Indole-3-carboxaldehyde alleviates acetaminophen-induced liver injury via inhibition of oxidative stress and apoptosis.

Drug-induced liver injury (DILI) occurs frequently and can be life-threatening. Increasing researches suggest that acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury. Indole-3-carboxaldehyde (I3A) alleviates hepatic inflammation, fibrosis and atherosclerosis, suggesting a potential role in different disease development. However, the question of whether and how I3A protects against acetaminophen-induced liver injury remains unanswered. In this study, we demonstrated that I3A treatment effectively mitigates acetaminophen-induced liver injury. Serum alanine/aspartate aminotransferases (ALT/AST), liver malondialdehyde (MDA) activity, liver glutathione (GSH), and superoxide dismutase (SOD) levels confirmed the protective effect of I3A against APAP-induced liver injury. Liver histological examination provided further evidence of I3A-induced protection. Mechanistically, I3A reduced the expression of apoptosis-related factors and oxidative stress, alleviating disease symptoms. Finally, I3A treatment improved survival in mice receiving a lethal dose of APAP. In conclusion, our study demonstrates that I3A modulates hepatotoxicity and can be used as a potential therapeutic agent for DILI.

[Study based on the acetaldehyde dehydrogenase 2 gene polymorphism and acetaminophen-induced liver injury].

Objective: To explore the association between aldehyde dehydrogenase 2 (ALDH2) gene polymorphisms and abnormal liver function-induced by acetaminophen (APAP) drugs. Methods: An ALDH2 gene knockout mouse model was constructed using CRISPR/Cas9 gene editing technology. The obtained heterozygous mice were mated with opposite sex of heterozygotes. Genomic DNA was extracted from the tail of the offspring mouse. The polymerase chain reaction (PCR) method was used to determine the ALDH2 genotype. APAP was further used to induce acute drug-induced liver injury models in wild-type and ALDH2 knockout mice. Blood and liver tissues of mice were collected for liver function index, HE staining, F4/80 immunohistochemistry, and other detections. The intergroup mean was compared using a one-way ANOVA. The LSD- t test was used for pairwise comparison. Results: ALDH2 knockout mice were bred successfully. The genotyping of the offspring was segregated into the wild-type (ALDH2(+/+)), heterozygous mutant (ALDH2(+/-)), and homozygous mutant (ALDH2(-/-)), respectively. Biochemical and histological results after APAP modeling showed that the level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBil) was not significantly increased in the blank control group (P < 0.05), while the ALT, AST,ALP, and TBil were all elevated in the APAP experimental group. The levels of ALT (P  = 0.004), AST (P = 0.002), and TBil (P = 0.012) were significantly elevated among the mutant group compared to those in the wild-type group, and the expression levels of these indicators were also significantly elevated among the homozygous mutant group compared to those in the heterozygous mutant group (P = 0.003, 0 and 0.006). In addition, the ALP levels were higher in the heterozygous mutation group than those in the homozygous mutant group (P = 0.085) and wild-type group mice, but the difference was only statistically significant compared to wild-type mice (P = 0.002). HE staining results showed that mice in the APAP experimental group had hepatocyte degeneration, necrosis, and increased inflammatory cell infiltration, which was mostly evident in mutant mice. Simultaneously, the F4/80 immunohistochemical staining results showed that brown granules were visible in the liver tissue of APAP experimental group mice, and its expression levels were significantly enhanced compared to the blank control group. Conclusion: APAP-induced liver function abnormalities were associated with the ALDH2 gene polymorphism. The liver injury symptoms were increased in ALDH2 mutant mice following APAP modeling, and the ALDH2 gene defect may alleviate, to some extent, APAP-induced liver function abnormalities.

The protective effect of Enteromorpha prolifera polysaccharide on alcoholic liver injury in C57BL/6 mice.

