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.

Transcriptomic Analysis Identifies Complement Component 3 as a Potential Predictive Biomarker for Chemotherapy Resistance in Colorectal Cancer.

Objective: 5-fluorouracil- and oxaliplatin-based FOLFOX regimens are mainstay chemotherapeutics for colorectal cancer (CRC) but drug resistance represents a major therapeutic challenge. To improve patient survival, there is a need to identify resistance genes to better understand the mechanisms underlying chemotherapy resistance. Methods: Transcriptomic datasets were retrieved from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and combined with our own microarray data. Weighted gene co-expression network analysis (WGCNA) was used to dissect the functional networks and hub genes associated with FOLFOX resistance and cancer recurrence. We then conducted analysis of prognosis, profiling of tumor infiltrating immune cells, and pathway overrepresentation analysis to comprehensively elucidate the biological impact of the identified hub gene in CRC. Results: WGCNA analysis identified the complement component 3 (C3) gene as the only hub gene associated with both FOLFOX chemotherapy resistance and CRC recurrence after FOLFOX chemotherapy. Subsequent survival analysis confirmed that high C3 expression confers poor progression-free survival, disease-free survival, and recurrence-free survival. Further correlational analysis revealed significant negative association of C3 expression with sensitivity to oxaliplatin, but not 5-fluorouracil. Moreover, in silico analysis of tumor immune cell infiltration suggested the change of C3 expression could affect tumor microenvironment. Finally, gene set enrichment analysis (GSEA) revealed a hyperactivation of pathways contributing to invasion, metastasis, lymph node spread, and oxaliplatin resistance in CRC samples with C3 overexpression. Conclusion: Our results suggest that high C3 expression is a debilitating factor for FOLFOX chemotherapy, especially for oxaliplatin sensitivity, and C3 may represent a novel biomarker for treatment decision of CRC.

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.

Circulating T Cells Exhibit Different TIM3/Galectin-9 Expression in Patients with Obesity and Obesity-Related Diabetes.

AIMS: Obesity is highly associated with type 2 diabetes mellitus (T2DM). The TIM3/galectin-9 pathway plays an important role in immune tolerance. Herein, we aimed to investigate the expression of TIM3 and galectin-9 in peripheral blood and to evaluate their clinical significance in patients with obesity and obesity-related T2DM. METHODS: We performed flow cytometry on peripheral blood samples from healthy donors (HC), patients with simple obesity (OB), and patients with obesity comorbid T2DM (OD). The expression of TIM3 on CD3+, CD4+, and CD8+ T cells was determined. The level of galectin-9 in plasma was detected by ELISA. RESULTS: We demonstrated the enhancement of TIM3 on CD3+, CD4+, and CD8+ T cells in the OB group when compared with healthy controls, while it was decreased significantly in the OD group. The TIM3+CD8+ T cells of the OB group were positively correlated with risk factors including BMI, body fat rate, and hipline. The concentration of galectin-9 of the OD group in plasma was significantly higher than that of healthy donors and the OB group. Moreover, the level of galectin-9 of the OD group was positively correlated with fasting insulin and C-peptide, which were two clinical features that represented pancreatic islet function in T2DM. CONCLUSIONS: Our results suggested that TIM3 and galectin-9 may be potential biomarkers related to the pathogenesis of obesity-related T2DM.

The influence of maternal body mass index, maternal diabetes mellitus, and maternal smoking during pregnancy on the risk of childhood-onset type 1 diabetes mellitus in the offspring: Systematic review and meta-analysis of observational studies.

There is emerging evidence that events occurring before and shortly after birth may be important in determining the risk of childhood-onset type 1 diabetes mellitus (T1DM). We aimed to summarize and synthesize the associations between maternal body mass index (BMI), maternal diabetes mellitus (DM), and maternal smoking during pregnancy and the risk of childhood-onset T1DM in the offspring by performing a systematic review and meta-analysis of observational studies. A random effects model was used to generate the summary risk estimates. The PubMed and Web of Science databases were searched to identify relevant observational studies. Twenty one observational studies were included in the present meta-analysis. Compared with offspring of mothers with normal weight, offspring of women with overweight or obesity were at an increased risk of developing childhood-onset T1DM (overweight: relative risk [RR] 1.09, 95% confidence interval [CI], 1.03-1.15; obesity: RR 1.25, 95% CI, 1.16-1.34; per 5 kg m-2 increase in BMI: RR 1.10, 95% CI, 1.06-1.13). No association was found for maternal underweight (RR 0.92, 95% CI, 0.75-1.13). Maternal DM was associated with an increased risk of childhood-onset T1DM (RR 3.26, 95% CI, 2.84-3.74). Regarding the type of maternal DM, the greatest risk of T1DM in the offspring appeared to be conferred by maternal T1DM (RR 4.46, 95% CI, 2.89-6.89), followed by maternal gestational diabetes mellitus (RR 1.66, 95% CI, 1.16-2.36), and lastly by maternal type 2 diabetes mellitus (RR 1.11, 95% CI, 0.69-1.80). Additional analysis of studies comparing maternal versus paternal T1DM within the same population revealed that offspring of fathers with T1DM had a 1.5 times higher risk of developing childhood-onset T1DM than offspring of mothers with T1DM (RR 9.58, 95% CI, 6.33-14.48 vs. RR 6.24, 95% CI, 5.52-7.07). Furthermore, a reduced risk of childhood-onset T1DM was observed in infants born to mothers who smoked during pregnancy compared with infants born to mothers who did not smoke during pregnancy (RR 0.79, 95% CI, 0.71-0.87). In summary, our findings add further evidence that early-life events or environmental factors may play a role in modulating infants' risk of developing T1DM later in life.

