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      Combination of Ginsenoside Rg1 and Astragaloside IV reduces oxidative stress and inhibits TGF-β1/Smads signaling cascade on renal fibrosis in rats with diabetic nephropathy

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          Abstract

          Introduction

          Anti-oxidative stress and inhibition of TGF-β1/Smads signaling cascade are essential therapeutic strategies for diabetic nephropathy (DN). In this study, we aimed to explore the effect of combination of Ginsenoside Rg1 and Astragaloside IV on oxidative stress and TGF-β1/Smads signaling in DN rats.

          Materials and methods

          Wistar rats were divided into five groups: N group, M group (streptozotocin [STZ], intraperitoneally), G group (STZ rats with Ginsenoside Rg1, intragastrically [ig]), A group (STZ rats with Astragaloside IV, ig) and C group (STZ rats with Ginsenoside Rg1 and Astragaloside IV, ig). The levels of methane dicarboxylic aldehyde (MDA), catalase (CAT), glutathione peroxidase (GSH-PX), total anti-oxidative capacity (T-AOC), blood urea nitrogen (BUN), β 2-microglobulin (β 2-MG), serum creatinine (SCr) and urinary creatinine (UCr) were detected in all the groups. The left kidneys of the rats were harvested to detect the expression of TGF-β1, Smad2/3, Smad7 and CTGF by immunohistochemical staining, while the right kidneys were used to detect the mRNA expression of TGF-β1, Smad7 and CTGF by real-time PCR.

          Results

          Rats in G group, A group and C group had lower level of MDA but higher levels of CAT, GSH-PX and T-AOC compared with rats in M group. Rats in C group showed the best anti-oxidative stress level. G group, A group and C group treatments significantly decreased the levels of BUN, SCr, β 2-MG and UCr. In addition, C group treatment showed the best kidney protective effect. G group, A group and C group treatments significantly diminish ED both factor and mRNA overexpression of TGF-β1 and CTGF but increase Smad7 expression in kidney tissue.

          Conclusion

          The combination of Ginsenoside Rg1 and Astragaloside IV may potentially protect against DN by reducing oxidative stress and inhibiting TGF-β1/Smads signaling cascade.

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          Most cited references 36

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          Mechanisms of tubulointerstitial fibrosis.

          The pathologic paradigm for renal progression is advancing tubulointerstitial fibrosis. Whereas mechanisms underlying fibrogenesis have grown in scope and understanding in recent decades, effective human treatment to directly halt or even reverse fibrosis remains elusive. Here, we examine key features mediating the molecular and cellular basis of tubulointerstitial fibrosis and highlight new insights that may lead to novel therapies. How to prevent chronic kidney disease from progressing to renal failure awaits even deeper biochemical understanding.
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            TGF-β/Smad signaling in renal fibrosis

            TGF-β (transforming growth factor-β) is well identified as a central mediator in renal fibrosis. TGF-β initiates canonical and non-canonical pathways to exert multiple biological effects. Among them, Smad signaling is recognized as a major pathway of TGF-β signaling in progressive renal fibrosis. During fibrogenesis, Smad3 is highly activated, which is associated with the down-regulation of an inhibitory Smad7 via an ubiquitin E3-ligases-dependent degradation mechanism. The equilibrium shift between Smad3 and Smad7 leads to accumulation and activation of myofibroblasts, overproduction of ECM (extracellular matrix), and reduction in ECM degradation in the diseased kidney. Therefore, overexpression of Smad7 has been shown to be a therapeutic agent for renal fibrosis in various models of kidney diseases. In contrast, another downstream effecter of TGF-β/Smad signaling pathway, Smad2, exerts its renal protective role by counter-regulating the Smad3. Furthermore, recent studies demonstrated that Smad3 mediates renal fibrosis by down-regulating miR-29 and miR-200 but up-regulating miR-21 and miR-192. Thus, overexpression of miR-29 and miR-200 or down-regulation of miR-21 and miR-192 is capable of attenuating Smad3-mediated renal fibrosis in various mouse models of chronic kidney diseases (CKD). Taken together, TGF-β/Smad signaling plays an important role in renal fibrosis. Targeting TGF-β/Smad3 signaling may represent a specific and effective therapy for CKD associated with renal fibrosis.
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              TRAF4 promotes TGF-β receptor signaling and drives breast cancer metastasis.

              TGF-β signaling is a therapeutic target in advanced cancers. We identified tumor necrosis factor receptor-associated factor 4 (TRAF4) as a key component mediating pro-oncogenic TGF-β-induced SMAD and non-SMAD signaling. Upon TGF-β stimulation, TRAF4 is recruited to the active TGF-β receptor complex, where it antagonizes E3 ligase SMURF2 and facilitates the recruitment of deubiquitinase USP15 to the TGF-β type I receptor (TβRI). Both processes contribute to TβRI stabilization on the plasma membrane and thereby enhance TGF-β signaling. In addition, the TGF-β receptor-TRAF4 interaction triggers Lys 63-linked TRAF4 polyubiquitylation and subsequent activation of the TGF-β-activated kinase (TAK)1. TRAF4 is required for efficient TGF-β-induced migration, epithelial-to-mesenchymal transition, and breast cancer metastasis. Elevated TRAF4 expression correlated with increased levels of phosphorylated SMAD2 and phosphorylated TAK1 as well as poor prognosis among breast cancer patients. Our results demonstrate that TRAF4 can regulate the TGF-β pathway and is a key determinant in breast cancer pathogenesis.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2018
                18 October 2018
                : 12
                : 3517-3524
                Affiliations
                Department of Pharmacology, Jilin University, Jilin, Changchun, China, caoxia@ 123456jlu.edu.cn
                Author notes
                Correspondence: Xia Cao, Department of Pharmacology, School of Pharmacy, Jilin University, Jilin, Changchun 130021, China, Email caoxia@ 123456jlu.edu.cn
                Article
                dddt-12-3517
                10.2147/DDDT.S171286
                6201993
                © 2018 Du et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed

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                Original Research

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