Hepatocyte Damage Research Articles

Exploring Haptoglobin as a Promising Marker for Severe Liver Diseases: A Comprehensive Review

Liver damage is a common symptom of many diseases, including metabolic disorders and cancers. Such patient condition requires effective examinations aimed at prompt diagnosis and implementation of the most appropriate treatment for a specific disease. Haptoglobin, the subject of many studies, has proven to be a protein that can be used as a biomarker of liver damage, thereby aiding not only in the diagnosis but also in the treatment, resulting in more favorable prognoses regarding patient longevity and quality of life.The aim of this study is to elucidate the role of haptoglobin as a diagnostic and prognostic biomarker in cases of liver damage.This is a review of scientific literature and analysis of clinical data regarding haptoglobin levels in liver damage were conducted to assess the reliability of haptoglobin as a biomarker.This paper primarily utilized the latest publications produced after 2015. PubMed and Google Scholar were used to find relevant publications. All cited works provided useful information to achieve the aim of our article.Analysis of the literature suggests that haptoglobin levels may be significantly associated with the development and severity of liver damage. It may serve as a suitable biomarker for diagnosing diseases that coincide with hepatocyte damage, thus improving the diagnosis of these diseases and increasing the chance of appropriate treatment, which may contribute to prolonging and improving the patient's quality of life.Haptoglobin appears to be a promising biomarker in liver damage; however, further research is necessary to confirm its diagnostic and prognostic accuracy. Haptoglobin exists in various genotypic forms, each characteristic of different disease entities. Understanding the mechanisms regulating haptoglobin levels may lead to a better understanding of liver damage pathogenesis and the development of more effective therapies, increasing the chance of patient recovery and improving their quality of life.

Triptolide induces hepatotoxicity by promoting ferroptosis through Nrf2 degradation

BackgroundTriptolide (TP), a principal active substance from Tripterygium wilfordii, exhibits various pharmacological effects. However, its potential hepatotoxicity has always been a significant concern in clinical applications.PurposeThis research aimed to explore the involvement of ferroptosis in TP-mediated hepatic injury and the underlying mechanisms.MethodsIn this study, in vitro and in vivo experiments were involved. Hepatocyte damage caused by TP was evaluated using MTT assays, liver enzyme measurement and H&E staining technique. Ferroptosis was assessed by measuring iron level, lipid peroxide, glutathione (GSH), mitochondrial morphology and the key protein/mRNA expression implicated in ferroptosis. To verify the contribution of ferroptosis to TP-induced liver damage, the ferroptosis inhibitor Ferrostatin-1 (Fer-1) and a plasmid for overexpressing glutathione peroxidase 4 (GPX4) were employed. Subsequently, nuclear factor erythroid 2-related factor 2 (Nrf2) knockout mice and Nrf2 overexpression plasmid were utilized to investigate the underlying mechanisms. Nontargeted lipidomics was used to analyze lipid metabolism in mouse liver. Moreover, the cellular thermal shift assay (CETSA), cycloheximide (CHX) and MG132 treatments, and immunoprecipitation (IP) assays were applied to validate the binding of TP to Nrf2 and their interactions.ResultsTP triggered ferroptosis in hepatocytes, as indicated by iron accumulation and lipid peroxidation. Ferroptosis was responsible for TP-induced hepatic injury. During the process of TP-induced liver damage, the Nrf2 signaling pathway was significantly suppressed. Notably, the deletion of Nrf2 in mice aggravated the extent of liver injury and ferroptosis associated with TP, whereas enhancing Nrf2 expression in cells significantly reduced TP-induced ferroptosis. Additionally, dysregulation of lipid metabolism was associated with TP-induced liver injury. TP may directly bind to Nrf2 and enhance its degradation through the ubiquitin–proteasome pathway, thereby inhibiting or reducing Nrf2 expression.ConclusionIn summary, the suppression of Nrf2 by TP facilitated the occurrence of ferroptosis, resulting in liver damage.Graphical abstract

