizing instances of under-attenuation.

Objectives: Noise is one of the most common exposures, and occupational noise-induced hearing loss (NIHL) is highly prevalent. In addition to NIHL, noise is linked to numerous non-auditory health effects. The Occupational Safety and Health Administration (OSHA) maintains the Integrated Management Information System (IMIS) database of compliance-related measurements performed in various industries across the USA. The goal of the current study was to describe and analyse personal noise measurements available through the OSHA IMIS, identifying industries with elevated personal noise levels or increasing trends in worker exposure over time., Methods: Through a Freedom of Information Act request, we obtained OSHA's noise measurements collected and stored in IMIS between 1979 and 2013 and analysed permissible exposure limit (PEL) and action level (AL) criteria measurements by two-digit industry code., Results: The manufacturing industry represented 87.8% of the 93 920 PEL measurements and 84.6% of the 58 073 AL measurements. The highest mean noise levels were found among the agriculture, forestry, fishing and hunting industry for PEL (93.1 dBA) and the mining, quarrying and oil and gas extraction group for AL (93.3 dBA). Overall, measurements generally showed a decreasing trend in noise levels and exceedances of AL and PEL by year, although this was not true for all industries., Conclusions: Our results suggest that, despite reductions in noise over time, further noise control interventions are warranted both inside and outside of the manufacturing industry. Further reductions in occupational noise exposures across many industries are necessary to continue to reduce the risk of occupational NIHL., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Phosphatase and tension homolog deleted on chromosome 10 (PTEN) was considered as a promising target in type 2 diabetes mellitus (T2DM) because of its negative effects on insulin resistance. Alteration in DNA methylation is thought to play a role in the pathogenesis of T2DM. The aim of the present study was to quantitatively evaluate the promoter methylation of PTEN in Uyghur patients with mild T2DM. We evaluated methylation levels in 21 CpG sites from -2515 bp to -2186 bp relative to the translation initiation site in 55 cases of T2DM and 50 cases of normal glucose tolerance (NGT) using the MassARRAY spectrometry. In addition, PTEN mRNA and protein levels were measured by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blotting to determine whether DNA methylation alterations were responsible for PTEN expression. Compared with NGT groups, the PTEN mRNA expression was significantly higher in Uyghur patients with mild T2DM groups. We also showed that PTEN protein expression was upregulated in Uyghur patients with mild T2DM groups, but the level of protein kinase B (AKT) was downregulated. PTEN methylation in T2DM patients was significantly lower than that in NGT groups. In addition, 2 CpG units demonstrated a significant difference between the NGT and Uyghur patients with mild T2DM groups. Furthermore, there was a negative association between promoter methylation and PTEN expression. Together, these findings suggest that epigenetic inactivation of PTEN plays an important role in Uyghur patients with mild T2DM. The aberrant methylation of CpG sites within the PTEN promoter may serve as a potential candidate biomarker for T2DM in the Uyghur population.

Objective: A dramatic gap exists between the clinical practice and guidelines for the dyslipidemia control in patients with diabetes. It is still uncertain which routinely available lipid measure is more applicable in estimation of insulin sensitivity and blood glucose control. The present study aims to investigate associations of routine lipid profiles with insulin resistance and diabetes, respectively., Methods: We conducted a population-based study in 9764 Chinese participants. The homeostasis model assessment of insulin resistance was calculated to estimate insulin sensitivity. Diabetes was diagnosed according to the 1999 World Health Organization diagnostic criteria., Results: Participants with insulin resistance or diabetes presented with significantly higher triglycerides (TG), Non-high-density lipoprotein cholesterol (Non-HDL-C), Non-HDL-C/HDL-C, TG/HDL-C and lower HDL-C when compared with control subjects (all P < 0.0001). Such lipid measures were significantly correlated with fasting insulin, fasting plasma glucose (FPG), oral glucose tolerance test (OGTT) 2 h glucose and Hemoglobin A1c (HbA1c) in Pearson's correlation analysis and multivariate linear regression analysis (all P < 0.0001). In logistic regression analysis, subjects were more likely to have prevalent insulin resistance and diabetes with the elevated quartiles of TG, Non-HDL-C, Non-HDL-C/HDL-C and TG/HDL-C (all P < 0.05). TG/HDL-C ratio, compare with other lipid parameters, have shown the strongest correlation with increased odds of insulin resistance and diabetes., Conclusion: Our study suggests a discordant association of lipid parameters with blood glucose level and TG/HDL-C is a better marker for evaluating insulin resistance and diabetes in Chinese population when compared with other routine lipid measures., (Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Diabetes elevates matrix metalloproteinase (MMP)-9 levels in the skin and its keratinocytes, and activated MMP-9 impairs skin wound healing. Epigenetic regulation of the DNA methylation status within the MMP-9 promoter plays an important role in the alteration of MMP-9 expression. Our aim was to investigate the role and mechanism of growth arrest and DNA damage-inducible 45a (GADD45a), a well-known DNA demethylation regulatory protein that mediates DNA methylation, in the regulation of MMP-9 expression. In this study, we showed that GADD45a was markedly upregulated in skin tissues from patients with diabetic foot ulcers, in diabetic rats, and in human keratinocyte (HaCaT) cells exposed to advanced glycation end products. We observed a substantial positive correlation between the levels of GADD45a and MMP-9 expression. Knockdown of GADD45a ameliorated the increase in MMP-9 transcription induced by a diabetic condition by inhibiting demethylation in the MMP-9 promoter and promoted diabetic HaCaT cell migration, but GADD45a knockdown did not affect HaCaT cell proliferation or apoptosis. Additionally, we demonstrated that overexpression of GADD45a activated MMP-9 expression by inducing promoter demethylation. Moreover, we found that GADD45a binds to the promoter of MMP-9 and recruits thymine-DNA glycosylase for base excision repair-mediated demethylation in diabetic HaCaT cells and diabetic rat skin. Our results reveal a mechanism in which GADD45a is required for demethylation of the MMP-9 promoter and the induction of diabetic wound healing. The inhibition of GADD45a might be a therapeutic strategy for diabetic foot ulcers., (Copyright © 2018 Endocrine Society.)

