title: Citral alleviates an accelerated and severe lupus nephritis model by inhibiting the activation signal of NLRP3 inflammasome and enhancing Nrf2 activation.
abstract: BACKGROUND
  Lupus nephritis (LN) is a major complication of systemic lupus erythematosus. NLRP3 inflammasome activation, reactive oxygen species (ROS) and mononuclear leukocyte infiltration in the kidney have been shown to provoke the acceleration and deterioration of LN, such as accelerated and severe LN (ASLN). Development of a novel therapeutic remedy based on these molecular events to prevent the progression of the disease is clinically warranted.
  
  
  METHODS
  Citral (3,7-dimethyl-2,6-octadienal), a major active compound in a Chinese herbal medicine Litsea cubeba, was used to test its renoprotective effects in a lipopolysaccharide (LPS)-induced mouse ASLN model by examining NLRP3 inflammasome activation, ROS and COX-2 production as well as Nrf2 activation. The analysis of mechanisms of action of Citral also involved its effects on IL-1β secretion and signaling pathways of NLRP3 inflammasome in LPS-primed peritoneal macrophages or J774A macrophages.
  
  
  RESULTS
  Attenuated proteinuria, renal function impairment, and renal histopathology, the latter including intrinsic cell proliferation, cellular crescents, neutrophil influx, fibrinoid necrosis in the glomerulus, and peri-glomerular infiltration of mononuclear leukocytes as well as glomerulonephritis activity score were observed in Citral-treated ASLN mice. In addition, Citral inhibited NLRP3 inflammasome activation and levels of ROS, NAD(P)H oxidase subunit p47(phox), or COX-2, and it enhanced the activation of nuclear factor E2-related factor 2 (Nrf2). In LPS-primed macrophages, Citral reduced ATP-induced IL-1β secretion and caspase-1 activation, but did not affect LPS-induced NLRP3 protein expression.
  
  
  CONCLUSIONS
  Our data show that Citral alleviates the mouse ASLN model by inhibition of the activation signal, but not the priming signal, of NLRP3 inflammasome and enhanced activation of Nrf2 antioxidant signaling.
authors.affiliation: Graduate Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan. shukmanka@gmail.com.
authors.forename: Shuk-Man
authors.initials: SM
authors.lastname: Ka
authors.affiliation: Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec. 2, Cheng-Gung Road, Taipei, Taiwan, ROC. linjungchen@gmail.com.
authors.forename: Jung-Chen
authors.initials: JC
authors.lastname: Lin
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan. scootlin@gmail.com.
authors.forename: Tsai-Jung
authors.initials: TJ
authors.lastname: Lin
authors.affiliation: Division of Rheumatology/Immunology and Allergy, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. lfc10399@yahoo.com.tw.
authors.forename: Feng-Cheng
authors.initials: FC
authors.lastname: Liu
authors.affiliation: Department of Cosmeceutics, China Medical University, Taichung, Taiwan. kuoping@mail.cmu.edu.tw.
authors.forename: Louis Kuoping
authors.initials: LK
authors.lastname: Chao
authors.affiliation: Division of Wood Cellulose, Taiwan Forestry Research Institute, Taipei, Taiwan. chenlung@tfri.gov.tw.
authors.forename: Chen-Lung
authors.initials: CL
authors.lastname: Ho
authors.affiliation: Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan. facade0207@gmail.com.
authors.forename: Li-Tzu
authors.initials: LT
authors.lastname: Yeh
authors.affiliation: Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan. sytwu@ndmctsgh.edu.tw.
authors.forename: Huey-Kang
authors.initials: HK
authors.lastname: Sytwu
authors.affiliation: Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec. 2, Cheng-Gung Road, Taipei, Taiwan, ROC. kuofenghua@gmail.com.|Department of Biotechnology and Animal Science, National Ilan University, Sec. 1, Shen-Lung Road, Ilan, 260, Taiwan, ROC. kuofenghua@gmail.com.
authors.forename: Kuo-Feng
authors.initials: KF
authors.lastname: Hua
authors.affiliation: Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec. 2, Cheng-Gung Road, Taipei, Taiwan, ROC. annchen31717@gmail.com.
authors.forename: Ann
authors.initials: A
authors.lastname: Chen
mesh_terms: D000080462:Acyclic Monoterpenes; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D058847:Inflammasomes / Q000037:antagonists & inhibitors / Q000378:metabolism; D032862:Litsea; D008181:Lupus Nephritis / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D008814:Mice, Inbred NZB; D039821:Monoterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D000080462:Acyclic Monoterpenes; D002352:Carrier Proteins; D004365:Drugs, Chinese Herbal; D058847:Inflammasomes; D039821:Monoterpenes; D051267:NF-E2-Related Factor 2; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C495636:Nfe2l2 protein, mouse; C492716:Nlrp3 protein, mouse; C007076:citral