N-glycosylation Modification Reveals Insights into the Oxidative Reactions of Liver in Wuzhishan Pigs

Although porcine liver contributes to their growth and development by nutrition production and energy supply, oxidative stress-induced hepatocyte damage is inevitable during metabolism. N-glycosylation is a common modification in oxidation; nevertheless, the effects of N-glycosylation on pig liver oxidative reactions remain undefined. In this study, liver proteins with N-glycosylation were detected in Wuzhishan (WZS) pigs between 4 and 8 months old and Large White (LW) pigs at 4 months old based on LC-MS/MS. The results showed that the number of differentially expressed proteins (DEPs) was larger between different pig cultivars than that between WZS pigs at various growth periods. The enriched pathways of DEPs were mainly related to oxidative reactions, and 10 proteins were finally selected that primarily consisted of CYPs, GSTs and HSPs with expressions significantly correlating to liver size and weight. The oxidative genes shared N-glycosylation-modified models of N-x-S and N-G. Five out of 10 proteins were upregulated in WZS pigs compared to LW pigs at 4 months old, while five proteins increased in WZS pigs from 4 to 8 months old. In conclusion, this research provides valuable information on the N-glycosylation motifs in liver oxidation genes of WZS pigs.

The Impact of Methamphetamine on Liver Injury in Iraqi Male Addicts

Methamphetamine (METH) is a powerful stimulant that affects neurochemical processes controlling heart rate, appetite, blood pressure, body temperature, and wakefulness, making it highly susceptible to abuse. Liver enzymes such as ALT, AST, ALP, and GGT are crucial for liver function. Albumin, a protein synthesized by healthy liver cells, serves as an indicator of chronic liver disease. Additionally, hepatocytes produce bile acids, which are essential for the secretion of bile salts into the bile canaliculi. Disruption in this secretion results in the accumulation of bile salts in the canaliculi, leading to intrahepatic cholestasis. METH-induced liver toxicity involves disruptions in hepatic metabolism, oxidative stress, and increased body temperature, affecting cellular processes such as cell division and the cell cycle and potentially accelerating liver cell apoptosis. The study explores the link between liver toxicity and hepatocyte damage in Iraqi males suffering from addiction. This is a case-control study, conducted at Ibn-Rushed Psychiatric Hospital in Baghdad from July 2023 to February 2024, involved 196 males, with addiction durations exceeding 24 months with varying degrees of methamphetamine (METH) addiction. The study included 187 healthy male controls with no history of drug addiction. Participants were aged 18 to 40 years. Diagnosis was confirmed using a drug test screening card administered by a specialist. The study included liver function tests (ALT, AST, ALP, and GGT), total bilirubin, and albumin concentration assessments. Significant differences were observed between the addicts and controls, particularly a marked decrease in serum albumin concentration in the addicted males. The ROC curve classification model at various thresholds demonstrated that liver enzymes, especially ALT, ALP, and GGT, exhibited increased sensitivity to METH addiction. A histopathological examination was conducted on a deceased 38-year-old male who had a six-year history of chronic amphetamine addiction to confirm liver injury and the resulting elevation of liver enzymes. The findings of this study indicate that METH greatly affects liver function, suggested to the importance of following a preventative measures and effective treatment approaches for monitoring METH addiction progress.

Taxifolin attenuates hepatic ischemia-reperfusion injury by enhancing PINK1/Parkin-mediated mitophagy.