An alcohol-induced liver injury model was induced in C57BL/6 mice to assess the protective efficacy of Enteromorpha prolifera polysaccharides (EP) against liver damage. Histological alterations in the liver were examined following hematoxylin-eosin (H&E) staining. Biochemical assay kits and ELISA kits were employed to analyze serum and liver biochemical parameters, as well as the activity of antioxidant enzymes and alcohol metabolism-related enzymes. The presence of oxidative stress-related proteins in the liver was detected using western blotting. Liquid chromatography and mass spectrometry were used to profile serum metabolites in mice. The findings demonstrated that EP-H (100 mg/Kg) reduced serum ALT and AST activity by 2.31-fold and 2.32-fold, respectively, when compared to the alcohol-induced liver injury group. H&E staining revealed a significant attenuation of microvesicular steatosis and ballooning pathology in the EP-H group compared to the model group. EP administration was found to enhance alcohol metabolism by regulating metabolite-related enzymes (ADH and ALDH) and decreasing CYP2E1 expression. EP also modulated the Nrf2/HO-1 signaling pathway to bolster hepatic antioxidant capacity. Furthermore, EP restored the levels of lipid metabolites (Glycine, Butanoyl-CoA, and Acetyl-CoA) to normalcy. In summary, EP confers protection to the liver through the regulation of antioxidant activity and lipid metabolites in the murine liver.

Identification of a novel FOXO3 agonist that protects against alcohol induced liver injury.

Alcohol-related liver disease (ALD) is a global healthcare concern which caused by excessive alcohol consumption with limited treatment options. The pathogenesis of ALD is complex and involves in hepatocyte damage, hepatic inflammation, increased gut permeability and microbiome dysbiosis. FOXO3 is a well-recognized transcription factor which associated with longevity via promoting antioxidant stress response, preventing senescence and cell death, and inhibiting inflammation. We and many others have reported that FOXO3-/- mice develop more severe liver injury in response to alcohol. In the present study, we aimed to develop compounds that activate FOXO3 and further investigate their effects in alcohol induced liver injury. Through virtual screening, we discovered series of small molecular compounds that showed high affinity to FOXO3. We confirmed effects of compounds on FOXO3 target gene expression, as well as antioxidant and anti-apoptotic effects in vitro. Subsequently we evaluated the protective efficacy of compounds in alcohol induced liver injury in vivo. As a result, the leading compound we identified, 214991, activated downstream target genes expression of FOXO3, inhibited intracellular ROS accumulation and cell apoptosis induced by H2O2 and sorafenib. By using Lieber-DeCarli alcohol feeding mouse model, 214991 showed protective effects against alcohol-induced liver inflammation, macrophage and neutrophil infiltration, and steatosis. These findings not only reinforce the potential of FOXO3 as a valuable target for therapeutic intervention of ALD, but also suggested that compound 214991 as a promising candidate for the development of innovative therapeutic strategies of ALD.

Diagnosis, toxicological mechanism, and detoxification for hepatotoxicity induced by pyrrolizidine alkaloids from herbal medicines or other plants.

Pyrrolizidine alkaloids (PAs) are one type of phytotoxins distributed in various plants, including many medicinal herbs. Many organs might suffer injuries from the intake of PAs, and the liver is the most susceptible one. The diagnosis, toxicological mechanism, and detoxification of PAs-induced hepatotoxicity have been studied for several decades, which is of great significance for its prevention, diagnosis, and therapy. When the liver was exposed to PAs, liver sinusoidal endothelial cells (LSECs) loss, hemorrhage, liver parenchymal cells death, nodular regeneration, Kupffer cells activation, and fibrogenesis occurred. These pathological changes classified the PAs-induced liver injury as acute, sub-acute, and chronic type. PAs metabolic activation, mitochondria injury, glutathione (GSH) depletion, inflammation, and LSECs damage-induced activation of the coagulation system were well recognized to play critical roles in the pathological process of PAs-induced hepatotoxicity. A lot of natural compounds like glycyrrhizic acid, (-)-epicatechin, quercetin, baicalein, chlorogenic acid, and so on were demonstrated to be effective in alleviating PAs-induced liver injury, which rendered them huge potential to be developed into therapeutic drugs for PAs poisoning in clinics. This review presents updated information about the diagnosis, toxicological mechanism, and detoxification studies on PAs-induced hepatotoxicity.

Are silymarin and N-acetylcysteine able to prevent liver damage mediated by multiple factors? Findings against ethanol plus LPS-induced liver injury in mice.

