PMID- 35563088
OWN - NLM
STAT- MEDLINE
DCOM- 20220517
LR  - 20220716
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 23
IP  - 9
DP  - 2022 Apr 23
TI  - Urolithin A Inactivation of TLR3/TRIF Signaling to Block the NF-kappaB/STAT1 Axis 
      Reduces Inflammation and Enhances Antioxidant Defense in Poly(I:C)-Induced 
      RAW264.7 Cells.
LID - 10.3390/ijms23094697 [doi]
LID - 4697
AB  - Urolithin A is an active compound of gut-microbiota-derived metabolites of 
      polyphenol ellagic acid that has anti-aging, antioxidative, and anti-inflammatory 
      effects. However, the effects of urolithin A on polyinosinic acid-polycytidylic 
      acid (poly(I:C))-induced inflammation remain unclear. Poly(I:C) is a 
      double-stranded RNA (dsRNA) similar to a virus and is recognized by Toll-like 
      receptor-3 (TLR3), inducing an inflammatory response in immune cells, such as 
      macrophages. Inflammation is a natural defense process of the innate immune 
      system. Therefore, we used poly(I:C)-induced RAW264.7 cells and attenuated the 
      inflammation induced by urolithin A. First, our data suggested that 1-30 muM 
      urolithin A does not reduce RAW264.7 cell viability, whereas 1 muM urolithin A is 
      sufficient for antioxidation and the decreased production of tumor necrosis 
      factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), and C-C chemokine 
      ligand 5. The inflammation-related proteins cyclooxygenase-2 and inducible nitric 
      oxide synthase were also downregulated by urolithin A. Next, 1 muM urolithin A 
      inhibited the levels of interferon (INF)-alpha and INF-beta. Urolithin A was applied to 
      investigate the blockade of the TLR3 signaling pathway in poly(I:C)-induced 
      RAW264.7 cells. Moreover, the TLR3 signaling pathway, subsequent 
      inflammatory-related pathways, and antioxidation pathways showed changes in 
      nuclear factor-kappaB (NF-kappaB) signaling and blocked ERK/mitogen-activated protein 
      kinase (MAPK) signaling. Urolithin A enhanced catalase (CAT) and superoxide 
      dismutase (SOD) activities, but decreased malondialdehyde (MDA) levels in 
      poly(I:C)-induced RAW264.7 cells. Thus, our results suggest that urolithin A 
      inhibits TLR3-activated inflammatory and oxidative-associated pathways in 
      macrophages, and that this inhibition is induced by poly(I:C). Therefore, 
      urolithin A may have antiviral effects and could be used to treat 
      viral-infection-related diseases.
FAU - Huang, Wen-Chung
AU  - Huang WC
AUID- ORCID: 0000-0001-7141-8971
AD  - Research Center for Food and Cosmetic Safety, Graduate Institute of Health 
      Industry Technology, College of Human Ecology, Chang Gung University of Science 
      and Technology, Taoyuan City 33303, Taiwan.
AD  - Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang 
      Gung Memorial Hospital, Linkou, Taoyuan City 33303, Taiwan.
AD  - Department of Pediatrics, New Taipei Municipal Tu Cheng Hospital, Chang Gung 
      Memorial Hospital, and Chang Gung University, New Taipei City 23678, Taiwan.
FAU - Liou, Chian-Jiun
AU  - Liou CJ
AUID- ORCID: 0000-0002-2949-7060
AD  - Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang 
      Gung Memorial Hospital, Linkou, Taoyuan City 33303, Taiwan.
AD  - Department of Nursing, Division of Basic Medical Sciences, Research Center for 
      Chinese Herbal Medicine, and Graduate Institute of Health Industry Technology, 
      Chang Gung University of Science and Technology, Taoyuan 33303, Taiwan.
FAU - Shen, Szu-Chuan
AU  - Shen SC
AD  - Graduate Program of Nutrition Science, National Taiwan Normal University, 88 
      Ting-Chow Rd, Sec 4, Taipei 11677, Taiwan.