Hepatic ischemia-reperfusion (I/R) injury stands as a recurring clinical challenge in liver transplantation, leading to mitochondrial dysfunction and cellular imbalance. Mitochondria, crucial for hepatocyte metabolism, are significantly damaged during hepatic I/R and the extent of mitochondrial damage correlates with hepatocyte injury. PINK1/Parkin-mediated mitophagy, is a specialized form of cellular autophagy, that maintains mitochondrial quality by identifying and removing damaged mitochondria, thereby restoring cellular homeostasis. Taxifolin (TAX), a natural flavonoid, possesses antioxidant, anti-inflammatory and anticancer properties. This study aimed at investigating the effects of TAX on hepatic I/R and the underlying mechanisms. C57BL/6 mice were pretreated with TAX or vehicle control, followed by 60 minutes of 70% hepatic ischemia. After 6 hours of reperfusion, the mice were euthanized. In vitro, TAX-pretreated primary hepatocytes were subjected to oxygen glucose deprivation/reperfusion (OGD/R). Hepatic I/R caused mitochondrial damage and apoptosis in hepatocytes, but TAX pretreatment mitigated these effects by normalizing mitochondrial membrane potential and inhibiting reducing apoptotic protein expression. TAX exerted its protective effects by enhancing mitophagy via the PINK1/Parkin pathway. Moreover, silencing the PINK1 gene in primary hepatocytes reversed the beneficial effects of TAX. The results of the study demonstrate that promoting mitophagy through the PINK1/Parkin pathway restores mitochondrial function and protects the liver from I/R, suggesting that it may have therapeutic potential for the treatment of hepatic I/R.

Curcumol ameliorates alcohol and high-fat diet-induced fatty liver disease via modulation of the Ceruloplasmin/iron overload/mtDNA signaling pathway.

Fatty liver disease (FLD), a chronic liver disease characterized by excessive lipid deposition, is affecting more and more people worldwide owing to the increasing global incidence of obesity and heavy alcohol consumption. However, there is still no effective strategy for prevention or treatment of alcohol and high-fat diet (HFD)-induced FLD. The purpose of this study was to investigate the effect of curcumol on alcohol and HFD-induced FLD and the underlying molecular mechanisms. The results showed that curcumol ameliorated alcohol and HFD-induced hepatocyte injury in vivo and in vitro, and the mechanism might be related to its up-regulation of ceruloplasmin and subsequent alleviation of iron overload. Moreover, curcumol inhibited alcohol and HFD-induced mitochondrial damage and mtDNA release in hepatocytes by modulating iron overload. Furthermore, curcumol's inhibition of mtDNA release could suppress the activation of cGAS-STING and subsequent inflammation, and this phenomenon could be reversed by cGAS overexpression. Notably, alcohol and HFD-induced mtDNA release from hepatocytes contributed to HSC activation and this effect could be weakened by curcumol. In conclusion, these findings elucidated that curcumol ameliorated alcohol and HFD-induced FLD via modulating ceruloplasmin/iron overload/mtDNA signaling pathway, which lead to the inhibition of inflammation and HSCs activation.

Green Tea Yoghurt with Encapsulated Lacticaseibacillus paracasei E1 Improves Hepatocyte Damage in High-Fat High-Fructose Diet Mice by Reducing MDA and Increasing SOD

Green Tea Yoghurt with Encapsulated Lacticaseibacillus paracasei E1 Improves Hepatocyte Damage in High-Fat High-Fructose Diet Mice by Reducing MDA and Increasing SOD

Etomidate Inhibits Hepatic Ischemia-Reperfusion Injury Depending on the Activation of Nrf2-HO-1 Signaling Pathway.

