Effect of Astilbin on Experimental Diabetic Nephropathy in vivo and in vitro
School of Pharmacy, Yantai University, Yantai, P. R. China.Planta Medica (Impact Factor: 2.15). 07/2009; 75(14):1470-5. DOI: 10.1055/s-0029-1185802
Astilbin, a flavonoid compound, was isolated from the rhizome of Smilax glabra Roxb. This study was conducted to investigate the efficacy of astilbin on experimental diabetic nephropathy (DN) in vivo and in vitro and its possible mechanisms. Astilbin was added in high glucose stimulated HK-2 cells, streptozotocin-induced experimental DN, randomized to receive intragastric ( I. G.) astilbin to observe its anti-renal lesion effect. Results showed that astilbin inhibited high glucose stimulated HK-2 cell production of transforming growth factor-beta1 (TGF-beta1) and connective tissue growth factor (CTGF) in vitro, especially CTGF; analogic results was also found in vivo. I. G. of astilbin 2.5 mg/kg or 5 mg/kg significantly ameliorated renal function, reduced kidney index, while it increased body weight and survival time in animals. In addition there was no significant difference in blood glucose level between the STZ-treated group and the astilbin groups. Furthermore, astilbin ameliorated the pathological progress of renal morphology. Astilbin can exert an early renal protective role to DN, inhibit production of TGF-beta1 and especially of CTGF. We suggest that astilbin inhibition of CTGF may be a potential target in DN therapy. This work provides the first evidence for astilbin as a new candidate of DN therapeutic medicine.
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ABSTRACT: Diabetic nephropathy characterized as mesangial fibrosis and glomerulosclerosis results in renal failure and end-stage renal diseases. Enhanced expression and secretion of connective tissue growth factor (CTGF) play an important role in the expansion of glomerular mesangial matrix mostly composed of type IV collagen. Isoliquiritigenin can prevent various renal injuries via its anti-inflammatory action. However, the effect of isoliquiritigenin on diabetic nephropathy has never been explored. The present study was to investigate whether nontoxic isoliquiritigenin inhibited high glucose (HG)-induced mesangial fibrosis by retarding formation of type IV collagen as well as CTGF in human mesangial cells (HRMC). Serum starved cells were cultured in media containing 5.5 mM glucose plus 27.5 mM mannitol as an osmotic control or 33 mM glucose for 3 days with and without 1-20 microM isoliquiritigenin. Exposure of cells to HG caused marked increases in collagen secretion and CTGF expression, which was dose-dependently reversed by isoliquiritigenin at the transcriptional levels. Additionally, isoliquiritigenin boosted HG-plummeted type matrix metalloproteinase-1 (MT-1 MMP) expression and dampened HG-elevated tissue inhibitor of MMP-2 (TIMP-2) expression, facilitating the degradation of mesangial matrix. Isoliquiritigenin inhibited HG-upregulated CTGF and TIMP-2 expression via disturbing TGF-beta1 signaling in HRMC, as evidenced by TGF-beta receptor I kinase (TGF-beta RI) inhibitor. HG-activated SMAD2 through autocrine TGF-beta signaling was repealed by > or =10 microM isoliquiritigenin. HG induced SMAD4 expression of HRMC and obliterated antagonistic SMAD7, whereas isoliquiritigenin suppressed induction of TGF-beta RII and TGF-beta RI with blunting their downstream SMAD signaling. The results demonstrate that the bioactive isoliquiritigenin in licorice diminished mesangial matrix accumulation in response to ambient HG through retarding TGF-beta1-SMAD signaling transduction. Therefore, isoliquiritigenin may be a potential therapeutic agent for the prevention and treatment of mesangial fibrosis and glomerulosclerosis leading to diabetic nephropathy due to longstanding diabetes mellitus.
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ABSTRACT: Diabetes is one of the most prevalent chronic diseases throughout the world. The majority of its complications arise from vascular- related inflammation apparently initiated by endothelial cell injury. One cause of this injury has been attributed to hyperglycaemia induced reactive oxygen species. Consequently, current drug developmental strategy has targeted specific inflammatory and oxidative stress pathways for the prevention of diabetic vascular complications. Herbal medicines have traditionally been used for the treatment of diabetes and its complications. In fact, current pre-clinical and clinical studies have demonstrated that many of them exhibit potent anti- inflammatory and anti-oxidative properties, and have also identified the active phytochemicals responsible for their activities. The present review summarises the latest research on the molecular mechanisms of diabetic vascular complications, and evaluates the level of scientific evidence for common herbal medicines and their bioactive phytochemicals. These agents have been shown to be effective through various mechanisms, particularly the NF-κB signalling pathways. Overall, herbal medicines and nutraceuticals, as well as their bioactive components, which exhibit anti-inflammatory and anti-oxidative properties, provide a promising approach for the prevention and treatment of diabetic complications.
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ABSTRACT: Development of diabetic nephropathy with fibrosis is associated with hypereglycemia-linked inflammation. Increased levels of proinflammatory factors have been found in diabetic patients with nephropathy. The present study was to test the hypothesis that isoangustone A, a novel compound present in licorice, can inhibit renal fibrosis and inflammation inflamed by high glucose (HG) in human mesangial cells through disturbing transforming growth factor β (TGF-β) and nuclear facor κB (NF-κB) pathways. Serum-starved mesangial cells were cultured in 33 mmol/L glucose media. Cells were treated with 1-20 μmol/L isoangustone A isolated from Glycyrrhiza uralensis licorice for three days. Exposure of cells to HG elevated connective tissue growth factor and collagen production, which was dose-dependently reversed by isoangustone A. Isoangustone A boosted HG-plummeted membrane type matrix metalloproteinase (MMP)-1 expression and diminished HG-elevated tissue inhibitor of MMP-2 expression. HG activated mesangial TGF-β1-SMAD-responsive signaling, which was repealed by ≥10 μmol/L isoangustone A. Furthermore, HG upregulated intracellular cell adhesion molecule-1 (ICAM-1) level and monocyte chemoattractant protein-1 (MCP-1) mRNA expression, and such increases were dose-dependently suppressed by isoangustone A most likely through hampering TGF-β signaling pathways. Blockade of NF-κB signaling appeared to be responsible for attenuating HG-triggered induction of ICAM-1 and MCP-1. Our findings provide the first evidence that isoangustone A dampens mesangial sclerosis associated with inflammation in response to HG through hindering TGF-β and NF-κB signaling.
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