Resveratrol prevents diabetic nephropathy by reducing chronic inflammation and improving the blood glucose memory effect in non-obese diabetic mice.

Chronic inflammation plays an important role in the development of diabetic nephropathy. Advanced glycation end product receptor (RAGE), nuclear factor kappa B (NF-κB) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) are involved in the development of inflammation. Resveratrol is a plant antitoxin; it is believed to have anti-inflammatory effects and can improve blood glucose. We speculate that resveratrol treatment can protect renal function by reducing blood glucose, decreasing the expression of inflammatory factors. Non-obese diabetic (NOD) mice were randomly divided into three groups: T1DM, insulin (INS) and resveratrol (Res) groups. Mice without diabetes were classified as the non-diabetic control group (NOD-C group). The blood glucose (BG) level, blood urea nitrogen (BUN) level, serum creatinine (SCr) level and 24-h urinary microalbumin quantitative (UMA) were measured. The glomerulosclerosis index and basement membrane thickness were calculated under light and electron microscopes. The expression levels of RAGE, NF-кB (P65) and NOX4 in renal tissues were detected by Western blot analysis. We found that resveratrol treatment significantly reduced blood glucose within 28 days of the experiment, but the hypoglycemic effect was not lasting. At the same time, resveratrol reduced BUN, SCr, 24 h UMA and the expression of the inflammatory factors RAGE, NF-кB (P65) and NOX4 and improved the renal pathological structure. We believe that resveratrol improves renal function not only by its anti-inflammatory effect but also by improving the metabolic memory of hyperglycemia.

Long non-coding RNA MALAT1 promotes cardiac remodeling in hypertensive rats by inhibiting the transcription of MyoD.

Hypertension is the leading preventable cause of premature deaths worldwide. Although long non-coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (MALAT1) has been identified to play important roles in the development of cardiovascular diseases, the regulatory function of lncRNA MALAT1 in hypertension remains poorly understood. This study aimed to explore the role of lncRNA MALAT1 in spontaneously hypertensive rats (SHRs). LncRNA MALAT1 was determined to be elevated and MyoD to be reduced in myocardial tissues and thoracic aortic vascular tissues of SHRs. Over-expression of lncRNA MALAT1 caused severe myocardial fibrosis in SHRs. In addition, lncRNA MALAT1 over-expression in vitro enhanced arterial smooth muscle cells (ASMCs) activity and fibrosis of SHRs, which, was rescued by over-expressed MyoD. Furthermore, lncRNA MALAT1 transcripts were found to be highly enriched in the nucleus, and lncRNA MALAT1 suppressed the transactivation of MyoD. Moreover, lncRNA MALAT1 was found to recruit Suv39h1 to MyoD-binding loci, leading to H3K9me3 trimethylation and down-regulation of the target gene. Taken conjointly, this study revealed an important role of lncRNA MALAT1 in promoting cardiac remodeling in hypertensive rats by inhibiting the transcription of MyoD. These results highlight the value of lncRNA MALAT1 as a therapeutic target for the management of hypertension.

Protective effect of umbilical cord mesenchymal stem cells combined with resveratrol against renal podocyte damage in NOD mice.

