Rebalancing TGF‐β/Smad7 signaling via Compound kushen injection in hepatic stellate cells protects against liver fibrosis and hepatocarcinogenesis

Yang, Yang; Sun, Mayu; Li, Weida; Liu, Chaobao; Jiang, Zheshun; Gu, Pengfei; Li, Jingquan; Wang, Wei; You, Rongli; Ba, Qian; Li, Xiaoguang; Wang, Hui

doi:10.1002/ctm2.410

Cited by 58 publications

(21 citation statements)

References 51 publications

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“…Transforming growth factor−β1 (TGF−β1) is believed to be the most potent fibrogenic cytokine, stimulating HSCs activation (Tsukamoto et al, 2011;Chen et al, 2021). It is reported that strategies targeting at disrupting TGF−β1 synthesis and/or signaling pathways markedly reduce liver fibrosis (Li et al, 2021;Sun et al, 2021;Yang et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Effective delivery of osteopontin small interference RNA using exosomes suppresses liver fibrosis via TGF-β1 signaling

et al. 2022

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Objective and aims: Osteopontin (OPN), an oxidant stress sensitive cytokine, plays a central role in liver fibrosis. While OPN expression can be reduced by small interfering RNA (siRNA), the challenge to deliver siRNA safely and effectively into liver remains unresolved. Exosomes are promising natural nanocarriers for drug delivery that are able to enter cells with different biological barriers efficiently. In this study, we used exosomes as a delivery vehicle to target OPN in liver fibrosis.Methods: Exosomes selectively home to fibrotic liver according to small animal imaging system. Electroporation technique was used to engineer exosomes to carry siRNA targeting OPN (ExosiRNA−OPN). Primary hepatic stellate cells (HSCs) were isolated and treated with ExosiRNA−OPN to assess the effect on activated HSCs (aHSCs). Immunofluorescence for α−SMA, an aHSCs marker, and sirius red staining were performed to assess ECM deposition. Finally, plasma OPN from patients with liver fibrosis was identified by ELISA assay.Results: Exosome-mediated siRNA delivery systems show high uptake and low toxicity. Besides, ExosiRNA−OPN suppressed HSCs activation and ECM deposition and more efficiently improved liver function when compared to naked siRNA-OPN. Moreover, ExosiRNA−OPN was assumed inhibiting TGF-β1 signaling activation, along with other fibrotic-related genes based on a GEO datasheet of liver fibrosis samples for correlation analyzes. ExosiRNA−OPN inhibited TGF-β1 signaling by decreasing high-mobility group box-1 (HMGB1). Plasma proteins from chronic HBV-induced fibrosis patients were identified that patients with high OPN expression correlates with more advanced fibrosis progression.Discussion: This study shows that exosome-mediated siRNA-OPN delivery may be an effective option for the treatment of liver fibrosis.

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Section: Introductionmentioning

confidence: 99%

Effective delivery of osteopontin small interference RNA using exosomes suppresses liver fibrosis via TGF-β1 signaling

et al. 2022

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“…39 Upon hepatocellular injury, nonparenchymal cells, especially Kupffer cells, secrete proinflammatory/profibrogenic factors that rapidly attack and activate the HSCs and eventually lead to liver fibrosis. 40 HSCs are the predominant pathogenic cells that are responsible for the overproduction of fibrillar collagens in liver fibrosis. Therefore, substantial efforts that target HSCs have been made for the treatment of liver fibrosis that show promising results.…”

Section: Discussionmentioning

confidence: 99%

Collagen-binding fibroblast growth factor ameliorates liver fibrosis in murine bile duct ligation injury

Shi

Wei

et al. 2022

J Biomater Appl

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Cholestatic liver injury, characterized by liver fibrosis, has increasingly become a global health problem, with no effective treatment available. Hepatic stellate cells (HSCs) differentiate into myofibroblasts, leading to excessive deposition of the extracellular matrix (ECM), which is a feature of liver fibrosis. Basic fibroblast growth factor (bFGF) has proven antifibrotic effects in chronic liver disease; however, the lack of an effective delivery system to the injury site reduces its therapeutic efficacy. The aim of this study was to assess the therapeutic effect of collagen-binding bFGF (CBD-bFGF) for the treatment of liver fibrosis in a murine bile duct ligation (BDL) model. We found that CBD-bFGF treatment significantly alleviated liver injury in the early phase of BDL injury, and was associated with decreased necroptotic cell death and inflammatory response. Moreover, CBD-bFGF had enhanced therapeutic effects for liver fibrosis on day 7 after surgery compared to those obtained with native bFGF treatment. In vitro, CBD-bFGF treatment notably inhibited TGF-β1-induced LX-2 cell activation, migration, and contraction compared with native bFGF. In conclusion, CBD-bFGF may be a promising treatment for hepatic fibrosis.

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“…Furthermore, Smad7 was identified as a key target of CKI in the treatment of liver fibrosis. CKI up-regulated Smad7, inhibited TNF-βR1, and suppressed TNF-β/Smad signaling pathway to prevent the development of chronic liver fibrosis and HCC ( 62 ). NHE-06 exerted a strong anti-inflammatory activity on HCC through the suppression of NF-κB/IL-6/STAT3 signaling and TGF-α and PTSG2.…”

Section: The Immunoregulatory Patterns Of Chinese Medicine Compounds In Cancer Therapymentioning

confidence: 99%

Anti-Tumor Effects of Chinese Medicine Compounds by Regulating Immune Cells in Microenvironment

Chen

Wang

et al. 2021

Front. Oncol.

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As the main cause of death in the world, cancer is one of the major health threats for humans. In recent years, traditional Chinese medicine has gained great attention in oncology due to the features of multi-targets, multi-pathways, and slight side effects. Moreover, lots of traditional Chinese medicine can exert immunomodulatory effects in vivo. In the tumor microenvironment, tumor cells, immune cells as well as other stromal cells often coexist. With the development of cancer, tumor cells proliferate uncontrollably, metastasize aggressively, and modulate the proportion and status of immune cells to debilitate the antitumor immunity. Reversal of immunosuppressive tumor microenvironment plays an essential role in cancer prevention and therapy. Immunotherapy has become the most promising strategy for cancer therapy. Chinese medicine compounds can stimulate the activation and function of immune cells, such as promoting the maturation of dendritic cells and inducing the differentiation of myeloid-derived suppressor cells to dendritic cells and macrophages. In the present review, we summarize and discuss the effects of Chinese medicine compounds on immune cells in the tumor microenvironment, including innate immune cells (dendritic cells, natural killer cells, macrophages, and myeloid-derived suppressor cells) and adaptive immune cells (CD4+/CD8+ T lymphocytes and regulatory T cells), and the various immunomodulatory roles of Chinese medicine compounds in cancer therapy such as improving tumor-derived inflammation, enhancing the immunity after surgery or chemotherapy, blocking the immune checkpoints, et al., aiming to provide more thoughts for the anti-tumor mechanisms and applications of Chinese medicine compounds in terms of tumor immunity.

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Rebalancing TGF‐β/Smad7 signaling via Compound kushen injection in hepatic stellate cells protects against liver fibrosis and hepatocarcinogenesis

Cited by 58 publications

References 51 publications

Effective delivery of osteopontin small interference RNA using exosomes suppresses liver fibrosis via TGF-β1 signaling

Effective delivery of osteopontin small interference RNA using exosomes suppresses liver fibrosis via TGF-β1 signaling

Collagen-binding fibroblast growth factor ameliorates liver fibrosis in murine bile duct ligation injury

Anti-Tumor Effects of Chinese Medicine Compounds by Regulating Immune Cells in Microenvironment

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