Hepatic ischemia-reperfusion (I/R) injury (HIRI) is recognized as a local aseptic inflammatory response driven by innate immunity and is considered a leading cause of early organ dysfunction and failure following liver transplantation. Etomidate (Eto), an anesthetic drug known for its ability to inhibit inflammatory response and apoptosis, was the focus of our investigation. In this study, we conducted hepatic I/R surgery invivo on C57 mice, analyzing liver damage through histopathology. Additionally, primary hepatocytes isolated from mice were cultured and subjected to hypoxia/reoxygenation (H/R) insult in vitro, with cell activity assessed using the CCK8 assay and immunofluorescence staining employed to analyze liver inflammatory cell infiltration and apoptosis. Results showed that Eto effectively inhibited liver injury, inflammatory response, and apoptosis induced by HIRI surgery, with the greatest effect observed at an Eto concentration of 10 mg/kg. Furthermore, Eto also showed the ability to inhibit H/R-induced cell damage, inflammatory activation, and apoptosis in primary hepatocytes. Further mechanistic studies revealed that Eto could promote the activation of the Nrf2-HO-1 signaling pathway, and the protective effect of Eto on HIRI was nullified when the Nrf2 inhibitor ML385 was utilized. This study highlights the potential of Eto to protect against HIRI by promoting the Nrf2-HO-1 signaling axis.

Targeted Delivery to Dying Cells Through P-Selectin-PSGL-1 Axis: A Promising Strategy for Enhanced Drug Efficacy in Liver Injury Models.

To minimize off-target adverse effects and improve drug efficacy, various tissue-specific drug delivery systems have been developed. However, even in diseased organs, both normal and stressed, dying cells coexist, and a targeted delivery system specifically for dying cells has yet to be explored to mitigate off-target effects within the same organ. This study aimed to establish such a system. By examining the surfaces of dying cells in vitro, we identified P-selectin glycoprotein ligand-1 (PSGL-1) as a universal marker for dying cells, positioning it as a potential target for selective drug delivery. We demonstrated that liposomes conjugated with the PSGL-1 binding protein P-selectin had significantly greater binding efficiency to dying cells compared to control proteins such as E-selectin, L-selectin, galectin-1, and C-type lectin-like receptor 2. Using thioacetamide (TAA) to induce hepatitis and hepatocyte damage in mice, we assessed the effectiveness of our P-selectin-based delivery system. In vivo, P-selectin-conjugated liposomes effectively delivered fluorescent dye and the apoptosis inhibitor z-DEVD to TAA-damaged livers in wild-type mice, but not in PSGL-1 knockout mice. In TAA-treated wild-type mice, unconjugated liposomes required a 100-fold higher z-DEVD dose compared to P-selectin-conjugated liposomes to achieve a comparable, albeit less effective, therapeutic outcome in lowering plasma alanine transaminase levels and alleviating thrombocytopenia. This emphasizes that P-selectin conjugation enhances drug delivery efficiency by approximately 100-fold in mice. These results suggest that P-selectin-based liposomes could be a promising strategy for targeted drug delivery, enabling both diagnosis and treatment by specifically delivering cell-labeling agents and rescue agents to dying cells via the P-selectin-PSGL-1 axis at the individual cell level.

AdipoRon Alleviates Liver Injury by Protecting Hepatocytes from Mitochondrial Damage Caused by Ionizing Radiation

Radiation liver injury is a common complication of hepatocellular carcinoma radiotherapy. It is mainly caused by irreversible damage to the DNA of hepatocellular cells directly by radiation, which seriously interferes with metabolism and causes cell death. AdipoRon can maintain lipid metabolism and stabilize blood sugar by activating adiponectin receptor 1 (AdipoR1). However, the role of AdipoRon/AdipoR1 in the regulation of ionizing radiation (IR)-induced mitochondrial damage remains unclear. In this study, we aimed to elucidate the roles of AdipoRon/AdipoR1 in IR-induced mitochondrial damage in normal hepatocyte cells. We found that AdipoRon treatment rescued IR-induced liver damage in mice and mitochondrial damage in normal hepatocytes in vivo and in vitro. AdipoR1 deficiency exacerbated IR-induced oxidative stress, mitochondrial dynamics, and biogenesis disorder. Mechanistically, the absence of AdipoR1 inhibits the activity of adenosine monophosphate-activated protein kinase α (AMPKα), subsequently leading to disrupted mitochondrial dynamics by decreasing mitofusin (MFN) and increasing dynamin-related protein 1 (DRP1) protein expression. It also controls mitochondrial biogenesis by suppressing the peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC1α) and transcription factor A (TFAM) signaling pathway, ultimately resulting in impaired mitochondrial function. To sum up, AdipoRon/AdipoR1 maintain mitochondrial function by regulating mitochondrial dynamics and biogenesis through the AdipoR1-AMPKα signaling pathway. This study reveals the significant role of AdipoR1 in regulating IR-induced mitochondrial damage in hepatocytes and offers a novel approach to protecting against damage caused by IR.

