Xiaozhi formula attenuates non-alcoholic fatty liver disease by regulating lipid metabolism via activation of AMPK and PPAR pathways.

BACKGROUND: Xiaozhi formula (XZF) is a practical Chinese herbal formula for the treatment of non-alcoholic fatty liver disease (NAFLD), which possesses an authorized patent certificate issued by the State Intellectual Property Office of China (ZL202211392355.0). However, the underlying mechanism by which XZF treats NAFLD remains unclear. PURPOSE: This study aimed to explore the main component of XZF and its mechanism of action in NAFLD treatment. METHODS: UHPLC-Q-Orbitrap HRMS was used to identify the components of the XZF. A high-fat diet (HFD)-induced NAFLD mouse model was used to demonstrate the effectiveness of XZF. Body weight, liver weight, and white fat weight were recorded to evaluate the therapeutic efficacy of XZF. H&E and Oil Red O staining were applied to observe the extent of hepatic steatosis. Liver damage, lipid metabolism, and glucose metabolism were detected by relevant assay kits. Moreover, the intraperitoneal insulin tolerance test and the intraperitoneal glucose tolerance test were employed to evaluate the efficacy of XZF in insulin homeostasis. Hepatocyte oxidative damage markers were detected to assess the efficacy of XZF in preventing oxidative stress. Label-free proteomics was used to investigate the underlying mechanism of XZF in NAFLD. RT-qPCR was used to calculate the expression levels of lipid metabolism genes. Western blot analysis was applied to detect the hepatic protein expression of AMPK, p-AMPK, PPARɑ, CPT1, and PPARγ. RESULTS: 120 compounds were preliminarily identified from XZF by UHPLC-Q-Orbitrap HRMS. XZF could alleviate HFD-induced obesity, white adipocyte size, lipid accumulation, and hepatic steatosis in mice. Additionally, XZF could normalize glucose levels, improve glucolipid metabolism disorders, and prevent oxidative stress damage induced by HFD. Furthermore, the proteomic analysis showed that the major pathways in fatty acid metabolism and the PPAR signaling pathway were significantly impacted by XZF treatment. The expression levels of several lipolytic and ß-oxidation genes were up-regulated, while the expression of fatty acid synthesis genes declined in the HFD + XZF group. Mechanically, XZF treatment enhanced the expression of p-AMPK, PPARɑ, and CPT-1 and suppressed the expression of PPARγ in the livers of NAFLD mice, indicating that XZF could activate the AMPK and PPAR pathways to attenuate NALFD progression. CONCLUSION: XZF could attenuate NAFLD by moderating lipid metabolism by activating AMPK and PPAR signaling pathways.

Shenge Formula attenuates high-fat diet-induced obesity and fatty liver via inhibiting ACOX1.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide. Shenge Formula (SGF) is a traditional Chinese medicine that has been used in the clinical treatment of NAFLD, and its therapeutic potential in patients and NAFLD animal models has been demonstrated in numerous studies. However, its underlying mechanism for treating NAFLD remains unclear. PURPOSE: The aim of this study was to investigate the mechanism of SGF in the treatment of NAFLD using the proteomics strategy. METHODS: Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was used to determine the main components of SGF. A mouse model of nonalcoholic fatty liver disease was constructed by feeding mice with a high-fat diet for 16 weeks. SGF was administered for an additional 8 weeks, and metformin was used as a positive control. Liver sections were subjected to histopathological assessments. LC-MS/MS was used for the label-free quantitative proteomic analysis of liver tissues. Candidate proteins and pathways were validated both in vivo and in vitro through qRT-PCR, western blot, and immunohistochemistry. The functions of the validated pathways were further investigated using the inhibition strategy. RESULTS: Thirty-nine ingredients were identified in SGF extracts, which were considered to be key compounds in the treatment of NAFLD. SGF administration attenuated obesity and fatty liver by reducing the body weight and liver weight in HFD-fed mice. It also relieved HFD-induced insulin resistance. More importantly, hepatic steatosis was significantly attenuated by SGF administration both in vivo and in vitro. Proteomic profiling of mouse liver tissues identified 184 differential expressed proteins (DEPs) associated with SGF treatment. Bioinformatic analysis of DEPs revealed that regulating the lipid metabolism and energy consumption process of hepatocytes was the main role of SGF in NAFLD treatment. This also indicated that ACOX1 might be the potential target of SGF, which was subsequently verified both in vitro and in vivo. The results demonstrated that SGF inhibited ACOX1 activity, thereby activating PPARα and upregulating CPT1A expression. Increased CPT1A expression promoted mitochondrial ß-oxidation, leading to reduced lipid accumulation in hepatocytes. CONCLUSIONS: Overall, our findings confirmed the protective effect of SGF against NAFLD and revealed the underlying molecular mechanism of regulating lipid metabolism.

