Acute Liver Injury Research Articles

Ursolic Acid Ameliorates Alcoholic Liver Injury through Attenuating Oxidative Stress-Mediated Ferroptosis and Modulating Gut Microbiota.

Ursolic acid (UA), a triterpenoid found in plants, has many health benefits for liver function. However, understanding how UA intervenes in alcohol-induced ferroptosis remains unclear because of the lack of research. This study explored the protective effects of UA on alcohol-induced liver injury and further elucidated its mechanism of action. Using a mouse model, acute liver injury was induced via high-dose alcohol gavage, and UA's protective effects were assessed by analyzing serum and liver indicators. The results indicated that UA has a significant protective effect against alcohol-induced liver injury in mice. UA significantly decreased serum ALT, AST, TC, and TG levels. Histopathological examination revealed that UA significantly ameliorated liver damage. UA increased ADH, ALDH, and CYP2E1 enzyme expression levels and alleviated alcohol-induced oxidative damage by regulating alcohol metabolism. Moreover, UA increased SOD and GSH-Px levels and lowered the MDA levels in the liver. Furthermore, UA regulated ACC expression by activating the LKB1/AMPK pathway, thereby inhibiting lipid synthesis and peroxidation. UA also upregulated the expression of GPX4 and SLC7A11 in the liver and exerted hepatoprotective effects by inhibiting alcohol-induced ferroptosis. Additionally, 16S rRNA amplicon sequencing showed that excessive alcohol consumption significantly affected the composition of the mouse gut microbiota, with UA intervention proving to be beneficial for improving gut microbiota imbalance. We also validated the protective effects of UA on alcohol-treated HepG2 cells at the cellular level. In summary, these results revealed that UA can alleviate alcoholic liver injury by inhibiting oxidative stress-mediated ferroptosis and regulating gut microbiota. These findings suggest that UA may serve as a functional component in the prevention of alcoholic liver disease.

Catalpol ameliorates liver fibrosis via inhibiting aerobic glycolysis by EphA2/FAK/Src signaling pathway

BackgroundHepatic fibrosis is a pathological process in a variety of acute or chronic liver injuries. Catalpol (CAT), an iridoid glycoside found in Rehmannia glutinosa, has several pharmacological properties, including anti-inflammatory, antidiabetic and anti-fibrotic effects. Nevertheless, there is currently no report on whether CAT regulates the aerobic glycolysis of hepatic stellate cells (HSCs) to inhibit liver fibrosis. ObjectiveThis study aimed to investigate the protective effects of CAT on hepatic fibrosis and elucidate its underlying mechanisms. MethodsTo explore whether CAT improved liver fibrosis in vivo and in vitro, hepatic fibrosis was induced to mice by intraperitoneally injecting carbon tetrachloride (CCl4). Additionally, LX-2 cells were stimulated with transforming growth factor-β (TGF-β) to simulate fibrosis in vitro. Serum markers of liver injury were examined by using an automatic biochemical analyzer. Histopathological staining, Immunofluorescence (IF) staining, Western blot (WB) analysis, co-immunoprecipitation (Co-IP), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), etc. were employed to identify the targeting between CAT and EphA2 and detect the expression of aerobic glycolysis related proteins, fiber markers and signaling pathways that are responsible for CAT's anti-fibrotic effects of CAT. ResultsResults showed that CAT significantly inhibited hepatic injury, fibrogenesis and inflammation in mice treated with CCl4. This was demonstrated by the enhancement of fibrosis markers, liver function indices, and histopathology. In addition, CAT significantly inhibited the activation of HSCs in TGF-β-induced LX-2 cells, as indicated by decreased proliferation, migration, and expression of collagen I and a-SMA. The study results also suggested that CAT may exert anti-fibrotic effects by inhibiting glycolysis in activated HSCs and in CCl4-treated mice. Mechanistically, CAT directly targets Ephrin type-A receptor 2 (EphA2) to reduce binding with focal adhesion kinases (FAK) and significantly inhibits the FAK/Src pathway. In addition, the pharmacological inhibition of EphA2 cannot further increase the therapeutic effects of CAT on liver fibrosis in vivo and in vitro. ConclusionThe study findings generally demonstrated that CAT presented a novel therapeutic method to treat hepatic fibrosis; this method which inhibits the aerobic glycolysis of activated HSCs through the EphA2/FAK/Src signaling pathway.

