PMID- 33130474
OWN - NLM
STAT- MEDLINE
DCOM- 20210115
LR  - 20240226
IS  - 1618-095X (Electronic)
IS  - 0944-7113 (Linking)
VI  - 80
DP  - 2021 Jan
TI  - Celastrol ameliorates Propionibacterium acnes/LPS-induced liver damage and 
      MSU-induced gouty arthritis via inhibiting K63 deubiquitination of NLRP3.
PG  - 153398
LID - S0944-7113(20)30229-4 [pii]
LID - 10.1016/j.phymed.2020.153398 [doi]
AB  - BACKGROUND: Celastrol, a pentacyclic triterpenoid quinonemethide isolated from 
      several spp. of Celastraceae family, exhibits anti-inflammatory activities in a 
      variety of diseases including arthritis. PURPOSE: This study aims to investigate 
      whether the inhibition of NLRP3 inflammasome is engaged in the anti-inflammatory 
      activities of celastrol and delineate the underlying mechanism. METHODS: The 
      influence of celastrol on NLRP3 inflammasome activation was firstly studied in 
      lipopolysaccharide (LPS)-primed mouse bone marrow-derived macrophages (BMDMs) and 
      phorbol 12-myristate 13-acetate (PMA)-primed THP-1 cells treated with nigericin. 
      Reconstituted inflammasome was also established by co-transfecting NLRP3, ASC, 
      pro-caspase-1 and pro-IL-1beta in HEK293T cells. The changes of inflammasome 
      components including NLRP3, ASC, pro-caspase-1/caspase-1 and pro-IL-1beta/IL-1beta were 
      examined by enzyme-linked immunosorbent assay (ELISA), western blotting and 
      immunofluorescence. Furthermore, Propionibacterium acnes (P. acnes)/LPS-induced 
      liver injury and monosodium urate (MSU)-induced gouty arthritis in mice were 
      employed in vivo to validate the inhibitory effect of celastrol on NLRP3 
      inflammasome. RESULTS: Celastrol significantly suppressed the cleavage of 
      pro-caspase-1 and pro-IL-1beta, while not affecting the protein expressions of 
      NLRP3, ASC, pro-caspase-1 and pro-IL-1beta in THP-1 cells, BMDMs and HEK293T cells. 
      Celastrol suppressed NLRP3 inflammasome activation and alleviated P. 
      acnes/LPS-induced liver damage and MSU-induced gouty arthritis. Mechanism study 
      revealed that celastrol could interdict K63 deubiquitination of NLRP3, which may 
      concern interaction of celastrol and BRCA1/BRCA2-containing complex subunit 3 
      (BRCC3), and thereby prohibited the formation of NLRP3, ASC and pro-caspase-1 
      complex to block the generation of mature IL-1beta. CONCLUSION: Celastrol suppresses 
      NLRP3 inflammasome activation in P. acnes/LPS-induced liver damage and 
      MSU-induced gouty arthritis via inhibiting K63 deubiquitination of NLRP3, which 
      presents a novel insight into inhibition of celastrol on NLRP3 inflammasome and 
      provides more evidences for its application in the therapy of 
      inflammation-related diseases.
CI  - Copyright (c) 2020 Elsevier GmbH. All rights reserved.
FAU - Yan, Chang-Yu
AU  - Yan CY
AD  - Guangdong Province Research and Development Center for Chinese Medicine in 
      Disease Susceptibility, College of Pharmacy, Jinan University, Guangzhou 510632, 
      China; International Cooperative Laboratory of Traditional Chinese Medicine 
      Modernization and Innovative Drug Development of Chinese Ministry of Education 
      (MOE), College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong 
      Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs 
      Research, College of Pharmacy, Jinan University, Guangzhou 510632, China; 
      Guangdong Perfect Institute for Health Science & Technology, Ltd., Zhongshan 
      528400, China.
FAU - Ouyang, Shu-Hua
AU  - Ouyang SH
AD  - Guangdong Province Research and Development Center for Chinese Medicine in 
      Disease Susceptibility, College of Pharmacy, Jinan University, Guangzhou 510632, 
      China; International Cooperative Laboratory of Traditional Chinese Medicine 
      Modernization and Innovative Drug Development of Chinese Ministry of Education 
      (MOE), College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong 
      Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs 
      Research, College of Pharmacy, Jinan University, Guangzhou 510632, China.
FAU - Wang, Xi
AU  - Wang X
AD  - Guangdong Province Research and Development Center for Chinese Medicine in 
      Disease Susceptibility, College of Pharmacy, Jinan University, Guangzhou 510632, 
      China; International Cooperative Laboratory of Traditional Chinese Medicine 
      Modernization and Innovative Drug Development of Chinese Ministry of Education 
      (MOE), College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong 
      Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs 
      Research, College of Pharmacy, Jinan University, Guangzhou 510632, China.
FAU - Wu, Yan-Ping
AU  - Wu YP
AD  - Guangdong Province Research and Development Center for Chinese Medicine in 
      Disease Susceptibility, College of Pharmacy, Jinan University, Guangzhou 510632, 
      China; International Cooperative Laboratory of Traditional Chinese Medicine 
      Modernization and Innovative Drug Development of Chinese Ministry of Education 
      (MOE), College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong 
      Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs 
      Research, College of Pharmacy, Jinan University, Guangzhou 510632, China.
FAU - Sun, Wan-Yang
AU  - Sun WY
AD  - Guangdong Province Research and Development Center for Chinese Medicine in 
      Disease Susceptibility, College of Pharmacy, Jinan University, Guangzhou 510632, 
      China; International Cooperative Laboratory of Traditional Chinese Medicine 
      Modernization and Innovative Drug Development of Chinese Ministry of Education 
      (MOE), College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong 
      Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs 
      Research, College of Pharmacy, Jinan University, Guangzhou 510632, China.
