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Liver fibrosis is the inevitable course for the progression of chronic hepatitis B to liver cirrhosis and is also the most important risk factor for hepatocarcinogenesis, and therefore, blocking and reversing liver fibrosis is an important strategy to effectively reduce the development of chronic hepatitis B cirrhosis and liver cancer. There are currently no effective drugs and measures for the treatment of liver fibrosis in Western medicine, and traditional Chinese medicine (TCM) has unique advantages in the treatment of liver fibrosis; however, due to a lack of strict and standardized clinical research, there is still no high-quality evidence for support from the aspect of evidence-based medicine (EBM). With subsidies from National Science and Technology Major Project in the 12th and 13th five-year plans, the authors conducted a multicenter, randomized, double-blind, placebo-controlled clinical trial on compound Biejia Ruangan tablets combined with entecavir in blocking and reversing chronic hepatitis B liver fibrosis. With liver biopsy as the gold standard, 1000 patients were enrolled to confirm the efficacy of compound Biejia Ruangan tablets combined with entecavir in blocking and reversing liver fibrosis and cirrhosis, and this study has become the first clinical trial investigating the anti-liver fibrosis effect of TCM supported by high-quality EBM evidence, bringing great hope to patients with chronic liver diseases and helping TCM move towards the world. This article introduces these research findings and reviews the current status and challenges of TCM in blocking and reversing liver fibrosis.
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ObjectiveTo explore and establish the liver injury risk prediction model of indirect toxicity of Chinese medicinals under the condition of compound formulas， and provide new ideas and methods for the study of evaluation of liver injury of Chinese medicinals based on indirect toxicity. MethodsTaking Buguzhi （Fructus Psoraleae） pre-parations as model drug， the combined Chinese medicinals with Buguzhi （Fructus Psoraleae） of high frequency are screened out， and their components and action targets were obtained through TCMSP， TCMIP and PharmMapper databases. The association strength value and risk value of Chinese medicinals that acted on the nuclear factor κB （NF-κB） pathway were analyzed. For those having greater values than the median association strength value and risk value were regarded as indirect Chinese medicinals of liver injury risk. In this way， a prediction model of liver injury risk of Chinese medicinals was constructed based on immune activation-related indirect liver injury process （taking NF-κB pathway as an example）. And verification of the prediction model was performed using Heshouwu （Radix Polygoni Multiflori） preparations. ResultsThe prediction model of liver injury risk based on important immunoactivated pathway （taking NF-κB pathway as an example） found that Yinyanghuo （Herba Epimedii） （association strength value = 0.18， risk value = 0.25） was a Chinese medicinal with potential risk of indirect liver injury within Buguzhi （Fructus Psoraleae） prepartions， which may increase the risk of liver injury by positively regulating Bruton's tyrosine kinase （Btk） and protein kinase C theta （PKCθ） on NF-κB pathway. Further verification of prediction model by Heshouwu （Radix Polygoni Multiflori） preparations showed that Buguzhi （Fructus Psoraleae） （association strength value = 0.25， risk value = 0.33） and Tusizi （Semen Cuscutae） （Semen Cuscutae， association strength value = 0.34， risk value = 0.33） may increase the liver injury risk of Heshouzu. ConclusionThe liver injury risk prediction model of indirect toxicity of Chinese medicinals has been constructed in this study， providing metho-dological reference for the identification of Chinese medicinals of indirect liver injury risk under the condition of compound formulas.
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In recent years, the potential hepatotoxicity of green tea extract (GTE) has attracted more and more attention. With reference to the current studies on liver injury caused by GTE and the latest drug hepatotoxicity classification, this article systematically elaborates on the objectivity and causal mechanisms of liver injury caused by GTE. Based on the main risk factors for liver injury caused by GTE, this article also proposes recommendations for safe and rational use of such products, so as to provide valuable insights for in-depth research on the mechanism of liver injury caused by GTE and risk prevention and control, and meanwhile, it also provides an important reference for the therapeutic use of GTE to improve health conditions.