Study on the action mechanism of the Polygonum perfoliatum L. on non-alcoholic fatty liver disease, based on network pharmacology and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine (TCM) holds that non-alcoholic fatty liver disease (NAFLD) belong to the category of "thoracic fullness". Polygonum perfoliatum L. (PPL), a Chinese medicinal herb with the effect of treating thoracic fullness, was recorded in the ancient Chinese medicine book "Supplements to Compendium of Materia Medica". It has been used since ancient times to treat NAFLD. However, the underlying mechanism and active components of PPL against NAFLD remains unclear. AIM OF STUDY: To identify the main active components and the anti-NAFLD mechanism of PPL. MATERIALS AND METHODS: Network pharmacology, UPLC/QE-HFX analysis, and molecular docking were employed to determine the main bioactive compounds and key targets of PPL for the NAFLD treatment. This effect was further validated with administration of PPL (200 mg/kg and 400 mg/kg) to NAFLD model mice for 5 weeks. Systemic signs of obesity, biochemical parameters, and histological changes were characterized. Immunohistochemistry, western blot, and PCR analysis were conducted to elucidate the mechanistic pathways through which PPL exerts its effects. RESULTS: Network pharmacology revealed 77 crossover genes between the PPL and NAFLD. The kyoto encyclopedia of genes and genomes (KEGG) analysis show that PPL treat NAFLD mainly regulating glucose-lipid metabolism mediated by PI3K/AKT signal pathway. The Gene Ontology (GO) enrichment analysis show that PPL treat NAFLD mainly regulating inflammation mediated by cytokine-mediated signaling pathway. In accordance with the anticipated outcomes, administration of PPL in a dose-dependent manner effectively mitigated insulin resistance induced by a high-fat diet (HFD) by activating the PI3K/AKT signaling pathway. Histopathological evaluation corroborated the hepatoprotective effects of PPL against HFD-induced hepatic steatosis, as evidenced by the inhibition of de novo fatty acid synthesis and promotion of fatty acid ß-oxidation (FAO). Further research showed that PPL blocked cytokine production by inhibiting the NF-κB pathway, thereby reducing immune cell infiltration. Furthermore, five flavonoids from PPL, including quercetin, baicalein, galangin, apigenin, and genistein were identified as key compounds based on ingredient-target-pathway network analysis. Molecular docking show that these active compounds have favorable binding interactions with AKT1, PIK3R1, and MAPK1, further confirming the impact of PPL on the PI3K/AKT pathway. CONCLUSIONS: Through the combination of network pharmacology prediction and experimental validation, this work determined that therapeutic effect of PPL on NAFLD, and such protective effect is mediated by activating PI3K/AKT-mediated glucolipid metabolism pathway and hepatic NF-κB-mediated cytokine signaling pathway.

Electroacupuncture Pretreatment at Zusanli (ST36) Ameliorates Hepatic Ischemia/Reperfusion Injury in Mice by Reducing Oxidative Stress via Activating Vagus Nerve-Dependent Nrf2 Pathway.

