Journal
FRONTIERS IN PHARMACOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2021.611610
Keywords
cholestatic liver injury; toll-like receptor 4; nuclear factor kappa B; cytokines and chemokines; Yinchen and Gancao decoction
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Funding
- National Natural Science Foundation of China [81874364]
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine
- National Key New Drug Creation and Manufacturing Program
- Ministry of Science and Technology [2017ZX09304002]
- Shanghai three-year action plan to further accelerate the development of traditional Chinese medicine [ZY (20182020)-CCCX-2003-10]
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The study found that YGD with a high proportion of Gancao has a protective effect on ANIT-induced IC mice by inhibiting the inflammatory response. On the other hand, YGD with a high proportion of Yinchen may exacerbate the condition of IC mice, leading to liver cell damage and inflammation.
Cholestasis is a pathological state that leads to serious liver disease; however, therapeutic options remain limited. Yinchen and Gancao are often used in combination at different ratios in traditional Chinese formulae for the treatment of jaundice and cholestasis. In the present study, we investigated the effect of decoctions containing different ratios of Yinchen and Gancao (YGD) on alpha-naphthyl isothiocyanate (ANIT)-treated intrahepatic cholestasis (IC) in mice, and further explored the underlying mechanism. Treatment with 0:4 and 1:4 YGD significantly reduced plasma total bile acid (TBA), total bilirubin (TBIL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) activities; decreased unconjugated and conjugated bile acid levels; and improved hepatocyte necrosis and inflammatory cells recruitment to hepatic sinusoids. Moreover, the expression levels of Toll-like receptor 4 (TLR4), -1 beta (IL-1 beta), IL-6, alpha (TNF-alpha), C-C ligand 2 (CCL2), and C-X-C ligand 2 (CXCL2) in the liver were significantly reduced. However, treatment with 4:1 and 4:0 YGD increased plasma TBA, TBIL, AST, ALT, and ALP activities and aggravated liver cell injury and inflammation. Moreover, the mRNA expression of the bile salt export pump (BSEP) in the liver was significantly increased in mice treated with 4:0 YGD. The present study demonstrates that YGD containing a high proportion of Gancao, which inhibits the TLR4/NF-kappa B pathway and reduces the inflammatory response, had protective effects against ANIT-treated IC in mice. However, YGD containing a high proportion of Yinchen aggravated the ANIT-treated IC in mice, which may be related to upregulation of BSEP and ing bile acid regurgitation from damage cholangiocytes to liver in ANIT-treated IC mice.
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