TY - JOUR
T1 - Ginsenoside Rd ameliorates colitis by inducing p62-driven mitophagy-mediated NLRP3 inflammasome inactivation in mice
AU - Liu, Chao
AU - Wang, Jianing
AU - Yang, Yan
AU - Liu, Xiuting
AU - Zhu, Yubing
AU - Zou, Jianjun
AU - Peng, Sishi
AU - Le, Thi Ha
AU - Chen, Yu
AU - Zhao, Shuli
AU - He, Bangshun
AU - Mi, Qiongyu
AU - Zhang, Xu
AU - Du, Qianming
N1 - Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/9
Y1 - 2018/9
N2 - Previous studies reported that Ginsenoside Rd (Rd) had anti-inflammatory and anti-cancer effects. However, the molecular mechanism underlying the inhibition effect of Rd on colitis in mice hasn't been clarified clearly. Here, in our study, we detected the effects of Rd on dextran sulfate sodium (DSS)-induced murine colitis, and found that oral administration of Rd dose-dependently alleviated DSS-induced body weight loss, colon length shortening and colonic pathological damage with lower myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activities and higher glutathione level. In addition, the production of pro-inflammatory cytokines (IL-1β TNF-a and IL-6) in both serum and colonic tissues were significantly down-regulated by Rd administration. The activation of NLRP3 inflammasome was also suppressed in Rd-treated group, resulting in reduced caspase-1 production and IL-1β secretion. In vitro, Rd remarkably inhibited NLRP3 inflammasome activation which was mostly dependent on the mitochondrial translocation of p62 and mitophagy. Importantly, Rd-driven inhibition of the NLRP3 inflammasome was significantly blocked by various autophagy inhibitors. Furthermore, upregulation of AMPK/ULK1 signaling pathway accounted for Rd-induced autophagy, which was also seen in vivo. In conclusion, our results demonstrated the function of Rd on the inhibition NLRP3 inflammasome and its potential application for the treatment of NLRP3-associated diseases.
AB - Previous studies reported that Ginsenoside Rd (Rd) had anti-inflammatory and anti-cancer effects. However, the molecular mechanism underlying the inhibition effect of Rd on colitis in mice hasn't been clarified clearly. Here, in our study, we detected the effects of Rd on dextran sulfate sodium (DSS)-induced murine colitis, and found that oral administration of Rd dose-dependently alleviated DSS-induced body weight loss, colon length shortening and colonic pathological damage with lower myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activities and higher glutathione level. In addition, the production of pro-inflammatory cytokines (IL-1β TNF-a and IL-6) in both serum and colonic tissues were significantly down-regulated by Rd administration. The activation of NLRP3 inflammasome was also suppressed in Rd-treated group, resulting in reduced caspase-1 production and IL-1β secretion. In vitro, Rd remarkably inhibited NLRP3 inflammasome activation which was mostly dependent on the mitochondrial translocation of p62 and mitophagy. Importantly, Rd-driven inhibition of the NLRP3 inflammasome was significantly blocked by various autophagy inhibitors. Furthermore, upregulation of AMPK/ULK1 signaling pathway accounted for Rd-induced autophagy, which was also seen in vivo. In conclusion, our results demonstrated the function of Rd on the inhibition NLRP3 inflammasome and its potential application for the treatment of NLRP3-associated diseases.
KW - Ginsenoside Rd
KW - Inflammation
KW - NLRP3 Inflammasome
KW - P62
KW - Ulcerative colitis
UR - http://www.scopus.com/inward/record.url?scp=85050378268&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2018.07.010
DO - 10.1016/j.bcp.2018.07.010
M3 - Article
C2 - 30012462
AN - SCOPUS:85050378268
SN - 0006-2952
VL - 155
SP - 366
EP - 379
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
ER -