| Cholestasis refers to a series of clinical syndromes caused by abnormal bile formation,secretion and excretion,as well as mechanical or functional disturbance of bile flow in extrahepatic and extrahepatic bile ducts,and then allowing bile components to enter the blood.Hepatobiliary diseases with cholestasis as the main manifestation and pathological changes in the liver caused by various reasons are collectively referred to as cholestatic liver disease.Cholestasis is a group of clinical syndromes that can involve the liver,lungs,intestines,and skin all over the body.It is difficult to treat and requires consideration of both specimens.Western medical treatment is not applicable to all patients,and additional hormones are required in case of severe ineffectiveness.If the treatment is still ineffective or is discontinued and recurrence of the disease occurs,there is no other way.Traditional Chinese medicine(TCM)has a long history of treating liver and gallbladder diseases,and it may play a therapeutic role through multiple channels and multiple targets.Cholestasis overlaps with “jaundice” in TCM theory.Excavating TCM classics,conducting basic research,and accumulating more practical data may provide new strategies for the treatment of cholestasis with TCM.From the perspective of TCM,Forsythia suspensa is slightly cold in nature,bitter in taste,and enters the heart,liver,and gallbladder meridians.It is a commonly used TCM in clinical practice.The dried fruit of the plant,Forsythiae Fructus(FF,named Lianqiao),could be classified into green Forsythiae Fructus(GF,called Qingqiao)and ripe Forsythiae Fructus(RF,called Laoqiao).Compared with its heat-clearing effect,there are relatively few studies on the detoxification effect of FF.The liver is the largest detoxification organ in the human body.Modern research on FF has investigated its liver protection effect.In essence,protecting the liver is to help the human body detoxify,which can also partially reflect the detoxification effect of FF.The ancient classic “Shang-Han Lun”(Treatise on Exogenous Febrile Diseases)records the “Ma-huang Lian-Qiao Chi-Xiao-Dou Tang”(Ephedra Forsythiae Adzuki-bean decoction)for treating jaundice.Until the Qing Dynasty,there was a prescription of“Lian-Qiao Chi-Dou decoction” established with reference to this prescription to treat jaundice.FF is used in the treatment of cholestasis.There are references for ancient medicine,but there is a lack of modern empirical research,and there is no conclusion whether to choose GF or RF.Based on this,this study intends to deeply excavate the ancient literature on the treatment of cholestasis by FF.Network pharmacology was used to predict the pathways and targets that FF may be used in the treatment of cholestatic liver diseases,and molecular docking was used to analyze the interaction between the components of FF and the key targets of cholestasis.On the basis of analyzing the differences in the chemical components of GF and RF,the study selected the pathological model of cholestasis,compared the differences in the application effects of GF and RF,and preliminarily explored the direct and indirect mechanisms and chemical basis of the differences between the two.It provides a reference for the treatment of cholestatic liver disease and the selection of GF and RF.The specific content is as follows.1.We focused on the ancient TCM literature such as “Huang-Di Nei-Jing”,“Shang-Han Lun”,“Wen-Bing Tiao-Bian”,“Yi-Zong Jin-Jian”,“Lin-Zheng Zhi-Nan Yi-An” and “Yi-Xue Zhong-Zhong-Can-Xi Lu”,to examine the medicinal value of FF,in order to clarify the origin and explore the history of its use in the treatment of cholestatic liver disease.The study clarified that the “Lian-Yao” used in Zhang Zhongjing’s original prescription is the root of “Lian-Qiao”,which is very crucial in the formula.It is now replaced by FF,which can play a medicinal role in the treatment of "jaundice".FF can clear heat and detoxify the body,reduce swelling and disperse nodules,dredge the liver and stimulate bile,and is used in the treatment of complex liver and biliary diseases.2.Predictive analysis of network pharmacology and molecular docking showed that FF can regulate the synthesis,secretion and transport of bile acid(BA).There is a good interaction between the active ingredients of FF and BA targets,and its anti-cholestasis effect may be related to this.An obstructive jaundice(OJ)model constructed by BDL surgery found that RF has better anti-cholestasis effect,which is different from that of GF.It is related to better regulation of the BA pathway with nuclear receptor(FXR),bile salt export pump(BSEP),bile acid synthase(CYP7A1),and Small Heterodimer Partner(SHP)as core targets.3.Using a non-targeted metabolomics strategy,it was found that the intestinal metabolic disorder of BDL rats was mainly manifested by a sharp decrease in BA-related intestinal metabolites,while intestinal bile acids were significantly restored after administration of RF.High-throughput sequencing results revealed dysbiosis of the intestinal flora in BDL rats.The relative abundance of intestinal bacteria closely associated with primary and secondary BA production decreased,and those intestinal bacteria that correlated with BA levels and cholestasis pathophysiochemical indicators were screened based on Spearman correlation analysis.These bacteria also showed consistent variation with disease severity among the groups.For key bacteria with narrow distribution,i.e.secondary BA producing bacteria represented by Lachnospiraceae,RF was able to increase their relative abundance.For the more commonly distributed primary BA producing bacteria,i.e.BSH bacteria,RF can respond by enhancing replaceable bacteria,allowing the BA metabolic flow disrupted by BDL to be restored,indirectly promoting BA metabolic detoxification,reducing liver damage and thus relieving biliary stasis in the organism.Unlike RF,GF had no obvious effect,but had a tendency to promote the proliferation of conditionally pathogenic bacteria,which is detrimental to disease treatment.The way that RF improves intestinal metabolic disorders by regulating intestinal microecology may explain the difference between it and GF in the face of cholestatic pressure.4.A comparative analysis of the chemical composition of the two species of FF showed that GF and RF,which originated from the same plant,contained similar chemical components,and the difference was mainly in the content of various components and the ratio between them.From GF to RF,the originally abundant glycosides are gradually hydrolyzed to produce small molecules of secondary metabolites and lower sugars.The former may be more active and more easily absorbed into the blood to exert better medicinal effects.Low-grade sugars,especially the higher proportion of beneficial sugars in RF,have anti-inflammatory,anti-endotoxic and oxidative stress-reducing effects.They can promote the growth of “good bacteria”,protect the intestinal tract and liver,and help detoxify and protect the liver.The glycosides in GF may need to be metabolized by normal intestinal bacteria under physiological conditions in order to exert their medicinal effects,which is difficult to achieve under the pathological conditions of cholestasis.Conversely,a higher proportion of harmful sugars in GF will also exacerbate intestinal disorders in experimental animals,which is not beneficial to disease improvement.This suggests that the different performance of GF and RF in the face of cholestasis is closely related to the quality and quantity of the active ingredients they contain.According to the results of this study,it is more reasonable to differentiate the use of the two in different scenarios.GF may be better at clearing the lung heat,while RF is more suitable for detoxification and liver protection. |
PDF Full Text Request