1. Inhibiting effect of ginsenosides on inflammatory response in organ fibrosis
After an organ is injured, white blood cells accumulate at the site of the injury and attract various adhesion molecules, monocytes and macrophages, producing an excess of nitric oxide and inflammatory cytokines, and eventually forming an inflammatory response. An ongoing inflammatory response causes fibrosis to build up, making it more severe. Therefore, the alleviation of inflammation is one of the important ways to prevent organ fibrosis.
Chronic viral hepatitis and autoimmune hepatitis are important causes of chronic inflammatory diseases in the liver. Studies have shown that by eliminating pathogens (viruses) or inhibiting immune responses (lymphocyte proliferation and infiltration), inflammatory activities can be rapidly and continuously suppressed, and the fibrosis process can be stopped or even reversed. Ginsenosides have a good inhibitory effect on inflammation of the liver disease. Xiao et al. found that ginsenoside Rg1 can alleviate liver steatosis, reduce intracellular triacylglycerol content, ALT and AST levels, and inhibit the release of inflammatory cytokines. The effect may be related to the adenosine Monophosphate activated protein kinase (AMPK)/nuclear factor-κB (NF-κB) signaling pathway.
After lung tissue injury, activation of macrophages releases a large number of inflammatory cytokines, and the increase of inflammatory factors will further expand pulmonary fibrosis caused by lung tissue inflammation. Luo Wenjuan et al. found that ginsenoside Rb1 can significantly inhibit the release of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β and other inflammatory factors, thus alleviating lung inflammation. In addition, Zhu Zhiyang et al. found that ginsenoside Rb1 can inhibit PI3K/PROTEIN kinase B (PROTEIN kinase B, PI3K/PI3K) by inhibiting PI3K/PI3K. Akt signaling pathway protects lipopolysaccharid-induced cardiomyocyte inflammation.
Pure compound CK derived from ginsenoside is the main intestinal metabolite of ginsenoside. CK inhibits the production of pro-inflammatory cytokines and reduces the level of pro-inflammatory cytokines in renal tissues by down-regulating NF-κB signaling pathway. Analysis of kidney gene expressions of IL-1β, TNF-α, Monocyte chemoattractant protein-1 (McP-1) and IL-6 showed that CK inhibited the production of these pro-inflammatory cytokines in diseased kidneys. Nucleotide binding oligomerizationdomain-like receptor family Pyrin domain protein (NUCLEOtide binding oligomerizationDomain-like receptor family Pyrin domain protein) was significantly inhibited 3, NLRP3) activation of inflammatory body and monocyte infiltration, and down-regulation of renal NLRP3 inflammatory body activation-related signaling pathways. Hsu et al. found that NLRP3 inflammatory body was associated with renal inflammation and fibrosis in mice with unilateral ureteral occlusion. CK inhibited NLRP3 inflammatory body activation by significantly reducing NLRP3 and caspase-1 activity and IL-1β protein level in kidney and urine IL-1β level. The inhibition of NLRP3 inflammatory bodies in macrophages may be produced by inhibiting phosphorylated signal transduction erand Activator of transcription 3 (P-STAT3).
2. Effects of ginsenosides on EMT in organ fibrosis
EMT is the process by which epithelial cells lose cell polarity and cell adhesion, acquire migration and invasion properties, and become mesenchymal cells. EMT is first observed during embryogenesis and is critical for the development of tissues and organs. EMT and its inverse process play an important role in tumor progression, wound healing and organ fibrosis.
In the liver, epithelial cells can acquire fibroblast properties by EMT and participate in fibrogenesis. This makes EMT one of the potential targets for tissue anti-fibrosis strategies. Prevention of the development of EMT can control and even reverse liver fibrosis. In terms of improving liver fibrosis, ginsenoside Rg1 can inhibit EMT of HSC-T6 cells in vitro, and similar results have been obtained in vivo.
EMT is also a key step in the pathogenesis of pulmonary fibrosis. TGF-β1 signaling pathway, as the master switch of EMT, co-regulates emT-mediated pulmonary fibrosis with PI3K/Akt, Notch and Wnt signaling pathways. Zhou Ping et al. found that total saponins of Panax notoginseng can reduce the content of hydroxyproline acid and expression of TGF-β1 in lung tissues, and play a role in the treatment of pulmonary fibrosis by inhibiting EMT. It has been found that ginsenoside Rg3 can reduce the invasion of lung cancer by inhibiting EMT, and 20(R) -ginsenoside Rg3 can affect the EMT of colorectal cancer stem cells, thus changing their cancer characteristics.
Cardiac fibroblasts are traditionally believed to be derived from direct differentiation of embryonic mesenchymal cells. However, recent studies have found that fibroblasts can also be generated during the transformation from endothelial cells to stromal cells. Endothelial cells show reduced intercellular connectivity and reduced expression of platelet endothelial cell-adhesion molecule-1 (PECAM-1/ CD31) under pathological conditions, and stem cells also acquire the ability to proliferate and metastasized. And expressed mesenchymal cell markers such as α-smooth muscle actin (α-SMA). Ginsenoside Rb3 can reduce oxidative stress, repair endothelial damage and protect myocardial function. Yang et al. found that ginsenoside Rb3 affected EMT of cardiac microvascular endothelial cells after coxsackievirus B3 (CVB3) infection. The levels of Proline-rich protein Tyrosine kinase 2 protein (Pyk2), PI3K, Akt and CD31 in ginsenoside Rb3 group were higher than those in CVB3 group, while the α-SMA level was lower. The results showed that ginsenoside Rb3 inhibited EMT of CMV epithelial cells after CVB3 infection through the Pyk2-PI3K-Akt signaling pathway.
Shi et al. found that ginsenoside Rg1 inhibits EMT in diabetic nephropathy rat podocyte through activation of Glycogen Synthase kinase 3 beta (GSK3β) /β -catenin pathway. Impaired autophagy leads to podocyte damage and proteinuria, while resumed autophagy repairs damaged podocytes. Ginsenoside Rg1 reverses podocyte epithelial-interstitial transformation through autophagy, and significantly reduces renal fibrosis and podocyte epithelial-interstitial transformation in diabetic rats, suggesting its therapeutic potential for diabetic nephropathy and other glomerular diseases.
