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Hepatic fibrosis （HF） is a pathological process of abnormal repair of liver tissue structure caused by chronic liver injury， and its pathogenesis has not been fully clarified. Related studies have shown that programmed cell death may be associated with the onset of HF， and traditional Chinese medicine （TCM） has a significant effect in regulating programmed cell death to intervene against HF. This article reviews the main mechanism of the influence of programmed cell death on HF and discusses the possible mechanism of TCM regulation of programmed cell death in improving HF， which provides new ideas for TCM prevention and treatment of HF.
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Hepatic encephalopathy is a clinical syndrome of central nervous system dysfunction caused by liver insufficiency.It severely affects the quality of life of patients and may lead to death.Accurate prediction of the risk of developing hepatic encephalopathy is crucial for early intervention and treatment.In order to identify the risk of hepatic encephalopathy in patients in advance,many studies have been devoted to efforts to develop tools and methods to identify the risk of hepatic encephalopathy as early as possible,so as to develop preventive and early management strategies.Most conventional hepatic encephalopathy risk prediction models currently assess the prob-ability of a patient developing hepatic encephalopathy by analysing factors such as clinical data and biochemical indicators,however,their accuracy,sensitivity and positive predictive value are not high.The application of artificial intelligence to clinical predictive modelling is a very hot and promising area,which can use large amounts of data and complex algorithms to improve the accuracy and efficiency of diagnosis and prognosis.To date,there have been few studies using AI techniques to predict hepatic encephalopathy.Therefore,this paper reviews the research progress of hepatic encephalopathy risk prediction models,and also discusses the prospect of AI application in hepatic encephalopathy risk prediction models.It also points out the challenges and future research directions of AI in HE risk prediction model research in order to promote the development and clinical application of hepatic encephalopathy risk prediction models.
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In recent years,the morbidity and mortality of hepatocellular carcinoma(HCC)have been increasing worldwide,and the treatment strategies for HCC are still insufficient,which highlights the importance of exploring the pathogenesis and progression of HCC.Transient receptor potential(TRP)pathway is an important non-selective cation pathway,which is closely related to inflammatory response and sensory conduction.At present,a number of studies have shown that TRP pathway is also involved in the occurrence and development of HCC,inducing HCC invasion and migration.However,the overall potential mechanism and possible signal transduction pathways of TRP pathway in HCC remain unclear.Therefore,this article discusses the abnormal expression of TRP pathway in HCC,and reviews the key biological events of TRP pathway involved in the formation and progression of HCC,such as chronic liver inflammation-fibrosis progression,HCC cell proliferation,migration,apoptosis and HCC stem cell generation,and looks forward to its application prospect in HCC treatment.The aim is to better un-derstand the significance of TRP pathway in HCC,help to find new therapeutic targets and effective drugs,and open up a new situation for future clinical treatment.
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The Wnt signaling pathway plays an important role in maintaining liver homeostasis and liver regeneration. In healthy livers， the Wnt signaling pathway is mostly inactive， but it is continuously overactivated during cell renewal or regeneration processes， as well as in certain pathological conditions， diseases， precancerous states， and cancers. Persistent liver cell injury often leads to chronic liver diseases such as liver fibrosis， liver cirrhosis， and liver cancer. This article summarizes the basic structural features of the Wnt signaling pathway and analyzes its important role in the pathological progression of various liver diseases， so as to provide new ideas for the prevention and treatment of liver diseases in clinical practice.
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Acute liver failure （ALF） is one of the most critical liver diseases in clinical practice and seriously affects the life and health of Chinese people. Due to its high morbidity and mortality rates， unclear pathogenesis， and limited treatment methods， ALF has become a major problem that needs to be solved urgently in the field of liver diseases. In recent years， more and more studies have shown that endoplasmic reticulum stress is a key biological process in the progression of ALF， and the IRE1α/TRAF2/JNK pathway， as a part of endoplasmic reticulum stress signaling， plays a role in amplifying inflammatory response， promoting hepatocyte apoptosis， and inhibiting liver regeneration ability during the progression of diseases. As a traditional treasure of China， traditional Chinese medicine has become a research hotspot in search for effective prevention and treatment drugs for ALF from monomers of Chinese herbs. This article elaborates on the mechanism of action of the IRE1α/TRAF2/JNK pathway in the progression of ALF and summarizes the potential value of several monomers of Chinese herbs in regulating this pathway， such as salidroside， Fructus Broussonetiae， Fructus Psoraleae+Schisandra chinensis， baicalein， genipin， kaempferol， resveratrol， sea buckthorn polysaccharide extract， and luteol， in order to provide a reference for further research and clinical practice of ALF.
