title: Cannabinoid receptors are involved in the protective effect of a novel curcumin derivative C66 against CCl4-induced liver fibrosis.
abstract: Liver fibrosis is one of the major causes of morbidity and mortality worldwide and lacks efficient therapy. Recent studies suggest the curcumin protects liver from fibrosis. However, curcumin itself is in low bioavailable concentration when administered orally, and the protective mechanism remains poorly understood. The current study aimed to investigate whether a more stable derivative of curcumin, C66, protects against CCl4-inudced liver fibrosis and examine the underlying mechanism involving cannabinoid receptor (CB receptor). At a dose lower than curcumin itself, C66 displayed a superior anti-fibrotic effect. C66 significantly reduced collagen deposition, pro-inflammatory cytokine expression, and liver enzyme activities. Mechanistic study revealed that C66 treatment decreased CCl4-induced cannabinoid receptor 1 (CB1 receptor) expression and increased cannabinoid receptor 2 (CB2 receptor) expression, along with an inhibition of JNK/NF-κB-mediated inflammatory signaling. In conclusion, this curcumin derivative attenuates liver fibrosis likely involving a CB/JNK/NF-κB-mediated pathway.
authors.affiliation: Hepatology Institute of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Si-Si
authors.initials: SS
authors.lastname: Huang
authors.affiliation: Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, Zhejiang University, Hangzhou, China.
authors.forename: Da-zhi
authors.initials: DZ
authors.lastname: Chen
authors.affiliation: Hepatology Institute of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: He
authors.initials: H
authors.lastname: Wu
authors.affiliation: Hepatology Institute of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Rui-Cong
authors.initials: RC
authors.lastname: Chen
authors.affiliation: Hepatology Institute of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Shan-Jie
authors.initials: SJ
authors.lastname: Du
authors.affiliation: Hepatology Institute of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Jia-Jia
authors.initials: JJ
authors.lastname: Dong
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
authors.affiliation: Hepatology Institute of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Lan-Man
authors.initials: LM
authors.lastname: Xu
authors.affiliation: Hepatology Institute of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Wang
authors.affiliation: Liver Cancer Therapy and Research Center, People's Liberation Army 302 Hospital, Beijing 100039, China.
authors.forename: Yong-Ping
authors.initials: YP
authors.lastname: Yang
authors.affiliation: Hepatology Institute of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Zhen-Ping
authors.initials: ZP
authors.lastname: Yu
authors.affiliation: Hepatology Institute of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA. Electronic address: wenke.feng@louisville.edu.
authors.forename: Wen-Ke
authors.initials: WK
authors.lastname: Feng
authors.affiliation: Hepatology Institute of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: 13505777281@163.com.
authors.forename: Yong-Ping
authors.initials: YP
authors.lastname: Chen
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000494:pharmacology*; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D019610:Cytoprotection / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D043882:Receptors, Cannabinoid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016328:NF-kappa B; D043882:Receptors, Cannabinoid; D002251:Carbon Tetrachloride; D048031:JNK Mitogen-Activated Protein Kinases; D003474:Curcumin
keywords: (2E,6E)−2,6-bis(2-(Trifluoromethyl)Benzylidene)Cyclohexanone; Cannabinoid receptor; JNK; Liver fibrosis; NF-κB