title: β-Caryophyllene protects against alcoholic steatohepatitis by attenuating inflammation and metabolic dysregulation in mice.
abstract: β-Caryophyllene (BCP) is a plant-derived FDA approved food additive with anti-inflammatory properties. Some of its beneficial effects in vivo are reported to involve activation of cannabinoid CB2receptors that are predominantly expressed in immune cells. Here, we evaluated the translational potential of BCP using a well-established model of chronic and binge alcohol-induced liver injury.
  
  
  
  In this study, we investigated the effects of BCP on liver injury induced by chronic plus binge alcohol feeding in mice in vivo by using biochemical assays, real-time PCR and histology analyses. Serum and hepatic BCP levels were also determined by GC/MS.
  
  
  
  Chronic treatment with BCP alleviated the chronic and binge alcohol-induced liver injury and inflammation by attenuating the pro-inflammatory phenotypic `M1` switch of Kupffer cells and by decreasing the expression of vascular adhesion molecules intercellular adhesion molecule 1, E-Selectin and P-Selectin, as well as the neutrophil infiltration. It also beneficially influenced hepatic metabolic dysregulation (steatosis, protein hyperacetylation and PPAR-α signalling). These protective effects of BCP against alcohol-induced liver injury were attenuated in CB2receptor knockout mice, indicating that the beneficial effects of this natural product in liver injury involve activation of these receptors. Following acute or chronic administration, BCP was detectable both in the serum and liver tissue homogenates but not in the brain.
  
  
  
  Given the safety of BCP in humans, this food additive has a high translational potential in treating or preventing hepatic injury associated with oxidative stress, inflammation and steatosis.
  
  
  
  This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.
authors.affiliation: Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA.
authors.forename: Zoltan V
authors.initials: ZV
authors.lastname: Varga
authors.affiliation: Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA.
authors.forename: Csaba
authors.initials: C
authors.lastname: Matyas
authors.affiliation: Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA.
authors.forename: Katalin
authors.initials: K
authors.lastname: Erdelyi
authors.affiliation: Laboratory of Physiologic Studies, National Institutes of Health/NIAAA, Bethesda, MD, USA.
authors.forename: Resat
authors.initials: R
authors.lastname: Cinar
authors.affiliation: Institute of Biochemistry and Molecular Medicine, National Center of Competence in Research TransCure, University of Bern, Bern, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Nieri
authors.affiliation: Institute of Biochemistry and Molecular Medicine, National Center of Competence in Research TransCure, University of Bern, Bern, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Chicca
authors.affiliation: Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA.
authors.forename: Balazs Tamas
authors.initials: BT
authors.lastname: Nemeth
authors.affiliation: Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA.
authors.forename: Janos
authors.initials: J
authors.lastname: Paloczi
authors.affiliation: Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA.
authors.forename: Tamas
authors.initials: T
authors.lastname: Lajtos
authors.affiliation: Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA.
authors.forename: Lukas
authors.initials: L
authors.lastname: Corey
authors.affiliation: Departments of Surgery, Rutgers New Jersey Medical School, Newark, NJ, USA.
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Hasko
authors.affiliation: Laboratory of Liver Diseases, National Institutes of Health/NIAAA, Bethesda, MD, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.affiliation: Laboratory of Physiologic Studies, National Institutes of Health/NIAAA, Bethesda, MD, USA.
authors.forename: George
authors.initials: G
authors.lastname: Kunos
authors.affiliation: Institute of Biochemistry and Molecular Medicine, National Center of Competence in Research TransCure, University of Bern, Bern, Switzerland.
authors.forename: Jürg
authors.initials: J
authors.lastname: Gertsch
authors.affiliation: Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA.
authors.forename: Pal
authors.initials: P
authors.lastname: Pacher
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001921:Brain / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy*; D019040:E-Selectin / Q000096:biosynthesis; D000431:Ethanol / Q000493:pharmacokinetics / Q000633:toxicity*; D005234:Fatty Liver / Q000139:chemically induced / Q000188:drug therapy*; D007249:Inflammation / Q000188:drug therapy*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007728:Kupffer Cells / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects; D019007:P-Selectin / Q000096:biosynthesis; D047493:PPAR alpha / Q000378:metabolism; D000081223:Polycyclic Sesquiterpenes; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics; D012717:Sesquiterpenes / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D019040:E-Selectin; D019007:P-Selectin; D047493:PPAR alpha; D000081223:Polycyclic Sesquiterpenes; D043885:Receptor, Cannabinoid, CB2; D012717:Sesquiterpenes; D018799:Intercellular Adhesion Molecule-1; D000431:Ethanol; C024714:caryophyllene