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ObjectiveTo investigate the role and possible mechanism of action of rhubarb decoction （RD） retention enema in improving inflammatory damage of brain tissue in a rat model of mild hepatic encephalopathy （MHE）. MethodsA total of 60 male Sprague-Dawley rats were divided into blank group （CON group with 6 rats） and chronic liver cirrhosis modeling group with 54 rats using the complete randomization method. After 12 weeks， 40 rats with successful modeling which were confirmed to meet the requirements for MHE model by the Morris water maze test were randomly divided into model group （MOD group）， lactulose group （LT group）， low-dose RD group （RD1 group）， middle-dose RD group （RD2 group）， and high-dose RD group （RD3 group）， with 8 rats in each group. The rats in the CON group and the MOD group were given retention enema with 2 mL of normal saline once a day； the rats in the LT group were given retention enema with 2 mL of lactulose at a dose of 22.5% once a day； the rats in the RD1， RD2， and RD3 groups were given retention enema with 2 mL RD at a dose of 2.5， 5.0， and 7.5 g/kg， respectively， once a day. After 10 days of treatment， the Morris water maze test was performed to analyze the spatial learning and memory abilities of rats. The rats were analyzed from the following aspects： behavioral status； the serum levels of alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， interleukin-1β （IL-1β）， interleukin-6 （IL-6）， and tumor necrosis factor-α （TNF-α） and the level of blood ammonia； pathological changes of liver tissue and brain tissue； the mRNA and protein expression levels of phosphatidylinositol 3-kinase （PI3K）， protein kinase B （AKT）， and mammalian target of rapamycin （mTOR） in brain tissue. A one-way analysis of variance was used for comparison of continuous data between multiple groups， and the least significant difference t-test was used for further comparison between two groups. ResultsCompared with the MOD group， the RD1， RD2， and RD3 groups had a significantly shorter escape latency （all P<0.01）， significant reductions in the levels of ALT， AST， IL-1β， IL-6， TNF-α， and blood ammonia （all P<0.05）， significant alleviation of the degeneration， necrosis， and inflammation of hepatocytes and brain cells， and significant reductions in the mRNA and protein expression levels of PI3K， AKT， and mTOR in brain tissue （all P<0.05）， and the RD3 group had a better treatment outcome than the RD1 and RD2 groups. ConclusionRetention enema with RD can improve cognitive function and inflammatory damage of brain tissue in MHE rats， possibly by regulating the PI3K/AKT/mTOR signaling pathway.
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As a novel star molecule, gasdermin D (GSDMD) plays an important role in the amplification of immune inflammatory response and the process of pyroptosis. After being cleaved and activated by caspase-1, the N-terminal of GSDMD is rapidly released, which anchors on the cell membrane and forms pores, thereby leading to pyroptosis, accompanied by the release of a large amount of the strong proinflammatory factors IL-1β and IL-18. Acute/chronic liver inflammatory response and cell death are the common pathological features of liver diseases such as viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease, autoimmune liver disease, liver failure, and hepatocellular carcinoma. This article summarizes the basic structural characteristics of GSDMD and elaborates on its important role in the pathological progression of various liver diseases. In addition, it is proposed that prevention and treatment strategies with GSDMD as a potential therapeutic target can provide new ideas for further studies on the clinical prevention and treatment of liver diseases.
