title: Xanthohumol isolated from Humulus lupulus prevents thrombosis without increased bleeding risk by inhibiting platelet activation and mtDNA release.
abstract: As the global population has reached 7 billion and the baby boom generation reaches old age, thrombosis has become the major contributor to the global disease burden. It has been reported that, in moderate doses, beer may protect against thrombosis. Xanthohumol (XN), an antioxidant, is found at high concentrations in hop cones (Humulus lupulus L.) and is a common ingredient of beer. Here, the aim of the present work was to investigate the effects of XN on antithrombotic and antiplatelet activities, and study its mechanism.
  
  
  
  Using ferric chloride-induced carotid artery injury, inferior vena cava ligation model, and platelet function tests, we demonstrated that XN uniquely prevents both venous and arterial thrombosis by inhibiting platelet activation. Interestingly, in tail bleeding time studies, XN did not increase bleeding risk, which is recognized as a major limitation of current antithrombotic therapies. We also demonstrated that XN induces Sirt1 expression and thereby decreases reactive oxygen species (ROS) overload, prevents mitochondrial dysfunction, and reduces activated platelet-induced mitochondrial hyperpolarization, respiratory disorders, and associated membrane damage at low concentrations. In mitochondrial function assays designed to detect amounts of extracellular mitochondrial DNA (mtDNA), we found that XN prevents mtDNA release, which induces platelet activation in a DC-SIGN-dependent manner.
  
  
  
  XN exemplifies a promising new class of antiplatelet agents that are highly effective at inhibiting platelet activation by decreasing ROS accumulation and platelet mtDNA release without incurring a bleeding risk. This study has also provided novel insights into mechanisms of thrombotic diseases with possible therapeutic implications.
authors.affiliation: Laboratory of Ethnopharmacology, Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, the State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
authors.forename: Guang
authors.initials: G
authors.lastname: Xin
authors.affiliation: Laboratory of Ethnopharmacology, Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, the State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Zeliang
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Clinical Laboratory, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.
authors.forename: Chengjie
authors.initials: C
authors.lastname: Ji
authors.affiliation: Laboratory of Ethnopharmacology, Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, the State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Huajie
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Gu
authors.affiliation: Laboratory of Ethnopharmacology, Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, the State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Limei
authors.initials: L
authors.lastname: Ma
authors.affiliation: Clinical Laboratory, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.
authors.forename: Wenfang
authors.initials: W
authors.lastname: Huang
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.affiliation: Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Jwu-Lai
authors.initials: JL
authors.lastname: Yeh
authors.affiliation: Laboratory of Ethnopharmacology, Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, the State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Chaoyi
authors.initials: C
authors.lastname: Qin
authors.affiliation: Laboratory of Ethnopharmacology, Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, the State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wen
authors.affiliation: Laboratory of Ethnopharmacology, Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, the State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Xing
authors.affiliation: Department of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xia
authors.affiliation: Laboratory of Ethnopharmacology, Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, the State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Li
authors.affiliation: Laboratory of Ethnopharmacology, Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, the State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China; College of Mathematics, Sichuan University, Chengdu, Sichuan, China. Electronic address: niuhai@scu.edu.cn.
authors.forename: Hai
authors.initials: H
authors.lastname: Niu
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan. Electronic address: khlee@unc.edu.
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Laboratory of Ethnopharmacology, Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, the State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. Electronic address: huangwen@scu.edu.cn.
authors.forename: Wen
authors.initials: W
authors.lastname: Huang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001515:Beer; D002339:Carotid Arteries / Q000187:drug effects* / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002712:Chlorides / Q000008:administration & dosage; D004272:DNA, Mitochondrial / Q000235:genetics; D003713:Dendritic Cells / Q000502:physiology*; D005290:Ferric Compounds / Q000008:administration & dosage; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D005419:Flavonoids / Q000378:metabolism / Q000627:therapeutic use*; D006470:Hemorrhage; D006801:Humans; D027582:Humulus / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015539:Platelet Activation; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D011427:Propiophenones / Q000378:metabolism / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D012306:Risk; D056564:Sirtuin 1 / Q000378:metabolism; D013927:Thrombosis / Q000517:prevention & control*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D000975:Antioxidants; D015815:Cell Adhesion Molecules; D002712:Chlorides; D004272:DNA, Mitochondrial; D005290:Ferric Compounds; D005343:Fibrinolytic Agents; D005419:Flavonoids; D037181:Lectins, C-Type; D010975:Platelet Aggregation Inhibitors; D011427:Propiophenones; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; D056564:Sirtuin 1; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C470545:Sirt1 protein, mouse; C104536:xanthohumol; C024555:ferric chloride
keywords: Beer; Bleeding risk; Mitochondrial DNA; Thrombosis; Xanthohumol