Thyroid Hormone-Mediated Selective Autophagy and Its Implications in Countering Metabolic Dysfunction-Associated Steatotic Liver Disease.

The influence of thyroid hormone (TH) on liver metabolism has attracted the attention of pharmacologists seeking new treatments for metabolic dysfunction-associated steatotic liver disease (MASLD), an increasingly common metabolic disorder. In this context, the selective induction of autophagy by TH in preclinical models has been identified as a promising mechanism. In this process, TH clears intrahepatic fat through lipophagy while protecting against inflammation and mitochondrial damage in hepatocytes via mitophagy. Furthermore, TH-induced aggrephagy may represent a protective mechanism to mitigate the development of MASLD-associated hepatocellular carcinoma. Considering the defects in autophagy observed during the progression of human MASLD, the induction of autophagy by TH, its metabolites, and its analogs represent a novel strategy to combat hepatic damage across the MASLD spectrum.

Blockade of 11β-hydroxysteroid dehydrogenase type 1 ameliorates metabolic dysfunction-associated steatotic liver disease and fibrosis

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a key enzyme involved in the conversion of cortisone to active cortisol in the liver. Elevated cortisol levels can trigger oxidative stress, inflammation, and hepatocyte damage, highlighting the importance of 11β-HSD1 inhibition as a potential therapeutic approach. This study aimed to explore the effects of INU-101, an inhibitor of 11β-HSD1, on the development of metabolic dysfunction-associated steatotic liver disease (MASLD) and fibrosis. Our findings demonstrated that INU-101 effectively mitigated cortisol-induced lipid accumulation, reactive oxygen species generation, and hepatocyte apoptosis. Furthermore, 11β-HSD1 inhibition suppressed hepatic stellate cell activation by modulating β-catenin and phosphorylated SMAD2/3. INU-101 administration significantly reduced hepatic lipid accumulation and liver fibrosis in mice fed fast-food diet. This study suggests that INU-101 holds promise as a clinical candidate for treating MASLD and fibrosis, offering potential therapeutic benefits by targeting the intricate processes involving 11β-HSD1 and cortisol regulation in the liver.

Anxiolytic, memory improvement, hepatoprotective, and antioxidant effects of Thymus vulgaris on alcohol withdrawal syndrome in mice

Introduction: Thymus vulgaris is a plant used in Cameroon to alleviate and treat hangover symptoms. This study was conducted to assess the anxiolytic, memory-improving, hepatoprotective, and antioxidant effects of T. vulgaris on alcohol withdrawal syndrome. Methods: In this preclinical study 42 mice were grouped into seven equal sets of normal control, negative control, positive control (piracetam; 200 mg/kg), and test (T. vulgaris; 25, 50, 100, or 200 mg/kg) groups. All mice (except those of the normal control) were administered ethanol by gavage once daily for 28 days. After alcohol withdrawal, behavioral assessments (elevated plus maze, Y-maze, and open field) were performed from day 29 to day 31, one hour following appropriate treatments. Mice were euthanized on day 32 and the brains and the livers were used for histopathological assessment and oxidative stress parameters evaluation. Results: In the elevated plus maze test, T. vulgaris at 100 and 200 mg/kg significantly (P < 0.001) increased the number of entries and the time spent in the open arms. The plant extract (200 mg/kg) significantly (P < 0.001) increased the spontaneous alternation percentage in the Y maze. T. vulgaris administration decreased malondialdehyde (MDA) and nitric oxide (NO) in the brain and liver and increased glutathione (GSH) and catalase (CAT). The plant extract reduced the neuronal degeneration and hepatocyte damage induced by chronic alcohol administration. Conclusion: T. vulgaris had anxiolytic, memory-enhancing, and hepatoprotective properties against alcohol toxicity. These results may justify the use of thyme in traditional pharmacopeia in the management of alcohol use disorders (AUDs).