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Objective: Although some studies have linked Asari Radix et Rhizoma (Asari Radix) administration to hepatocellular carcinoma (HCC), few studies have examined the association between the development of HCC and use of Asari Radix among patients in mainland China. This study aimed to evaluate the real-world association between Asari Radix and HCC in patients to strengthen the understanding of Asari Radix safety. Methods: A retrospective cohort study among hepatitis B virus (HBV)-monoinfected patients and non-HBV-monoinfected patients were performed. Patients over 18 years of age were eligible for inclusion. Prescription records of inpatients and outpatients were inquired to distinguish Asari Radix users and nonusers. The risk of developing HCC among Asari Radix users and nonusers in the HBV cohort and the non-HBV cohort was analyzed. Results: There were 49 500 HBV and 133 148 non-HBV patients involved in the two cohorts. Among HBV patients (2 901 users; 46 599 nonusers), the prevalence of HCC in Asari Radix users was lower than that in nonusers (145.70 vs. 265.43 per 10
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Objective To investigate the clinical applicability and different characteristics of three commonly used diagnostic methods for drug-induced liver injury from the two aspects of liver injury induced by Western medicine and liver injury induced by traditional Chinese medicine. Methods A prospective cohort study was performed for 289 hospitalized patients with acute drug-induced liver injury who were admitted to The Fifth Medical Center of Chinese PLA General Hospital from January 2015 to December 2020 and did not receive integrated traditional Chinese and Western medicine therapy, among whom 187 patients had herb-induced liver injury and 102 had Western medicine-induced liver injury. The 289 patients were diagnosed by the integrated evidence chain (IEC), Roussel Uclaf Causality Assessment Method (RUCAM), and the Structured Expert Opinion Process (SEOP) method, and related data at acute onset were collected, including general information, latency period, detailed medication, and laboratory markers such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase, alkaline phosphatase, and total bilirubin. A statistical analysis was performed to investigate the consistency between IEC, RUCAM, and SEOP in the diagnosis of Western medicine-induced liver injury and herb-induced liver injury and their own applicability. The Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data; the chi-square was used for comparison of categorical data. Results The hepatocellular type was the main type of clinical liver injury in both Western medicine-induced liver injury and herb-induced liver injury, accounting for 81.4% and 74.3%, respectively, and laboratory examination showed higher levels of ALT and AST. Western medicine-induced liver injury cases were diagnosed by IEC, RUCAM, and SEOP, with a clinical diagnosis rate of 65.7%, 100%, and 63.7%, respectively, and the constituent ratio of Western medicine-induced liver injury was 23.2%, 35.3%, and 22.5%, respectively. Herb-induced liver injury cases were diagnosed by these three methods, with a clinical diagnosis rate of 47.6%, 100%, and 29.9%, respectively, and the constituent ratio of herb-induced liver injury was 30.8%, 64.7%, and 19.4%, respectively. The consistency test of the three diagnostic methods showed that in the diagnosis of Western medicine-induced liver injury cases, there was good consistency between IEC and SEOP (Kappa=0.785, P 0.05) and between RUCAM and SEOP (Kappa=0.117, P > 0.05); in the diagnosis of herb-induced liver injury cases, there was poor consistency between RUCAM and SEOP (Kappa=0.066, P > 0.05), while there was good consistency between RUCAM and IEC (Kappa=0.026, P < 0.05) and between IEC and SEOP (Kappa=0.437, P < 0.05). Conclusion The IEC method shows good applicability for both Western medicine-induced liver injury and herb-induced liver injury, and there is good consistency between IEC and SEOP in the diagnosis of Western medicine-induced liver injury cases, while there is a relatively low level of consistency between IEC and SEOP in the diagnosis of herb-induced liver injury. There is poor consistency between RUCAM and the other two methods. In the clinical diagnosis of Western medicine-induced liver injury, IEC, RUCAM, and SEOP should be used in combination to accurately judge the causal relationship between drugs and liver injury.
