Dendrobium officinale Polysaccharide Protected CCl4-Induced Liver Fibrosis Through Intestinal Homeostasis and the LPS-TLR4-NF-κB Signaling Pathway

Abstract

We explored the therapeutic effects of Dendrobium officinale polysaccharide (DOP) on CCl 4-induced liver fibrosis with respect to the intestinal hepatic axis using a rat model. Histopathological staining results showed that DOP alleviated extensive fibrous tissue proliferation in interstitium and lessened intestinal mucosal damage. Western blot and PCR results showed that DOP maintained intestinal balance by upregulating the expression of tight junction proteins such as occludin, claudin-1, ZO-1, and Bcl-2 proteins while downregulating the expression of Bax and caspase-3 proteins in the intestine. The transepithelial electrical resistance (TEER) value of the LPS-induced Caco-2 monolayer cell model was increased after DOP administration. These illustrated that DOP can protect the intestinal mucosal barrier function. DOP also inhibited activation of the LPS-TLR4-NF-κB signaling pathway to reduce the contents of inflammatory factors TGF-β and TNF-α, increased the expression of anti-inflammatory factor IL-10, and significantly decreased α-SMA and collagen I expression. These results indicated that DOP maintained intestinal homeostasis by enhancing tight junctions between intestinal cells and reducing apoptosis, thereby inhibiting activation of the LPS-TLR4-NF-κB signaling pathway to protect against liver fibrosis.

Antisense Tissue Factor Oligodeoxynucleotides Protected Diethyl Nitrosamine/Carbon Tetrachloride-Induced Liver Fibrosis Through Toll Like Receptor4-Tissue Factor-Protease Activated Receptor1 Pathway

“…Firstly, it was proclaimed that thrombin activates PAR1 on both HSCs and Kupffer cells with subsequent progression of fibrosis (Fiorucci et al, 2004;Rullier et al, 2008). Secondly, thrombin was reported as a critical mediator in LPS-induced liver damage (Rondina et al, 2011) and gut-derived-LPS through TLR4 activation was significantly involved in CCl4-induced liver fibrosis (Seki et al, 2007;Rondina et al, 2011;Wang et al, 2020). Accordingly, blockage of thrombin formation through inhibition of TF FIGURE 9 | Scatter plots of the correlation between TF and the assessed liver enzymes activities, inflammatory and fibrotic markers as well as between PAR1 and TLR4 expression.…”

Extracellular histones stimulate collagen expressionin vitroand promote liver fibrogenesis in a mouse modelviathe TLR4-MyD88 signaling pathway

“…TLR4 recognizes LPS from Gram-negative bacteria as well as histones released following cell death. TLR4 can activate nuclear factor-κB via MyD88[ 40 , 44 , 52 , 53 ]. The TLR4-MyD88 pathway has been demonstrated to promote liver fibrosis in a mouse BDL model by enhancing transforming growth factor (TGF)-β signaling[ 50 ].…”

Extracellular histones stimulate collagen expression and potentially promote liver fibrogenesis via TLR4-MyD88 signalling pathway

“…TLR4 recognizes LPS from Gram negative bacteria as well as histones released after cell death. TLR4 can activate NFkB via MyD88 [40, 44, 52, 53] . The TLR4/MyD88 pathway has been demonstrated to promote liver fibrosis in a mouse bile duct ligation model by enhancing TGF-β signalling [50] .…”