S100a16 deficiency prevents hepatic stellate cells activation and liver fibrosis via inhibiting CXCR4 expression

Zhang, Wensong; Zhang, Rihua; Ge, Yaoqi; Wang, Dan; Hu, Yifang; Qin, Xiaoxuan; Kan, Jingbao; Liu, Yun

doi:10.1016/j.metabol.2022.155271

Cited by 15 publications

(13 citation statements)

References 34 publications

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“…Of interest here, the key role of extracellular S100A11 in hepatic fibrosis is highlighted by pharmacological evidence indicating that Tranilast, an inhibitor of S100A11 binding to RAGE [ 128 ], prevents not only liver inflammation in rats fed an MCD, but also fibrosis development [ 129 ]. Finally, S100A16 is predominantly expressed in HSCs and its mRNA expression is significantly increased with NASH in humans [ 143 ]. In this regard, a recent genetic study using both S100A16 knockout and transgenic mice highlighted a hepatic pro-fibrotic role for intracellular S100A16 in HSCs [ 143 ].…”

Section: S100 Proteins In Nafld/nash and Hcc Developmentmentioning

confidence: 99%

“…Finally, S100A16 is predominantly expressed in HSCs and its mRNA expression is significantly increased with NASH in humans [ 143 ]. In this regard, a recent genetic study using both S100A16 knockout and transgenic mice highlighted a hepatic pro-fibrotic role for intracellular S100A16 in HSCs [ 143 ]. Here, S100A16 expression appears to induce p53 degradation in HSCs, which in turn promotes activation of these cells via CXCR4-dependent mechanisms [ 143 ].…”

Section: S100 Proteins In Nafld/nash and Hcc Developmentmentioning

confidence: 99%

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S100 Proteins in Fatty Liver Disease and Hepatocellular Carcinoma

Delangre

Oppliger

Berkcan

et al. 2022

IJMS

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Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent and slow progressing hepatic pathology characterized by different stages of increasing severity which can ultimately give rise to the development of hepatocellular carcinoma (HCC). Besides drastic lifestyle changes, few drugs are effective to some extent alleviate NAFLD and HCC remains a poorly curable cancer. Among the deregulated molecular mechanisms promoting NAFLD and HCC, several members of the S100 proteins family appear to play an important role in the development of hepatic steatosis, non-alcoholic steatohepatitis (NASH) and HCC. Specific members of this Ca2+-binding protein family are indeed significantly overexpressed in either parenchymal or non-parenchymal liver cells, where they exert pleiotropic pathological functions driving NAFLD/NASH to severe stages and/or cancer development. The aberrant activity of S100 specific isoforms has also been reported to drive malignancy in liver cancers. Herein, we discuss the implication of several key members of this family, e.g., S100A4, S100A6, S100A8, S100A9 and S100A11, in NAFLD and HCC, with a particular focus on their intracellular versus extracellular functions in different hepatic cell types. Their clinical relevance as non-invasive diagnostic/prognostic biomarkers for the different stages of NAFLD and HCC, or their pharmacological targeting for therapeutic purpose, is further debated.

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Section: S100 Proteins In Nafld/nash and Hcc Developmentmentioning

confidence: 99%

Section: S100 Proteins In Nafld/nash and Hcc Developmentmentioning

confidence: 99%

S100 Proteins in Fatty Liver Disease and Hepatocellular Carcinoma

Delangre

Oppliger

Berkcan

et al. 2022

IJMS

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“…CXCR4 expression can be considered as a potential biomarker for the pro‐inflammatory response level in the liver based on the fact that CXCR4 is overexpressed in liver inflammation, [ 36 ] liver fibrosis, [ 37‐39 ] cirrhosis, [ 40 ] liver cancer tissues, while not in normal liver tissue. [ 41 ] We thus examined the effects of NPs on the expression of CXCR4.…”

Section: Resultsmentioning

confidence: 99%

Balancing and Therapeutic Roles of CXCR4‐Inhibiting Nanomedicine via Synergetic Regulation of Hepatic Stellate Cells and Extracellular Matrix in Liver Injury^†

Huan,

Chen,

et al. 2023

Chin. J. Chem.