Background and Purpose: Current pharmacological approaches to prevent hepatic ischemia/reperfusion injury (IRI) are limited. To mitigate hepatic injury, more research is needed to improve the understanding of hepatic IRI. Depending on traditional Chinese medicine (TCM) theory, acupuncture therapy has been used for the treatment of ischemic diseases with good efficacy. However, the efficacy and mechanism of acupuncture for hepatic IRI are still unclear. Methods: Blood provided to the left and middle lobe of mice livers was blocked with a non-invasive clamp and then the clamps were removed for reperfusion to establish a liver IRI model. Quantitative proteomics approach was used to evaluate the impact of EA pretreatment on liver tissue proteome in the IRI group. Serum biochemistry was used to detect liver injury, inflammation, and oxidative stress levels. H&E staining and TUNEL staining were used to detect hepatocyte injury and apoptosis. Immunohistochemistry and ELISA were used to detect the degree of inflammatory cell infiltration and the level of inflammation. The anti-inflammatory and antioxidant capacities were detected by Quantitative RT-PCR and Western blotting. Results: We found that EA at Zusanli (ST36) has a protective effect on hepatic IRI in mice by alleviating oxidative stress, hepatocyte death, and inflammation response. Nuclear factor E2-related factor 2 (Nrf2) as a crucial target was regulated by EA and was then successfully validated. The Nrf2 inhibitor ML385 and cervical vagotomy eliminated the protective effect in the EA treatment group. Conclusion: This study firstly demonstrated that EA pretreatment at ST36 significantly ameliorates hepatic IRI in mice by inhibiting oxidative stress via activating the Nrf2 signal pathway, which was vagus nerve-dependent.

Quantitative proteomics reveals Polygonum perfoliatum L. ameliorates hepatic steatosis by promoting PPARs/CPT1A/CPT2-mediated fatty acid ß-oxidation.

Non-alcoholic fatty liver disease (NAFLD) is a predominant contributor to end-stage liver disease in the forthcoming decades. Polygonum perfoliatum L. (PPL) is an herbal medicine with anti-lipid peroxidation and anti-inflammatory properties. However, detailed hepatoprotective effects of PPL against NAFLD and its underlying mechanisms are not fully understood. Here, we found that PPL protects against high fat diet (HFD)-induced hepatic steatosis, lipid peroxidation, and glucose-lipid metabolism dysfunction in NAFLD mice. We therefore performed a label-free quantitative proteomic profiling analysis to determine the effect of PPL treatment on liver tissue proteomics and identified that activated PPARs/CPT1A/CPT2-mediated hepatic fatty acid ß-oxidation (FAO) process was significantly altered. In vitro treatment of hepatocytes with PPL confirmed this altered process and FAO inhibitor etomoxir (ETO) attenuated the lipid-lowering activity of PPL in hepatocytes. Ultra-high-performance liquid chromatography/Q Exactive-HFX (UPLC/QE-HFX) was used to determine the material basis of anti-NAFLD activity of PPL. Our results have demonstrated the efficacy and potential mechanisms of PPL as an effective pharmacological therapy of NAFLD.

Yin-chen Wu-ling powder alleviate cholestatic liver disease: Network pharmacological analysis and experimental validation.