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Inflammation is closely associated with the development of cancer. Tumor-associated macrophages (TAM) actively participate in tumor-related inflammation and promote tumor growth and metastasis, while under certain conditions, TAM also show cytotoxicity and tumor killing activity and thus inhibit the progression of cancer. Crosstalk between TAM and neighboring cells is closely associated with the progression of hepatocellular carcinoma (HCC) and drug resistance during treatment. This article summarizes the role of macrophages in HCC and the crosstalk between macrophages and other cells, so as to provide new strategies for the clinical diagnosis and treatment of HCC.
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Liver failure is a common end-stage liver disease syndrome in clinical practice characterized by massive necrosis of hepatocytes leading to rapid liver failure, and it is currently believed that excessive inflammation and immune response are the core mechanisms of this disease. Endogenous lipid mediators are involved in the regulation of a variety of inflammatory processes, including initiation, maintenance, and regression, and eicosanoids and pro-decomposition lipid mediators, as well as their complex metabolic pathways and transduction signals, play a key role in the regulation of these processes. This article reviews the key role of endogenous lipid mediators in the pathophysiological mechanism of inflammation and immune dysfunction in liver failure and the potential significance and new therapeutic opportunities of lipid immune pathway in liver failure, in order to provide new ideas for the clinical diagnosis and treatment of liver failure.
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Glycolysis is an important biological event in the metabolic reprogramming process of primary liver cancer.Its is mainly regulated by key rate-limiting enzymes in the glycolysis pathway,including hexokinase(HK),pyruvate kinase(PK),phosphofructokinase(PFK),and lactate dehydrogenase(LDH).Moreover,it can also be regulated by multiple mechanisms such as glucose transporters(GLUTS),monocarboxylic acid transporters(MCT),PI3K/AKT/mTORC signaling pathway and hypoxia induction factor(HIF).More and more studies have proved that key glycolytic enzymes and regulatory factors play important roles in hepatocellular carcinoma(HCC)cell proliferation,invasion,metastasis,immune escape,and drug resistance.Currently,with the continuous in-depth research on the mechanism of glycolysis,clinical therapies targeting glycolysis has become a new therapeutic strategy for HCC treatment.This article aims to summarize the research progress of key glycolytic enzymes and regulatory factors in the occurrence and development of primary liver cancer,hoping to provide help for the prevention and treatment of liver cancer.
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ObjectiveTo systematically evaluate the efficacy and safety of integrated traditional Chinese and western medicine in the treatment of chronic liver failure（CLF）. MethodSeveral databases was searched from the establishment date of these databases to January， 2023， including China National Knowledge Infrastructure（CNKI）， WanFang Data Knowledge Service Platform（WanFang）， China Biomedical Literature Database（CBM）， VIP Chinese Science and Technology Journal Database（VIP）， Cochrane Library， Embase and PubMed. The randomized controlled trial（RCT） conforming to the treatment of CLF with integrated traditional Chinese and western medicine were screened and included， the control group was treated with basic western medicine， and the test group was treated with traditional Chinese medicine on the basis of western medicine. Then， the Cochrane risk bias assessment tool was used to evaluate the quality of the included literature， and Meta analysis was performed by RevMan 5.3 software. ResultEleven literatures with a total of 1 110 patients were included， and Meta analysis showed that the integrated traditional Chinese and western medicine was better than western medicine alone in the treatment of patients with CLF in improving the overall effective rate［relative risk（RR）=1.36， 95% confidence interval（CI） （1.27， 1.46）， P<0.000 01］， reducing the mortality［RR=0.35， 95% CI（0.23， 0.53）， P<0.000 01）］， reducing alanine aminotransferase（ALT） level［mean difference（MD）=-38.73， 95% CI（-54.59， -22.87）， P<0.000 01］， reducing the aspartate aminotransferase（AST） level［MD=-58.16， 95% CI（-83.45， -32.79）， P<0.000 01］ and reducing the total bilirubin（TBil） level［MD=-69.21， 95% CI（-94.15， -30.53）， P<0.000 01］， promoting serum albumin（ALB） level［MD=3.24， 95% CI（0.82， 5.66）， P=0.009］ and prothrombin activity（PTA） level［MD=5.44， 95% CI（3.38， 7.50）， P<0.000 01］， and improving the traditional Chinese medicine（TCM） symptom score［MD=-4.28， 95% CI（-8.39， -0.17）， P=0.04］. ConclusionThe treatment of CLF with integrated traditional Chinese and western medicine has good clinical efficacy and safety. However， due to the limitations of the quality and quantity of the included literature， the above conclusions still need to be verified by larger scale of high-quality RCT， which is worthy of further expansion of the study.