Assessing the Impact of Clove (Syzygium Aromaticum) Extract on Intestinal and Hepatic Histological Alterations in Broiler Chickens Infected with Salmonella typhimurium

This study investigated effects of aqueous and ethanolic clove extracts in small intestine and liver of chickens exposed to Salmonella typhimurium. Two hundred fifty-day-old chicks were divided into five groups. Group 1 served as the control and received a basic diet.Group 2 was orally infected with Salmonella typhimurium. Group 3 received same infection but was treated with Ciprofloxacin. Groups 4 and 5 were infected but received treatments of aqueous and ethanolic clove extracts, respectively. The findings revealed that Group 1 exhibited normal small intestine, while Group 2 displayed severe abnormalities, including flattened mucosa, damaged villi, and inflammation. Group 3 showed improvements, increased cell growth and goblet cells in the small intestine. Group 4 displayed nearly normal intestinal features. Group 5 had fully restored intestinal health. In the liver, Group 1 showed typical hepatic structure, whereas Group 2 exhibited signs of inflammation and hepatocyte necrosis. Group 3 displayed severe hepatocyte damage, while Group 4 demonstrated restored liver structure with slight sinusoidal dilation. Group 5 had a well-preserved hepatic architecture with minor inflammation. Administration of 2 mg/kg of aqueous and ethanolic clove extracts demonstrated alleviate histological alterations in small intestine and liver caused by Salmonella typhimurium infection. Notably, the aqueous extract is more effective than ethanolic extract in reducing liver and intestine damage.

Study of liver function test and Vitronectin as biomarker for liver cell in Iraqi chronic myeloid leukemia (CML) patients with nucleophosmin 1(NPM) mutation

A cancer cell's behavior is determined by changes at the DNA level, according to the research on leukemia disease that is now available, particularly the molecular and clinical investigations. The current study was designed to evaluate the level of some liver biomarkers serum transaminase AST and ALT along with level of Vitronectin (VTN) as marker for hepatocyte damage in Iraqi chronic myeloid leukemia (CML) patients. The effect of a nucleophosmin 1(NPM) mutation in the level of these markers was compared with CML patients who did not have this mutation. The study included 60 patients with CML (17 male and 43 female). The data of current study recorded mutation in about 30% among the studied samples. The results of the statistical analysis of the number of blood cells showed a highly significant increase in blood cells (RBC, WBC and platelets) and damage to the liver tissue. It was evident through the level AST and VTN level which increased significantly at p≤0.05. On the other hand, the data showed significant differences between those with mutation and without regarding VTN. There were non-significant differences between those with mutation and without regarding to AST and ALT at p-value ≤ 0.05. The study proved an effect of CML on the vital liver functions and it also proved that a mutation (NPM-1) in the nucleofosmin protein reduced the negative effect of the disease on the functional activity of the liver.

Modulation of liver metabolism and gut microbiota by Alhagi-honey alleviated heat stress-induced liver damage