BACKGROUND: The role of chronic inflammation initiated by persistent hyperglycemia in podocyte injury has attracted increasing attention. The advanced glycation end products (RAGE) receptor- nuclear factor-kappa B (NF-кB) signaling pathway is involved in the occurrence of inflammation. We speculate that treatment with human umbilical cord mesenchymal stem cells (hUCMSCs) combined with resveratrol can block this signaling pathway and protect podocyte function. METHODS: Non obesity diabetes(NOD) mice were randomly divided into 5 groups: NOD-T1DM, Res, hUCMSCs, hUCMSCs + Res and insulin (INS)groups. Mice without diabetes were classified as NOD control group(NOD group). Blood glucose(BG), blood urea nitrogen(BUN), serum creatinine(SCr), 24-h urine albumin excretion rate (UAER) were measured. The expression of nephrin, WT1 and RAGE, MCP-1 in renal tissues were detected by Western blot, expression of NF-кB protein(P65) was determined by immunohistochemistry. RESULTS: The combined treatment of hUCMSCs and Resveratrol can reduce BG, BUN, SCr, 24-h UAER, and the expression of the inflammatory factors MCP-1, RAGE and NF-кB; increase the number of podocytes and the expression of the podocyte-related proteins nephrin and WT1 in type 1 diabetes mellitus, and improve renal pathological structure. CONCLUSIONS: Combining of hUCMSCs and resveratrol can better protect renal podocyte function, and the effects on the reduction of blood glucose and renal injury are better than those obtained by insulin treatment. This indicated that the combination of Res and hUCMSCs may be a novel therapeutic method for the treatment of DN.

miR-370 promotes high glucose-induced podocyte injuries by inhibiting angiotensin II type 1 receptor-associated protein.

miRNAs expression profiles in podocyte injuries have been reported in different models in vivo and in vitro. In the present study, miR-370 was elevated in high glucose-stimulated podocyte, and the post-transcriptional mechanism of miR-370 was investigated in high glucose-induced podocyte injuries. The gene and protein levels were assayed by RT-qPCR and Western blotting, respectively. Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining was used to evaluate the apoptosis in high glucose-stimulated podocyte. The targeted genes were predicted by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. The results demonstrated that over-activation of miR-370 was verified in high glucose-treated podocytes, while miR-370 repression protected against high glucose-induced apoptosis, cell membrane, and DNA damage in podocytes. We also found that AGTRAP as a direct target of miR-370 served as an opposite effect to miR-370, and overexpression of AGTRAP blocked high glucose-induced podocytes dysfunction. In conclusions, high glucose-induced podocytes damage by activating miR-370 signaling targeted to inhibit the expression of AGTRAP, representing a novel and promising therapeutic target for the treatment of DN.

Detection rate of prostate cancer following biopsy among the northern Han Chinese population: a single-center retrospective study of 1022 cases.

BACKGROUND: Prostate cancer is known to have ethnic and regional differences. The study aimed to clinically evaluate the detection rate of prostate cancer on transrectal ultrasonography (TRUS)-guided prostate biopsy and analyze its characteristics among the northern Han Chinese population at a single center. METHODS: Between October 2009 and September 2016, a total of 1027 Chinese men, who had undergone TRUS-guided prostate biopsy at Qingdao Municipal Hospital, were retrospectively analyzed. Prostate biopsies were performed in the case of an abnormally elevated serum PSA level, and/or abnormal digital rectal examination (DRE) findings, and/or suspicious prostatic imaging findings. RESULTS: Of the 1022 men enrolled in the analysis, 438 patients (42.8%) were diagnosed with prostate adenocarcinoma histologically. When serum PSA levels were divided into five subgroups (less than 4.0, 4.0 to 10.0, 10.0 to 20.0, 20.0 to 100.0, and ≥ 100.0 ng/ml), the detection rates of prostate cancer were 12.4, 15.9, 34.1, 66.2, and 93.8%, respectively. With serum PSA levels of 4.0 to 10.0 ng/ml, the cancer detection rates for a normal DRE and a suspect DRE finding were 13.5 and 58.2%, respectively. Accordingly, the cancer detection rates for a normal imaging and a suspect imaging finding were 13.5 and 58.2%, respectively. Besides, a large proportion of the patients were in the clinically advanced stage. CONCLUSIONS: The present study data reported a relatively higher prostate cancer detection rate of 42.8% and that the majority of the patients presented with clinically advanced prostate cancers within a local clinical urologic practice. An early detection and screening program for prostate cancer is of great need to reduce the burden from this disease among the northern Han Chinese population.

Comparison of a multiple daily insulin injection regimen (glargine or detemir once daily plus prandial insulin aspart) and continuous subcutaneous insulin infusion (aspart) in short-term intensive insulin therapy for poorly controlled type 2 diabetes patients.