This study investigated the effect of N-acetylcysteine (NAC) and silymarin (SIL) in the liver of mice exposed to ethanol and lipopolysaccharides (LPS). Mice were divided into four groups (n = 6): naive, vehicle, NAC (200 mg/kg), and SIL (200 mg/kg). Treatments were given orally (po) once daily for 10 days. Liver injury was induced by administration of ethanol (30%, po) for 10 days, once daily, followed by a single administration of LPS (2 mg/kg, ip) 24 h before euthanasia. After the treatment period, animals were euthanized, and liver and blood samples were collected. NAC, but not SIL, prevented the increase in oxalacetic glutamic transaminase (OGT) and pyruvic glutamic transaminase (PGT) serum levels. NAC and SIL did not restore levels of reduced glutathione or hepatic malonaldehyde. The treatments with NAC or SIL showed no difference in the activity of glutathione S-transferase, superoxide dismutase, and catalase compared to vehicle group. Myeloperoxidase and N-acetylglucosaminidase activities are increased, as well as the IL-6 and IL-10 levels in the liver. The treatment with NAC, but not SIL, reduced the N-acetylglucosamines activity and the IL-6 and IL-10 amount in the liver. Histological findings revealed microsteatosis in the vehicle group, which was not prevented by SIL but was partially reduced in animals receiving NAC. Unlike other liver injury models, NAC (200 mg/kg) or SIL (200 mg/kg) did not positively affect antioxidant patterns in liver tissue of animals exposed to ethanol plus LPS, but NAC treatment displays anti-inflammatory properties in this model.

Comparative study between the effect of mesenchymal stem cells microvesicles versus ozone on induced liver injury in adult male albino rats (Histological & Immunohistochemical study).

Liver disease accounts for approximately 2 million deaths er year worldwide. Liver fibrisis results from chronic injury to the liver. If not effectively treated in time, liver fibrosis may transform into liver cirrhosis. MVs are recognized as potential biomarkers and important theraputic tools for a wide sectrum of diseases. Medical ozone has the ability to protect the body against pathological conditions caused by oxidative stress. The influence of ozone and MVs on CCL4 induced liver fibrosis was investigated in this study. Forty-eight adult male albino rats were divided into four equal groups. I control, II CCL4 group, III ozone and IV microvesicles groups. Liver fibrosis was induced in group II, III & IV using 12 SC injections (0.5 ml/kg body weight) of CCL4 dissolved in olive oil twice ber week for weeks. Blood samples were obtained to estimate serum ALT & AST. Liver tissues were processed for measurment of GSH & SOD, light and electron microscopic examination. H&E staine sections og group II showed dilated congested sinusoids and centralveins, mononuclear infiltrations, vacuolations and dark nuclei. Ultrastructurally, group II revealed irregular heterochromatic nuclei of hepatocytes, small scanty mitochondria & vacuolations. Morphometric & statistical analyses were performed. Group III showed some improvement, however, group IV showed more imrovement. The results indicates that MVs caused marked improvement than ozone against CCL4 induced liver damage via antioxidant & antiinflammatory properties.

Visualization of production and remediation of acetaminophen-induced liver injury by a carboxylesterase-2 enzyme-activatable near-infrared fluorescent probe.

Acetaminophen (APAP) overdose, also known as APAP poisoning, may directly result in hepatic injury, acute liver failure and even death. Nowadays, APAP-induced liver injury (AILI) has become an urgent public health issue in the developing world so the early accurate diagnosis and the revelation of underlying molecular mechanism of AILI are of great significance. As a major detoxifying organ, liver is responsible for metabolizing chemical substances, in which human carboxylesterase-2 (CES2) is present. Hence, we chose CES2 as an effective biomarker for evaluating AILI. By developing a CES2-activatable and water-soluble fluorescent probe PFQ-E with superior affinity (Km = 5.9 µM), great sensitivity (limit of detection = 1.05 ng/mL), near-infrared emission (655 nm) and large Stokes shift (135 nm), activity and distribution of CES2 in cells were determined or imaged effectively. More importantly, the APAP-induced hepatotoxicity and the underlying molecular mechanism of pathogenesis of AILI were investigated by measuring the "light-up" response of PFQ-E towards endogenous CES2 in vivo for the first time. Based on the superior performance of the probe PFQ-E for sensing CES2, we believe that it has broad potential in clinical diagnosis and therapy response evaluation of AILI.