Alhagi-honey (AH) is a well-established traditional ethnic medicine with advantageous effects against diarrhea and headaches. We aimed to explore the preventive effect of AH on liver damage induced by heat stress (HS) and its underlying mechanism. HS models were established by thermostat, and mice were treated at 39 ℃ for 10 h, lasting for 7 days. Hematoxylin–eosin (H&E) staining and Periodic Acid-Schiff (PAS) staining were used for histological observation, and transmission electron microscopy (TEM) was used for ultrastructure examination of hepatocytes. Gut microbiota (GM) composition and liver metabolites were respectively analyzed by 16S rRNA sequencing and non-targeted metabolome sequencing. AH pretreatment alleviated liver damage caused by heat stress in mice. The main manifestation was that AH alleviated serum aspartate transferase (AST) and aspartate transaminase (ALT). It was found that AH improved symptoms of hepatocyte damage. In addition, the relative abundance of f_Rikenellaceae, g_Incertae_Sedis and s_Staphylococcus_Orisratti, g_Lachnoclostridium, g_GCA-900066575, and s_Alistipes_inops were modified by AH and these bacterial genera showed association with 6 metabolites (2- (3,4-dihydroxyphenyl) acetamide, 3-hydroxy-3-methylpentanedioic acid, PC (17:0/17:1), Y-L-Glutamy-L-glutamic acid, L-Isoleucine, 5-Methyluridine, 8,8-dimethyl-2-phenyl-4H,8H-pyrano [2, 3-h] chromen-4-one). The Pearson analysis also showed a strong correlation between these microbes and 2 risk indicators (AST and ALT) of liver damage. AH alleviated HS-induced liver damage by regulating liver metabolism and maintaining normal GM. It demonstrated that AH held potential as a prophylactic drug for the prevention of HS-induced liver damage.

Triptolide-induced acute liver injury and its mechanism with estradiol in regulating macrophage-mediated inflammation and hepatocyte function

Triptolide (TP), a diterpene from Tripterygium wilfordii, exhibits potent anti-inflammatory, immunomodulatory, and antitumor properties but is limited by severe hepatotoxicity. This study investigates sex differences in TP-induced liver injury and the protective role of estradiol (E2) in modulating macrophage-mediated inflammation and hepatocyte function. An acute liver injury model was established in male and female Balb/c mice using intraperitoneal TP injection. Liver function tests, histological analyses, and immunohistochemical staining were performed. THP-1 macrophage and various liver cell lines were used to study the effects of TP and E2 in vitro. Virtual screening, molecular docking, luciferase assays, and qPCR were employed to identify potential targets and elucidate underlying mechanisms. TP caused more severe liver injury in female mice, evidenced by increased liver indices, aspartate aminotransferase (AST) levels, and extensive hepatocyte damage. TP promoted M1 macrophage polarization, enhancing inflammation, particularly in female mice. E2 mitigated TP-induced inflammatory responses by downregulating pro-inflammatory cytokines and macrophage activation markers. Molecular docking and functional assays identified Nuclear receptor subfamily 1 group I member 2 (NR1I2) as a key target mediating the protective effects of E2. The study highlights significant sex differences in TP-induced hepatotoxicity, with females being more susceptible. E2 exerts protective effects against TP-induced liver injury by modulating immune responses, presenting a potential therapeutic approach to mitigate drug-induced liver injury (DILI). Further research on NR1I2 could lead to targeted therapies for reducing drug-induced liver damage.

Excess glucose alone induces hepatocyte damage due to oxidative stress and endoplasmic reticulum stress

Type 2 diabetes mellitus (DM) is a significant risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC). With the increasing prevalence of type 2 DM and MASLD due to lifestyle changes, understanding their impact on liver health is crucial. However, the hepatocellular damage caused by glucose alone is unknown. This study investigates the effect of excess glucose on hepatocytes, focusing on oxidative stress, endoplasmic reticulum stress (ER stress), apoptosis, autophagy, and cell proliferation. We treated an immortalized-human hepatocyte cell line with excess glucose and analyzed. Excess glucose induced oxidative stress and ER stress in a time- and concentration-dependent manner, leading to apoptosis. Oxidative stress and ER stress were independently induced by excess glucose. Proteasome inhibitors and palmitic acid exacerbated glucose-induced stress, leading to the formation of Mallory-Denk body-like inclusion bodies. Despite these stresses, autophagic flux was not altered. Excess glucose also caused DNA damage but did not affect cell proliferation. This suggests that glucose itself can contribute to the progression of metabolic dysfunction-associated steatohepatitis (MASH) and carcinogenesis of HCC in patients with type 2 DM. Managing blood glucose levels is crucial to prevent hepatocyte damage and associated complications.