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ObjectiveTo investigate the therapeutic effect of rhubarb decoction （RD） retention enema on a rat model of minimal hepatic encephalopathy （MHE） and its mechanism of action based on bile acid （BA） metabolomics. MethodsA total of 55 male Sprague－Dawley rats were randomly divided into blank group （NC group with 10 rats）， hepatic encephalopathy group （HE group with 15 rats）， MHE group with 15 rats， and MHE+rhubarb decoction treatment group （MHEY group with 15 rats）. Intraperitoneal injection of carbon tetrachloride （CCl4） and thioacetamide （TAA） was performed to establish a rat model of MHE or HE， and the rats were sacrificed after 2 weeks of administration. The serum levels of aspartate aminotransferase （AST）， alanine aminotransferase （ALT）， alkaline phosphatase （ALP）， total bilirubin （TBil）， and total bile acid （TBA） and the concentration of blood ammonia were measured； the colonic contents were collected to measure pH value； liver and brain tissue samples were collected， and HE staining was used to observe the histopathological changes of the liver； the bile was collected， and liquid chromatography－mass spectrometry was used to perform BA－targeted metabolomics analysis. Continuous data were expressed as mean±standard deviation； a one－way analysis of variance was used for comparison between multiple groups， and the least significant difference t－test was used for further comparison between two groups. ResultsCompared with the NC group， the HE group and the MHE group had a significant increase in searching platform latency （after modelling and after administration） and a significant reduction in the number of platform crossings （all P<0.05）； compared with the MHE group， the MHEY group had a significant reduction in searching platform latency （after administration） and a significant increase in the number of platform crossings， and the HE group had a significant increase in searching platform latency and a significant reduction in the number of platform crossings （all P<0.05）. Compared with the NC group， the HE group and the MHE group had significant increases in AST， ALT， ALP， TBil， TBA， blood ammonia， and colon pH value （all P<0.05）； compared with the MHE group， the MHEY group had significant reductions in AST， ALT， ALP， TBil， TBA， blood ammonia， and colon pH value （all P<0.05）， and the HE group had significant increases in AST， ALT， ALP， TBil， TBA， blood ammonia， and colon pH value （all P<0.05）. The MHE group had significantly lower TBA， primary BA， and secondary BA than the NC group （all P<0.05）； compared with the MHE group， the HE group had significantly lower TBA and primary BA （all P<0.05）， and the MHEY group had significantly higher TBA and primary BA （all P<0.05）. Compared with the NC group， the MHE group had significant reductions in GCDCA， GUDCA， GHDCA， TCDCA， TUDCA， GLCA， and TLCA （all P<0.05） and significant increases in γ－MCA， THCA， 7－KDCA， AlloLCA， and α－MCA （all P<0.05）， and compared with the MHE group， the MHEY group had significant increases in THDCA， TMCA， TCDCA， TUDCA， and TLCA （all P<0.05）. ConclusionRD retention enema can improve liver injury and cognitive function in a rat model of MHE induced by CCl4 and TAA by regulating the enterohepatic circulation of BA， possibly by increasing the synthesis of taurine－binding BA.
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Liver failure is an acute and critical disease in the field of liver diseases， and liver failure in China is mainly caused by hepatitis B virus （HBV） infection. Professor Mao Dewen has made remarkable achievements in the prevention and treatment of HBV-related liver failure in basic and clinical research by using the detoxicating， stasis-resolving， and Yang-warming method， and in particular， with this method as the technical core， the new clinical prevention and treatment regimen for reconstructing immune balance in HBV-related liver failure lays a foundation for synergistic integrated traditional Chinese and Western medicine therapy for HBV-related liver failure， highlights the therapeutic advantages of traditional Chinese medicine， and makes breakthroughs in the technical and therapeutic bottlenecks of current clinical treatment of HBV-related liver failure， thereby attempting to reduce the incidence and mortality rates of liver failure.