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Objective To investigate the potential medication risk by identifying and analyzing the features of liver-related adverse drug reaction (ADR) in pregnant women. Methods A retrospective study was performed for the reports on liver-related ADR in pregnant women from January 1, 2012 to December 31, 2016 in HILI Cloud (hilicloud.net). Main clinical features and medication rules were analyzed, and reporting odds ratio ( ROR ) was used to analyze the relative risk of related drugs. Results Methotrexate, mifepristone, and ritodrine were the high-frequency drugs reported for liver-related ADR in pregnant women and were mainly used for termination of ectopic pregnancy and treatment of hydatidiform mole. The relative risk analysis of liver-related ADR showed that in pregnant women, the use of methotrexate ( ROR =37.52, 95% confidence interval [ CI ]=31.35-44.89), progesterone ( ROR =7.33, 95% CI : 2.75-19.59), and dydrogesterone ( ROR =6.58, 95% CI : 2.20-19.69) was strongly associated with the risk of liver injury, and the association of methotrexate with the risk of liver injury in pregnant women was significantly stronger than that in non-pregnant women ( ROR =1.71, 95% CI : 1.47-4.36). Conclusion The potential risk of liver injury should be taken seriously in pregnant women using the drugs such as methotrexate and progesterone, so as to avoid serious adverse reactions.
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Inflammasomes play an important role in the innate immunity of the liver; however, the excessive activation of inflammasomes can lead to liver inflammation and injury. The mechanism of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome-mediated liver injury has been extensively studied. Related studies have shown that the development of various liver diseases may be associated with the excessive activation of inflammasomes, especially NLRP3 inflammasome. This article reviews inflammasomes, the activation mechanism of NLRP3 inflammasome, and the role of NLRP3 inflammasome in different liver diseases, so as to provide a reference for the treatment targets of liver diseases from the perspective of NLRP3 inflammasome.
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Objective To establish the intelligent identification method for the big data of liver injury-related adverse drug reaction (ADR) based on the construction of text database. Methods With the keywords including "drug-induced liver injury" and "abnormal liver function" and a search time of January 1, 2012 to December 31, 2016, 5% (4152 cases) of the case reports of liver injury-related ADR were retrieved and extracted from the China Adverse Drug Reaction Monitoring System, and then based on clinical reevaluation by physicians, these cases were classified into "negative cases", "suspected cases", and "confirmed cases". On this basis, key elements (including ADR name, biochemical parameter, and clinical symptoms) were identified. An intelligent identification method for liver injury-related ADR was established based on the correlation analysis between key elements and clinical reevaluation and the receiver operating characteristic (ROC) curve for determining cut-off values, and the method of cross validation was used to evaluate the performance of this intelligent identification method. Results The formula for the evaluation and identification of liver injury-related ADR was as follows: total score (M)=symptom score+index score+ADR name score. This formula showed the best discriminatory ability to distinguish "negative case" from "suspected case" or "confirmed case" at M=5 (area under the ROC curve [AUC]=0.97), with a sensitivity of 99.57% and a specificity of 84.61%, and it showed the best discriminatory ability to distinguish "confirmed case" from "suspected case" or "negative case" at M=12 (AUC=0.938), with a sensitivity of 87.93% and a specificity of 85.98%. Conclusion This method provides reference and basis for intelligent identification and evaluation of big data on liver injury-related ADR and is expected to effectively reduce the burden of manual processing of ADR big data and provide effective tools and methodological demonstration for early risk signal identification and warning of liver injury-related ADR.
