Astragaloside IV attenuates high glucose-induced EMT by inhibiting the TGF-β/Smad pathway in renal proximal tubular epithelial cells

Wang, Yaning; Zhao, Shili; Y, Su; Feng, Jian; Wang, Shuai; Liao, Xiaoming; Wang, Lina; Li, Jingchun; Meng, Ping; Li, Hongyan; Zhang, Yunfang

doi:10.1042/bsr20190987

Cited by 23 publications

(22 citation statements)

References 33 publications

(44 reference statements)

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“…This protective effect has been observed in cardiomyocytes, renal tubular epithelial cells and retinal capillary endothelial cells exposed to high glucose. 4,26,27 In addition, these reports also show the anti-apoptotic and anti-oxidant properties of AS-IV. Similarly, in the current study, we also observed that through AS-IV treatment, cell apoptosis and oxidative stress originally induced by STZ have been alleviated to a certain extent.…”

Section: Discussionmentioning

confidence: 78%

Astragaloside IV Ameliorates Streptozotocin Induced Pancreatic β-Cell Apoptosis and Dysfunction Through SIRT1/P53 and Akt/GSK3β/Nrf2 Signaling Pathways

Lin¹,

Xu²,

Zheng³

et al. 2022

DMSO

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Background: Absolute or relative lack of insulin secretion caused by pancreatic β-cell dysfunction can lead to diabetes. Astragaloside IV (AS-IV), the main components of the traditional Chinese medicine Astragalus, has anti-oxidant, anti-inflammatory and antiapoptotic properties, and exerts anti-diabetic pharmacological effects. Purpose: To explore whether AS-IV can protect the apoptosis and dysfunction of pancreatic β-cells induced by streptozotocin (STZ) and its underlying molecular mechanism. Methods: STZ-induced pancreatic β-cell line INS-1 was treated with different concentrations of AS-IV, then cell viability, apoptosis, oxidative stress and insulin secretion was assessed by CCK-8, TUNEL staining, Western blot, commercial kits and qRT-PCR, respectively. The expression of proteins involved in Sirtuin 1 (SIRT1)/p53 and Akt/glycogen synthase kinase-3 β (GSK3β)/nuclear factor E2-related factor 2 (Nrf2) signaling was measured by Western blot assay. Besides, Akt inhibitor MK-2206 and SIRT1 inhibitor EX-527 were used to co-treat STZ-induced INS-1 cells in the presence of AS-IV, and the above experiments were repeated. Results: AS-IV increased the cell viability of INS-1 cells induced by STZ. AS-IV also reduced the increase in apoptosis rate and reversed STZ-induced down-regulation of Bcl-2 and upregulation of Bax and Cleaved caspase 3. In addition, AS-IV significantly reduced STZinduced malondialdehyde upregulation and reduced superoxide dismutase and glutathione peroxidase levels. Furthermore, the use of AS-IV was found to increase the insulin secretion capacity of INS-1 cells with impaired function, along with the increase of the mRNA levels of insulin 1 and insulin 2. Mechanism studies further showed that MK-2206 and EX-527 reversed the protective effect of AS-IV against STZ-induced injury on INS-1 cells. Conclusion: AS-IV exerted cytoprotective effect on STZ-induced INS-1 cells through regulating SIRT1/p53 and Akt/GSK3β/Nrf2 signaling pathways. These findings are expected to provide new supplements to the molecular mechanism of AS-IV in the treatment of diabetes.

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Section: Discussionmentioning

confidence: 78%

Astragaloside IV Ameliorates Streptozotocin Induced Pancreatic β-Cell Apoptosis and Dysfunction Through SIRT1/P53 and Akt/GSK3β/Nrf2 Signaling Pathways

Lin¹,

Xu²,

Zheng³

et al. 2022

DMSO

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“…In agreement with this, our previous studies have reported that JPYSF notably reduced the increased levels of fibronectin and type IV collagen in renal fibrosis of 5/6 Nx rats ( Liu et al, 2018 ). Moreover, it has been reported that astragaloside IV up-regulates the decreased expressions of E-cadherin and occludin, whereas it down-regulates expressions of N-cadherin and vimentin in high glucose-induced EMT cells ( Wang YN et al, 2020 ). Therefore, we assume that JPYSF could regulate other epithelial markers and mesenchymal markers.…”

Section: Discussionmentioning

confidence: 99%

“…In brief, A. mongholicus , A. macrocephala , D. oppositifolia , C. deserticola , A. kravanh , S. miltiorrhiza , R. palmatum , and G. uralensis were mixed in the ratio of 30:10:30:10:10:15:10:6. The detailed methods were as described previously ( Wang YN et al, 2020 ). The extract was freeze-dried and stored at −80°C.…”

Section: Methodsmentioning

confidence: 99%

Network Pharmacology and Experimental Verification Strategies to Illustrate the Mechanism of Jian-Pi-Yi-Shen Formula in Suppressing Epithelial–Mesenchymal Transition

Zhao

Wang

et al. 2022

Front. Pharmacol.