BACKGROUND: Yin-chen Wu-ling Powder (YWP) has potential therapeutic effects on cholestatic liver disease (CLD), however, its active compounds and conceivable mechanism are as yet indistinct. METHODS: The network pharmacology and gene function annotation examined the multiple active ingredients, potential targets, and possible mechanisms of YWP in CLD treatment. Then the molecular docking reassured the reliability of the core compounds including the key genes and farnesoid X receptor (FXR). Finally, The Mdr2-/- mice were used to test the effect and mechanism of YWP against CLD. RESULTS: The network analysis identified nine main active ingredients, including quercetin, capillarisin, eupalitin, isorhamnetin, skrofulein, genkwanin, cerevisterol, gederagenin, and sitosterol. The PPI network predicted the ten hub genes involved were AKT1, MAPK1, MAPK14, IL6, RXRA, ESR1, IL10, NCOA1, CAV1, and EGFR. The KEGG and GO analysis showed that YWP might contribute to CLD treatment through the PI3K/Akt and MAKP signalings to manage pathological reactions, for instance, inflammatory responses. The molecular docking displayed a functional similarity among the core compounds with ursodeoxycholic acid (UDCA) and Obeticholic acid (OCA) on the effects on AKT1, MAPK1, MAPK14, RXRA, and ESR, and the affinity to FXR. In addition, the YWP could significantly attenuate hepatic injury and improve inflammatory response in Mdr2-/- mice. The mechanism exploration showed that YWP mainly decreased inflammatory response by inhibiting AKT/P38MAPK signaling. CONCLUSION: This study firstly revealed the multiple active ingredients, potential targets, and possible mechanism of YWP to treat CLD based on network pharmacology Analysis and molecular docking. YWP could alleviate cholestasis in Mdr2-/- mice by impairing inflammation via inhibiting AKT/P38MAPK Signaling.

Ancient Herbal Formula Mahuang Lianqiao Chixiaodou Decoction Protects Acute and Acute-on-Chronic Liver Failure via Inhibiting von Willebrand Factor Signaling.

BACKGROUND: Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) are characterized by systemic inflammation and high mortality, but there is no effective clinical treatment. As a classic traditional Chinese medicine (TCM) formula, MaHuang-LianQiao-ChiXiaoDou decoction (MHLQD) has been used clinically for centuries to treat liver diseases. METHODS: The LPS/D-GalN-induced ALF mice model and the CCl4+LPS/D-GalN-induced ACLF mice model were used to observe the therapeutic effects of MHLQD on mice mortality, hepatocytes death, liver injury, and immune responses. RESULTS: MHLQD treatment significantly improved mice mortality. Liver injury and systemic and hepatic immune responses were also ameliorated after MHLQD treatment. Mechanistically, proteomic changes in MHLQD-treated liver tissues were analyzed and the result showed that the thrombogenic von Willebrand factor (VWF) was significantly inhibited in MHLQD-treated ALF and ACLF models. Histological staining and western blotting confirmed that VWF/RAP1B/ITGB3 signaling was suppressed in MHLQD-treated ALF and ACLF models. Furthermore, mice treated with the VWF inhibitor ADAMTS13 showed a reduced therapeutic effect from MHLQD treatment. CONCLUSIONS: Our study indicated that MHLQD is an effective herbal formula for the treatment of ALF and ACLF, which might be attributed to the protection of hepatocytes from death via VWF/RAP1B/ITGB3 signaling.

Application of herbs and active ingredients ameliorate non-alcoholic fatty liver disease under the guidance of traditional Chinese medicine.

Non-alcoholic fatty liver disease (NAFLD) is a global health problem, and its prevalence has been on the rise in recent years. Traditional Chinese Medicine (TCM) contains a wealth of therapeutic resources and has been in use for thousands of years regarding the prevention of liver disease and has been shown to be effective in the treatment of NAFLD in China. but the molecular mechanisms behind it have not been elucidated. In this article, we have updated and summarized the research and evidence concerning herbs and their active ingredients for the treatment in vivo and vitro models of NAFLD or NASH, by searching PubMed, Web of Science and SciFinder databases. In particular, we have found that most of the herbs and active ingredients reported so far have the effect of clearing heat and dispelling dampness, which is consistent with the concept of dampness-heat syndrome, in TCM theory. we have attempted to establish the TCM theory and modern pharmacological mechanisms links between herbs and monomers according to their TCM efficacy, experiment models, targets of modulation and amelioration of NAFLD pathology. Thus, we provide ideas and perspectives for further exploration of the pathogenesis of NAFLD and herbal therapy, helping to further the scientific connotation of TCM theories and promote the modernization of TCM.