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Aristolochic acids (AAs) have long been considered as a potent carcinogen due to its nephrotoxicity. Aristolochic acid I (AAI) reacts with DNA to form covalent aristolactam (AL)-DNA adducts, leading to subsequent A to T transversion mutation, commonly referred as AA mutational signature. Previous research inferred that AAs were widely implicated in liver cancer throughout Asia. In this study, we explored whether AAs exposure was the main cause of liver cancer in the context of HBV infection in mainland China. Totally 1256 liver cancer samples were randomly retrieved from 3 medical centers and a refined bioanalytical method was used to detect AAI-DNA adducts. 5.10% of these samples could be identified as AAI positive exposure. Whole genome sequencing suggested 8.41% of 107 liver cancer patients exhibited the dominant AA mutational signature, indicating a relatively low overall AAI exposure rate. In animal models, long-term administration of AAI barely increased liver tumorigenesis in adult mice, opposite from its tumor-inducing role when subjected to infant mice. Furthermore, AAI induced dose-dependent accumulation of AA-DNA adduct in target organs in adult mice, with the most detected in kidney instead of liver. Taken together, our data indicate that AA exposure was not the major threat of liver cancer in adulthood.
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Psoraleae Fructus (PF) is a well-known traditional herbal medicine in China, and it is widely used for osteoporosis, vitiligo, and other diseases in clinical settings. However, liver injury caused by PF and its preparations has been frequently reported in recent years. Our previous studies have demonstrated that PF could cause idiosyncratic drug-induced liver injury (IDILI), but the mechanism underlying its hepatotoxicity remains unclear. This paper reports that bavachin isolated from PF enhances the specific stimuli-induced activation of the NLRP3 inflammasome and leads to hepatotoxicity. Bavachin boosts the secretion of IL-1β and caspase-1 caused by ATP or nigericin but not those induced by poly(I:C), monosodium urate crystal, or intracellular lipopolysaccharide. Bavachin does not affect AIM2 or NLRC4 inflammasome activation. Mechanistically, bavachin specifically increases the production of nigericin-induced mitochondrial reactive oxygen species among the most important upstream events in the activation of the NLRP3 inflammasome. Bavachin increases the levels of aspartate transaminase and alanine aminotransferase in serum and hepatocyte injury accompanied by the secretion of IL-1β via a mouse model of lipopolysaccharide-mediated susceptibility to IDILI. These results suggest that bavachin specifically enhances the ATP- or nigericin-induced activation of the NLRP3 inflammasome. Bavachin also potentially contributes to PF-induced idiosyncratic hepatotoxicity. Moreover, bavachin and PF should be evaded among patients with diseases linked to the ATP- or nigericin-mediated activation of the NLRP3 inflammasome, which may be a dangerous factor for liver injury.
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Animals , Humans , Mice , Adenosine Triphosphate , Chemical and Drug Induced Liver Injury/etiology , Flavonoids , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , NigericinABSTRACT
[This corrects the article DOI: 10.1016/j.apsb.2019.02.003.].
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Aberrant activation of NLRP3 inflammasome has been implicated in the pathogenesis of diverse inflammation-related diseases, and pharmacological molecules targeting NLRP3 inflammasome are of considerable value to identifying potential therapeutic interventions. Cardamonin (CDN), the major active ingredient of the traditional Chinese medicinal herb , has exerted an excellent anti-inflammatory activity, but the mechanism underlying this role is not fully understood. Here, we show that CDN blocks canonical and noncanonical NLRP3 inflammasome activation triggered by multiple stimuli. Moreover, the suppression of CDN on inflammasome activation is specific to NLRP3, not to NLRC4 or AIM2 inflammasome. Besides, the inhibitory effect is not dependent on the expression of NF-B-mediated inflammasome precursor proteins. We also demonstrate that CDN suppresses the NLRP3 inflammasome through blocking ASC oligomerization and speckle formation in a dose-dependent manner. Importantly, CDN improves the survival of mice suffering from lethal septic shock and attenuates IL-1 production induced by LPS , which is shown to be NLRP3 dependent. In conclusion, our results identify CDN as a broad-spectrum and specific inhibitor of NLRP3 inflammasome and a candidate therapeutic drug for treating NLRP3 inflammasome-driven diseases.