Involvement of BRD4 in Alcoholic Liver Injury: Autophagy Modulation via Regulation of the SIRT1/Beclin1 Axis

Alcoholic liver disease (ALD) caused by chronic alcohol abuse involves complex processes from steatosis to fibrosis, cirrhosis, and hepatocellular carcinoma, posing a global health issue. Bromodomain protein 4 (BRD4) typically serves as a “reader” modulating the functions of transcription factors involved in various biological processes and disease progression. However, the specific mechanisms underlying alcoholic liver injury remain unclear. In this study, we detected aberrant BRD4 expression in the alcohol-induced ALD mouse model of chronic and binge ethanol feeding developed by the National Institute on Alcohol Abuse and Alcoholism, consistent with the in vitro results in Aml-12 mouse hepatocytes. Blocking and inhibiting BRD4 restored the impaired autophagic flux and lysosomal functions in alcohol-treated Aml-12 cells, whereas BRD4 overexpression reduced the expression levels of autophagy marker and lysosomal genes. Furthermore, mouse BRD4 knockdown, mediated by a short hairpin RNA carried by the adeno-associated virus serotype 8, significantly attenuated the alcohol-induced hepatocyte damage, including lipid deposition and inflammatory cell infiltration. Mechanistically, BRD4 overexpression in alcoholic liver injury inhibited the expression of sirtuin (SIRT)1 in Aml-12 cells. Chromatin immunoprecipitation and dual-luciferase reporter assays revealed that BRD4 functions as a transcription factor and suppressor, actively binding to the SIRT1 promoter region and inhibiting its transcription. SIRT1 activated autophagy, which was suppressed in alcoholic liver injury via Beclin1 deacetylation. In conclusion, our study revealed that BRD4 negatively regulated the SIRT1/Beclin1 axis and that its deficiency alleviated alcohol-induced liver injury in mice, thus providing a new strategy for ALD treatment.

Comparative Study on Hepatoprotective Effects of Traditional Herbs, Roots of Angelica gigas Nakai, Glycyrrhiza uralensis Fischer, Zizyphus jujuba Mill., and Fruits of Paeonia lactiflora Pall., on Ethanol-Induced Liver Injury in Mice.

Alcohol-associated liver disease (ALD) is a major cause of chronic liver disease, with few effective treatments besides alcohol abstinence. Angelicae Gigantis Radix (AG), Glycyrrhizae Radix et Rhizoma (GR), Paeoniae Radix (PR), and Zizyphi Fructus (ZF) are traditional herbs used to treat various ailments, including liver diseases. While several studies have reported the beneficial effects of GR on ALD, the effects of AG, PR, and ZF remain underexplored. Therefore, their efficacy and mechanisms against ALD were investigated using an alcohol-related liver injury model. The model was induced by ethanol gavage in C57BL/6J mice for 14 days, followed by oral administration of AG, GR, PR, and ZF one hour post-induction. The administration of these herbs reduced liver weight, and improved serum biomarkers of liver injury (ALT, AST, albumin). The herbs enhanced hepatic antioxidant capacity (GSH, SOD, catalase) and suppressed the production of proinflammatory cytokines (TNF-α, IL-1β) and apoptotic changes (caspase-3). The mechanisms of action involved lipid-lowering gene modulation through regulation of the cytochrome P450 2E1/Sirtuin 1/Nrf2 pathways. Histopathological and immunohistochemical analyses revealed that these herbs attenuated hepatocyte damage and steatosis via antioxidant, anti-inflammatory, and antiapoptotic effects. These findings suggest that traditional herbs, particularly AG, could be promising alternative therapies for treating ALD.