Small Molecule-Mediated Stage-Specific Reprogramming of MSCs to Hepatocyte-Like Cells and Hepatic Tissue for Liver Injury Treatment.

Derivation of hepatocytes from stem cells has been established through various protocols involving growth factor (GF) and small molecule (SM) agents, among others. However, mesenchymal stem cell-based derivation of hepatocytes still remains expensive due to the use of a cocktail of growth factors, and a long duration of differentiation is needed, thus limiting its potential clinical application. In this study, we developed a chemically defined differentiation strategy that is exclusively based on SM and takes 14days, while the GF-based protocol requires 23-28days. We optimized a stage-specific differentiation protocol for the differentiation of rat bone marrow-derived mesenchymal stem cells (MSCs) into functional hepatocyte-like cells (dHeps) that involved four stages, i.e., definitive endoderm (DE), hepatic competence (HC), hepatic specification (HS) and hepatic differentiation and growth. We further generated hepatic tissue using human decellularized liver extracellular matrix and compared it with hepatic tissue derived from the growth factor-based protocol at the transcriptional level. dHep, upon transplantation in a rat model of acute liver injury (ALI), was capable of ameliorating liver injury in rats and improving liver function and tissue damage compared to those in the ALI model. In summary, this is the first study in which hepatocytes and hepatic tissue were derived from MSCs utilizing a stage-specific strategy by exclusively using SM as a differentiation factor.

Near-Infrared Fluorescent Probe Reveals Elevated Mitochondrial Viscosity during Acute Alcoholic Liver Injury.

Acute alcoholic liver injury (AALI) has become an important cause of liver disease worldwide, and there is an urgent need to develop noninvasive and sensitive methods to detect and evaluate AALI. We report herein three novel but readily available mitochondrial targeting fluorescence probes (ICR, ICJ, and ICQ) for AALI detection. These probes contain different electron-donating groups, among which ICQ exhibits NIR fluorescence (740 nm), a large Stokes shift (110 nm), and a sensitive response to viscosity (73-fold enhancement in fluorescence from water to glycerol), making it suitable for in vivo imaging. ICQ also exhibits an excellent ability to image mitochondrial viscosity changes in cells. More importantly, ICQ can target the liver selectively and image the viscosity changes in the liver noninvasively. Through establishing an AALI mouse model, ICQ was successfully applied to the in situ imaging changes in liver viscosity during the AALI process. The results showed a significant increase in liver viscosity in AALI mice, indicating that viscosity can serve as a marker for AALI, and ICQ is a promising noninvasive and sensitive tool for detecting and evaluating AALI.

CTGF regulated by ATF6 inhibits vascular endothelial inflammation and reduces hepatic ischemia–reperfusion injury

Vascular endothelial inflammation is crucial in hepatic ischemia–reperfusion injury (IRI). Our previous research has shown that connective tissue growth factor (CTGF), secreted by endothelial cells, protects against acute liver injury, but its upstream mechanism is unclear. We aimed to clarify the protective role of CTGF in endothelial cell inflammation during IRI and reveal the regulation between endoplasmic reticulum stress-induced activating transcription factor 6 (ATF6) and CTGF. Hypoxia/reoxygenation in endothelial cells, hepatic IRI in mice and clinical specimens were used to examine the relationships between CTGF and inflammatory factors and determine how ATF6 regulates CTGF and reduces damage. We found that activating ATF6 promoted CTGF expression and reduced liver damage in hepatic IRI. In vitro, activated ATF6 upregulated CTGF and downregulated inflammation, while ATF6 inhibition had the opposite effect. Dual-luciferase assays and chromatin immunoprecipitation confirmed that activated ATF6 binds to the CTGF promoter, enhancing its expression. Activated ATF6 increases CTGF and reduces extracellular regulated protein kinase 1/2 (ERK1/2) phosphorylation, decreasing inflammatory factors. Conversely, inhibiting ATF6 decreases CTGF and increases the phosphorylation of ERK1/2, increasing inflammatory factor levels. ERK1/2 inhibition reverses this effect. Clinical samples have shown that CTGF increases after IRI, inversely correlating with inflammatory cytokines. Therefore, ATF6 activation during liver IRI enhances CTGF expression and reduces endothelial inflammation via ERK1/2 inhibition, providing a novel target for diagnosing and treating liver IRI.