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Aim To explore the protective effects and underlying mechanisms of Liu weiwuling Tablets (LW-WL)in concanavalin A (ConA)induced acute immu-nological liver injury in mice.Methods Mice were randomly divided into control,model,Bicyclol,LW-WL low dose (8 g·kg-1 )and LWWL high dose (16 g ·kg-1 )group.The medicattion was performed once daily for seven consecutive days,then the model of im-munological liver injury was prepared by intravenous injection of ConA (15mg·kg-1)in the tail of mice in each group except for the control group one hour after the last treatment.The pathological changes of liver tissues of mice were evaluated by HE staining with, and the levels of alanine amino transferase (ALT),as-partate aminotransferase (AST),and total bilirubin (TBIL)in serum were analyzed by colorimetric meth-od;the level of interleukin 12 (IL-12 ),interferon-γ(IFN-γ),tumor necrosis factor-α(TNF-α),interleu-kin 4 (IL-4)and interleukin 10 (IL-10)in liver was measured by real-time quantitative polymerase chain reaction (RT-qPCR);the changes of Th1 (IFN-γ) and Th2 (IL-4)cells were observed by flow cytometric (FCM)analysis;the expression of Th1/Th2 transcrip-tion factor T-bet/GATA-3 in liver tissue was detected by Western blot.Results Compared with normal con-trol group,the serum ALT,AST and TBIL were signif-icantly increased in model group, the pathological damage of the liver tissue was severe,and the necrosis and apoptosis of hepatic cells were large, which showed that the model was successful .Compared with model group,both low and high dose of LWWL could significantly reduce ALT,AST,TBIL levels in serum induced by ConA;Th1 cells in the spleen decreased, while Th2 cells increased;the expressions of IL-12, IFN-γand TNF-αmRNA were significantly inhibited with IL-4 and IL-10 mRNA expression elevated in mouse liver tissue;the expression of GATA-3 protein was up-regulated,T-bet protein expression showing no significant changes.Conclusion LWWL could regu-late Th1/Th2 balance,thus inhibiting the acute immu-nity hepatic injury induced by ConA.
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Although oxymatrine (OMT) has been shown to directly inhibit the replication of hepatitis B virus (HBV), limited research has been done with this drug. In the present study, the antiviral effect of OMT was investigated in an immunocompetent mouse model of chronic HBV infection. The infection was achieved by tail vein injection of a large volume of DNA solution. OMT (2.2, 6.7 and 20 mg/kg) was administered by daily intraperitoneal injection for 6 weeks. The efficacy of OMT was evaluated by the levels of HBV DNA, hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) and hepatitis B core antigen (HBcAg). The immunoregulatory activity of OMT was evaluated by serum ELISA and flow cytometry. Results shows that OMT at 20 mg/kg inhibited HBV replication, and it was more efficient than entecavir (ETV) in the elimination of serum HBsAg and intrahepatic HBcAg. In addition, OMT accelerated the production of interferon-(IFN-) in a dose-dependent manner in CD4T cells. Our findings demonstrate the beneficial effects of OMT on the enhancement of immunological function and in the control of HBV antigens. The findings suggest this drug to be a good antiviral therapeutic candidate for the treatment of HBV infection.