Epigenetics may affect the susceptibility for type 2 diabetes mellitus (T2DM). Previously, our studies have shown that the hypomethylation of human miR-375 promoter may contribute to the pathogenesis of T2DM. However, the methylation pattern of miR-375 promoter in T2DM is not yet fully understood. In this study, the DNA methylation status of the different region of miR-375 promoter in Chinese Han population with T2DM were explored. 100 Han patients with T2DM and 100 Han healthy controls with normal glucose tolerance (NGT) were collected. Then the transcription level of pre-miR-375 and mature miR-375 were examined using quantitative real-time PCR and the methylation status of 27 CpG sites in the miR-375 promoter was determined by MassARRAY Spectrometry. The relative expression of mature miR-375 was shown as fold difference relative to miR-16 (3.0-fold, P =0.0260) and pre-miR-375 was markedly unregulated (2.6-fold, P =0.0415) in Han T2DM samples. Aberrant methylation was significantly higher within the amplicon of the miR-375 promoter in T2DMs than in NGTs, an average of 10.27% and 7.24% (P=0.0004; Figure 3A), respectively. Further, one CpG unit (CpG&#95;26.27) was significantly hypermethylated in T2DM samples compared with NGT. Together, our results highlights for the first time that aberrant hypermethylation is a common event in Han T2DM, suggesting that the aberrant methylation of the CpG sites within miR-375 promoter may serve as a potential candidate biomarker for T2DM in the Chinese Han population., Competing Interests: None., (IJCEP Copyright © 2017.)

Purpose: There is a paucity of biomarkers to predict failure in human papillomavirus-positive (HPV + ) oropharyngeal squamous cell carcinoma (OPSCC) following curative therapy. E6/E7 viral oncoproteins are constitutively expressed in HPV + tumors and highly immunogenic, resulting in readily detected serum antibodies. The purpose of this study is to determine whether serum E6 and E7 antibody levels can potentially serve as a biomarker of recurrence in patients with HPV+OPSCC. Experimental Design: We evaluated E6/E7 antibody levels in patients with previously untreated, advanced stage (III, IVa-b), HPV+OPSCC receiving definitive chemoradiation under a uniform protocol from 2003 to 2010. Baseline and longitudinal serum samples were obtained from our archived repository. E6/E7 serum levels were measured using a glutathione- S -transferase capture ELISA and quantified by approximating the area under the dilution curve, and were analyzed using ANOVA and linear mixed model for longitudinal analysis. Results: We compared 22 HPV+OPSCC patients who developed recurrence with 30 patients who remained disease-free. There were no differences in T classification, N classification, disease subsite, or smoking status between the groups. In a longitudinal analysis, recurrent patients had significantly higher E6 and E7 serum antibody levels than the nonrecurrent patients over the follow-up period ( P = 0.02 and P = 0.002, respectively). Patients who recurred had a lower clearance of E7 antibody than patients who remained disease-free ( P = 0.0016). Conclusions: Patients with HPV+OPSCC whose disease recurs have a lower clearance of E6 and E7 antibodies than patients who do not have recurrence. The ratio of E7 antibody at disease recurrence compared with baseline is potentially a clinically significant measurement of disease status in HPV+OPSCC. Clin Cancer Res; 23(11); 2723-9. ©2016 AACR ., (©2016 American Association for Cancer Research.)

