Knowledge-Based Discovery of the Role and Mechanism of Resveratrol in Improving Glomerular Tether Cell Proliferation and Apoptosis in Diabetic Nephropathy.

To investigate the effects and mechanisms of resveratrol on glucolipid metabolism in diabetic humans. In this paper, we introduced the knowledge discovery theory into the data processing of the factors related to the pathogenesis of type 2 diabetes for the first time, and identified valid, potentially useful, and understandable pathogenesis patterns from a large amount of measured data. A data mining C4.5 algorithm was used to classify 17072 validated cross-sectional health survey data from the whole population according to the characteristics of type ρ diabetes data. A human model of diabetes mellitus was prepared by high sugar and high fat diet plus low dose streptozotocin (STZ, 35 mg/kg) and randomly grouped into four groups: the normal control group, the model group, the resveratrol group, and the pioglitazone group. 8 animals in each group were treated with the corresponding drugs for 8 weeks. Hepatic steatosis and damage were significantly reduced compared with the model group as observed by HE staining. Resveratrol has obvious effects on regulating glucolipid metabolism, and its mechanism of action is associated with its ability to increase the antioxidant activity of the body, activate the Akt signaling pathway, and improve liver pathological damage.

You-gui Pill ameliorates renal tubulointerstitial fibrosis via inhibition of TGF-ß/Smad signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: You-gui Pill (YGP), a traditional Chinese medicinal prescription, was widely used to warm and recuperate "kidney-yang" clinically for hundreds of years in China. Recent studies found that YGP had a potential benefit for renoprotection. AIM OF THE STUDY: The present study aimed to elucidate the in vivo and in vitro efficacy of YGP on renal tubulointerstitial fibrosis, and the molecular mechanism is also investigated. MATERIALS AND METHODS: Rat renal tubulointerstitial fibrosis model was elicited by unilateral ureteral obstruction (UUO). Sprague-Dawley rats underwent UUO and were studied after 14 days. Animals were randomly subjected to six groups: sham, UUO, UUO/YGP (0.14, 0.42, 1.26g/kg/d), and UUO/enalapril (10mg/kg/d). HE, Masson and ELISA were used for evaluate renal injury and function. Immunohistochemical analysis and western blot were used to detect the expressions of α-SMA, fibronectin, collagen matrix and Smads. In vitro studies were investigated in TGF-ß1-stiumlated NRK-49F cell line. RESULTS: Oral administration of YGP significantly decreased UUO-induced inflammatory cell infiltration, tubular atrophy and interstitial fibrosis, and there was no significant difference between YGP at 1.26g/kg and enalapril at 10mg/kg treatment (P>0.05). Meanwhile, serum creatinine and blood urea nitrogen levels were reduced dramatically (P<0.01). In coincide with the decreased of TGF-ß1, α-SMA, fibronectin and collagen matrix expressions were also declined with YGP treatment in both UUO kidneys and TGF-ß1-stimulated NRK-49F cell line. Additionally, nuclear translocation of p-Smad2/3 was markedly down-regulated by YGP (P<0.001), with a relative mild up-regulated expression of Smad7 (P<0.05). CONCLUSIONS: Our findings demonstrate that YGP had a renoprotective effect in ameliorating renal tubulointerstitial fibrosis, and this activity possibly via suppression of the TGF-ß and its downstream regulatory signaling pathway, including Smad2/3.

Astragaloside IV inhibits renal tubulointerstitial fibrosis by blocking TGF-ß/Smad signaling pathway in vivo and in vitro.

Astragaloside IV (AS-IV) is a major active ingredient from Radix astragali, which has been considered as a renoprotective agent; however, its molecular mechanisms are unclear. Thus, we designed to investigate the renoprotective effects and mechanisms of AS-IV in rat model of renal fibrosis induced by unilateral ureteral obstruction (UUO) in vivo and TGF-ß1-stimulated rat renal fibroblasts (NRK-49F) in vitro. Sprague-Dawley rats were randomly divided into six groups: sham operation, UUO, UUO/AS-IV (3.3, 10, 33 mg·kg(-1)·d(-1)), and UUO/enalapril (4 mg·kg(-1)·d(-1)). Renal function, tubulointerstitial damage index score, extracellular matrix (ECM) deposition, and the expressions of TGF-ß1, connective tissue growth factor (CTGF), α-SMA, fibronectin, collagen I, III, Smad2/3, phosphorylated-Smad2/3, and Smad7 were measured. In addition, the expressions of CTGF, α-SMA, fibronectin, collagen I, III, Smad2/3, phosphorylated-Smad2/3, and Smad7 were measured in TGF-ß1-stiumlated NRK-49F cell line. AS-IV significantly decreased UUO-induced renal fibrosis and functional impairment, which are associated with inhibition of TGF-ß1, CTGF, α-SMA, and collagen matrix expression, and a decrease in serum creatinine and urea nitrogen. The renoprotective effects of AS-IV on fibrosis were associated with up-regulation of Smad7, thereby blocking up-regulations of TGF-ß1, CTGF, and α-SMA, and activation of phosphorylated-Smad2/3. These effects were further conformed in NRK-49F cell line stimulated by TGF-ß1. Moreover, knockdown of Smad7 gene in NRK-49F cells was able to prevent AS-IV-induced inhibition to Smad2/3 signaling activation, expression of CTGF, α-SMA, and ECM proteins in response to TGF-ß1. Renal tubulointerstitial fibrosis was attenuated by treatment with AS-IV, which was closely related to induction of Smad7, thereby inhibiting TGF-ß/Smad signaling.