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Comprehensive SummaryInflammation is associated with different stages of liver disease, including acute injury, fibrosis, cirrhosis, and hepatoma. During the progression of liver inflammation, activation of hepatic stellate cells (HSCs) and extracellular matrix (ECM) deposition are critical pathologies, and thus the combined therapy using HSCs and ECM as targets represents a promising strategy in the treatment of liver injury. Here, a novel CXCR4‐inhibiting nanomedicine that can simultaneously deliver AMD3100 (CXCR4 antagonist) and siPAI‐1 (siRNA of plasminogen activator inhibitor‐1) was designed and developed to reverse liver fibrosis by inhibiting HSCs activation and degrading ECM deposition. With this goal in mind, a Zn (II) coordinated polymeric AMD3100 named PAMD/Zn polymer with siRNA delivery and CXCR4 antagonism capabilities was synthesized. Overall, our results suggest that PAMD/Zn recruits pro‐inflammatory cells for fibrogenesis and inhibits the activation of HSCs for fibrolysis at various stages of liver injury. Its use in conjunction with PAI‐1 silencing achieved satisfactory therapeutic efficacy in liver injury and fibrosis. The derivative CXCR4‐inhibiting nanomedicine is a versatile platform that offers valuable benefits for the treatment of liver diseases.This article is protected by copyright. All rights reserved.

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“…Decreased PI3K expression and AKT phosphorylation can delay renal fibrosis through the PI3K/AKT/mTOR signaling cascade in HN rat renal hypertrophy model ( Zhou et al, 2022 ). Changes in the expression of P53 and AKT were also associated with liver fibrosis ( Zhang et al, 2022 ). We interpret the underlying molecular mechanism by which AZD6738 inhibited TGF-β1-induced fibrotic response in HConFs based on the existing evidence mentioned above.…”

Section: Discussionmentioning

confidence: 99%

AZD6738 Inhibits fibrotic response of conjunctival fibroblasts by regulating checkpoint kinase 1/P53 and PI3K/AKT pathways

Longxiang

Lan

et al. 2022

Front. Pharmacol.

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Trabeculectomy can effectively reduce intraocular pressure (IOP) in glaucoma patients, the long-term surgical failure is due to the excessive proliferation and fibrotic response of conjunctival fibroblasts which causes the subconjunctival scar and non-functional filtering bleb. In this study, we demonstrated that AZD6738 (Ceralasertib), a novel potent ataxia telangiectasia and Rad3-related (ATR) kinase inhibitor, can inhibit the fibrotic response of conjunctival fibroblasts for the first time. Our in vitro study demonstrated that AZD6738 inhibited the level and the phosphorylation of checkpoint kinase 1 (CHK1), reduced TGF-β1-induced cell proliferation and migration, and induced apoptosis of human conjunctival fibroblasts (HConFs) in the high-dose group (5 μM). Low-dose AZD6738 (0.1 μM) inhibited the phosphorylation of CHK1 and reduce fibrotic response but did not promote apoptosis of HConFs. Further molecular research indicated that AZD6738 regulates survival and apoptosis of HConFs by balancing the CHK1/P53 and PI3K/AKT pathways, and inhibiting TGF-β1-induced fibrotic response including myofibroblast activation and relative extracellular matrix (ECM) protein synthesis such as fibronectin (FN), collagen Ⅰ (COL1) and collagen Ⅳ (COL4) through a dual pharmacological mechanism. Hence, our results show that AZD6738 inhibits fibrotic responses in cultured HConFs in vitro and may become a potential therapeutic option for anti-subconjunctival scarring after trabeculectomy.

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S100a16 deficiency prevents hepatic stellate cells activation and liver fibrosis via inhibiting CXCR4 expression

Cited by 15 publications

References 34 publications

S100 Proteins in Fatty Liver Disease and Hepatocellular Carcinoma

S100 Proteins in Fatty Liver Disease and Hepatocellular Carcinoma

Balancing and Therapeutic Roles of CXCR4‐Inhibiting Nanomedicine via Synergetic Regulation of Hepatic Stellate Cells and Extracellular Matrix in Liver Injury^†

AZD6738 Inhibits fibrotic response of conjunctival fibroblasts by regulating checkpoint kinase 1/P53 and PI3K/AKT pathways

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S100a16 deficiency prevents hepatic stellate cells activation and liver fibrosis via inhibiting CXCR4 expression

Cited by 15 publications

References 34 publications

S100 Proteins in Fatty Liver Disease and Hepatocellular Carcinoma

S100 Proteins in Fatty Liver Disease and Hepatocellular Carcinoma

Balancing and Therapeutic Roles of CXCR4‐Inhibiting Nanomedicine via Synergetic Regulation of Hepatic Stellate Cells and Extracellular Matrix in Liver Injury†

AZD6738 Inhibits fibrotic response of conjunctival fibroblasts by regulating checkpoint kinase 1/P53 and PI3K/AKT pathways

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Balancing and Therapeutic Roles of CXCR4‐Inhibiting Nanomedicine via Synergetic Regulation of Hepatic Stellate Cells and Extracellular Matrix in Liver Injury^†