Aims. To examine the potential differences between multiple daily injection (MDI) regimens based on new long-acting insulin analogues (glargine or detemir) plus prandial insulin aspart and continuous subcutaneous insulin aspart infusion (CSII) in patients with poorly controlled type 2 diabetes. Methods. Patients (n = 119) with poorly controlled type 2 diabetes of a duration exceeding five years were randomly assigned into three groups: Group A treated with CSII using insulin aspart; Group B treated with glargine-based MDI and Group C treated with detemir-based MDI. Results. Good glycemic control was achieved by patients in Group A in a significantly shorter duration than patients in Groups B and C. Total daily insulin, basal insulin dose and dose per kg body weight in Group A were significantly less than those in Groups B and C. Daily blood glucose fluctuation in Group A was significantly less than that in Groups B and C. There were no differences between Groups B and C. Conclusions. Aspart-based CSII may achieve good blood glucose control with less insulin doses over a shorter period compared with glargine or detemir-based MDI. No differences between glargine- and detemir-based MDI were detected in poorly controlled subjects with type 2 diabetes.

Nonalcoholic fatty liver disease and microvascular complications in type 2 diabetes.

AIM: To evaluate the correlation between nonalcoholic fatty liver disease (NAFLD) and microvascular complications in type 2 diabetes mellitus (T2DM). METHODS: Data were obtained from 1217 inpatients with T2DM (757 females, 460 males; aged 63.39 ± 12.28 years). NAFLD was diagnosed by hepatic ultrasonography. Diabetic nephropathy (DN), diabetic peripheral neuropathy (DPN), and diabetic retinopathy (DR) were diagnosed according to their respective criteria. The prevalence of NAFLD and the independent correlations of clinical characteristics with NAFLD were determined by cross-tabulation and logistic regression, respectively. RESULTS: Approximately 61% of inpatients with T2DM in Qingdao, China had NAFLD, which decreased significantly with increase in age and prolonged course of diabetes. The prevalence of NAFLD in patients presenting with DN, DPN and DR was 49.4%, 57.2% and 54.9%, respectively. These rates were significantly lower than those of patients without DN, DPN and DR (65.9%, 65.6% and 66.1%, respectively, P < 0.05). Participants with NAFLD had greater body weight, waist circumference (WC), body mass index (BMI), fasting blood glucose (FBG), hemoglobin A1c, alanine aminotransferase, aspartate aminotransferase, γ-glutamyltransferase, blood pressure, as well as triglyceride (TG) levels and lower high-density lipoprotein (HDL) concentration than those without NAFLD (P < 0.05). NAFLD was positively correlated with BMI, WC, TG, FBG, diastolic blood pressure, and systolic blood pressure but negatively correlated with the duration of diabetes, DR, DPN, DN, and HDL. CONCLUSION: Despite the benign nature of NAFLD, efforts should be directed toward early diagnosis, intensive blood glucose and blood pressure control, and effective dyslipidemia correction.

The effect of metformin on food intake and its potential role in hypothalamic regulation in obese diabetic rats.

Metformin appears to be involved in altering energy expenditure and thermogenesis, and could affect hypothalamic feeding circuits. However, it is not clear whether metformin is able to cross the blood-brain barrier (BBB) to reach the hypothalamus and exert a direct effect on the central nervous system. Here we show the presence of metformin in cerebrospinal fluid (CSF) of diabetic rats administered orally with metformin which was confirmed by detecting the concentration of metformin with liquid chromatography-tandem mass spectrometry. Food intake of diabetic rats treated with metformin was reduced, and glucose homeostasis was gained. Expression of orexigenic peptides neuropeptide Y (NPY) and agouti-related protein (AgRP) decreased in the hypothalamus of metformin-treated diabetic rats, though anorexigenic peptides pro-opiomelanocortin (POMC) did not change significantly. The phosphorylation of signal transducer and activator of transcription 3 (STAT3) was increased but phosphorylated AMP-activated kinase (AMPK) was similar in the hypothalamus of metformin-treated diabetic rats. Our findings suggest that metformin may cross BBB and play a central mechanism on regulation of food intake in the hypothalamus. The anorexic effect of metformin may be mediated by inhibition of NPY and AgRP gene expression through the STAT3 signaling pathway.

