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Combination of active components of Xiexin decoction ameliorates renal fibrosis through the inhibition of NF-?B and TGF-?1/Smad pathways in db/db diabetic mice.

ABSTRACT: Xiexin decoction, a herbal therapeutic agent commonly used in traditional Chinese medicine, is recognized for its beneficial effects on diabetic nephropathy exerted through the combined action of multiple components, including Rhizoma Coptidis alkaloids (A), Radix et Rhizoma Rhei polysaccharides (P), and Radix Scutellaria flavones (F). Our previous studies have shown that a combination of A, P, and F (APF) exhibits renoprotective effects against diabetic nephropathy. This study was aimed at determining the effects of APF on renal fibrosis in diabetic nephropathy and elucidating the underlying molecular mechanisms. To evaluate the effects of APF, in vivo, db/db diabetic mice were orally administered a low or high dose of APF (300 or 600 mg/kg, respectively) once a day for 8 weeks. We evaluated the blood and urine indices of metabolic and renal function, renal tissue histopathology, renal inflammation, and fibrosis. APF treatment significantly ameliorated glucose and lipid metabolism dysfunction, decreased urinary albumin excretion, normalized creatinine clearance, and reduced the morphological changes in renal tissue. Additionally, APF administration in db/db diabetic mice reduced the elevated levels of renal inflammation mediators such as intercellular adhesion molecule-1, monocyte chemotactic protein-1, tumor necrosis factor-?, interleukin-1?, and active nuclear factor ?B (NF-?B). APF treatment also reduced type I and IV collagen, transforming growth factor-?1 (TGF-?1), and TGF-?1 type II receptor expression levels, and decreased the phosphorylation of Smad2/3 in the kidneys of db/db diabetic mice. These results suggest that APF reduces renal fibrosis in diabetic nephropathy through the NF-?B and TGF-?1/Smad signaling pathways. In vitro, APF treatment reduced cell proliferation and protein expression of ?-smooth muscle actin, collagen I, TGF-?1 and NF-?B in mesangial cells cultured with high glucose concentrations. Our findings indicate that treatment with multi-component herbal therapeutic formulations may be a useful approach for the treatment of diabetic nephropathy.

SUBMITTER: Wu JS

PROVIDER: S-EPMC4372382 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Combination of active components of Xiexin decoction ameliorates renal fibrosis through the inhibition of NF-κB and TGF-β1/Smad pathways in db/db diabetic mice.

Wu Jia-Sheng JS Shi Rong R Lu Xiong X Ma Yue-Ming YM Cheng Neng-Neng NN

PloS one 20150324 3

Xiexin decoction, a herbal therapeutic agent commonly used in traditional Chinese medicine, is recognized for its beneficial effects on diabetic nephropathy exerted through the combined action of multiple components, including Rhizoma Coptidis alkaloids (A), Radix et Rhizoma Rhei polysaccharides (P), and Radix Scutellaria flavones (F). Our previous studies have shown that a combination of A, P, and F (APF) exhibits renoprotective effects against diabetic nephropathy. This study was aimed at dete ...[more]

PMID: 25803610

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Project description:Purpose: Our study clarifies the mechanism of Huangqi decoction (HQD) against DKD in diabetic db/db mice. Methods: Eight-week-old male diabetic db/db mice were randomly divided into four groups: Model (1% CMC), HQD-L (0.12 g/kg), HQD-M (0.36 g/kg), and HQD-H (1.08 g/kg) groups. Non-diabetic db/m mice were used as a control group. These mice received HQD treatment for 8 weeks continuously. After 8 weeks of feeding, kidneys were harvested to observe the kidney function, pathological changes, micro-assay study, and the protein expression levels. Results: HQD treatment improved the albumin/creatine ratio (ACR) and 24 h urinary albumin, prevented the pathological phenotypes of increased glomerular volume, widened mesangial areas, the proliferation of mesangial matrix, the disappearance of foot processes, the decreased expression of nephrin and the number of podocytes. The expression profile chips were assessed to reveal the global transcriptional response and predict related functions, diseases and pathways. To verify this, we found that HQD treatment activated the protein expressions of BMP1, BMP7, BMPR2, and active-Rap1 and inhibited Smad1 and phospho-ERK. In addition, HQD could improve lipid deposition in the kidneys of db/db mice. Conclusion: HQD prevents the progression of DKD in db/db mice by regulating the transcription of BMPs and their downstream target genes, inhibiting the phosphorylation of ERK and Smad1 by promoting the binding of Rap1 to GTP and regulating the lipid metabolism dysfunction. These provide a new idea for the treatment of DKD. Overall, HQD had a significant protective effect against DKD. This may be related to the fact that HQD promotes the transcription of BMPs and their downstream target genes by upregulating BMPR-II and regulates the phosphorylation of ERK and Smad by promoting the binding of Rap1 to GTP. In addition, HQD also has a noticeable role in regulating lipid metabolism dysfunction in DKD, which provides a new idea for future research on HQD.

Project description:PurposePathological fibrosis of the myodural bridge (MDB) affects cerebrospinal fluid circulation. However, no optimal drug treatments are available. We aimed to explore the antifibrotic effect of resveratrol on bleomycin-induced pathological fibrosis of the MDB and its underlying mechanisms.MethodsGenes common to the potential targets of resveratrol were determined using network pharmacology, genes related to muscle and tendon fibrosis were acquired from the GeneCards database, and genes related to MDB development were determined using Venny. These genes were considered potential resveratrol treatment targets in bleomycin-induced pathological fibrosis of the MDB and were annotated using bioinformatics methods. We validated the intersected genes using quantitative real-time polymerase chain reaction (qRT-PCR) and performed molecular docking analysis to calculate the binding activity between the target gene and resveratrol. Hematoxylin and eosin and Masson staining were used to detect the morphological changes in bleomycin-induced fibrosis of the MDB following resveratrol treatment. We used qRT-PCR and immunohistochemistry to evaluate the expression of the sirtuin 3 (SIRT3)/transforming growth factor-β1 (TGF-β1)/Smad pathway and the profibrotic markers α-smooth muscle actin (α-SMA) and Collagen Ⅰ.ResultsThrough network pharmacology and bioinformatics analyses, we identified four core intersected genes, and SIRT3 expression was validated using qRT-PCR. Molecular docking analysis revealed that resveratrol had good binding affinity for SIRT3. Resveratrol ameliorated morphological abnormalities in bleomycin-induced pathological fibrosis of the MDB by inhibiting fibroblast activation and excessive collagen fiber deposition. Resveratrol exerted its antifibrotic effect by regulating the SIRT3/TGF-β1/Smad pathway.ConclusionResveratrol has an antifibrotic effect in bleomycin-induced pathological fibrosis of the MDB in vivo and may be considered a novel therapeutic strategy.

Dataset Information

Combination of active components of Xiexin decoction ameliorates renal fibrosis through the inhibition of NF-?B and TGF-?1/Smad pathways in db/db diabetic mice.

Publications

Combination of active components of Xiexin decoction ameliorates renal fibrosis through the inhibition of NF-κB and TGF-β1/Smad pathways in db/db diabetic mice.

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