Ginsenoside Rk2, a Dehydroprotopanaxadiol Saponin, Alleviates Alcoholic Liver Disease Via Regulating NLRP3 and NLRP6 Inflammasome Signaling Pathways in Mice

Overview

Journal J Pharm Anal

Specialty Chemistry

Date 2023 Oct 16

PMID 37842661

Authors

Jian Zou

Rujie Yang

Ruibing Feng

Jiayue Liu

Jian-Bo Wan

Affiliations

Soon will be listed here.

Abstract

Heavy alcohol consumption results in alcoholic liver disease (ALD) with inadequate therapeutic options. Here, we first report the potential beneficial effects of ginsenoside Rk2 (Rk2), a rare dehydroprotopanaxadiol saponin isolated from streamed ginseng, against alcoholic liver injury in mice. Chronic-plus-single-binge ethanol feeding caused severe liver injury, as manifested by significantly elevated serum aminotransferase levels, hepatic histological changes, increased lipid accumulation, oxidative stress, and inflammation in the liver. These deleterious effects were alleviated by the treatment with Rk2 (5 and 30 mg/kg). Acting as an nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inhibitor, Rk2 ameliorates alcohol-induced liver inflammation by inhibiting NLRP3 inflammasome signaling in the liver. Meanwhile, the treatment with Rk2 alleviated the alcohol-induced intestinal barrier dysfunction via enhancing NLRP6 inflammasome in the intestine. Our findings indicate that Rk2 is a promising agent for the prevention and treatment of ALD and other NLPR3-driven diseases.

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References

de Carvalho Ribeiro M, Szabo G . Role of the Inflammasome in Liver Disease. Annu Rev Pathol. 2021; 17:345-365. PMC: 10501045. DOI: 10.1146/annurev-pathmechdis-032521-102529. View

Wlodarska M, Thaiss C, Nowarski R, Henao-Mejia J, Zhang J, Brown E . NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Cell. 2014; 156(5):1045-59. PMC: 4017640. DOI: 10.1016/j.cell.2014.01.026. View

Peng Y, French B, Tillman B, Morgan T, French S . The inflammasome in alcoholic hepatitis: Its relationship with Mallory-Denk body formation. Exp Mol Pathol. 2014; 97(2):305-13. PMC: 4177273. DOI: 10.1016/j.yexmp.2014.08.006. View

Le Dare B, Ferron P, Gicquel T . The Purinergic P2X7 Receptor-NLRP3 Inflammasome Pathway: A New Target in Alcoholic Liver Disease?. Int J Mol Sci. 2021; 22(4). PMC: 7926651. DOI: 10.3390/ijms22042139. View

He Y, Varadarajan S, Munoz-Planillo R, Burberry A, Nakamura Y, Nunez G . 3,4-methylenedioxy-β-nitrostyrene inhibits NLRP3 inflammasome activation by blocking assembly of the inflammasome. J Biol Chem. 2013; 289(2):1142-50. PMC: 3887181. DOI: 10.1074/jbc.M113.515080. View

Normand S, Delanoye-Crespin A, Bressenot A, Huot L, Grandjean T, Peyrin-Biroulet L . Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury. Proc Natl Acad Sci U S A. 2011; 108(23):9601-6. PMC: 3111299. DOI: 10.1073/pnas.1100981108. View

Ji X, Li L, Lu P, Li X, Tian D, Liu M . NLRP6 exerts a protective role via NF-kB with involvement of CCL20 in a mouse model of alcoholic hepatitis. Biochem Biophys Res Commun. 2020; 528(3):485-492. DOI: 10.1016/j.bbrc.2020.05.171. View

Chen G, Stappenbeck T . Mucus, it is not just a static barrier. Sci Signal. 2014; 7(323):pe11. DOI: 10.1126/scisignal.2005357. View

Feng R, Chen J, Liu C, Xia F, Xiao Z, Zhang X . A combination of Pueraria lobata and Silybum marianum protects against alcoholic liver disease in mice. Phytomedicine. 2019; 58:152824. DOI: 10.1016/j.phymed.2019.152824. View

10.

Zou J, Yan C, Wan J . Red yeast rice ameliorates non-alcoholic fatty liver disease through inhibiting lipid synthesis and NF-κB/NLRP3 inflammasome-mediated hepatic inflammation in mice. Chin Med. 2022; 17(1):17. PMC: 8788078. DOI: 10.1186/s13020-022-00573-z. View

11.

Tung N, Quang T, Son J, Koo J, Hong H, Koh Y . Inhibitory effect of ginsenosides from steamed ginseng-leaves and flowers on the LPS-stimulated IL-12 production in bone marrow-derived dendritic cells. Arch Pharm Res. 2011; 34(4):681-5. DOI: 10.1007/s12272-011-0419-2. View

12.

Mainz R, Albers S, Haque M, Sonntag R, Treichel N, Clavel T . NLRP6 Inflammasome Modulates Disease Progression in a Chronic-Plus-Binge Mouse Model of Alcoholic Liver Disease. Cells. 2022; 11(2). PMC: 8773606. DOI: 10.3390/cells11020182. View

13.

Gao B, Bataller R . Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology. 2011; 141(5):1572-85. PMC: 3214974. DOI: 10.1053/j.gastro.2011.09.002. View

14.

Birchenough G, Nystrom E, Johansson M, Hansson G . A sentinel goblet cell guards the colonic crypt by triggering Nlrp6-dependent Muc2 secretion. Science. 2016; 352(6293):1535-42. PMC: 5148821. DOI: 10.1126/science.aaf7419. View

15.

Jin G, Lu J, Lan H, Lu Y, Shen X, Xu X . Protective effect of ginsenoside Rh2 against Toxoplasma gondii infection-induced neuronal injury through binding TgCDPK1 and NLRP3 to inhibit microglial NLRP3 inflammasome signaling pathway. Int Immunopharmacol. 2022; 112:109176. DOI: 10.1016/j.intimp.2022.109176. View

16.

Rao R . Endotoxemia and gut barrier dysfunction in alcoholic liver disease. Hepatology. 2009; 50(2):638-44. PMC: 6209509. DOI: 10.1002/hep.23009. View

17.

DeSantis D, Ko C, Liu Y, Liu X, Hise A, Nunez G . Alcohol-induced liver injury is modulated by Nlrp3 and Nlrc4 inflammasomes in mice. Mediators Inflamm. 2014; 2013:751374. PMC: 3876912. DOI: 10.1155/2013/751374. View

18.

Antoni L, Nuding S, Wehkamp J, Stange E . Intestinal barrier in inflammatory bowel disease. World J Gastroenterol. 2014; 20(5):1165-79. PMC: 3921501. DOI: 10.3748/wjg.v20.i5.1165. View

19.

Jafari R, Almqvist H, Axelsson H, Ignatushchenko M, Lundback T, Nordlund P . The cellular thermal shift assay for evaluating drug target interactions in cells. Nat Protoc. 2014; 9(9):2100-22. DOI: 10.1038/nprot.2014.138. View

20.

Cocco M, Pellegrini C, Martinez-Banaclocha H, Giorgis M, Marini E, Costale A . Development of an Acrylate Derivative Targeting the NLRP3 Inflammasome for the Treatment of Inflammatory Bowel Disease. J Med Chem. 2017; 60(9):3656-3671. DOI: 10.1021/acs.jmedchem.6b01624. View