MicroRNA-497 induced by Clonorchis sinensis enhances the TGF-β/Smad signaling pathway to promote hepatic fibrosis by targeting Smad7

Zhou, Qian-Yang; Yang, Huimin; Liu, Jixin; Xu, Na; Li, Jing; Shen, Liping; Zhang, Yuzhao; Koda, Stephane; Zhang, Beibei; Yu, Qian; Chen, Jiaxu; Zheng, Kuiyang; Yan, Chao

doi:10.1186/s13071-021-04972-3

Cited by 15 publications

(8 citation statements)

References 42 publications

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“…Smad2 and Smad3 mainly promote HF, while Smad7 inhibits TGF-β1 signaling, thereby inhibiting HF ( 39 ). Specifically, Smad7 is a negative regulatory protein participating in the TGF-β/Smad signaling pathway, which acts in a competitive fashion against TGF-βRI to prevent phosphorylation of Smad2/3, thus inhibiting the activation of the TGF-β/Smad cascade ( 40 ). The present study demonstrated that, compared with the NASH-F group, TIIA markedly reduced α-SMA mRNA and protein expression in the rat liver tissue, indicating that TIIA could inhibit the activation of HSCs and reduce the synthesis of ECM, thereby preventing the development of NASH-F.…”

Section: Discussionmentioning

confidence: 99%

Tanshinone IIA regulates the TGF‑β1/Smad signaling pathway to ameliorate non‑alcoholic steatohepatitis‑related fibrosis

Zhang

et al. 2022

Exp Ther Med

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Tanshinone IIA (TIIA) is a major component extracted from the traditional herbal medicine Salvia miltiorrhiza and has been indicated to play a role in the treatment of organ fibrosis. However, the evidence supporting its antifibrotic effect is insufficient and the underlying mechanism is unclear. To investigate the therapeutic effect of TIIA on non-alcoholic steatohepatitis-related fibrosis (NASH-F), the present study used a methionine choline deficiency diet to induce NASH-F in rats, and explored the effect of TIIA on the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway. Wistar rats were randomly divided into control, NASH-F and TIIA groups. After 8 weeks of treatment, the levels of serum markers associated with liver function and fibrosis were measured, liver fat vacuoles and inflammation were assessed by haematoxylin and eosin staining, and liver fibrosis was assessed by Masson's trichrome staining. TGF-β1, Smad2, Smad3, Smad7 and α-smooth muscle actin (α-SMA) mRNA expression, and TGF-β1, Smad2/3, phosphorylated (p)-Smad2/3, Smad7 and α-SMA protein levels were determined. The results revealed that TIIA could remarkably ameliorate liver fat vacuoles and inflammation in NASH-F rats, and could decrease the levels of serum aspartate aminotransferase, alanine aminotransferase, total bilirubin, total bile acid, hyaluronic acid, type Ⅳ collagen, laminin and type III collagen, while increasing the levels of total cholesterol and triglycerides; however, this was not statistically significance. TIIA markedly suppressed the increased TGF-β1, Smad2, Smad3 and α-SMA mRNA expression levels observed in the liver of NASH-F rats, while it increased the mRNA expression level of Smad7. Similarly, TIIA suppressed the increased TGF-β1, p-Smad2/3 and α-SMA protein levels observed in the liver of NASH-F rats, while it increased the protein expression level of Smad7 in vitro and in vivo . TIIA had no significant cytotoxic effect at 10, 20, 40 and 80 µmol/l on human LX-2 cell. In conclusion, the findings of the present study indicated that TIIA alleviated NASH-F by regulating the TGF-β1/Smad signaling pathway. TIIA may be a useful tool in the prevention and treatment of NASH-F.

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Section: Discussionmentioning

confidence: 99%

Tanshinone IIA regulates the TGF‑β1/Smad signaling pathway to ameliorate non‑alcoholic steatohepatitis‑related fibrosis

Zhang

et al. 2022

Exp Ther Med

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“…The mRNA expression level of TGF-β1 was measured based on previous studies [ 35 , 36 ]. Total RNA was extracted from HaCaT cells by using an RNA Extraction Kit (Tiangen, China).…”

