Therapeutic potential of genipin in various acute liver injury, fulminant hepatitis, NAFLD and other non-cancer liver diseases: More friend than foe. (September 2020)

• Record Type: Journal Article
• Authors: Fan, Xiaofei; Lin, Lin; Cui, Binxin; Zhao, Tianming; Mao, Lihong; Song, Yan; Wang, Xiaoyu; Feng, Hongjuan; Qingxiang, Yu; Zhang, Jie; Jiang, Kui; Cao, Xiaocang; Wang, Bangmao; Sun, Chao
• Is Part Of: Pharmacological research. Volume 159(2020)
• Publication Date: 2020-09
• Subjects: ALF acute liver failure -- NAFLD non-alcoholic fatty liver disease -- TCM traditional Chinese medicine -- YCHD Yin-Chen-Hao decoction -- ICHT inchinkoto -- Mrp2 multidrug resistance-associated protein 2 -- GSH glutathione -- PAMPs pathogen associated molecular patterns -- DAMPs amage associated molecular patterns -- TLRs toll-like receptors -- HMGB1 high mobility group protein-1 -- mtDNA mitochondrial DNA -- MAPKs mitogen-activated protein kinases -- ConA concanavalin A -- GalN D-Galactosamine -- LPS lipopolysaccharide -- ROS reactive oxygen species -- iNOS inducible nitric oxidative synthase -- Nrf2 nuclear factor erythroid 2-related factor 2 -- ARE antioxidant response element -- HO-1 heme oxygenase-1 -- I/R ischemia/reperfusion -- HCC hepatocellular carcinoma -- RCD regulated cell death -- TRAIL TNF-related apoptosis-inducing ligand -- CLP cecal ligation and puncture -- LC3-II microtubule-associated protein-1 light chain 3-II -- ALI acute liver injury -- RIP receptor-interacting protein -- MLKL mixed lineage kinase domain-like protein -- HFD high-fat diet -- UCP2 uncoupling protein 2 -- ATP adenosine triphosphate -- AMPK AMP-activated protein kinase -- PA palmitic acid -- HSC hepatic stellate cell -- PPARα peroxisomal proliferator-activated receptor α; Traditional Chinese medicine -- Genipin -- Liver disease -- Regulated cell death -- Toxicity; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2020.104945
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Genipin is an aglycone derived from the geniposide, the most abundant iridoid glucoside constituent of Gardenia jasminoides Ellis. For decades, genipin is the focus of studies as a versatile compound in the treatment of various pathogenic conditions. In particularly, Gardenia jasminoides Ellis has long been used in traditional Chinese medicine for the prevention and treatment of liver disease. Mounting experimental data has proved genipin possesses therapeutic potential for cholestatic, septic, ischemia/reperfusion-triggered acute liver injury, fulminant hepatitis and NAFLD. This critical review is a reflection on the valuable lessons from decades of research regarding pharmacological activities of genipin. Of note, genipin represents choleretic effect by potentiating bilirubin disposal and enhancement of genes in charge of the efflux of a number of organic anions. The anti-inflammatory capability of genipin is mediated by suppression of the production and function of pro-inflammatory cytokines and inflammasome. Moreover, genipin modulates various transcription factor and signal transduction pathway. Genipin appears to trigger the upregulation of several key genes encoding antioxidant and xenobiotic-metabolizing enzymes. Furthermore, the medicinal impact of genipin extends to modulation of regulated cell death, including autophagic cell death, apoptosis, necroptosis and pyroptosis, and modulation of quality of cellular organelle. Another crucial effect of genipin appears to be linked to dual role in targeting uncoupling protein 2 (UCP2). As a typical UCP2-inhibiting compound, genipin could inhibit AMP-activated protein kinase or NF-κB in circumstance. On the contrary, reactive oxygen species production and cellular lipid deposits mediated by genipin through the upregulation of UCP2 is observed in liver steatosis, suggesting the precise role of genipin is disease-specific. Collectively, we comprehensively summarize the mechanisms and pathways associated with the hepatoprotective activity of genipin and discuss potential toxic impact. Notably, our focus is the direct medicinal effect of genipin itself, whereas its utility as a crosslinking agent in tissue engineering is out of scope for the current review. Further studies are therefore required to disentangle these complicated pharmacological properties to confer this natural agent a far greater potency.