Increased expression of CYP17 and CYP11B1 in subclinical Cushing's syndrome due to adrenal adenomas.

OBJECTIVES: To determine whether steroidogenic enzyme expression is associated with the steroid secretory pattern of subclinical Cushing's syndrome (SCS) by investigating the mRNA and protein expression of CYP17 and CYP11B1 in SCS adenomas, normal adrenal cortices (NA), non-functional adrenal adenomas (NFA) and cortisol-producing adenomas (CPA). METHODS: Total RNA and protein were extracted from 20 CPA, six SCS, 15 NFA, and eight NA. Real-time quantitative polymerase chain reaction (PCR) and western blotting analysis were performed to determine the mRNA and protein expression of CYP17 and CYP11B1 in different tissues. The expression of CYP17 and CYP11B1 in the adrenocortical tumors was compared expression in NA. RESULTS: Expression of both CYP11B1 and CYP17 mRNA and protein was detected in all samples tested. The expression of CYP11B1 mRNA and protein was significantly higher in the CPA group than in the other groups and was slightly higher in SCS samples compared with NA and NFA samples (all P < 0.05). There was no significant difference in CYP11B1 mRNA and protein expression between NA and NFA samples (P > 0.05). The expression of CYP17 mRNA and protein in different tissues was similar to that of CYP11B1. Neither CYP11B1 nor CYP17 mRNA and protein expression was correlated with plasma cortisol or adrenocorticotrophin levels (all P > 0.05). CONCLUSIONS: In conclusion, CYP11B1 and CYP17 are overexpressed in subclinical CPA and their overexpression accounts for the increased production of cortisol that is characteristic of CPA.

Influence of blood glucose on the expression of glucose trans-porter proteins 1 and 3 in the brain of diabetic rats.

BACKGROUND: The delivery of glucose from the blood to the brain involves its passage across the endothelial cells of the blood-brain barrier (BBB), which is mediated by the facilitative glucose transporter protein 1 (GLUT(1)), and then across the neural cell membranes, which is mediated by GLUT(3). This study aimed to evaluate the dynamic influence of hyperglycemia on the expression of these GLUTs by measuring their expression in the brain at different blood glucose levels in a rat model of diabetes. This might help to determine the proper blood glucose threshold level in the treatment of diabetic apoplexy. METHODS: Diabetes mellitus was induced with streptozotocin (STZ) in 30 rats. The rats were randomly divided into 3 groups: diabetic group without blood glucose control (group DM1), diabetic rats treated with low dose insulin (group DM2), and diabetic rats treated with high dose insulin (group DM3). The mRNA and protein levels of GLUT(1) and GLUT(3) were assayed by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry, respectively. RESULTS: Compared with normal control rats, the GLUT(1) mRNA was reduced by 46.08%, 29.80%, 19.22% (P < 0.01) in DM1, DM2, and DM3 group, respectively; and the GLUT(3) mRNA was reduced by 75.00%, 46.75%, and 17.89% (P < 0.01) in DM1, DM2, and DM3 group, respectively. The abundance of GLUT(1) and GLUT(3) proteins had negative correlation with the blood glucose level (P < 0.01). The density of microvessels in the brain of diabetic rats did not change significantly compared with normal rats. CONCLUSIONS: Chronic hyperglycemia downregulates GLUT(1) and GLUT(3) expression at both mRNA and protein levels in the rat brain, which is not due to the decrease of the density of microvessels. The downregulation of GLUT(1) and GLUT(3) expression might be the adaptive reaction of the body to prevent excessive glucose entering the cell that may lead to cell damage.