Notoginsenoside R1 (R1) is the main bioactive component in Panax notoginseng, an old herb medicine widely used in Asian countries in the treatment of microcirculatory diseases. However, little is known about the effect of R1 on inflammatory bowel disease (IBD). The present study demonstrated that R1 alleviated the severity of dextran sulfate sodium-induced colitis in mice by decreasing the activity of myeloperoxidase, the production of cytokines, the expression of proinflammatory genes, and the phosphorylation of IkB kinase, IkBa, and p65 in the colon. Further studies indicated that R1 dose-dependently activated human/mouse pregnane X receptor (PXR), a known target for decreasing inflammation in IBD, and upregulated the expression of genes involved in xenobiotic metabolism in colorectal cells and the colon. Ligand pocket-filling mutant (S247W/C284W or S247W/ C284W/S208W) of the human PXR abrogated the effect of R1 on PXR activation. Time-resolved fluorescence resonance energy transfer PXR competitive binding assay confirmed R1 (ligand) binding affinity. In addition, PXR overexpression inhibited nuclear factor-kB (NF-kB)-luciferase activity, which was potentiated by R1 treatment. PXR knockdown by small interfering RNA demonstrated the necessity of PXR in R1-induced upregulation of the expression of xenobiotic-metabolizing enzymes and downregulation of NF-kB activity. Finally, the anti-inflammatory effect of R1 was confirmed in trinitrobenzene sulfonic acid-induced colitis in mice. These findings suggest that R1 attenuates experimental IBD possibly via the activation of intestinal PXR signaling.
Background & Aims: It has recently been reported that thymosin beta-4 (Tβ4) has anti-fibrogenic effects in human hepatic stellate cells (HSCs) in vitro, but the mechanisms underlying these effects remain unclear. The aim of this study was to investigate the roles of Tβ4 in the proliferation, migration, and activation of HSCs. Methods: Enzyme-linked immunosorbent assays (ELISA), immunohistochemistry, and western blot assays were utilized to determine the expression levels of Tβ4 in serum, liver tissues, and LX-2 cells. Tβ4 was depleted in LX-2 cells using small interfering RNAs (siRNAs). Cell proliferation was analyzed using cell counting kit-8 (CCK-8) viability assays, and cell migration was investigated using wound-healing and transwell migration assays. Results: The expression of Tβ4 was significantly reduced during the progression of liver fibrosis. The depletion of Tβ4 significantly promoted the proliferation and migration of LX-2 cells via the activation of the PI3K/Akt signaling pathway. The pro-migratory and pro-proliferative effects of Tβ4 depletion in LX-2 cells can be counteracted by treatment with the Akt inhibitor MK-2206. In addition, Tβ4 depletion was also associated with the activation of HSCs via the enhanced expression of α-smooth muscle actin (α-SMA) and vimentin. Conclusions: Our results suggest that Tβ4 participates in liver fibrosis by inhibiting the migration, proliferation, and activation of HSCs and that Tβ4 may be an effective target in the treatment of liver fibrosis.
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