FAU - Duan, Wen-Jun
AU  - Duan WJ
AD  - Guangdong Province Research and Development Center for Chinese Medicine in 
      Disease Susceptibility, College of Pharmacy, Jinan University, Guangzhou 510632, 
      China; International Cooperative Laboratory of Traditional Chinese Medicine 
      Modernization and Innovative Drug Development of Chinese Ministry of Education 
      (MOE), College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong 
      Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs 
      Research, College of Pharmacy, Jinan University, Guangzhou 510632, China.
FAU - Liang, Lei
AU  - Liang L
AD  - Guangdong Province Research and Development Center for Chinese Medicine in 
      Disease Susceptibility, College of Pharmacy, Jinan University, Guangzhou 510632, 
      China; International Cooperative Laboratory of Traditional Chinese Medicine 
      Modernization and Innovative Drug Development of Chinese Ministry of Education 
      (MOE), College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong 
      Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs 
      Research, College of Pharmacy, Jinan University, Guangzhou 510632, China.
FAU - Luo, Xiang
AU  - Luo X
AD  - Guangdong Province Research and Development Center for Chinese Medicine in 
      Disease Susceptibility, College of Pharmacy, Jinan University, Guangzhou 510632, 
      China; International Cooperative Laboratory of Traditional Chinese Medicine 
      Modernization and Innovative Drug Development of Chinese Ministry of Education 
      (MOE), College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong 
      Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs 
      Research, College of Pharmacy, Jinan University, Guangzhou 510632, China.
FAU - Kurihara, Hiroshi
AU  - Kurihara H
AD  - Guangdong Province Research and Development Center for Chinese Medicine in 
      Disease Susceptibility, College of Pharmacy, Jinan University, Guangzhou 510632, 
      China; International Cooperative Laboratory of Traditional Chinese Medicine 
      Modernization and Innovative Drug Development of Chinese Ministry of Education 
      (MOE), College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong 
      Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs 
      Research, College of Pharmacy, Jinan University, Guangzhou 510632, China; 
      Guangdong Perfect Institute for Health Science & Technology, Ltd., Zhongshan 
      528400, China.
FAU - Li, Yi-Fang
AU  - Li YF
AD  - Guangdong Province Research and Development Center for Chinese Medicine in 
      Disease Susceptibility, College of Pharmacy, Jinan University, Guangzhou 510632, 
      China; International Cooperative Laboratory of Traditional Chinese Medicine 
      Modernization and Innovative Drug Development of Chinese Ministry of Education 
      (MOE), College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong 
      Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs 
      Research, College of Pharmacy, Jinan University, Guangzhou 510632, China. 
      Electronic address: liyifang706@jnu.edu.cn.
FAU - He, Rong-Rong
AU  - He RR
AD  - Guangdong Province Research and Development Center for Chinese Medicine in 
      Disease Susceptibility, College of Pharmacy, Jinan University, Guangzhou 510632, 
      China; International Cooperative Laboratory of Traditional Chinese Medicine 
      Modernization and Innovative Drug Development of Chinese Ministry of Education 
      (MOE), College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangdong 
      Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs 
      Research, College of Pharmacy, Jinan University, Guangzhou 510632, China. 
      Electronic address: rongronghe@jnu.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20201024
PL  - Germany
TA  - Phytomedicine
JT  - Phytomedicine : international journal of phytotherapy and phytopharmacology
JID - 9438794
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 0 (Inflammasomes)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (NLRP3 protein, human)
RN  - 0 (Nlrp3 protein, mouse)
RN  - 0 (Pentacyclic Triterpenes)
RN  - 0 (Triterpenes)
RN  - 268B43MJ25 (Uric Acid)
RN  - K3Z4F929H6 (Lysine)
RN  - L8GG98663L (celastrol)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents, Non-Steroidal/*pharmacology
MH  - Arthritis, Gouty/chemically induced/*drug therapy/metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - Inflammasomes/drug effects/metabolism
MH  - Lipopolysaccharides/toxicity
MH  - Liver/*drug effects/microbiology/pathology
MH  - Lysine/metabolism
MH  - Macrophages/drug effects/metabolism
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Mice, Mutant Strains
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/genetics/*metabolism
MH  - Pentacyclic Triterpenes
MH  - Propionibacterium acnes/pathogenicity
MH  - THP-1 Cells
MH  - Triterpenes/*pharmacology
MH  - Ubiquitination/drug effects
MH  - Uric Acid/toxicity
MH  - Mice
OTO - NOTNLM
OT  - Celastrol
OT  - Deubiquitination
OT  - Gouty arthritis
OT  - IL-1beta
OT  - Liver injury
OT  - NLRP3 inflammasome
EDAT- 2020/11/02 06:00
MHDA- 2021/01/16 06:00
CRDT- 2020/11/01 20:38
PHST- 2020/07/29 00:00 [received]
PHST- 2020/10/07 00:00 [revised]
PHST- 2020/10/23 00:00 [accepted]
PHST- 2020/11/02 06:00 [pubmed]
PHST- 2021/01/16 06:00 [medline]
PHST- 2020/11/01 20:38 [entrez]
AID - S0944-7113(20)30229-4 [pii]
AID - 10.1016/j.phymed.2020.153398 [doi]
PST - ppublish
SO  - Phytomedicine. 2021 Jan;80:153398. doi: 10.1016/j.phymed.2020.153398. Epub 2020 
      Oct 24.