Blood pressure and kidney cancer risk: meta-analysis of prospective studies.

BACKGROUND: Globally, kidney cancer is the twelfth most common cancer, accounting for 337 860 cases recorded in 2012. By 2020, this number has been estimated to reach 412 929 or increase by 22%. Over the past few decades, a number of prospective studies have investigated the association between blood pressure (BP) and risk of kidney cancer, using either recorded BP levels or reported hypertension as the principal exposure variable. However, the relation of BP to kidney cancer remains incompletely understood, and the data on sex-specific differences in risk estimates have been inconsistent. METHOD: PubMed and Web of Science databases were searched for studies assessing the association between BP and kidney cancer through July 2016. The summary relative risk with 95% confidence intervals was calculated using a random-effects model. RESULT: A total of 18 prospective studies with 8097 kidney cancer cases from 3 628 479 participants were included in our meta-analysis. History of hypertension was associated with 67% increased risk of kidney cancer. Significant heterogeneity and evidence of publication bias were observed. However, the results remain unchanged after introducing the trim and fill method to correct the publication bias. Accordingly, each 10-mmHg increase in SBP and DBP was associated with 10 and 22% increased risk of kidney cancer. CONCLUSION: Collectively, the present meta-analysis of 18 prospective studies provides further support for a positive association between hypertension and kidney cancer risk.

Calcium intake and breast cancer risk: meta-analysis of prospective cohort studies.

Findings from observational studies have suggested a possible relation between Ca and breast cancer risk. However, the results of these studies are inconclusive, and the dose-response relationship between Ca intake and risk of breast cancer remains to be determined. A meta-analysis of prospective studies was conducted to address these issues. PubMed and Embase databases were searched for relevant studies concerning the association between Ca intake and breast cancer up to March 2016. The summary relative risks (RR) with 95 % CI were calculated with a random-effects model. The final analysis included eleven prospective cohort studies involving 26 606 cases and 872 895 participants. The overall RR of breast cancer for high v. low intake of Ca was 0·92 (95 % CI 0·85, 0·99), with moderate heterogeneity (P=0·026, I 2=44·2 %). In the subgroup analysis, the inverse association appeared stronger for premenopausal breast cancer (RR 0·75; 95 % CI 0·59, 0·96) than for postmenopausal breast cancer (RR 0·94; 95 % CI 0·87, 1·01). Dose-response analysis revealed that each 300 mg/d increase in Ca intake was associated with 2 % (RR 0·98; 95 % CI 0·96, 0·99), 8 % (RR 0·92; 95 % CI 0·87, 0·98) and 2 % (RR 0·98; 95 % CI 0·97, 0·99) reduction in the risk of total, premenopausal and postmenopausal breast cancer, respectively. Our findings suggest an inverse dose-response association between Ca intake and risk of breast cancer.

Identifying at-risk foot among hospitalized patients with type 2 diabetes: A cross-sectional study in one Chinese tertiary hospital.

OBJECTIVE: To investigate the prevalence of diabetic at-risk foot and its associated factors. METHODS: A total of 838 hospitalized patients with type 2 diabetes were screened for at-risk foot. Neural and vascular disorders were evaluated by assessing vibration perception thresholds and ankle brachial indexes (ABIs). After excluding 12 patients with abnormally high ABIs, remaining individuals with neural and/or vascular disorder were identified as at-risk patients and further classified into three subtypes: isolated neural disorder, isolated vascular disorder and mixed disorder. Potential associated factors were examined using Logistic regression models. RESULTS: In the final sample of 826 individuals, the prevalence of diabetic at-risk foot was 30.6%. Among all at-risk patients, isolated neural disorders (69.6%) were more common than mixed (16.2%) or isolated vascular disorders (14.2%). Isolated neural and vascular disorders shared specific risk factors, including age per 20-year increment (odds ratio [95% CI], 3.73 [2.59-5.37] and 4.01 [1.98-8.11]), diabetic duration ≥10 years (1.69 [1.13-2.54] and 3.29 [1.49-7.24]) and systolic blood pressure ≥140 mmHg (1.96 [1.31-2.93] and 2.90 [1.38-6.10]) respectively. In addition, isolated neural disorders were associated with a heavy smoking history (95%CI 2.69 [1.15-6.31]), increased high-sensitivity C-reactive protein levels (95%CI 1.30 [1.04-1.62]) and mild obesity (95%CI 0.49 [0.20-1.24]). Isolated vascular disorders were linked with decreased high density lipoprotein (HDL) cholesterol levels (95%CI 3.42 [1.31-8.96]) and increased triglycerides levels (95%CI 2.74 [1.26-5.97]). CONCLUSIONS: Diabetic at-risk foot is epidemic among hospitalized patients with type 2 diabetes. Aging, long-term diabetes, hypertension, smoking, inflammatory response and dyslipidemia may be associated with the prevalence of diabetic at-risk foot.