Bushen Jianpi Formula Combined with Entecavir for the Treatment of HBeAg-Negative Chronic Hepatitis B: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

Background: Bushen Jianpi formula (BSJPF, also known as Lingmao formula) is a traditional Chinese medicine for chronic hepatitis B (CHB). The previous study has suggested that the treatment combination of BSJPF and entecavir (ETV) can achieve a significant loss of hepatitis B e antigen (HBeAg) and a significant decrease in serum level of hepatitis B virus (HBV) DNA in HBeAg-positive CHB patients with mildly elevated alanine aminotransferase. Objective: This study aimed to evaluate the efficacy and safety of BSJPF combined with ETV for treating HBeAg-negative CHB patients. Methods: A total of 640 patients were assigned randomly to the treatment group (receiving BSJPF combined with ETV for 96 weeks) or the control group (receiving a placebo combined with ETV for 96 weeks) in a 1 : 1 ratio. The primary endpoints are the rate of loss of hepatitis B surface antigen (HBsAg). The secondary outcomes included the rate of decrease in the HBsAg concentration to ≥1 lg·IU/mL, the HBV DNA suppression, the decline of the level of covalently closed circular DNA (cccDNA) in the liver, histological improvements, and the rate of ALT normalization. Results: The rate of HBsAg loss in the treatment group was significantly higher than that of the control group (5.5% versus 1.8%, P=0.031). There were 11.1% of patients in the treatment group who recorded a reduction in HBsAg ≥1 lg·IU/mL, which is better than 5.9% of patients in the control group (P=0.043). There was no significant difference between the two groups with regard to the rate of HBV DNA clearance, the reduction in intrahepatic cccDNA, and the rate of ALT normalization (P > 0.05). The rate of liver fibrosis improvement in the treatment group was better than that of the control group (35.5% versus 11.8%, P=0.031), but there was no difference in necroinflammatory improvement (P > 0.05). The adverse events (AEs) were similar between the two groups, except for the abnormal kidney function, with 2.2% in the control group and 0.0% in the treatment group (P=0.028). Conclusion: The combination of BSJPF and ETV can increase the rate of HBsAg loss and the rate of histological fibrosis improvement without serious adverse events in CHB patients. Trial Registration. This trial is registered with ChiCTR-IOR-16009880 on November 16, 2016-retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=16836.

LuQi Formula Regulates NLRP3 Inflammasome to Relieve Myocardial-Infarction-Induced Cardiac Remodeling in Mice.

