Methyl helicterate inhibits hepatic stellate cell activation through downregulating the ERK1/2 signaling pathway

Wei, Yuansong; Zhang, Xiaolin; Song, Wen; Huang, Shaode; Huang, Quanfang; Lu, Sheng; Bai, Facheng; Nie, Jinlan; Wei, Jinbin; Lu, Zhaojun; Lin, Xiaobo

doi:10.1002/jcb.28756

Cited by 4 publications

(5 citation statements)

References 37 publications

(56 reference statements)

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“…After 24 hours, cells were treated with drugs as described above for 168 hours. The cells were added methanol then fixed with 0.1% crystal violet for visualization of colonies 15 …”

Section: Methodsmentioning

confidence: 99%

Retracted: Tormentic acid inhibits hepatic stellate cells activation via blocking PI3K/Akt/mTOR and NF‐κB signalling pathways

Lin

Wei

et al. 2020

Cell Biochemistry & Function

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The present study was to investigate the inhibitory effect and underlying mechanism of Tormentic acid (TA) on hepatic stellate cells (HSCs). HSC‐T6 cells were stimulated with Platelet‐derived growth factor‐BB (PDGF‐BB) and TA, and then cell proliferation, apoptosis, inflammatory factor, and collagen‐related indicators were detected. In order to elucidate the potential mechanism, the PI3K/Akt/mTOR and NF‐κB signalling pathways were also detected. The results showed that TA treatment markedly inhibited PDGF‐BB‐stimulated HSC‐T6 cell activation, as evidenced by the inhibition of cell proliferation, migration and colony formation, as well as the decreased expression of TGF‐β and α‐SMA. TA treatment caused a significant increase in the activity of lactate dehydrogenase and significantly promoted cell apoptosis. TA treatment significantly reduced aspartate aminotransferase, alanine aminotransferase and total bilirubin activity. Importantly, TA inhibited the expression of collagen type I and III, alleviating the excessive deposition of extracellular matrix (ECM). Further experiments showed that TA administration significantly inhibited the phosphorylation of PI3K, Akt, FAK and mTOR and the protein expression of P70S6K, indicating the inhibition of the PI3K/Akt/mTOR pathway. Moreover, treatment with TA markedly decreased the phosphorylation of IκBα, NF‐κB p65 and IKKα/β, thereby blocking the NF‐κB signal transduction. In summary, this study demonstrates that TA significantly inhibits HSC activation and promotes cell apoptosis via the inhibition of the PI3K/Akt/mTOR and NF‐κB signalling pathways. Significance of the study Tormentic acid (TA) could inhibit HSC activation and alleviate collagen‐based ECM deposition, suggesting that TA exerted anti‐hepatic fibrosis. Further mechanism research revealed that the inhibition of TA on HSC activation might be through blocking the PI3K/Akt/mTOR and NF‐κB signalling pathways. These findings provided a new cue to understand the protective effect of TA against liver fibrosis, which may provide a potential nature medicine for the treatment of liver fibrosis.

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“…After 24 hours, cells were treated with drugs as described above for 168 hours. The cells were added methanol then fixed with 0.1% crystal violet for visualization of colonies 15 …”

Section: Methodsmentioning

confidence: 99%

Retracted: Tormentic acid inhibits hepatic stellate cells activation via blocking PI3K/Akt/mTOR and NF‐κB signalling pathways

Lin

Wei

et al. 2020

Cell Biochemistry & Function

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“…The influence of Fos on stellate cells has been reported in several studies. Wei et al showed that methyl helicterate treatment in hepatic stellate cells (HSCs) inhibited the expression of Fos, a downstream nuclear transcription factor of extracellular regulated protein kinases1/2 (ERK1/2) signaling pathway, and participated in many physiological processes (30). Gao et al showed that the transient induction of Fos gene activation and expression was involved in connective tissue growth factor (CCN2)-stimulated HSCs DNA synthesis and cell proliferation via activating ERK1/2 signaling pathway (31).…”

Section: Discussionmentioning

confidence: 99%

“…Wei et al. showed that methyl helicterate treatment in hepatic stellate cells (HSCs) inhibited the expression of Fos , a downstream nuclear transcription factor of extracellular regulated protein kinases1/2 (ERK1/2) signaling pathway, and participated in many physiological processes ( 30 ). Gao et al.…”