Protective effects of chlorogenic acid against cyclophosphamide induced liver injury in mice.

We investigated possible protective effects of chlorogenic acid (CGA) against cyclophosphamide (CP) induced hepatic injury in mice. We measured aminotransferase alanine transaminase (ALT) and aspartate transaminase (AST) levels in the serum. We assayed catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) in hepatic tissue. We assessed expression of nuclear transcription factor 2 (Nrf2) and Kelch sample related protein-1 (keap1) proteins in hepatic tissues using immunohistochemistry. The relative mRNA expression levels of heme oxygenase-1 (HO-1), NADH quinone oxidoreductase 1 (NQO1), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were determined using quantitative real-time polymerase chain reaction (qRT-PCR). Hematoxylin & eosin staining was used to assess liver histopathology. We found that administration of CGA prior to induction of injury by CP decreased serum ALT, AST and MDA expressions in hepatic tissue, while CAT, SOD, GSH and GSH-Px concentrations were increased. We found that hepatocytes of animals administered CGA gradually returned to normal morphology. CGA increased the protein expression of Nrf2 in murine hepatic tissue. Administration of CGA up-regulated mRNA expression levels of HO-1, NQO1, TNF-α and IL-6 in hepatic tissue. CGA exhibited a marked protective effect on CP induced liver injury in mice.

Clinical and Pathological Features of Immune Checkpoint Inhibitor-induced Liver Injury in Comparison with Drug-induced Liver Injury and Autoimmune Hepatitis.

BACKGROUND AND AIMS: Immune checkpoint inhibitors may cause various types of organ damage as immune-related adverse events, of which, liver damage is the most common. Herein, we evaluated the clinicopathological features of immune checkpoint inhibitor-related liver injury and investigated the differences between immune checkpoint inhibitor-related liver injury and drug-induced liver injury or autoimmune hepatitis. METHODS: We selected patients with ≥ grade 3 liver injury who were diagnosed with immune checkpoint inhibitor-related liver injury (n=15). Liver biopsies were performed in 10 of the 15 cases. We also selected cases in which a liver biopsy was performed and drug-induced liver injury (n=7) or autoimmune hepatitis [n=21: acute exacerbation (n=13) was diagnosed and cases of acute onset (n=8), in which liver function test results corresponded to ≥ grade 3]. RESULTS: Portal fibrosis and periportal activity scores were significantly higher in the acute exacerbation autoimmune hepatitis group than in the other groups. Portal and lobular activity were not different between the groups. Plasma cell infiltration showed a higher trend in the autoimmune hepatitis group than in the other groups. Granuloma formations were seen in 90% of immune checkpoint inhibitor-related liver injury cases. The CD4/8 ratio was significantly lower in the immune checkpoint inhibitor-related liver injury group than in the other groups. Patients with bile duct injury had poorer response to corticosteroid therapy than those without. CONCLUSIONS: There are some obvious differences among immune checkpoint inhibitor-related liver injury, drug-induced liver injury, and autoimmune hepatitis in liver histology. Liver biopsy is helpful for the diagnosis and severity evaluation of liver injury.

Evasion of host antioxidative response via disruption of NRF2 signaling in fatal Ehrlichia-induced liver injury.

