IFN-γ enhances the therapeutic efficacy of MSCs-derived exosome via miR-126-3p in diabetic wound healing by targeting SPRED1.

BACKGROUND AND AIMS: The traditional treatment of diabetic wounds is unsatisfactory. Exosomes isolated from bone marrow mesenchymal stem cells (BMSCs) promote the healing of diabetic wounds. However, whether the exosomes secreted by interferon (IFN)-γ-pretreated BMSCs have an enhanced therapeutic effect on diabetic wound healing and the relevant mechanisms remain unclear. METHODS: In this study, we isolated exosomes from the corresponding supernatants of BMSCs with (IExos) or without IFN-γ treatment (NExos). Human umbilical vein endothelial cells (HUVECs) were used to investigate the proliferation, migration, and tube formation under different treatments in vitro. Diabetic mice were induced by intraperitoneal administration of streptozotocin, and a circular full-thickness dermal defect was then made on the back of each mouse, followed by a multisite subcutaneous injection of phosphate buffered saline or exosomes. Hematoxylin-eosin (H&E) staining, Masson's trichrome staining, and histological analysis were performed to assess the speed and quality of wound healing. RESULTS: NExos treatment accelerated the healing of diabetic wounds by promoting angiogenesis in vivo and in vitro, and IExos exhibited superior therapeutic efficiency. MicroRNA (miR)-126-3p was significantly increased in IExos, and exosomal miR-126-3p promoted angiogenesis and diabetic wound healing via its transfer to HUVECs. miR-126-3p regulates SPRED1 by directly targeting the 3'-UTR. Mechanistically, IFN-γ-pretreated BMSCs secreted miR-126-3p-enriched exosomes, which enhanced the function of HUVECs and promoted angiogenesis via the SPRED1/Ras/Erk pathway. CONCLUSION: Exosomal miR-126-3p secreted from IFN-γ-pretreated BMSCs exhibited higher therapeutic efficacy than NExos in diabetic wound healing by promoting angiogenesis via the SPRED1/Ras/Erk axis.

Influencing factors for hepatic fat accumulation in patients with type 2 diabetes mellitus.

BACKGROUND: Non-alcoholic fatty liver disease has become the most common chronic liver disease worldwide, which originates from the accumulation of triglyceride (TG) in the liver. Patients with type 2 diabetes mellitus (T2DM) are considered to have a predisposition to hepatic steatosis. However, the influencing factors for hepatic fat accumulation in T2DM patients remain unclear. AIM: To investigate the influencing factors for hepatic fat accumulation in T2DM patients. METHODS: We enrolled 329 T2DM patients admitted to the Endocrinology Department of the First Affiliated Hospital of Soochow University, who underwent MR mDIXON-Quant examination to quantify the hepatic fat fraction (HFF). According to body mass index (BMI), the patients were divided into normal weight, overweight, and obese groups. The differences in general statistics, biochemical parameters, islet function, and HFF were compared among the three groups. The associations between HFF and other parameters and the influences of various parameters on the severity of hepatic fat accumulation were analyzed. RESULTS: The HFF of T2DM patients gradually increased in the normal weight, overweight, and obese groups (P < 0.05). Spearman correlation analysis showed that in T2DM patients, HFF was negatively correlated with age and high-density lipoprotein cholesterol (P < 0.05), whereas it was positively correlated with BMI, waist-hip ratio, fasting plasma glucose, alanine aminotransferase (ALT), aspartate aminotransferase, bilirubin, glutamyl transpeptidase, lactate dehydrogenase, albumin (ALB), uric acid (UA), total cholesterol, TG, low-density lipoprotein cholesterol (LDL-C), C-reactive protein, free triiodothyronine, fasting insulin, fasting C-peptide, and homeostasis model assessment of insulin resistance (P < 0.05). Multiple linear regression analysis showed significant positive influences of BMI, ALT, LDL-C, UA, and ALB on HFF in T2DM patients (P < 0.05). Binary logistic regression analysis showed that BMI, ALT, ALB, and LDL-C were independent risk factors for moderate to severe fatty liver in T2DM patients, and obesity increased the risk of being complicated with moderate to severe fatty liver by 4.03 times (P < 0.05). CONCLUSION: The HFF of T2DM patients increases with BMI. Higher BMI, ALT, ALB, and LDL-C are independent risk factors for moderate to severe fatty liver in T2DM patients.

Correlation of serum delta-like ligand-4 level with the severity of diabetic retinopathy.

BACKGROUND: Diabetic retinopathy (DR) is one of the most serious microvascular complications of type 2 diabetes mellitus (T2DM). Delta-like ligand-4 (DLL4) maintains the normal physiological microenvironment of the retina. However, the relationship between the level of DLL4 and the severity of DR remains unclear. METHODS: We retrospectively analyzed serum DLL4 levels and other laboratory and clinical data in 94 T2DM patients (35 patients without DR [NDR], 32 with non-proliferative DR [NPDR], 27 with proliferative DR [PDR]), and 30 healthy controls. RESULTS: The serum DLL4 level was significantly greater in the NDR group (43.38 ± 16.23 pg/mL), NPDR group (56.57 ± 25.89 pg/mL), and PDR group (74.97 ± 25.28 pg/mL) than in the healthy controls (29.9 ± 8.92 pg/mL; all p < 0.05). Among T2DM patients, the level of DLL4 increased as the severity of DR increased (p < 0.05). Logistic regression analysis demonstrated that DR was positively associated with DLL4, glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG), and duration of T2DM (all p < 0.05). Consistently, receiver operating characteristic (ROC) curve analysis also indicated that DLL4 was a potential candidate biomarker for identifying the severity of DR. CONCLUSIONS: T2DM patients, especially those with DR, have increased serum levels of DLL4. DLL4 may be used as a biomarker and an independent risk factor for DR, and targeting DLL4 may be a potential therapy in patients with DR.