Section: Methodsmentioning

confidence: 99%

Amphibian-derived peptide homodimer OA-GL17d promotes skin wound regeneration through the miR-663a/TGF-β1/Smad axis

et al. 2022

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Background Amphibian-derived peptides exhibit considerable potential in the discovery and development of new therapeutic interventions for clinically challenging chronic skin wounds. MicroRNAs (miRNAs) are also considered promising targets for the development of effective therapies against skin wounds. However, further research in this field is anticipated. This study aims to identify and provide a new peptide drug candidate, as well as to explore the underlying miRNA mechanisms and possible miRNA drug target for skin wound healing. Methods A combination of Edman degradation, mass spectrometry and cDNA cloning were adopted to determine the amino acid sequence of a peptide that was fractionated from the secretion of Odorrana andersonii frog skin using gel-filtration and reversed-phase high-performance liquid chromatography. The toxicity of the peptide was evaluated by Calcein-AM/propidium iodide (PI) double staining against human keratinocytes (HaCaT cells), hemolytic activity against mice blood cells and acute toxicity against mice. The stability of the peptide in plasma was also evaluated. The prohealing potency of the peptide was determined by MTS, scratch healing and a Transwell experiment against HaCaT cells, full-thickness injury wounds and scald wounds in the dorsal skin of mice. miRNA transcriptome sequencing analysis, enzyme-linked immunosorbent assay, real-time polymerase chain reaction and western blotting were performed to explore the molecular mechanisms. Results A novel peptide homodimer (named OA-GL17d) that contains a disulfide bond between the 16th cysteine residue of the peptide monomer and the sequence ‘GLFKWHPRCGEEQSMWT’ was identified. Analysis showed that OA-GL17d exhibited no hemolytic activity or acute toxicity, but effectively promoted keratinocyte proliferation and migration and strongly stimulated the repair of full-thickness injury wounds and scald wounds in the dorsal skin of mice. Mechanistically, OA-GL17d decreased the level of miR-663a to increase the level of transforming growth factor-β1 (TGF-β1) and activate the subsequent TGF-β1/Smad signaling pathway, thereby resulting in accelerated skin wound re-epithelialization and granular tissue formation. Conclusions Our results suggest that OA-GL17d is a new peptide drug candidate for skin wound repair. This study emphasizes the importance of exogenous peptides as molecular probes for exploring competing endogenous RNA mechanisms and indicates that miR-663a may be an effective target for promoting skin repair.

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“…TGF-β1 induces transcription, processing and maturation of pri-miR-21 through a Smad3-dependent pathway, while mature miR-21 promotes the development of fibrosis by targeting the inhibitory Smad gene-small mothers against decapentaplegic7[ 15 ]. Clonorchis sinensis promotes hepatic fibrosis by inducing miR-497 and activating the TGF-β/Smad pathway[ 17 ]. Pan et al [ 18 ] revealed that miR-16 plays an essential role in the phenotypic remodeling of myofibroblasts.…”

Section: Ncrnas In the Pathogenesis And Progression Of Liver Fibrosismentioning

confidence: 99%

Role of noncoding RNAs in liver fibrosis

Li¹,

Gong²,

Huang³

et al. 2023

World J Gastroenterol

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Liver fibrosis is a wound-healing response following chronic liver injury caused by hepatitis virus infection, obesity, or excessive alcohol. It is a dynamic and reversible process characterized by the activation of hepatic stellate cells and excess accumulation of extracellular matrix. Advanced fibrosis could lead to cirrhosis and even liver cancer, which has become a significant health burden worldwide. Many studies have revealed that noncoding RNAs (ncRNAs), including microRNAs, long noncoding RNAs and circular RNAs, are involved in the pathogenesis and development of liver fibrosis by regulating signaling pathways including transforming growth factor-β pathway, phosphatidylinositol 3-kinase/protein kinase B pathway, and Wnt/β-catenin pathway. NcRNAs in serum or exosomes have been reported to tentatively applied in the diagnosis and staging of liver fibrosis and combined with elastography to improve the accuracy of diagnosis. NcRNAs mimics, ncRNAs in mesenchymal stem cell-derived exosomes, and lipid nanoparticles-encapsulated ncRNAs have become promising therapeutic approaches for the treatment of liver fibrosis. In this review, we update the latest knowledge on ncRNAs in the pathogenesis and progression of liver fibrosis, and discuss the potentials and challenges to use these ncRNAs for diagnosis, staging and treatment of liver fibrosis. All these will help us to develop a comprehensive understanding of the role of ncRNAs in liver fibrosis.

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MicroRNA-497 induced by Clonorchis sinensis enhances the TGF-β/Smad signaling pathway to promote hepatic fibrosis by targeting Smad7

Cited by 15 publications

References 42 publications

Tanshinone IIA regulates the TGF‑β1/Smad signaling pathway to ameliorate non‑alcoholic steatohepatitis‑related fibrosis

Tanshinone IIA regulates the TGF‑β1/Smad signaling pathway to ameliorate non‑alcoholic steatohepatitis‑related fibrosis

Amphibian-derived peptide homodimer OA-GL17d promotes skin wound regeneration through the miR-663a/TGF-β1/Smad axis

Role of noncoding RNAs in liver fibrosis

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