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Jian-Pi-Yi-Shen formula (JPYSF), a traditional Chinese medicine, has been recommended to treat renal fibrosis for decades. Previous studies had shown that JPYSF could inhibit epithelial–mesenchymal transition (EMT), an important regulatory role in renal fibrosis. However, the mechanism of JPYSF action is largely unknown. In this study, network pharmacology and experimental verification were combined to elucidate and identify the potential mechanism of JPYSF against renal fibrosis by suppressing EMT at molecular and pathway levels. Network pharmacology was first performed to explore the mechanism of JPYSF against renal fibrosis targeting EMT, and then a 5/6 nephrectomy (5/6 Nx)-induced rat model of renal fibrosis was selected to verify the predictive results by Masson’s trichrome stains and western blot analysis. Two hundred and thirty-two compounds in JPYSF were selected for the network approach analysis, which identified 137 candidate targets of JPYSF and 4,796 known therapeutic targets of EMT. The results of the Gene Ontology (GO) function enrichment analysis included 2098, 88, and 133 GO terms for biological processes (BPs), molecular functions (MFs), and cell component entries, respectively. The top 10 enrichment items of BP annotations included a response to a steroid hormone, a metal ion, oxygen levels, and so on. Cellular composition (CC) is mainly enriched in membrane raft, membrane microdomain, membrane region, etc. The MF of JPYSF analysis on EMT was predominately involved in proximal promoter sequence-specific DNA binding, protein heterodimerization activity, RNA polymerase II proximal promoter sequence-specific DNA binding, and so on. The involvement signaling pathway of JPYSF in the treatment of renal fibrosis targeting EMT was associated with anti-fibrosis, anti-inflammation, podocyte protection, and metabolism regulation. Furthermore, the in vivo experiments confirmed that JPYSF effectively ameliorated interstitial fibrosis and inhibited the overexpression of α-SMA, Wnt3a, and β-catenin, and increased the expression of E-cadherin by wnt3a/β-catenin signaling pathway in 5/6 Nx-induced renal fibrosis rats. Using an integrative network pharmacology-based approach and experimental verification, the study showed that JPYSF had therapeutic effects on EMT by regulating multi-pathway, among which one proven pathway was the Wnt3a/β-catenin signaling pathway. These findings provide insights into the renoprotective effects of JPYSF against EMT, which could suggest directions for further research of JPYSF in attenuating renal fibrosis by suppressing EMT.

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“…However, whether the TGF- β 1/Smad signaling pathway function is vital in inhibiting the invasion and metastasis of PLC and Huh7 cells by I-125 seed remains to be further studied. According to the past studies, TGF- β 1 activator can activate the TGF- β 1 signaling pathway, promote epithelial-mesenchymal transition, and then promote tumor invasion and metastasis [ 8 , 33 ]. Therefore, we studied the role of the TGF- β 1 activator in the inhibitory of the I-125 seed-induced cell migration.…”

Section: Discussionmentioning

confidence: 99%

Iodine-125 Seeds Inhibit Carcinogenesis of Hepatocellular Carcinoma Cells by Suppressing Epithelial-Mesenchymal Transition via TGF-β1/Smad Signaling

Yang

Xiao

et al. 2022

Disease Markers

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To investigate the radioactive iodine-125 (I-125) seed on migrating and invading of hepatocellular carcinoma (HCC) cells and its mechanism, the irradiation of PLC and Huh7 cells was carried out with I-125 seeds in vitro. Cell counting kit 8 assay was employed to measure cell viability. Cell migration was evaluated by using wound-healing assay. Cell invasion was detected by Transwell assay; RT-PCR and Western blot were used for the detection of the mRNA and proteins of TGF-β1 signaling pathway-related genes. The viability of PLC and Huh7 cells declined in a dose-dependent manner with increasing irradiation from 0 Gy, 2 Gy, 4 Gy, and 6 Gy, to 8 Gy, respectively. The IC50 of PLC and Huh7 cells were 6.20 Gy and 5.39 Gy, respectively, after 24 h of irradiation. Migration and invasion abilities of I-125 group cells were greatly weakened ( P < 0.05 ) comparing with the control group. According to the outcomes of RT-PCR and WB, I-125 seed irradiation significantly inhibited the mRNA and protein expression of N-cadherin, vimentin, TGF-β1, p-Smad2/3, and Snail. But the mRNA and protein expressions of E-cadherin were enhanced. Rescue experiment demonstrates that TGF-β1 activator could reverse the inhibitory effects of I-125 on invasion and migration of cells. The results of in vivo experiments further verified that the I-125 seeds can inhibit the proliferation and TGF-β1 of xenographed PLC cells. In conclusion, I-125 seeds restrain the invasion and migration of HCC cells by suppressing epithelial to mesenchymal transition, which may associate with the inhibition of the TGF-β1 signaling.

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Astragaloside IV attenuates high glucose-induced EMT by inhibiting the TGF-β/Smad pathway in renal proximal tubular epithelial cells

Cited by 23 publications

References 33 publications

Astragaloside IV Ameliorates Streptozotocin Induced Pancreatic β-Cell Apoptosis and Dysfunction Through SIRT1/P53 and Akt/GSK3β/Nrf2 Signaling Pathways

Astragaloside IV Ameliorates Streptozotocin Induced Pancreatic β-Cell Apoptosis and Dysfunction Through SIRT1/P53 and Akt/GSK3β/Nrf2 Signaling Pathways

Network Pharmacology and Experimental Verification Strategies to Illustrate the Mechanism of Jian-Pi-Yi-Shen Formula in Suppressing Epithelial–Mesenchymal Transition

Iodine-125 Seeds Inhibit Carcinogenesis of Hepatocellular Carcinoma Cells by Suppressing Epithelial-Mesenchymal Transition via TGF-β1/Smad Signaling

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