BACKGROUND: Excessive activation of the nod-like receptor family pyrin domain containing 3(NLRP3) inflammasome plays a significant role in the progression of cardiac injury. In China, it has been well recognized that Chinese herbal medicine is markedly effective in treating cardiovascular diseases (CVDs). LuQi Formula (LQF) has been used clinically for more than 10 years and confirmed to be effective in improving cardiac function and inhibiting apoptosis. However, the specific mechanisms underlying its efficacy are mostly unknown. This study aimed to evaluate whether LQF could alleviate cardiac injury and apoptosis by regulating the NLRP3 inflammasome and the caspase-3/Bax pathway. PURPOSE: In this study, we investigated the effects of LQF on cardiac remodeling in a mouse model of myocardial infarction (MI) in vivo. METHODS: Forty male C57BL/6 mice were randomly divided into four groups: the sham group, the model group, the LQF group, and the perindopril group, with a sample size (n) of 10 mice in each group. Except the sham group, the other groups received left anterior descending (LAD) coronary artery ligation to induce MI and then treated with LQF, perindopril, or saline. Six weeks after MI, echocardiography was used to evaluate cardiac structure and function. Myocardial tissue morphology was observed by haematoxylin and eosin (H&E) staining, and heart samples were stained with Masson's trichrome to analyse myocardial fibrosis. Myocardial hypertrophy was observed by fluorescent wheat germ agglutinin (WGA) staining. The expressions of NLRP3, ASC, Cle-caspase-1, IL-1ß, TXNIP, Cle-caspase-3, Bcl-2, and Bax in heart tissues were assessed by western blot analysis. mRNA expressions of ANP and BNP in heart tissues were measured by RT-PCR. The expression of reactive oxygen species in myocardial tissue was detected by using a DCFH-DA probe. RESULTS: Echocardiographic analysis showed that compared with the model group, the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) in the LQF and perindopril group were increased (P < 0.05), left ventricular internal diameter end diastole (LVIDd) and left ventricular internal diameter end-systole (LVIDs) were reduced (P < 0.05), and H&E and Masson's trichrome staining of cardiac tissues showed that LQF and perindopril could partially reverse ventricular remodeling and alleviate myocardial fibrosis (P < 0.05). WGA fluorescence results showed that compared with the model group, myocardial hypertrophy was significantly reduced in the LQF and perindopril group. We also found that LQF and perindopril reduce the oxidative stress response in the heart of MI mice. The protein expression of NLRP3, ASC, Cle-caspase-1, IL-1ß, TXNIP, Cle-caspase-3, and Bax was downregulated in the LHF and perindopril treatment group, and Bcl-2 expression was upregulated. CONCLUSION: LQF and perindopril significantly attenuated cardiac injury and apoptosis in the MI model. In addition, we found that LQF effectively inhibited the activation of the NLRP3/ASC/caspase-1/IL-1ß cascade, decreased inflammatory infiltration, delayed ventricular remodeling, and downregulated caspase-3/Bax signaling, which can effectively reduce the apoptosis of cardiomyocytes. Perindopril showed the same mechanism.

Systematic elucidation of the mechanism of Jingyin granule in the treatment of Novel Coronavirus (COVID-19) Pneumonia via Network Pharmacology.

Background: Jingyin granule is one of the widely used traditional Chinese medicine mixture composed of multiple herbs in the treatment of respiratory system diseases. The mechanism of its therapeutic effects has still been obscure. The aim of this study is to use the network pharmacology approach for identification of the main active ingredients of Jingyin granule against COVID-19 targets and to explore their therapeutic mechanism. Material and Method: In this study, the ingredients of Jingyin granule were evaluated by the usage of Traditional Chinese Medicine Systems Pharmacology Database and Traditional Chinese Medicine Integrated Database, and the interactions between potential gene targets and ingredients were identified using the SwissTargetPrediction database. Meanwhile the possible efficient targets COVID-19 acts on were identified via Online Mendelian Inheritance in Man database, DisGeNET database and GeneCards database. In addition, functions, components and pathways were identified by Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Protein interaction, ingredients-targets network was established. Results: Our findings showed that numerous ingredients of Jingyin granule could act on COVID-19 with 88 target genes. GO enrichment analysis, KEGG pathway analysis, and protein-protein interaction network revealed that these targets were interrelated with regulation of immune function, directly targeting disease genes. Conclusions: Jingyin granule could be utilized to exert systematic pharmacological effects. Jingyin granule could directly target the major genes, and also regulate the immune system, acting as oblique disease treatment.

Long-Term Traditional Chinese Medicine Combined with NA Antiviral Therapy on Cirrhosis Incidence in Chronic Hepatitis B Patients in the Real-World Setting: A Retrospective Study.