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Sphingomyelinases (SMase) are the main enzymes that regulate the signaling pathway of sphingomyelin and the metabolism of related products, and they are involved in the key steps of the complex metabolic process of sphingomyelin. In recent years, many studies have shown that SMase is involved in the biological processes such as cell cycle arrest, cell migration, and inflammation and promotes the development and progression of hepatocellular carcinoma by regulating the apoptosis and proliferation of tumor stem cells. SMase has an important potential biological value in the development, progression, diagnosis, and treatment of hepatocellular carcinoma. This article summarizes the exact role of SMase in the development and progression of hepatocellular carcinoma, in order to provide new ideas and strategies for the clinical treatment of hepatocellular carcinoma and the development of new drugs.
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Glycolysis plays an important role in the development and progression of liver diseases and shows varying degrees of enhancement in different liver diseases, and it is closely associated with mitochondrial dysfunction (oxidative phosphorylation deficiency and reactive oxygen species production), which helps to fill energy production deficiency caused by impaired oxidative phosphorylation. Therefore, it might be possible to search for potential new therapies for liver diseases through targeted regulation of the key factors in aerobic glycolysis, such as hexokinase 2, pyruvate kinase M2, and other regulatory pathways. From the perspective of the association between glycolysis and liver diseases, this article elaborates on the therapeutic significance and potential value of glycolysis in liver diseases, in order to provide new ideas for the diagnosis and treatment of liver diseases.
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The cytochrome P450 (CYP) family is the most important drug-metabolizing enzyme in human body and is responsible for the metabolism of endogenous and exogenous compounds. As the main site of the expression of the CYP family, the liver is the metabolic center of drugs, and in recent years, the role of the CYP family in the liver has attracted wide attention from the scholars in China and globally. This article reviews the distribution differences of the CYP family from the aspects of anatomy, genetics, and genomics, changes in the expression of the CYP family in the pathological processes such as non-alcoholic fatty liver disease, alcoholic liver disease, liver fibrosis, liver cirrhosis, and hepatocellular carcinoma, and the effect of CYP family-mediated enzyme activity on the treatment effect of pharmacotherapy for metabolic-associated liver diseases, in order to provide important enlightenment for identifying key drug intervention targets in diseases and enhancing clinical efficacy and safety.
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Lysyl oxidase (LOX) family is a group of copper-containing amine oxidases composed of LOX and LOX-like proteins (LOXL1, LOXL2, LOXL3, and LOXL4). It is overexpressed in tumor tissue and promotes tumor metastasis through covalent cross-linking of extracellular matrix, with the functions of cell growth control, tumor inhibition, senescence, and chemotaxis. In recent years, more and more evidence has shown that LOX family members play a key role in the pathogenesis of hepatocellular carcinoma (HCC), suggesting that they have great potential as therapeutic targets. This article reviews the role of LOX family members in the development and progression of HCC and the intervention effect of traditional Chinese medicine extracts on HCC by regulating LOX family, in order to provide a reference for further research on the prevention and treatment of HCC.