Overexpression of matrix metalloproteinase-9 (MMP-9) is critical for diabetic chronic wounds involved in the refractory wound healing process. We aimed to develop a strategy through RNAi to decrease MMP-9 expression and improve diabetic wound healing. We had explored β-CD-(D 3 ) 7 as a gene carrier to take siRNA and effectively interfere with MMP-9 expression. It has been proven that β-CD-(D 3 ) 7 could be used as an effective siRNA delivery system. In this study, we want to know about the efficiency and safety of β-CD-(D 3 ) 7 /MMP-9 siRNA for improving wound healing in diabetic rats. β-CD-(D3)7/MMP-9 siRNA treated animals show lower levels of MMP-9 expression, which induce faster wound-close rates. Histological evaluation indicates that β-CD-(D3)7/MMP-9 siRNA significantly increases the content of collagen around the injured tissues. The number of neutrophilic ganulocytes was significantly decreased through treatment of β-CD-(D3)7/MMP-9 siRNA. In vivo fluorescence imaging assessment shows that β-CD-(D3)7/MMP-9 siRNA could not cause organ damage and organ accumulation. The results suggest that β-CD-(D 3 ) 7 /MMP-9 siRNA might be developed as a novel topical agent for the diabetic wounds treatment.

Background: Vitamin D status is related to obesity-related metabolic disorders. We investigated the risk of 25-hydroxyvitamin D [25(OH)D] deficiency among different metabolic phenotypes., Methods: This prospective cross-sectional study evaluated 1,292 individuals who were ≥40 years old. Participants were classified as metabolically healthy and normal weight (MHNW), metabolically obese but normal weight (MONW), metabolically healthy but obese (MHO) or metabolically unhealthy and obese (MUO). The demographic and clinical characteristics, as well as plasma 25(OH)D levels, were compared between the 4 groups., Results: The prevalences of MHNW, MONW, MHO and MUO were 32.1%, 19.3%, 17.9% and 30.7%, respectively. Approximately 58.5% participants had vitamin D deficiency, and vitamin D deficiency was more common in the MONW (68.7%) and MUO (73.6%) groups (MHNW, 42.7 and MHO, 50.2%). The MONW and MUO groups had lower 25(OH)D levels (versus the MHNW and the MHO groups). Among vitamin D-deficient participants, the MONW group exhibited increased risks of abdominal obesity (odds ratio [OR]: 3.28, P = 0.005), hypertension (OR: 3.08, P = 0.003) and elevated C-reactive protein (OR: 1.97, P = 0.03). In addition, the MUO group exhibited increased risks of hypertriglyceridemia (OR: 2.57, P = 0.001), insulin resistance (OR: 2.37, P = 0.001) and elevated C-reactive protein level (OR: 2.09, P = 0.003)., Conclusions: Individuals who were MONW and MUO had increased risks of vitamin D deficiency (versus MHNW and MHO), and individuals with vitamin D deficiency had worse metabolic status. Vitamin D supplementation may improve the metabolic status of individuals who are MONW or MUO., (Copyright © 2016 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Our objective was to evaluate the associations between habitual daytime napping and diabetes and whether it varies by sex, menopause, and sleep quality. We conducted a population-based cross-sectional study in 8621 eligible individuals aged 40 years or older. Information on daytime napping hours, night-time sleep duration, history of menstruation, and sleep quality was self-reported. Diabetes was diagnosed according to the 1999 World Health Organization diagnostic criteria. The prevalence of diabetes was 19.4 % in men and 15.6 % in women. Increased daytime napping hours were positively associated with parameters of glycometabolism in women, such as fasting plasma glucose, oral glucose tolerance test (OGTT) 2-h plasma glucose, and Hemoglobin A1c (HbA1c, all P for trend <0.05). In women, the prevalence of diabetes in no-habitual daytime napping group, 0-1-h daytime napping group, and more than 1-h daytime napping group were 14.5, 15.6, and 20.8 %, respectively (P for trend = 0.0004). A similar trend was detected in postmenopausal women (P for trend = 0.002). In multivariate logistic regression analysis, compared with no-habitual daytime napping postmenopausal women, those with daytime napping more than 1 h had higher prevalent diabetes (odds ratios 1.36, 95 % confidence interval, 1.04-1.77). In subgroup analysis of postmenopausal women, associations of daytime napping levels and prevalent diabetes were detected in older, overweight participants with good sleep quality who have not retired from work. In conclusion, our study suggests that habitual daytime napping is associated with prevalence of diabetes in postmenopausal women.