OBJECTIVE: To evaluate the impact of long-term Traditional Chinese Medicine (TCM) syndrome differentiation combined with antiviral therapy with Nucleos (t) ide analogues (NAs) on the incidence of cirrhosis in patients with chronic hepatitis B. METHODS: This retrospective cohort study included 521 patients with chronic hepatitis B who underwent a treatment course of ≥3 years from 1998-2019. Of the 521 patients, 261 were defined as TCM users while 260 were TCM nonusers (control group). All the enrolled subjects were followed up until February 2019 to measure the incidence and hazard ratio (HR) of cirrhosis, and the Cox proportional hazards regression model was used to analyze the independent factors affecting the occurrence of cirrhosis. RESULTS: The cumulative incidence of TCM users and nonusers was 6.9% and 13.5%, respectively (P=0.013). Results of the Kaplan-Meier analysis demonstrated that TCM users had a significantly lower cumulative incidence of cirrhosis than TCM nonusers (P=0.011), and TCM users had a significantly lower liver cirrhosis risk than TCM nonusers (adjusted HR = 0.416, 95% CI, 0.231-0.749). The histological evaluation revealed improved fibrosis in 45.0% of TCM users and 11.1% of TCM nonusers (P=0.033). The analysation of the prescriptions including total 119 single Chinese herbs medicinal demonstrated that "replenish qi and fortify the spleen," "clear heat and dispel dampness," and "soothe the liver and regulate qi" are the main treatment methods of TCM for CHB. CONCLUSIONS: Our study demonstrated that long-term TCM use may attenuate liver cirrhosis risk in patients with chronic hepatitis B (CHB).

Herbal Therapy for the Treatment of Acetaminophen-Associated Liver Injury: Recent Advances and Future Perspectives.

Acetaminophen (APAP) overdose is the leading cause of drug-induced liver injury worldwide, and mitochondrial oxidative stress is considered the major event responsible for APAP-associated liver injury (ALI). Despite the identification of N-acetyl cysteine, a reactive oxygen species scavenger that is regarded as an effective clinical treatment, therapeutic effectiveness remains limited due to rapid disease progression and diagnosis at a late phase, which leads to the need to explore various therapeutic approaches. Since the early 1990s, a number of natural products and herbs have been found to have hepatoprotective effects against APAP-induced hepatotoxicity in terms of acute liver failure prevention and therapeutic amelioration of ALI. In this review, we summarize the hepatoprotective effects and mechanisms of medicinal plants, including herbs and fruit extracts, along with future perspectives that may provide guidance to improve the current status of herbal therapy against ALI.

IFN-γ inhibits liver progenitor cell proliferation in HBV-infected patients and in 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet-fed mice.

BACKGROUND & AIMS: Proliferation of liver progenitor cells (LPCs) is associated with inflammation and fibrosis in chronic liver diseases. However, how inflammation and fibrosis affect LPCs remains obscure. METHODS: We examined the role of interferon (IFN)-γ, an important pro-inflammatory and anti-fibrotic cytokine, in LPC expansion in HBV-infected patients and in mice challenged with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)- or choline-deficient, ethionine-supplemented (CDE) diet as well as in primary LPCs and LPC cell line. RESULTS: The CK19 staining scores correlated with inflammation and fibrosis grades in the livers from 110 HBV-infected patients. Nine-month IFN-γ treatment decreased LPC numbers, inflammation, and fibrosis in these HBV-infected patients. Similarly, a two-week IFN-γ treatment also decreased LPC activation in DDC-treated mice. Disruption of IFN-γ or its signaling components (e.g., IFNGR, STAT1, and IRF-1) increased LPC proliferation and liver fibrosis in DDC-fed mice. In contrast, deletion of IFN-γ did not increase, but rather slightly reduced LPC proliferation in CDE-fed mice. In vitro, IFN-γ attenuated proliferation of the LPC cell line BMOL and of primary LPCs from wild type mice, but not STAT1(-/-) or IRF-1(-/-) mice. Furthermore, co-culture assays suggest that IFN-γ can indirectly promote LPC proliferation via the activation of macrophages but attenuate it via the inhibition of hepatic stellate cells. CONCLUSIONS: IFN-γ inhibits LPC expansion via the direct inhibition of LPC proliferation and indirect attenuation of liver fibrosis in the DDC model, but it may also enhance LPC expansion via the promotion of inflammation in the CDE model; thereby playing dual roles in regulating LPC proliferation in vivo.