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OBJECTIVE To study the protective effect and mechanism of Shiyifang medicinal wine （SYF） on knee osteoarthritis（KOA）of rabbit induced by papain . METHODS Thirty-five rabbits were randomly divided into blank group ，model group，positive group （Diclofenac diethylamine emulsion 200 mg/kg），SYF high -dose group （386 mg/kg）and SYF low -dose group（97 mg/kg），with 7 rabbits in each group （all had 4 males and 3 females）. Except for the blank group ，the other groups ’ rabbits were injected 0.5 mL papain mixture （containing 2% papain and 0.03 mol/L L -cysteine）into the right knee cavity on day 1， 4 and 7，to replicate KOA model . Blank group was given constant volume of normal saline . From the 15th day ，drugs were applied to right hind knee joints of rabbits in each group ，twice a day for 20 days. At the same time ，the diameter of right knee joints of rabbits was measured by vernier calipers at day 0，8，14 and 35 to calculate swelling degree . After the experiment ，the levels of IL-1β，TNF-α and PGE 2 in synovial tissue were determined by enzyme -linked immunosorbent assay . Hematoxylin-eosin（HE） staining was used to prepare the sections of synovial tissue ，and the pathological changes were observed . The relative mRNA expressions of TLR 4，MyD88 and NF - кB p 65 in the TLR 4/MyD88/NF- кB signaling pathway were detected by real -time quantitative polymerase chain reaction . The relative protein expressions of TLR 4，MyD88，NF-кB p 65 and p -NF-кB p 65 were detect by Western blot . RESULTS Compared with blank group，the degree of knee swelling could be increased in model group ，the pathological damage of synovial tissue was more serious ，and the levels of IL -1β，TNF-α and PGE 2 were increased significantly in synovial tissue （P＜0.05）. The relative expression levels of TLR 4，MyD88，NF-кB p 65 mRNAs and TLR 4，MyD88，p-NF-кB p 65 proteins were significantly increased（P＜0.05）. Compared with model group ，swelling degree of right hind knee and the pathological injury degree of synovial tissue were significantly improved in each treatment group ，while the levels of IL -1β，TNF-α and PGE 2 in synovial tissue were significantly decreased （P＜0.05）. The relative mRNA expressions of TLR 4，MyD88 and NF -кB p 65 and relative protein expressions of TLR 4，MyD88（except for SYF low -dose group ）and p -NF-кB p 65 were all significantly decreased （P＜0.05）. CONCLUSIONS SYF shows protective effect on KOA induced by papain ，the mechanism of which is associated with decreasing the levels of IL -1β，TNF-α and PGE 2 and down -regulating TLR 4/MyD88/NF-кB signaling pathway .
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Objective To investigate the mechanism of action of Xiaochaihu decoction in the treatment of hepatitis B based on network pharmacology. Methods The TCMSP database was used to obtain the main chemical components and action targets of the seven traditional Chinese medicines in Xiaochaihu decoction; the GeneCards and OMIM databases were used to obtain the targets associated with hepatitis B; the STRING online platform was used to construct a PPI network of potential targets, and R language was used to perform gene ontology (GO) functional enrichment analysis and KEGG pathway analysis; Cytoscape 3.7.2 was used to construct an "active component-core target" network and perform a topology analysis of this network; AutoDock vina and related software were used to perform molecular docking and visualized analysis of the active components with high value and the core targets in the network. Results A total of 193 main chemical components (including quercetin, kaempferol, wogonin, and naringenin) and 247 related targets were screened out, among which the key targets included RELA, MAPK1, TP53, ESR1, EGFR, and AKT1. A total of 2612 enrichment items were obtained by GO functional enrichment analysis, which were mainly involved in regulating the biological processes such as cell response to chemical stress, response to drugs, oxidative stress response, and lipopolysaccharide response. A total of 174 pathways were obtained by the KEGG pathway analysis, mainly involving hepatitis B, PI3K-AKT signaling pathway, and MAPK signaling pathway. Molecular docking results showed that the main active components had strong binding force to core targets, and the protein crystal complex had a stable conformation. Conclusion This study preliminarily shows that Xiaochaihu decoction exerts a therapeutic effect on hepatitis B through multiple components, targets, and pathways.
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Absent in melanoma 2 (AIM2) is a cytoplasmic double-stranded DNA (dsDNA) sensing protein that can recognize the dsDNA released during cell disturbance and pathogen invasion and trigger the activation of inflammasome cascade. Activation of inflammasomes leads to the maturation and release of inflammatory cytokines (interleukin-1β and interleukin-18), induces pyroptosis, and initiate innate immune response. Among these inflammasomes, AIM2 and its mechanism of action and clinical significance in liver diseases has become a research hotspot at present. This article summarizes and discusses the importance of AIM2 in the pathogenesis of various liver diseases including nonalcoholic fatty liver disease, hepatitis B virus infection, liver fibrosis, liver cirrhosis, and hepatocellular carcinoma, so as to provide new ideas and a reference for clinical treatment.