Introduction: Firefighters have high rate of injuries and illnesses, as well as exposures to high levels of noise. This study explored the relationship between noise exposure and injury among firefighters., Methods: We recruited firefighters undergoing vehicle extrication and structural collapse emergency response training at a highly realistic training facility. Demographics, health status, body mass index (BMI), and history of serious injuries (i.e. injuries requiring first aid treatment, treatment in a medical clinic or office, or treatment at a hospital) were assessed at baseline, and daily activities, injury events, and near misses were assessed daily via surveys. Participants' noise exposures were monitored for one 24-h period using noise dosimeters. We used a mixed-effects logistic regression model to estimate the odds of injury events and near misses associated with noise exposure as an independent variable., Results: Of 56 subjects, 20 (36%) reported that they had ever suffered a serious injury during firefighting activities, and 9 (16%) reported a serious injury within the past year. We estimated rates of 6.6 lifetime serious injuries per 100 FTE 16.1 serious injuries per 100 FTE within the past year. Our models indicated a significant increase in injury events and near misses among those with higher BMI, and as well as a dose-response relationship between near misses/injuries and increasing noise levels. Noise levels >90 dBA in the 30 min prior to time of injury or near miss were associated with substantially increased odds ratios for injury or near miss. Our models further indicated that perceived job demands were significantly associated with increased risk of injury or near miss., Conclusion: Our results suggest that noise exposures may need to be incorporated into injury prevention programs for firefighters to reduce injuries among this high-risk occupational group., (© The Author 2015. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.)

Aims: The effects of obesity on the micro vascular diseases have drawn much attention. The aim of the study was to investigate the relationship between obesity measures and albuminuria in Chinese population., Methods: We conducted a population-based cross-sectional study in 8600 subjects aged 40 years or older from a community in Guangzhou. Urinary albumin excretion and creatinine were measured and urinary albumin-to-creatinine ratio (ACR) was calculated as urinary albumin divided by creatinine. Low-grade albuminuria was classified as the highest quartile of ACR in participants without increased urinary albumin excretion. Increased urinary albumin excretion was defined according to the ACR ranges greater or equal than 30 mg/g., Results: Pearson's correlation analysis and multivariate linear regression analysis revealed that body mass index (BMI), waist circumference and body fat content were significantly correlated with ACR (all P<0.01). Prevalence of low-grade albuminuria and increased urinary albumin excretion gradually increased across the BMI, waist circumference and body fat content quartiles (all P for trend<0.0001). Compared with participants in quartile 1 of BMI, waist circumference and body fat content, participants in quartile 4 had increased prevalence of low-grade albuminuria and increased urinary albumin excretion in logistic regression analysis after adjustment for age, sex, physical activity, fasting plasma glucose, triglycerides, low-density lipoprotein cholesterol and HbA1c (all P<0.05)., Conclusion: Obesity measures are associated with urinary albumin excretion in middle-aged and elderly Chinese., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Steps in the genetic basis of pancreatic cancer (PC) have been recently identified, however, Studies focusing on the relationship between Jab1 and Smad4 in PC are rarely reported. This study was performed to examine the expression patterns and association of Jab1 and Smad4 in PC cells for gaining a further understanding of PC pathogenesis., Methods: Human pancreatic cancer cell line PANC-1 cells were infected with retrovirus vector containing GFP, HA-Jab1, siGFP, and siJab1 respectively. The expression of Jab1 and Smad4 in PANC-1 cells was analyzed by Western blot and immunocytochemistry. Subsequently, the effect of overexpression of Jab1 on cell proliferation inhibition mediated by TGF-β was examined with MTT colorimetry., Results: The expression of Smad4 in PANC-1 cells was inhibited after the overexpression of Jab1. Inversely, the expression of Smad4 was increased after the down-regulation of Jab1 silenced by SiRNA. Smad4 expression in PANC-1 cells was negatively correlated with Jab1 expression. In addition, the cell proliferation inhibitory effect induced by TGF-β in PANC-1 cells was attenuated after the overexpression of Jab1., Conclusions: The reverse correlation of Jab1 and Smad4 in PANC-1 cells may be involved in the Pathogenesis of PC. Jab1 can cause degradation of Smad4 via TGF-β signal pathway, consequently contributing to the proliferation of PC cells.