Ehrlichia is Gram negative obligate intracellular bacterium that cause human monocytotropic ehrlichiosis (HME). HME is characterized by acute liver damage and inflammation that may progress to fatal toxic shock. We previously showed that fatal ehrlichiosis is due to deleterious activation of inflammasome pathways, which causes excessive inflammation and liver injury. Mammalian cells have developed mechanisms to control oxidative stress via regulation of nuclear factor erythroid 2 related 2 (NRF2) signaling. However, the contribution of NRF2 signaling to Ehrlichia-induced inflammasome activation and liver damage remains elusive. In this study, we investigated the contribution of NRF2 signaling in hepatocytes (HCs) to the pathogenesis of Ehrlichia-induced liver injury following infection with virulent Ixodes ovatus Ehrlichia (IOE, AKA E. japonica). Employing murine model of fatal ehrlichiosis, we found that virulent IOE inhibited NRF2 signaling in liver tissue of infected mice and in HCs as evidenced by downregulation of NRF2 expression, and downstream target GPX4, as well as decreased NRF2 nuclear translocation, a key step in NRF2 activation. This was associated with activation of non-canonical inflammasomes pathway marked by activation of caspase 11, accumulation of reactive oxygen species (ROS), mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. Mechanistically, treatment of IOE-infected HCs with the antioxidant 3H-1,2-Dithiole-3-Thione (D3T), that induces NRF2 activation, attenuated oxidative stress and caspase 11 activation, as well as restored cell viability. Importantly, treatment of IOE-infected mice with D3T resulted in attenuated liver pathology, decreased inflammation, enhanced bacterial clearance, prolonged survival, and resistance to fatal ehrlichiosis. Our study reveals, for the first time, that targeting anti-oxidative signaling pathway is a key approach in the treatment of severe and potential Ehrlichia-induced acute liver injury and sepsis.

PGC1α deficiency reverses cholestasis-induced liver injury via attenuating hepatic inflammation and promoting bile duct remodeling.

OBJECTIVES: Cholestatic liver diseases are characterized by hepatocellular damage, cholangiocyte proliferation, and progressive fibrosis. Bile duct ligation (BDL) is widely used to resemble liver injuries induced by cholestasis. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α) was reported to play a critical role in multiple biological responses. Nevertheless, whether PGC1α is involved in bile acid metabolism and biliary disorders remains unclear. This study aimed to investigate the effect of PGC1α on hepatic responses after cholestatic injury. MATERIALS AND METHODS: Wild-type mice were subjected to BDL or sham surgery for 14 days and human liver specimens from patients with primary biliary cholangitis (PBC) were collected to detect the expression of PGC1α. Hepatic-specific PGC1α knockout mice (HKO) were constructed and subjected to BDL, in which the effects of PGC1α on cholestatic liver injury were demonstrated by biochemical and histopathological assessments, immunoblotting, and metabolomics. RESULTS: The expression of PGC1α was upregulated in the liver of PBC patients and murine models. Both in vivo and in vitro experiments supported the protective effects of PGC1α on cholestasis-induced hepatocyte injury. Infiltrated inflammatory cells after BDL were decreased in HKO mice. Inhibited Wnt/ß-Catenin pathway and enhanced Notch signaling promoted transdifferentiation of hepatic progenitor cells (HPC)/ hepatocytes into cholangiocytes, leading to the greater ductular reaction observed in the HKO mice. But bile acids metabolism and mitochondrial function were not affected due to hepatic PGC1α deficiency in cholestasis. CONCLUSIONS: Hepatic-specific deletion of PGC1α regulated liver regeneration by promoting ductular reactions, thereby exerting protective effects against BDL-induced liver injury, which could be a new potential therapeutic target.

Gentiopicroside ameliorates CCl4-induced liver injury in mice by regulating the PPAR-γ/Nrf2 and NF-κB/IκB signaling pathways.

OBJECTIVE: This study explored the mechanisms by which gentiopicroside protects against carbon tetrachloride (CCl4)-induced liver injury. METHODS: Male mice were randomly assigned to the control; CCl4; bifendate 100 mg/kg; or gentiopicroside 25, 50, or 100 mg/kg groups. Both vehicle and drugs were administered intragastrically for 7 days. Mice were administered CCl4 intraperitoneally 1 hour after the last drug dose. After 24 hours, we collected blood and liver samples for testing. RESULTS: Gentiopicroside significantly reduced serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase activities with corresponding reductions in hepatocyte denaturation and necrosis. Gentiopicroside enhanced superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities and glutathione levels and reduced heme oxygenase 1 (HO-1) activity and malondialdehyde levels in the liver, and these effects were attributed to peroxisome proliferator-activated receptor (PPAR)-γ/nuclear factor erythroid 2-related factor 2 (Nrf2) activation. Meanwhile, gentiopicroside significantly downregulated HO-1 and upregulated SOD and GSH-Px at the mRNA level in the liver. Furthermore, gentiopicroside significantly suppressed serum tumor necrosis factor-α and interleukin-1ß secretion, which was associated with the inhibition of nuclear factor-kappa B (NF-κB)/inhibitor of NF-κB (IκB). CONCLUSIONS: Gentiopicroside ameliorated CCl4-induced liver injury in mice via the PPAR-γ/Nrf2 and NF-κB/IκB pathways.

