SIRT4 overexpression protects against diabetic nephropathy by inhibiting podocyte apoptosis.

Diabetic nephropathy is a diabetic complication associated with capillary damage and increased mortality. Sirtuin 4 (SIRT4) plays an important role in mitochondrial function and the pathogenesis of metabolic diseases, including aging kidneys. The aim of the present study was to investigate the association between SIRT4 and diabetic nephropathy in a glucose-induced mouse podocyte model. A CCK-8 assay showed that glucose simulation significantly inhibited podocyte proliferation in a time- and concentration-dependent manner. Reverse transcription-quantitative polymerase chain reaction and western blot analysis showed that the mRNA and protein levels of SIRT4 were notably decreased in a concentration-dependent manner in glucose-simulated podocytes. However, SIRT4 overexpression increased proliferation and suppressed apoptosis, which was accompanied by increases in mitochondrial membrane potential and reduced production of reactive oxygen species (ROS). Notably, SIRT4 overexpression downregulated the expression of apoptosis-related proteins NOX1, Bax and phosphorylated p38 and upregulated the expression of Bcl-2 in glucose-simulated podocytes. In addition, SIRT4 overexpression significantly attenuated the inflammatory response, indicated by reductions in the levels of TNF-α, IL-1ß and IL-6. These results demonstrate for the first time that the overexpression of SIRT4 prevents glucose-induced podocyte apoptosis and ROS production and suggest that podocyte apoptosis represents an early pathological mechanism leading to diabetic nephropathy.

Silencing of USP22 suppresses high glucose-induced apoptosis, ROS production and inflammation in podocytes.

Ubiquitin-specific protease 22 (USP22) has been reported to mediate various cellular processes, including cell proliferation and apoptosis. However, its role in high glucose-induced podocytes and diabetic rats remains unknown. In the current study, podocytes were treated with different concentrations of d-glucose to establish a high glucose-induced injury model. Additionally, intravenous tail injection of rats with 65 mg kg(-1) of streptozotocin (STZ) was performed to establish a diabetic rat model. Our findings showed that the treatment of podocytes with high d-glucose significantly increased the USP22 expression level. Silencing of USP22 in podocytes attenuated high d-glucose-induced apoptosis and inflammatory responses, evidenced by increases in proliferation and MMP levels and decreases in the apoptotic rate, ROS production, the Bax/Bcl-2 ratio, caspase-3 expression and secretion of TNF-α, IL-1ß, IL-6 and TGF-ß1. In addition, podocytes with USP22 overexpression significantly enhanced the effect of high d-glucose-induced apoptosis and inflammatory responses. Similar to the protective effect of USP22 knockdown, resveratrol (RSV) depressed not only high d-glucose- and USP22 overexpression-induced cytotoxicity, but also the secretion of TNF-α, IL-1ß, IL-6 and TGF-ß1. Notably, silencing of USP22 in diabetic rats conferred a similar protective effect against high glucose-induced apoptosis and inflammation. Taken together, the findings of the present study have demonstrated for the first time that USP22 inhibition attenuates high glucose-induced podocyte injuries and inflammation.

Therapeutic effects of hydrogen saturated saline on rat diabetic model and insulin resistant model via reduction of oxidative stress.

BACKGROUND: Molecular hydrogen, as a novel antioxidant, has been proven effective in treating many diseases. This study aimed to evaluate the therapeutic effects of hydrogen saturated saline in treatment of a rat model of diabetes mellitus and a rat model of insulin resistant. METHODS: A rat diabetes mellitus model was established by feeding a high fat/high carbohydrate diet followed by injection of a small dose of streptozotocin, and an insulin resistant model was induced with a high glucose and high fat diet. Hydrogen saturated saline was administered to rats with both models conditions on a daily basis for eight weeks. A pioglitazone-treated group and normal saline-treated group served as positive and negative controls. The general condition, body weight, blood glucose, blood lipids, and serum insulin levels of rats were examined at the 8th week after treatment. The oxidative stress indices, including serum superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA) were also evaluated after eight weeks of treatment using the commercial kits. RESULTS: Hydrogen saturated saline showed great efficiency in improving the insulin sensitivity and lowering blood glucose and lipids. Meanwhile, the therapeutic effects of hydrogen saturated saline were superior to those of pioglitazone. Hydrogen saturated saline markedly attenuated the MDA level and elevated the levels of antioxidants SOD and GSH. CONCLUSION: Hydrogen saturated saline may improve the insulin resistance and alleviate the symptoms of diabetes mellitus by reducing the oxidative stress and enhancing the anti-oxidant system.

