Saikosaponin-d protects against liver fibrosis by regulating the estrogen receptor-β/NLRP3 inflammasome pathway

Lei, Lin; Zhou, Mi; Que, Renye; Chen, Yirong; Liu, Xiaolin; Zhang, Kehui; Shi, Zhe; Li, Yong

doi:10.1139/bcb-2020-0561

Cited by 20 publications

(11 citation statements)

References 31 publications

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“…ERβ activation by genistein (a natural phytoestrogen) improves hepatic lipid metabolism ( 264 ). ERβ is involved in the regulation of hepatic fibrosis ( 265 ). The anti-fibrotic effect of estrogen is mediated by ERβ but not by ERα or GPER1.…”

Section: Ers In the Manifestation Of Diseasesmentioning

confidence: 99%

Role of estrogen receptors in health and disease

Chen

Ouyang

2022

Front. Endocrinol.

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Estrogen receptors (ERs) regulate multiple complex physiological processes in humans. Abnormal ER signaling may result in various disorders, including reproductive system-related disorders (endometriosis, and breast, ovarian, and prostate cancer), bone-related abnormalities, lung cancer, cardiovascular disease, gastrointestinal disease, urogenital tract disease, neurodegenerative disorders, and cutaneous melanoma. ER alpha (ERα), ER beta (ERβ), and novel G-protein-coupled estrogen receptor 1 (GPER1) have been identified as the most prominent ERs. This review provides an overview of ERα, ERβ, and GPER1, as well as their functions in health and disease. Furthermore, the potential clinical applications and challenges are discussed.

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Section: Ers In the Manifestation Of Diseasesmentioning

confidence: 99%

Role of estrogen receptors in health and disease

Chen

Ouyang

2022

Front. Endocrinol.

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“…HF is a diffuse injury to hepatocytes accompanied by inflammation caused by various pathogenic factors. The central link to its occurrence is the excessive deposition of collagen-based extracellular matrix caused by the activation and proliferation of static HSCs ( Kong et al, 2020 ; Lin et al, 2021 ). Studies have confirmed that HF is reversible in the early stages; therefore, it is extremely important to prevent or slow down the occurrence and development of hepatic fibrosis ( Campana and Iredale 2017 ).…”

Section: Discussionmentioning

confidence: 99%

CaM/CaMKII mediates activation and proliferation of hepatic stellate cells regulated by ASIC1a

Liu

Hong

et al. 2022

Front. Pharmacol.

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The activation of hepatic stellate cells (HSCs) is closely related to hepatic fibrosis and plays a key role in its occurrence and development. In the damaged liver, inhibition of the activation, proliferation, and clearance of HSCs is an important therapeutic strategy. However, the mechanism underlying the activation of HSCs is not completely clear. Acid-sensitive ion channel 1a (ASIC1a) is a cation channel activated by extracellular acid, which is responsible for the transport of Ca2+ and Na+ and participates in the activation of HSCs and the occurrence and development of many inflammatory diseases, suggesting that ASIC1a plays an important role in liver fibrosis. A previous study by the project team found that when the membrane channel protein ASIC1a was opened, intracellular Ca2+ levels increased, the expression of CaM/CaMKII in HSCs was high, and HSC was activated and proliferated. Therefore, we established an SD rat model of hepatic fibrosis and induced HSC-T6 activation by stimulating ASIC1a with acid in vitro. In vivo, CCl4 was used to induce liver fibrosis in rats, and different doses of KN93 (0.5, 1, and 2 mg/kg/d) and colchicine (0.1 mg/kg/d) were administered. Eight weeks later, the activities of ALT and AST in serum were measured and hematoxylin-eosin and Masson staining in liver tissue, and immunohistochemistry analysis were performed in SD rats. The expressions of ASIC1a, α-SMA, Collagen-1, CaM, and CaMKII were detected. In vitro, we activated HSC-T6 cells by stimulating ASIC1a with acid. The results showed that inhibition of ASIC1a could improve acid-induced HSCs activation. In addition, CaM/CaMKII was expressed in HSC of rats with hepatic fibrosis regulated by ASIC1a. After blocking or silencing the expression of CaMKII, the fibrosis marker protein can be down-regulated. KN93 also reduced inflammation and improved the activation, proliferation and fibrosis of HSC. In summary, we concluded that CaM/CaMKII participates in ASIC1a regulation of the proliferation and activation of HSC and promotes the occurrence of liver fibrosis.

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“…Then, the SSd group was administered SSd (2 mg/kg; Sigma-Aldrich) in saline by oral gavage once a day for 8 weeks. SSd is a potential molecule for treating liver fibrosis and is a liver protectant in a mouse model [ 113 , 114 , 115 ]. In our preliminary studies, serum ALT and AST levels after 1 mg/kg of SSd did not differ significantly from those in the TAA group ( Figure S7 ).…”

Section: Methodsmentioning

confidence: 99%

The Ameliorative Effects of Saikosaponin in Thioacetamide-Induced Liver Injury and Non-Alcoholic Fatty Liver Disease in Mice

Chang

Lin

et al. 2021

IJMS

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Liver disorders are a major health concern. Saikosaponin-d (SSd) is an effective active ingredient extracted from Bupleurum falcatum, a traditional Chinese medicinal plant, with anti-inflammatory and antioxidant properties. However, its hepatoprotective properties and underlying mechanisms are unknown. We investigated the effects and underlying mechanisms of SSd treatment for thioacetamide (TAA)-induced liver injury and high-fat-diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in male C57BL/6 mice. The SSd group showed significantly higher food intake, body weight, and hepatic antioxidative enzymes (catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD)) and lower hepatic cyclooxygenase-2 (COX-2), serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and fibroblast growth factor-21 (FGF21) compared with controls, as well as reduced expression of inflammation-related genes (nuclear factor kappa B (NF-κB) and inducible nitric oxide synthase (iNOS)) messenger RNA (mRNA). In NAFLD mice, SSd reduced serum ALT, AST, triglycerides, fatty acid–binding protein 4 (FABP4) and sterol regulatory element–binding protein 1 (SREBP1) mRNA, and endoplasmic reticulum (ER)-stress-related proteins (phosphorylated eukaryotic initiation factor 2α subunit (p-eIF2α), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP). SSd has a hepatoprotective effect in liver injury by suppressing inflammatory responses and acting as an antioxidant.

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Saikosaponin-d protects against liver fibrosis by regulating the estrogen receptor-β/NLRP3 inflammasome pathway

Cited by 20 publications

References 31 publications

Role of estrogen receptors in health and disease

Role of estrogen receptors in health and disease

CaM/CaMKII mediates activation and proliferation of hepatic stellate cells regulated by ASIC1a

The Ameliorative Effects of Saikosaponin in Thioacetamide-Induced Liver Injury and Non-Alcoholic Fatty Liver Disease in Mice

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