N-Acetylcysteine may exert hepatoprotective effect by regulating Meteorin-Like levels in Adriamycin-induced liver injury.

Adriamycin (ADR) is an important chemotherapeutic drug, but it has serious side effects such as hepatotoxicity. This study aimed to evaluate whether N-acetylcysteine (NAC) has hepatoprotective effects against ADR-induced hepatotoxicity in rats. In addition, it was aimed to determine how Meteorin-Like (MtrnL), which has pleiotropic effects on immunology, inflammation, and metabolism, is affected by ADR and/or NAC applications in liver tissue. 28 rats were randomly assigned to one of four equal groups in the study: control (no treatment), NAC (150 mg/kg/day of NAC intraperitoneally (i.p), ADR (15 mg/kg only on the first day of the experiment), and ADR + NAC (ADR 15 mg/kg on the first day of the experiment + 150 mg/kg/day NAC i.p). After 15 days, liver enzyme levels in serum, oxidant/antioxidant parameters in liver tissue, histopathological changes, caspase 3 (Casp3) and heat shock protein 70 (HSP-70) immunoreactivities, and MtrnL levels were examined. Histopathological changes, liver enzyme levels, as well as HSP-70, and Casp3 immunoreactivities increased due to ADR application. Additionally, MtrnL levels in liver tissue were significantly increased as a result of ADR application. However, it was detected that the NAC application significantly regulated the ADR-induced changes. Furthermore, it was determined that NAC administration regulated the changes in ADR-induced oxidative stress parameters. We propose that NAC may exert a hepatoprotective effect by regulating ADR-induced altered oxidative stress parameters, MtrnL levels, Casp3, and HSP-70 immunoreactivities in the liver.

Cold stress causes liver damage by inducing ferroptosis through the p38 MAPK/Drp1 pathway.

Acute extreme cold exposure impairs human health and even causes hypothermia which threatens human life. Liver, as a hub in metabolism and thermogenesis, is vital for cold acclimatization. Although accumulating evidence has suggested that cold exposure can cause liver damage, the underlying mechanisms remain poorly understood. This study investigated the role and underlying mechanisms of ferroptosis in cold stress-induced liver damage. To evaluate the role of ferroptosis in cold stress-induced liver damage, rats were pretreated with ferroptosis inhibitor liproxstatin-1 (Lip-1) before exposed to -10 °C for 8 h. Core body temperature was recorded. The levels of ferroptosis-related indicators were examined with the corresponding assay kits or by western blotting. Hepatic pathological changes were analyzed by hematoxylin-eosin staining and ultrastructural observation. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured to assess liver function. Rats were also pretreated with p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 or Dynamin-related protein 1 (Drp1) inhibitor Mdivi-1 to determine the underlying mechanisms. We found that Lip-1 inhibited ferroptosis, attenuated hepatic pathological damages and blocked the increased ALT and AST levels in cold-exposed rats. Moreover, Mdivi-1 inhibited mitochondrial fission and suppressed ferroptosis. Furthermore, SB203580 and Mdivi-1 administration alleviated cold stress-induced liver injury. Our results suggested that cold stress caused liver damage partially by inducing ferroptosis through the p38 MAPK/Drp1 pathway. These findings might provide an effective preventive and therapeutic target for cold stress-induced liver injury.

Neutrophils exacerbate acetaminophen-induced liver injury by producing cytotoxic interferon-γ.

