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Glabridin Ameliorates Alcohol-Caused Liver Damage by Reducing Oxidative Stress and Inflammation via p38 MAPK/Nrf2/NF-κB Pathway

ABSTRACT: Licorice is a traditional and versatile herbal medicine and food. Glabridin (Gla) is a kind of isoflavone extracted from the licorice root, which has anti-obesity, anti-atherosclerotic, and antioxidative effects. Alcoholic liver disease (ALD) is a widespread liver disease induced by chronic alcohol consumption. However, studies demonstrating the effect of Gla on ALD are rare. The research explored the positive effect of Gla in C57BL/6J mice fed by the Lieber–DeCarli ethanol mice diet and HepG2 cells treated with ethanol. Gla alleviated ethanol-induced liver injury, including reducing liver vacuolation and lipid accumulation. The serum levels of inflammatory cytokines were decreased in the Gla-treated mice. The reactive oxygen species and apoptosis levels were attenuated and antioxidant enzyme activity levels were restored in ethanol-induced mice by Gla treatment. In vitro, Gla reduced ethanol-induced cytotoxicity, nuclear factor kappa B (NF-κB) nuclear translocation, and enhanced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) nuclear translocation. Anisomycin (an agonist of p38 MAPK) eliminated the positive role of Gla on ethanol-caused oxidative stress and inflammation. On the whole, Gla can alleviate alcoholic liver damage via the p38 MAPK/Nrf2/NF-κB pathway and may be used as a novel health product or drug to potentially alleviate ALD.

SUBMITTER: Wang M

PROVIDER: S-EPMC10180694 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Project description:BackgroundTo investigate the role and regulatory mechanisms of fargesin, one of the main components of Magnolia fargesii, in macrophage reprogramming and crosstalk across cartilage and synovium during osteoarthritis (OA) development.MethodsTen-week-old male C57BL/6 mice were randomized and assigned to vehicle, collagenase-induced OA (CIOA), or CIOA with intra-articular fargesin treatment groups. Articular cartilage degeneration was evaluated using the Osteoarthritis Research Society International (OARSI) score. Immunostaining and western blot analyses were conducted to detect relative protein. Raw264.7 cells were treated with LPS or IL-4 to investigate the role of polarized macrophages. ADTC5 cells were treated with IL-1β and conditioned medium was collected to investigate the crosstalk between chondrocytes and macrophages.ResultsFargesin attenuated articular cartilage degeneration and synovitis, resulting in substantially lower Osteoarthritis Research Society International (OARSI) and synovitis scores. In particular, significantly increased M2 polarization and decreased M1 polarization in synovial macrophages were found in fargesin-treated CIOA mice compared to controls. This was accompanied by downregulation of IL-6 and IL-1β and upregulation of IL-10 in serum. Conditioned medium (CM) from M1 macrophages treated with fargesin reduced the expression of matrix metalloproteinase-13, RUNX2, and type X collagen and increased Col2a1 and SOX9 in OA chondrocytes, but fargesin alone did not affect chondrocyte catabolic processes. Moreover, fargesin exerted protective effects by suppressing p38/ERK MAPK and p65/NF-κB signaling.ConclusionsThis study showed that fargesin switched the polarized phenotypes of macrophages from M1 to M2 subtypes and prevented cartilage degeneration partially by downregulating p38/ERK MAPK and p65/NF-κB signaling. Targeting macrophage reprogramming or blocking the crosstalk between macrophages and chondrocytes in early OA may be an effective preventive strategy.

Project description:ObjectiveInula britannica is a traditional Chinese medicinal and functional food with various effects such as anti-liver injury, hypoglycemia, antioxidants, and anti-tumor. The aim of this study was to investigate the protective effects and mechanisms of the ethanolic extract of I. britannica (EEIB) on alcohol-induced liver injury in mice.MethodsFifty-six female C57BL/6 mice were randomly divided into seven groups: control group (Con), ethanol feeding model group (EtOH), Silibinin positive treatment group (EtOH + Silibinin 100 mg/kg), EEIB treatment group (EtOH + EEIB 100, 200, and 400 mg/kg), and EEIB control group (EEIB 400 mg/kg). The National Institute on Alcohol Abuse and Alcoholism (NIAAA) ethanol-feeding model was used to study the effects of EEIB on alcohol-induced lipid metabolism, inflammation, oxidative stress, and fibril formation in mice by histopathological evaluation, immunofluorescence staining, Western blotting analysis and molecular docking.ResultsEEIB reduced liver indices to different degrees to normal levels and improved liver morphology in mice. EEIB inhibited alcohol-induced liver injury by activating the sirtuin 1 (SIRT1)-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway in the liver of alcohol-fed mice, in which sesquiterpenes may be the potential active ingredients, and also down-regulated the expression of alpha-smooth muscle actin (α-SMA), collagen alpha (Collagen I), tumor necrosis factor-alpha (TNF-α) and attenuated alcohol-induced liver injury. In addition, EEIB also activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, which alleviated alcohol-induced liver injury at the level of oxidative stress. Notably, the EEIB control group demonstrated that EEIB had no toxic effects in mice. EEIB reduced alcoholic liver injury in a dose-dependent manner. Its therapeutic efficacy was comparable to, if not better than, that of Silibinin when administered at a dose of 400 mg/kg.ConclusionEEIB showed significant therapeutic effects on alcohol-induced liver injury in mice, and its mechanism of action was related to the SIRT1-AMPK, nuclear factor-kappa B (NF-κB), and Nrf2 signaling pathways, in which sesquiterpenes may be the potential active ingredients.

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Glabridin Ameliorates Alcohol-Caused Liver Damage by Reducing Oxidative Stress and Inflammation via p38 MAPK/Nrf2/NF-κB Pathway

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