Reduced expression of transcription factor AP-2α is associated with gastric adenocarcinoma prognosis.

BACKGROUND: This study aims to investigate the expression and prognostic significance of activator protein 2α (AP-2α) in gastric adenocarcinoma. METHODOLOGY/PRINCIPAL FINDINGS: AP-2α expression was analyzed using real-time quantitative PCR (RT-qPCR), western blotting, and immunohistochemical staining methods on tissue samples from a consecutive series of 481 gastric adenocarcinoma patients who underwent resections between 2003 and 2006. The relationship between AP-2α expression, clinicopathological factors, and patient survival was investigated. RT- qPCR results showed that the expression of AP-2α mRNA was reduced in tumor tissue samples, compared with expression in matched adjacent non-tumor tissue samples (P = 0.009); this finding was confirmed by western blotting analysis (P = 0.012). Immunohistochemical staining data indicated that AP-2α expression was significantly decreased in 196 of 481 (40.7%) gastric adenocarcinoma cases; reduced AP-2α expression was also observed in patients with poorly differentiated tumors (P = 0.001) and total gastric carcinomas (P = 0.002), as well as in patients who underwent palliative tumor resection (P = 0.004). Additionally, reduced expression of AP-2α was more commonly observed in tumors that were staged as T4a/b (P = 0.018), N3 (P = 0.006), and M1 (P = 0.008). Kaplan-Meier survival curves revealed that reduced expression of AP-2α was associated with poor prognosis in gastric adenocarcinoma patients (P<0.001). Multivariate Cox analysis identified AP-2α expression as an independent prognostic factor for overall survival (HR = 1.512, 95% CI = 1.127-2.029, P = 0.006). CONCLUSIONS/SIGNIFICANCE: Our data suggest that AP-2α plays an important role in tumor progression and that reduced AP-2α expression independently predicts an unfavorable prognosis in gastric adenocarcinoma patients.

[Effect of compound Danshen Dripping Pill on carotid arterial intima-media in patients with type 2 diabetes mellitus].

OBJECTIVE: To investigate the effect of compound Danshen Dripping Pill (DSP) on carotid arterial intima-media thickness (IMT) in patients with type 2 diabetes mellitus (T2DM). METHODS: One hundred and thirty T2DM patients were assigned to four groups, 32 in the Group A, the control group treated with blood glucose (BG) and blood pressure (BP) controlling; 32 in the Group B, with BG, BP and blood lipid (BL) controlling, 32 in Group C with BG, BP, BL controlling and vitamin E administration, and 34 in Group D with BG, BP, BL controlling and DSP administration. Patients in Group D were subdivided by Chinese medicine syndrome differentiation into four types, 8 of Yin-deficiency with flourishing heat type (YDFH), 5 of both qi-yin deficient type (BQYD), 8 of both yin-yang deficient type (BYYD) and 13 of blood-stasis and qi-stagnant type (BSQS). Fasting blood glucose (FBG), BP and BL in patients were observed periodically, and IMT in them were measured by ultrasonography before treatment, as well as at the end of the 1st, 3rd, and 5th year of treatment to dynamically observe the changes of IMT and condition of plaque formation, and analyze the relation between them with FBG, BP and BL. RESULTS: The 5-year follow-up was performed in 105 patients. In the observation period, level of total cholesterol (TC) showed a decreasing trend and level of high density cholesterol (HDL-C) showed an increasing trend in all the 4 groups, the improvements in Group C and D were slightly better than those in Group B, while significantly superior to those in Group A; the changes of FBG and glycosylated hemoglobin (HbAlc) were insignificant in the 4 groups. IMT and numbers of atheroma plaque increased gradually in all groups in the observation period, however, the changes in Group D were lesser than those in other groups, showing significant difference (P < 0.01). It was showed that the increasing of cervical carotid IMT in T2DM patients was correlated with levels of HbAlc, HDL-C, LDL-C, triglyceride and TC, especially in Group D. CONCLUSION: DSP might delay the occurrence and development of diabetic macro-vascular disease.