Keratinocyte-derived small extracellular vesicles delay diabetic wound healing by triggering fibroblasts autophagy.

Keratinocyte 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.

Intermittent Fasting-Improved Glucose Homeostasis Is Not Entirely Dependent on Caloric Restriction in db/db Male Mice.

Intermittent fasting (IF), which involves prolonged fasting intervals accompanied by caloric restriction (CR), is an effective dietary treatment for obesity and diabetes. Although IF offers many benefits, it is difficult to determine whether these benefits are the consequences of CR. Every-other-day feeding (EODF) is a commonly used IF research model. This study was designed to identify factors, in addition to CR, responsible for the effects of EODF and the possible underlying mechanisms. Diabetic db/db mice were divided into three groups: ad libitum (AL), meal feeding (MF), and EODF. The MF model was used to attain a level of CR comparable to that of EODF, with food distribution evenly divided between 10:00 a.m. and 6:00 p.m., thereby minimizing the fasting interval. EODF yielded greater improvements in glucose homeostasis than MF in db/db mice by reducing fasting glucose levels and enhancing glucose tolerance. However, these effects on glucose metabolism were less pronounced in lean mice. Furthermore, ubiquitination of the liver-specific glucocorticoid (GC) receptor (GR) facilitated its degradation and downregulation of Kruppel-like factor 9 (KLF9), which ultimately suppressed liver gluconeogenesis in diabetic EODF mice. Although GR and KLF9 might mediate the metabolic benefits of EODF, the potential benefits of EODF might be limited by elevated serum GC levels in diabetic EODF mice. Overall, this study suggests that the metabolic benefits of EODF in improving glucose homeostasis are independent of CR, possibly because of the downstream effects of liver-specific GR degradation.

The association of FGF-21 with the risk of newly diagnosed type-2 diabetes mellitus: a cross-sectional study in Southern China.

BACKGROUND: This study investigated the relationship between fibroblast growth factor 21 (FGF-21) and newly diagnosed type-2 diabetes mellitus (T2DM). METHODS: In this cross-sectional study, FGF-21 and T2DM risk were analyzed using restricted cubic splines with univariate or multivariate logistic regression analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated via logistic regression analysis. Cluster and subgroup analyses were conducted to evaluate the associations between FGF-21 and diabetes in different subpopulations. Nomograms and ROC curves were used to explore the clinical utility of FGF-21 in the diabetes assessment model. RESULTS: High levels of FGF-21 were significantly associated with a high risk of T2DM after adjusting for confounding factors in both the total population and subpopulations (P for trend < 0.001). In the total population, the ORs of diabetes with increasing FGF-21 quartiles were 1.00 (reference), 1.24 (95% CI 0.56-2.80; quartile 2), 2.47 (95% CI 1.18-5.33; quartile 3), and 3.24 (95% CI 1.53-7.14; quartile 4) in Model 4 (P < 0.001), and the trend was consistent in different subpopulations. In addition, compared with the model constructed with conventional noninvasive indicators, the AUC of the model constructed by adding FGF-21 was increased from 0.668 (95% CI: 0.602-0.733) to 0.715 (95% CI: 0.654-0.777), indicating that FGF-21 could significantly improve the risk-assessment efficiency of type-2 diabetes. CONCLUSION: This study demonstrated that a high level of circulating FGF-21 was positively correlated with diabetes, and levels of FGF-21 could be an important biomarker for the assessment of diabetes risk.

Psychiatric disorders and Type 2 diabetes mellitus: A bidirectional Mendelian randomization.

BACKGROUND: Extensive observational evidence put forward the association between psychiatric disorders and type 2 diabetes mellitus (T2DM). However, causal relationships between these two diseases required further research. Thus, we evaluated the bidirection casual effect between five psychiatric disorders and T2DM using two-sample mendelian randomization (MR). METHODS: By selecting single nucleotide polymorphisms associated with T2DM and five psychiatric disorders (attention-deficit hyperactivity disorder (ADHD), major depressive disorder (MDD), schizophrenia, anxiety disorder and panic disorder), a bidirectional two-sample MR was applied to evaluate causality between these diseases. The inverse-variance weighted (IVW) method was used as the primary analysing approach for estimating possible causal effects. MR-Egger and weighted median were also conducted to verify the results. The funnel plot, Cochran's Q test and MR-Egger intercept test were used for sensitivity analyses. In addition, potential mediators were investigated by risk factor analyses. RESULTS: Genetic susceptibilities of ADHD and MDD would increase the risk of T2DM (ADHD: OR = 1.14, 95%CI 1.08-1.20; p = 5.7 × 10 - 6 ; MDD: OR = 1.22, 95%CI 1.09-1.36; p = 0.0004 ). In addition, genetic predisposition to T2DM was also associated with ADHD (OR = 1.09, 95%CI 1.04-1.14; p = 0.0004). Several risk factors of T2DM were implicated in the above causal associations, including smoking, high body mass index, waist-to-hip ratio and elevated serum triglycerides. CONCLUSION: Our studies indicated a causal effect of ADHD and MDD on increasing the risk of T2DM, which was potentially mediated by smoking and obesity-related phenotypes. Meanwhile, we found a causal effect of T2DM on ADHD. Thus, prevention strategies for T2DM should also include mental health and vice versa.