Astragaloside IV inhibits the up-regulation of Wnt/ß-catenin signaling in rats with unilateral ureteral obstruction.

OBJECTIVE: To investigate the effect of Astragaloside IV (AS-IV) on the regulation of the Wnt/ß-catenin signaling pathway in rats with unilateral ureteral obstruction (UUO). METHODS: Rat renal interstitial fibrosis models were prepared using unilateral ureteral ligation. Rats were randomly divided into sham group, sham group with AS-IV (33mg/kg), unilateral ureteral obstruction group, and unilateral ureteral obstruction group receiving varied doses of AS-IV (3.3, 10, and 33 mg/kg). Immunohistochemical analysis, real-time fluorescence quantitative PCR (FQ-PCR), and western blot were used to detect the expression of genes and proteins associated with the Wnt/ß-catenin signaling pathway in renal tissues. RESULTS: Levels of Wnt3, Wnt4, and Frizzled gene expression increased significantly in the UUO model; AS-IV was associated with the downregulation of the expression of Wnt3, Wnt4, Frizzled4, p-LRP5, p-LRP6, disheveled, ß-catenin, LEF-1, TCF-1, Snail, Jagged 1, Twist, MMP2, and MMP7 proteins in a concentration-dependent manner, while the expression of APC, CK1, and E-cadherin was increased. CONCLUSIONS: AS-IV effectively inhibits the up-regulation of proteins in the Wnt/ß-catenin signaling pathway in UUO-model rats, indicating its possible inhibitory effects on renal interstitial fibrosis.

Synergistic Effect of Zuo Jin Wan on DDP-Induced Apoptosis in Human Gastric Cancer SGC-7901/DDP Cells.

A traditional Chinese medicine (TCM) formula, Zuo Jin Wan (ZJW), has been found as an anticancer drug in human cancer. In this study, we investigated the synergistic effect of ZJW extracts on DDP-induced apoptosis in human gastric cancer SGC-7901/DDP cells. Our results demonstrated that ZJW extracts could increase the sensitivity of SGC-7901/DDP cells to DDP by increasing the concentration of DDP in cytoplasm and enhance the proapoptosis of DDP by upregulating the JNK and Bax expression, downregulating the Bcl-2 expression, increasing the accumulation of Cytochrome C in cytoplasm, and promoting the activities of caspase-3 and caspase-9. In vivo, ZJW extracts enhanced the inhibiting effect of DDP on tumor growth in SGC-7901/DDP xenograft model and upregulated the expression of p-JNK and Bax but downregulated the Bcl-2 expression in xenograft tumors. In conclusion, in vitro and in vivo, ZJW extracts could enhance the proapoptotic effect of DDP by promoting the activation of JNK and the expression of Bcl-2, inhibiting the Bax expression, followed by increasing the release of Cytochrome C from mitochondria to cytoplasm, and finally activating the caspase cade reaction. Our results implied that ZJW might serve as a synergistic drug with chemotherapeutic drugs DDP in the treatment of gastric cancer.

Reduced mir-29b-3p expression up-regulate CDK6 and contributes to IgA nephropathy.

IgA nephropathy (IgAN) is the most common glomerulonephritis and the etiology of which is complex and multiple, and the pathological damage of IgAN is diversified. MicroRNA is a kind of gene expression suppressor and recently, researchers have found that microRNAs may play an important role in the pathogenesis of IgAN. Herein, we found that miR-29b-3p not miR-29a or miR-29c was significantly down regulated in IgAN patients' renal tissues. Predicted by bioinformatics tools and confirmed by dual luciferase assay and western blot, we found that the expression of CDK6 was repressed by miR-29b-3p directly. Subsequently, we found that miR-29b-3p down-regulation caused CDK6 overexpression can promote NF-κB signal by phosphorylating p65 which may enhance inflammation during IgAN pathogenesis.