BACKGROUND: Drug (e.g., acetaminophen, APAP)-associated hepatotoxicity is the major cause of acute liver failure. Emerging evidence shows that initial tissue damage caused by APAP triggers molecular and cellular immune responses, which can modulate the severity of hepatoxicity. The pro-inflammatory and cytotoxic cytokine interferon (IFN)-γ has been reported as a key molecule contributing to APAP-induced liver injury (AILI). However, its cellular source remains undetermined. RESULTS: In the current study, we show that elevation of serum IFN-γ in patients with drug hepatotoxicity correlates with disease severity. Neutralization of IFN-γ in a mouse model of AILI effectively reduces hepatotoxicity. Strikingly, we reveal that IFN-γ is expressed primarily by hepatic neutrophils, not by conventional immune cells with known IFN-γ-producing capability, e.g., CD8+ T cells, CD4+ T cells, natural killer cells, or natural killer T cells. Upon encountering APAP-injured hepatocytes, neutrophils secrete cytotoxic IFN-γ further causing cell stress and damage, which can be abrogated in the presence of blocking antibodies for IFN-γ or IFN-γreceptor. Furthermore, removal of neutrophils in vivo substantially decreases hepatic IFN-γ levels concomitantly with reduced APAP hepatotoxicity, whereas adoptive transfer of IFN-γ-producing neutrophils confers IFN-γ-/- mice susceptibility to APAP administration. CONCLUSIONS: Our findings uncover a novel mechanism of neutrophil action in promoting AILI and provide new insights into immune modulation of the disease pathogenesis.

Protective role of thymoquinone in hyperlipidemia-induced liver injury in LDL-R-/-mice.

BACKGROUND: Hyperlipidemia, a heterogeneous group of disorders characterized by elevated plasma lipids in the blood, causes severe health problems, leading to fatty liver disease and nonalcoholic fatty liver disease. Thymoquinone, the major active chemical component of Nigella sativa, reportedly exerts a vast array of biological effects. Various studies have reported that Thymoquinone protects against liver injury. AIMS: The aim of this study was to investigate the possible protective effects of Thymoquinone against liver injury in hyperlipidemia-induced LDL-R-/- mice. METHODS: Eight-week-old male LDL-R-/- mice were randomly divided into three groups: a control group fed a normal diet and two groups fed a high-cholesterol diet or high-cholesterol diet mixed with Thymoquinone. All groups were fed different diets for 8 weeks. Blood samples were obtained from the inferior vena cava and collected in serum tubes. The samples were then stored at - 80 °C until used. Longitudinal sections of liver tissues were fixed in 10% formalin and then embedded in paraffin for histological evaluation. The remainder of the liver tissues were snap-frozen in liquid nitrogen for reverse transcription-polymerase chain reaction or western blotting. RESULTS: Our results demonstrated that Thymoquinone administration significantly reduced liver histological alterations by hyperlipidemia. Thymoquinone mitigated hyperlipidemia-induced liver injury as indicated by the suppression of metabolic characteristics, liver biochemical parameters, pyroptosis indicators, a macrophage marker, and the phosphatidylinositide 3-kinase signaling pathway. CONCLUSIONS: Thymoquinone is a potential therapeutic agent for hyperlipidemia-induced liver injury.

Lycopene attenuates silver nanoparticle-induced liver injury in albino mice.

Lycopene is a carotenoid widely used for its dominant antioxidant properties and beneficial health effects. Silver nanoparticles (AgNP) have gained attention for use in many medicinal and consumer products, leading to animal, human, and environmental exposure. This study investigated the dose-dependent effects of lycopene on AgNP-induced hepatotoxicity in albino mice. The four experimental groups, comprising eight albino mice each, were as follows: Group I, vehicle control (C); Group II, AgNP-treated (5 mg/kg/day) (AgNP); Group III, AgNP/lycopene-treated (5 + 10 mg/kg/day) (AgNP + LP10); and Group IV, AgNP/lycopene-treated (5 + 100 mg/kg/day) (AgNP + LP100). All solutions were orally administered to the mice once in a day for consecutive 14 days. The levels of serum aspartate transaminase, alanine transaminase, alkaline phosphatase, and total bilirubin were significantly higher in the AgNP-treated group than in the control group but significantly lower in the AgNP + LP100 group than in the AgNP-treated group. A significant decrease in reduced glutathione level and superoxide dismutase activity and an increase in lipid peroxidation were observed in the AgNP-treated group; these were significantly suppressed in the AgNP+LP100 as compared to AgNP-treated group. Histopathological examination showed substantial morphological alterations in hepatic tissues in the AgNP, which were adequately improved in the low and high dose lycopene-treated groups. The dose of 100 mg/kg/day of lycopene was more effective than 10 mg/kg/day, as pretreatment with high dose lycopene significantly diminished the adverse changes occurred due to AgNP in liver weight, hepatic architecture, serum functional markers, and antioxidant markers. Thus, present study shows that pretreatment with lycopene offers protection against AgNP-induced hepatotoxicity and oxidative stress.