FAU - Hu, Sindy
AU  - Hu S
AD  - Department of Cosmetic Science, College of Human Ecology, Chang Gung University 
      of Science and Technology, Guishan Dist., Taoyuan City 33303, Taiwan.
AD  - Department of Dermatology, Aesthetic Medical Center, Chang Gung Memorial 
      Hospital, Linkou, Taoyuan City 33303, Taiwan.
FAU - Chao, Jane C-J
AU  - Chao JC
AUID- ORCID: 0000-0002-3610-9580
AD  - School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical 
      University, 250 Wu-Hsing Street, Taipei 11031, Taiwan.
FAU - Hsiao, Chien-Yu
AU  - Hsiao CY
AUID- ORCID: 0000-0003-3301-8808
AD  - Department of Dermatology, Aesthetic Medical Center, Chang Gung Memorial 
      Hospital, Linkou, Taoyuan City 33303, Taiwan.
AD  - Department of Nutrition and Health Sciences, Research Center for Chinese Herbal 
      Medicine, College of Human Ecology, Chang Gung University of Science and 
      Technology, Taoyuan City 33303, Taiwan.
FAU - Wu, Shu-Ju
AU  - Wu SJ
AD  - Department of Dermatology, Aesthetic Medical Center, Chang Gung Memorial 
      Hospital, Linkou, Taoyuan City 33303, Taiwan.
AD  - Department of Nutrition and Health Sciences, Research Center for Chinese Herbal 
      Medicine, College of Human Ecology, Chang Gung University of Science and 
      Technology, Taoyuan City 33303, Taiwan.
LA  - eng
PT  - Journal Article
DEP - 20220423
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Adaptor Proteins, Vesicular Transport)
RN  - 0 (Antioxidants)
RN  - 0 (Coumarins)
RN  - 0 (NF-kappa B)
RN  - 0 (RNA, Double-Stranded)
RN  - 0 (STAT1 Transcription Factor)
RN  - 0 (Stat1 protein, mouse)
RN  - 0 (TLR3 protein, mouse)
RN  - 0 (Toll-Like Receptor 3)
RN  - 1143-70-0 (3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one)
RN  - O84C90HH2L (Poly I-C)
SB  - IM
MH  - Adaptor Proteins, Vesicular Transport/metabolism
MH  - Animals
MH  - Antioxidants/pharmacology
MH  - *Coumarins/pharmacology
MH  - Inflammation/chemically induced/drug therapy
MH  - Mice
MH  - *NF-kappa B/antagonists & inhibitors/metabolism
MH  - Poly I-C/pharmacology
MH  - RAW 264.7 Cells
MH  - RNA, Double-Stranded/pharmacology
MH  - STAT1 Transcription Factor/antagonists & inhibitors/metabolism
MH  - Signal Transduction
MH  - *Toll-Like Receptor 3/antagonists & inhibitors/metabolism
PMC - PMC9101441
OTO - NOTNLM
OT  - MAPK
OT  - NF-kappaB
OT  - TLR3
OT  - poly(I:C)
OT  - urolithin A
COIS- The authors declare no potential conflict of interest.
EDAT- 2022/05/15 06:00
MHDA- 2022/05/18 06:00
PMCR- 2022/04/23
CRDT- 2022/05/14 01:03
PHST- 2022/03/25 00:00 [received]
PHST- 2022/04/18 00:00 [revised]
PHST- 2022/04/20 00:00 [accepted]
PHST- 2022/05/14 01:03 [entrez]
PHST- 2022/05/15 06:00 [pubmed]
PHST- 2022/05/18 06:00 [medline]
PHST- 2022/04/23 00:00 [pmc-release]
AID - ijms23094697 [pii]
AID - ijms-23-04697 [pii]
AID - 10.3390/ijms23094697 [doi]
PST - epublish
SO  - Int J Mol Sci. 2022 Apr 23;23(9):4697. doi: 10.3390/ijms23094697.