Abstract
Infantile cholestatic hepatopathy (ICH) is a clinical syndrome characterized by the accumulation of cytotoxic bile acids in infancy, leading to serious liver cirrhosis or liver failure. The aetiology of ICH is complicated and some of them is unknown. Regardless of the aetiology, the finial pathology of ICH is hepatocyte apoptosis caused by severe and persistent cholestasis. It is already known that activation of calcium-sensing receptor (CaSR) could lead to the apoptosis of cardiomyocytes. However, the mechanism by CaSR-mediated cholestasis-related hepatocyte apoptosis is not fully understood. Li-Dan-He-Ji (LDHJ), a Traditional Chinese Medicine prescription, was developed to treat ICH. Another aim of this study was to investigate the possible mechanisms of LDHJ in cholestasis-related hepatocyte apoptosis. Using the primary hepatocytes, we first investigated the molecular mechanism of CaSR-mediated hepatocyte apoptosis in cholestasis. Then we prepared LDHJ granules and used ultra-high-performance liquid chromatography to identify the predominant drugs; confirmed the stability of the main substances; and for cell experiments screened forsythoside-A, emodin and chlorogenic acid as the three active substances of LDHJ granules. In the young rats with ANIT-induced intrahepatic cholestasis and the primary hepatocytes with TCDC-induced cholestasis-related hepatocyte apoptosis, the levels of liver injury and cholestasis-related biomarkers, calcium-sensing receptor (CaSR), hepatocyte apoptosis, Bax/Bcl-2 ratio, Cytochrome-C, caspase-3, phosphorylated-c-Jun NH2-terminal kinase (p-JNK)/JNK, and p-P38/P38 were all increased, while the levels of p-extracellular signal-regulated kinase (p-ERK)/ERK were decreased. However, LDHJ granules and its three active substances effectively reversed these changes. Furthermore, the three active substances reduced the increases in the intracellular calcium concentration ([Ca2+]i) and ROS levels and attenuated the dissipation of the mitochondria membrane potential in the TCDC-induced primary hepatocytes. The opposite results were obtained from the TCDC-induced primary hepatocytes treated with an agonist of CaSR (GdCl3) plus forsythoside-A, emodin or chlorogenic acid. Based on the results from in vivo and in vitro studies, LDHJ functions as an antagonist of CaSR to regulate hepatocyte apoptosis in cholestasis through the mitochondrial pathway and mitogen-activated protein kinase pathway.
Highlights
Infantile cholestatic hepatopathy (ICH) refers to common and complex liver diseases characterized by cholestasis in hepatocytes and bile ducts in infancy (Morgan et al, 2013)
The increased levels of these markers were attenuated by LDHJ granules and ursodeoxycholic acid (UDCA) (P < 0.05, P < 0.01)
LDHJ was developed by the Department of Integrated Traditional Chinese and Western Medicine, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science and Technology based on 30 years of experience in treating “foetal jaundice disease”
Summary
Infantile cholestatic hepatopathy (ICH) refers to common and complex liver diseases characterized by cholestasis in hepatocytes and bile ducts in infancy (Morgan et al, 2013). A timely and accurate aetiological diagnosis and the initiation of appropriate interventions are difficult to achieve in the early stage of ICH because the aetiology of ICH is unknown in approximately 5.85% to 28.21% of patients (Fischler and Lamireau, 2014; Gottesman et al, 2015). In patients with a clear aetiology of ICH, the disease spectrum varies widely. The drugs used to treat ICH are very limited, and ursodeoxycholic acid (UDCA) is a drug approved by the U.S Food and Drug Administration (FDA) for the treatment of cholestasis. The curative effects of UDCA are far from satisfactory, the complete response of some patients is not good and the clinical application of UDCA in infants is narrow due to the limited indications for the disease spectrum (Lammers et al, 2014). The optimal strategy for treatments targeting ICH may be to protect hepatocytes and prevent cholestasis-related hepatocyte apoptosis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