Scutellarin prevents acute alcohol-induced liver injury via inhibiting oxidative stress by regulating the Nrf2/HO-1 pathway and inhibiting inflammation by regulating the AKT, p38 MAPK/NF-κB pathways. / ç¯ç›èŠ±ä¹™ç´ é€šè¿‡è°ƒèŠ‚Nrf2/HO-1通路抑制氧化应激以及通过调节AKT、p38 MAPK/NF-κBé€šè·¯æŠ‘åˆ¶ç‚Žç—‡ååº”é¢„é˜²æ€¥æ€§é ’ç²¾æ€§è‚æŸä¼¤.

Alcoholic liver disease (ALD) is the most frequent liver disease worldwide, resulting in severe harm to personal health and posing a serious burden to public health. Based on the reported antioxidant and anti-inflammatory capacities of scutellarin (SCU), this study investigated its protective role in male BALB/c mice with acute alcoholic liver injury after oral administration (10, 25, and 50 mg/kg). The results indicated that SCU could lessen serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and improve the histopathological changes in acute alcoholic liver; it reduced alcohol-induced malondialdehyde (MDA) content and increased glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD) activity. Furthermore, SCU decreased tumor necrosis factor-|α (TNF-|α), interleukin-6 (IL-6), and IL-|1ß messenger RNA (mRNA) expression levels, weakened inducible nitric oxide synthase (iNOS) activity, and inhibited nucleotide-binding oligomerization domain (NOD)|-like receptor protein 3 (NLRP3) inflammasome activation. Mechanistically, SCU suppressed cytochrome P450 family 2 subfamily E member 1 (CYP2E1) upregulation triggered by alcohol, increased the expression of oxidative stress-related nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) pathways, and suppressed the inflammation-related degradation of inhibitor of nuclear factor-|κB (NF-|κB)|-|α (IκBα) as well as activation of NF|-|κB by mediating the protein kinase B (AKT) and p38 mitogen-activated protein kinase (MAPK) pathways. These findings demonstrate that SCU protects against acute alcoholic liver injury via inhibiting oxidative stress by regulating the Nrf2/HO-1 pathway and suppressing inflammation by regulating the AKT, p38 MAPK/NF-κB pathways.

Naringin and naringenin counteract taxol-induced liver injury in Wistar rats via suppression of oxidative stress, apoptosis and inflammation.

This research aimed to evaluate the preventing effects of naringin, naringenin, and their combination on liver injury induced by Taxol (paclitaxel) in Wistar rats. Male Wistar rats received 2 mg/kg Taxol intraperitoneal injections twice weekly on the second and fifth days of each week for 6 weeks. During the same period as Taxol administration, rats were given naringin, naringenin, or a combination of the two (10 mg/kg b.wt) every other day. Treatment with naringin and/or naringenin reduced the abnormally high serum levels of total bilirubin, aspartate transaminase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase, and gamma-glutamyl transferase in Taxol-treated rats. It also significantly increased the level of serum albumin, indicating an improvement in the liver. The perturbed histological liver changes were markedly improved due to the naringin and/or naringenin treatment in Taxol-administered rats. Additionally, the treatments reduced high hepatic lipid peroxidation and increased liver glutathione content as well as the activities of superoxide dismutase and glutathione peroxidase. Furthermore, the treatments reduced the levels of alpha-fetoprotein and caspase-3, a pro-apoptotic mediator. The naringin and naringenin mixture appeared more effective in improving organ function and structural integrity. In conclusion, naringin and naringenin are suggested to employ their hepatoprotective benefits via boosting the body's antioxidant defense system, reducing inflammation, and suppressing apoptosis.