Ginsenoside Rk2 Protects against Ulcerative Colitis via Inactivating ERK/MEK Pathway by SIRT1

Abstract

Background: Chinese traditional medicine is widely used in the treatment of ulcerative colitis (UC). Ginsenoside Rk2 is a newly discovered dammarane triterpenoid saponin isolated from ginseng. Our study aimed to investigate the effects of Ginsenoside Rk2 on UC.Methods: Human clones of colorectal adenocarcinoma Caco-2 cells and human intestinal epithelial THP-1 cells were co-cultured to establish a UC model in vitro. Cell viability and apoptosis were analyzed by cell counting kit 8 (CCK-8) and flow cytometry assay, respectively. Inflammatory cytokines' mRNA levels were measured by real-time quantitative polymerase chain reaction (RT-qPCR). Western blot was applied to examine the protein expression of apoptosis-associated proteins and the activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MEK) pathway. Furthermore, fisetin, an ERK kinase activator, was used to carry out rescue experiment. SRT1720, an activator of SIRT1, was applied to increase the SIRT1 protein levels while SIRT1 inhibitor nicotinamide (NAM) exerted the opposite effect.Results: Ginsenoside Rk2 promoted cell viability, suppressed cell apoptosis, and reduced the release of pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, IL-10, and tumor necrosis factor-α (TNF-α) of HT-29 cells in UC model in a concentration-dependent manner. Meanwhile, the inhibitory effects of Ginsenoside Rk2 on the ERK/MEK pathway strengthened with the increase of concentration, and was verified by fisetin application. Furthermore, the upregulation of SIRT1 induced by Ginsenoside Rk2 prompted dephosphorylation of ERK and MEK to attenuate ERK/MEK pathway activation and reduced inflammatory progress, which was confirmed by SRT1720 as well as NAM.Conclusions: Ginsenoside Rk2 inactivated ERK/MEK pathway by regulating SIRT1 to restore the cellular function of human intestinal epithelial THP-1 cells. Therefore, Ginsenoside Rk2 may be effective in the treatment of UC.

Ginsenosides: an immunomodulator for the treatment of colorectal cancer

“…In addition, the abnormal immune response-mediated inflammatory response is a key factor in promoting the carcinogenesis of ulcerative colitis (UC) to CRC, and slowing down the inflammatory process prevents the carcinogenesis of UC ( Yang et al, 2013 ; Li et al, 2021 ). Ginsenoside Rk2 reduce the secretion of pro-inflammatory cytokines, such as Interleukin-1 β (IL-1β), Interleukin-6 (IL-6), Interleukin-10 (IL-10), TNF-α, in the vitro UC model established by co-culturing Caco-2 cell clones with THP-1 cells in a concentration-dependent manner, and slow down the inflammatory process by inhibiting the activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MEK) pathway ( Huang et al, 2022 ).…”

Manipulating Microbiota in Inflammatory Bowel Disease Treatment: Clinical and Natural Product Interventions Explored

“…Ginsenosides are representative glycosides for the treatment of IBD [ 129 ]. Ginsenoside RK2 restored cellular function in human intestinal epithelial THP-1 cells by inactivating the ERK/MEK pathway and reducing the release of inflammatory factors [ 139 ]. Ginsenoside Rg1 can condition intestinal flora by inducing macrophage polarization, which reduces the abundance of Bacteroides and Staphylococcus and increases the levels of flora-associated metabolites [ 130 ].…”

Ginsenoside Rk2, a dehydroprotopanaxadiol saponin, alleviates alcoholic liver disease via regulating NLRP3 and NLRP6 inflammasome signaling pathways in mice

“…Rk2 is a rare dehydroprotopanaxadiol saponin isolated from steamed ginseng samples [ 33 ]. Only one study reported the bioactivity of Rk2 with protective effects against ulcerative colitis in vitro [ 34 ]. Therefore, this study aims to investigate the probable protective effects of Rk2 against alcoholic liver injury in mice and further elucidate its underlying mechanisms targeting hepatic NLRP3 and intestinal NLRP6 inflammasome signaling pathways.…”