PMID- 38072040
OWN - NLM
STAT- MEDLINE
DCOM- 20240126
LR  - 20240126
IS  - 1879-0712 (Electronic)
IS  - 0014-2999 (Linking)
VI  - 963
DP  - 2024 Jan 15
TI  - Xanthohumol attenuates collagen synthesis in scleroderma skin fibroblasts by 
      ROS/Nrf2/TGFbeta1/Smad3 pathway.
PG  - 176227
LID - S0014-2999(23)00741-0 [pii]
LID - 10.1016/j.ejphar.2023.176227 [doi]
AB  - Skin fibrosis, the most obvious clinical manifestation of systemic sclerosis 
      (SSc), has a high unmet need for treatment. Xanthohumol (Xn) has been shown to 
      have beneficial effects on fibrotic diseases, but its efficacy in SSc remains 
      unreported. This study aims to elucidate the effects and mechanisms of Xn on 
      collagen synthesis in SSc skin fibroblasts (SScF). We found increased collagen 
      production in SScF cultured in vitro, accompanied by dysregulated levels of 
      oxidative stress. Cell experiments showed that Xn inhibited cell proliferation 
      and promoted apoptosis. In addition, Xn was shown for the first time to 
      upregulate reactive oxygen species (ROS) and nuclear factor erythroid 2-related 
      factor 2 (Nrf2)levels in SScF, and when combined with the ROS scavenger 
      N-acetylcysteine (NAC), Nrf2 expression was decreased. Importantly, we 
      demonstrated that Xn significantly attenuated collagen synthesis by blocking the 
      fibrotic classical transforming growth factor beta 1 (TGFbeta1)/Smad3 pathway, which 
      interestingly was upregulated when combined with the Nrf2 inhibitor 385. Taken 
      together, Xn suppressed the TGFbeta1/Smad3 pathway to ameliorate collagen 
      overproduction by promoting ROS-induced oxidative stress damage and activating 
      Nrf2, suggesting that Xn administration may be an emerging therapeutic strategy 
      for skin fibrosis in SSc.
CI  - Copyright (c) 2023. Published by Elsevier B.V.
FAU - Xiao, Yu
AU  - Xiao Y
AD  - Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China; 
      Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, 
      China.
FAU - Huang, Zhongzhou
AU  - Huang Z
AD  - Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China; 
      Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, 
      China.
FAU - Wang, Yingyu
AU  - Wang Y
AD  - Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China; 
      Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, 
      China.
FAU - Wang, Yan
AU  - Wang Y
AD  - Central Lab, Huashan Hospital, Fudan University, Shanghai, China.
FAU - Yu, Ling
AU  - Yu L
AD  - Shanghai TCM-Integrated Hospital, Shanghai University of TCM, Shanghai, China.
FAU - Yang, Ji
AU  - Yang J
AD  - Division of Dermatology, Zhongshan Hospital, Fudan University, Shanghai, China.
FAU - Zou, Hejian
AU  - Zou H
AD  - Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China; 
      Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, 
      China.
FAU - Wan, Weiguo
AU  - Wan W
AD  - Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China; 
      Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, 
      China. Electronic address: wgwan1969@sina.com.
FAU - Yang, Xue
AU  - Yang X
AD  - Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China; 
      Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, 
      China. Electronic address: yangxue21@yeah.net.
LA  - eng
PT  - Journal Article
DEP - 20231208
PL  - Netherlands
TA  - Eur J Pharmacol
JT  - European journal of pharmacology
JID - 1254354
RN  - 9007-34-5 (Collagen)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Reactive Oxygen Species)
RN  - T4467YT1NT (xanthohumol)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (Smad3 Protein)
SB  - IM
MH  - Humans
MH  - Collagen/metabolism
MH  - Fibroblasts
MH  - Fibrosis
MH  - *NF-E2-Related Factor 2/drug effects/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - *Scleroderma, Systemic/drug therapy/metabolism/pathology
MH  - Skin
MH  - Transforming Growth Factor beta/drug effects/metabolism
MH  - Smad3 Protein/drug effects/metabolism
OTO - NOTNLM
OT  - Fibrosis
OT  - Oxidative stress
OT  - Systemic sclerosis
OT  - Xanthohumol
COIS- Declaration of competing interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/12/11 00:42
MHDA- 2024/01/08 06:43
CRDT- 2023/12/10 19:27
PHST- 2023/04/13 00:00 [received]
PHST- 2023/11/24 00:00 [revised]
PHST- 2023/11/27 00:00 [accepted]
PHST- 2024/01/08 06:43 [medline]
PHST- 2023/12/11 00:42 [pubmed]
PHST- 2023/12/10 19:27 [entrez]
AID - S0014-2999(23)00741-0 [pii]
AID - 10.1016/j.ejphar.2023.176227 [doi]
PST - ppublish
SO  - Eur J Pharmacol. 2024 Jan 15;963:176227. doi: 10.1016/j.ejphar.2023.176227. Epub 
      2023 Dec 8.