The association of liver enzymes with diabetes mellitus risk in different obesity subgroups: A population-based study.

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/m2 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/m2 [OR = 1.04, 95% CI (1.03-1.05)], and BMI ≥30.55 kg/m2 [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.

Prediction of early prognosis after traumatic brain injury by multifactor model.

AIMS: To design a model to predict the early prognosis of patients with traumatic brain injury (TBI) based on parameters that can be quickly obtained in emergency conditions from medical history, physical examination, and supplementary examinations. METHODS: The medical records of TBI patients who were hospitalized in two medical institutions between June 2015 and June 2021 were collected and analyzed. Patients were divided into the training set, validation set, and testing set. The possible predictive indicators were screened after analyzing the data of patients in the training set. Then prediction models were found based on the possible predictive indicators in the training set. Data of patients in the validation set and the testing set was provided to validate the predictive values of the models. RESULTS: Age, Glasgow coma scale score, Apolipoprotein E genotype, damage area, serum C-reactive protein, and interleukin-8 (IL-8) levels, and Marshall computed tomography score were found associated with early prognosis of TBI patients. The accuracy of the early prognosis prediction model (EPPM) was 80%, and the sensitivity and specificity of the EPPM were 78.8% and 80.8% in the training set. The accuracy of the EPPM was 79%, and the sensitivity and specificity of the EPPM were 66.7% and 86.2% in the validation set. The accuracy of the early EPPM was 69.1%, and the sensitivity and specificity of the EPPM were 67.9% and 77.8% in the testing set. CONCLUSION: Prediction models integrating general information, clinical manifestations, and auxiliary examination results may provide a reliable and rapid method to evaluate and predict the early prognosis of TBI patients.

APOE gene polymorphism alters cerebral oxygen saturation and quantitative EEG in early-stage traumatic brain injury.

OBJECTIVE: To investigate the influence of apolipoprotein E (APOE) gene polymorphism on regional cerebral oxygen saturation (rScO2) and quantitative electroencephalogram (QEEG) at the early phase of adult traumatic brain injury (TBI). METHODS: clinical data of TBI patients who were admitted to the neurosurgery intensive care unit (NICU) were retrospectively evaluated and studied, and data of healthy volunteers were recruited as control. The APOE genotypes were genotyped by quantitative fluorescent polymerase chain reaction (QF-PCR). The rScO2 and brainelectricalactivityof all the participants involved in this research were measured by near-infrared spectroscopy (NIRS) and QEEG respectively. RESULTS: The average rScO2 of TBI patients was significantly lower than that of the normal controls (P < 0.0001). And the EEG of the TBI patients has showed more irregular slow-wave activities than that of the normal controls. Furthermore, the above changes were more significant in the APOE ε4 carriers in the early stage of TBI patients. CONCLUSIONS: The APOE ε4 allele may be associated with poor rScO2 and more slow-wave activities at the early stage of TBI. SIGNIFICANCE: To clarify the effect of APOE gene polymorphism on the condition of patients with TBI may be helpful for the design and management of individualized treatment programs.

Artery and venous sinus occlusion image score (AVOIS): A novel method to evaluate occlusive cerebral arteries and venous diseases.

AIM: To establish an artery and venous sinus occlusion image score (AVOIS) which is compatible in both cerebral arteries and venous system diseases. METHODS: A total of 188 consecutive patients with the final diagnosis of anterior circulation infarct (ACI) and 56 consecutive patients with cerebral venous and sinus thrombosis (CVST) were retrospectively studied. The AVOIS was developed based on the severity of occlusive changes of main intracranial arteries and venous sinuses (present = 0, partial occlusion = 1, absent = 2), and divided into four groups (CVST group: 0, 1-5, 6-10, >10. ACI group: 0, 1-5, 6-10, >10) arbitrarily. A receiver operating characteristic (ROC) curve was applied to discover the sensitivity and specificity of AVOIS. The National Institutes of Health Stroke Scale (NIHSS), Clot Burden Score (CBS) were set as the reference. Logistic regression models were developed to adjust for baseline clinical variables and AVOIS. Length of hospital stay (LOS) was also evaluated using the Kaplan-Meier estimator. RESULTS: For the CVST group, a positive correlation between AVOIS and NIHSS was discovered (Spearman's ρ = 0.54, p < 0.001). For the ACI group, ROC showed relatively high sensitivity (84.8%) and specificity (81.8%). Besides, the probability of time to discharge was significantly different among the AVOIS subgroups as well (p < 0.001). CONCLUSION: The AVOIS can be used to evaluate the treatment of patients with acute stroke caused by cerebral venous sinus thrombosis and anterior circulation large vessel occlusion. It is a reliable and convenient method that may help prompt prognosis and guide the treatment of individual patients.