Section: Discussionmentioning

confidence: 99%

Screening and Identification of Key Genes for Activation of Islet Stellate Cell

et al. 2021

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BackgroundIt has been demonstrated that activated islet stellate cells (ISCs) play a critical role in islet fibrogenesis and significantly contribute to the progression of type 2 diabetes mellitus. However, the key molecules responsible for ISCs activation have not yet been determined. This study aimed to identify the potential key genes involved in diabetes-induced activation of ISCs.MethodStellate cells were isolated from three 10-week-old healthy male Wistar rats and three Goto-Kakizaki (GK) rats. Cells from each rat were primary cultured under the same condition. A Genome-wide transcriptional sequence of stellate cells was generated using the Hiseq3000 platform. The identified differentially expressed genes were validated using quantitative real-time PCR and western blotting in GK rats, high fat diet (HFD) rats, and their controls.ResultsA total of 204 differentially expressed genes (DEGs) between GK. ISCs and Wistar ISCs (W.ISCs) were identified, accounting for 0.58% of all the 35,362 genes detected. After the Gene Ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses, the mRNA levels of these genes were further confirmed by real-time PCR in cultured ISCs. We then selected Fos, Pdpn, Bad as the potential key genes for diabetes-induced activation of ISCs. Finally, we confirmed the protein expression levels of FOS, podoplanin, and Bad by western blotting and immunofluorescence in GK rats, HFD rats, and their controls. The results showed that the expression level of FOS was significantly decreased, while podoplanin and Bad were significantly increased in GK.ISCs and HFD rats compared with controls, which were consistent with the expression of α-smooth muscle actin.ConclusionsA total of 204 DEGs were found between the GK.ISCs and W.ISCs. After validating the expression of potential key genes from GK rats and HFD rats, Fos, Pdpn, and Bad might be potential key genes involved in diabetes-induced activation of ISCs.

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“…Numerous studies have confirmed that ERK1/2 signaling is the main regulator that promotes the progression of human hepatocellular carcinoma ( 30 – 34 ). ERK1/2 participates in liver injury in human liver stem cells ( 35 , 36 ). Also, the aggressive behavior of HCC cells has a positive relationship with the level of phosphorylated ERK and activated level of hepatic stellate cells (aHSCs) ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

Suppressing ERK Pathway Impairs Glycochenodeoxycholate-Mediated Survival and Drug-Resistance in Hepatocellular Carcinoma Cells

Zhou

Wang

et al. 2021

Front. Oncol.

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Glycochenodeoxycholate (GCDA), a toxic component in bile salts, is involved in carcinogenesis of gastrointestinal tumors. The objective of this research was to study the function of ERK1/2 in the GCDA-mediated survival and drug-resistance in hepatocellular carcinoma cells (HCCs). Firstly, extracellular signal-regulated kinase 1/2 (ERK1/2) was detected extensively expressed in liver cancer cells, and silencing ERK1/2 by RNA interference could suppress GCDA-stimulated survival and promote apoptosis. Furthermore, phosphorylation of endogenous ERK1/2 could be potently stimulated by GCDA in combination with enhanced chemoresistance in QGY-7703 hepatocellular carcinoma cells. The GCDA-mediated proliferation and chemoresistance could be impaired by PD98059, which acted as an inhibitor to block the phosphorylation of ERK1/2. Mechanistically, PD98059 was able to potently suppress GCDA-stimulated nuclear aggregation of ERK1/2 and p-ERK1/2, upregulate pro-survival protein Mcl-1 and downregulate pro-apoptotic protein Bim. The results of this study indicated that disruption of ERK1/2 by blocking phosphorylation or nuclear translocation may put forward new methods for solving the problem of GCDA-related proliferation and drug-resistance in liver cancer treatment.

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Methyl helicterate inhibits hepatic stellate cell activation through downregulating the ERK1/2 signaling pathway

Cited by 4 publications

References 37 publications

Retracted: Tormentic acid inhibits hepatic stellate cells activation via blocking PI3K/Akt/mTOR and NF‐κB signalling pathways

Retracted: Tormentic acid inhibits hepatic stellate cells activation via blocking PI3K/Akt/mTOR and NF‐κB signalling pathways

Screening and Identification of Key Genes for Activation of Islet Stellate Cell

Suppressing ERK Pathway Impairs Glycochenodeoxycholate-Mediated Survival and Drug-Resistance in Hepatocellular Carcinoma Cells

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