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Decoction is one of the most commonly used dosage forms of traditional Chinese medicine. The stability of chemical constituents in decoction is closely related to the clinical efficacy and safety. There were few reports about the influence of metal ions in the stability of chemical constituents in traditional Chinese medicine. However, there is no evidence that metal ions in decoction water need to be controlled. In this study, 2,3,5,4'-tetrahydroxy stilbene-2-O-β-D-glucoside (THSG), one of the main constituents in Polygoni Multiflori Radix was studied. Ordinary tap water, deionized water, and water containing different metal ions were used to investigate and compare the influence on THSG. The results showed that after storage in a dark place at the room temperature for 10 days, the degradation of THSG was 7% in deionized water, while undetectable in tap water. The content of THSG could be decreased by different kinds of metal ions, and the effect was concentration-dependent. Moreover, Fe3+ and Fe2+ showed the greatest influence at the same concentration; and our study has shown that THSG decreased more than 98% in Fe and Fe2+ solutions at 500 ppm concentration. In the same time we found out p-hydroxybenzaldehyde (molecular weight: 122.036 7) and 2,3,5-trihydroxybenzaldehyde-2-O-glycoside (molecular weight: 316.079 4) were the main degradation products of THSG in tap water and water containing Cu2+, Ca2+, Zn2+, Mg2+ and Al3+. The product of THSG dimer with a water molecule was found in water containing Fe3+ and Fe2+. The above results showed that the metal ions in water could significantly influence the stability of THSG in water, indicating that the clinical efficacy and safety of decoction would be affected if the metal ions in water were not under control. It's suggested that deionized water should be used in the preparation of decoction containing Polygoni Multiflori Radix in the clinic to avoid degradation of THSG. Meanwhile, decoction prepared by tap water should be taken by patients in a short time. Our investigation provides important information and reference about the influence of metal ions on the stability of decoctions in other traditional Chinese medicine that have unstable groups such as hydroxyls and unsaturated bonds, etc.
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The dosage-efficacy/toxicity relationship of the 50% alcohol extracts of Polygonum multiflorum was comparatively investigated on either normal or CCl4-induced chronic liver injury rats, by determining the general condition, serum biochemical indices and liver histopathology, coupled with the factor analysis. The dosages were 10 and 20 g raw materials per kg body weight. Compared with the normal control group, the normal high dose group showed significant increases of the serum alanine transaminase (ALT), total bilirubin (TBIL), high mobility group box 1 (HMGB-1) and interleukin-1β (IL-1β) (P < 0.05 or P < 0.01), as well the frequent incidences of inflammatory cell infiltration, hepatic sinus enlargement and fiber stripes formation in histopathological sections. Compared with the model control group, the model low dose group showed significant declines of serum ALT, aspartate transaminase (AST) and total bile acid (TBA) (P < 0.05), as well the alleviation of vacuoles of hepatocytes, but no amelioration of the inflammatory cell infiltration and fibrous tissue hyperplasia; moreover, the model high dose group showed significant degeneration declines of serum HMGB-1, tumor necrosis factor-α (TNF-α) and IL-1β (P < 0.05, P < 0.01), as well the evident alleviation of vacuoles degeneration of hepatocytes, inflammatory cells infiltration and fibrosis degree. The factor analysis showed that the low dosage treatment had almost neither injuring effect on the normal rats nor protective effect on the model rats; while the high dosage treatment showed observable injuring effect on the normal rats, expressed by the significant increases of the factor-1 (HMGB-1, TNF-α and IL-1β as the main contributors) and factor-2 (TBIL, ALT and TBA as the main contributors) relative to the normal control group. The liver protective effect of the high dosage treatment could be observed with the significant reduction of the factor-1, indicating the effective alleviation of the expression of inflammatory cytokines. In conclusion, it could illustrated the phenomenon of symptom-based prescription theory of Polygonum multiflorum on rat livers: the high dosage of the herb had either an injuring effect on normal rats, or a therapeutic effect on the rats with chronic liver injury.
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The Nano ultra-high performance liquid chromatography-electrospray ionization mass spectrometry tandem mass spectrometry(UPLC-ESI-MS/MS) was used to characterize the primary protein. Samples were digested by trypsin, followed by liquid chromatography-tandem mass spectrometry analysis and database search. Five peptides matched with tumor necrosis factor receptor and seven peptides matched with human IgG1 fragment of the Fc. Further analysis demonstrated that seven peptides all matched with the IgG1 Fc but only partly peptides matched with the other subtypes. RhTNFR:Fc is fused by IgG1 Fc but not other subtypes.