Apocynin alleviates thioacetamide-induced acute liver injury: Role of NOX1/NOX4/NF-κB/NLRP3 pathways

The liver has a distinctive capacity to regenerate, yet severe acute injury can be life-threatening if not treated appropriately. Inflammation and oxidative stress are central processes implicated in the pathophysiology of acute livery injury. NOX isoforms are important enzymes for ROS generation, NF-κB and NLRP3 activation, its inhibition could be vital in alleviating acute liver injury (ALI). Here in our study, we used apocynin, a natural occurring potent NOX inhibitor, to exploreits potential protective effect against thioacetamide (TAA)-induced ALI through modulating crucial oxidative and inflammatory pathways. Rats were injected once with TAA (500 mg/kg/i.p) and treated with apocynin (10 mg/kg/i.p) twice before TAA challenge. Sera and hepatic tissues were collected for biochemical, mRNA expression, western blot analysis and histopathological assessments. Pretreatment with apocynin improved liver dysfunction evidenced by decreased levels of aminotransferases, ALP, GGT and bilirubin. Apocynin reduced mRNA expression of NOX1 and NOX4 which in turn alleviated oxidative stress, as shown by reduction in MDA and NOx levels, and elevation in GSH levels andcatalase and SOD activities. Moreover, apocynin significantly reduced MPO gene expression. We also demonstrate that apocynin ameliorated inflammation through activating IκBα and suppressing IKKα, IKKβ, NF-κBp65 and p-NF-κBp65, IL-6 andTNF-α. Additionally, apocynin potentiated the gene expression of anti-inflammatory IL-10 and reduced levels of hepatic NLRP3, Caspase-1 and IL-1β. These results suggest that apocynin protects against ALI in association with the inhibition of NOX1 and NOX4 and regulating oxidative and inflammatory pathways.

Early brain neuroinflammatory and metabolic changes identified by dual tracer microPET imaging in mice with acute liver injury.

Acute liver injury (ALI) that progresses into acute liver failure (ALF) is a life-threatening condition with an increasing incidence and associated costs. Acetaminophen (N-acetyl-p-aminophenol, APAP) overdosing is among the leading causes of ALI and ALF in the Northern Hemisphere. Brain dysfunction defined as hepatic encephalopathy is one of the main diagnostic criteria for ALF. While neuroinflammation and brain metabolic alterations significantly contribute to hepatic encephalopathy, their evaluation at early stages of ALI remained challenging. To provide insights, we utilized post-mortem analysis and non-invasive brain micro positron emission tomography (microPET) imaging of mice with APAP-induced ALI. Male C57BL/6 mice were treated with vehicle or APAP (600 mg/kg, i.p.). Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), liver damage (using H&E staining), hepatic and serum IL-6 levels, and hippocampal IBA1 (using immunolabeling) were evaluated at 24h and 48h. Vehicle and APAP treated animals also underwent microPET imaging utilizing a dual tracer approach, including [ 11 C]-peripheral benzodiazepine receptor ([ 11 C]PBR28) to assess microglia/astrocyte activation and [ 18 F]-fluoro-2-deoxy-2-D-glucose ([ 18 F]FDG) to assess energy metabolism. Brain images were pre-processed and evaluated using conjunction and individual tracer uptake analysis. APAP-induced ALI and hepatic and systemic inflammation were detected at 24h and 48h by significantly elevated serum ALT and AST levels, hepatocellular damage, and increased hepatic and serum IL-6 levels. In parallel, increased microglial numbers, indicative for neuroinflammation were observed in the hippocampus of APAP-treated mice. MicroPET imaging revealed overlapping increases in [ 11 C]PBR28 and [ 18 F]FDG uptake in the hippocampus, thalamus, and habenular nucleus indicating microglial/astroglial activation and increased energy metabolism in APAP-treated mice (vs. vehicle-treated mice) at 24h. Similar significant increases were also found in the hypothalamus, thalamus, and cerebellum at 48h. The individual tracer uptake analyses (APAP vs vehicle) at 24h and 48h confirmed increases in these brain areas and indicated additional tracer- and region-specific effects including hippocampal alterations. Peripheral manifestations of APAP-induced ALI in mice are associated with brain neuroinflammatory and metabolic alterations at relatively early stages of disease progression, which can be non-invasively evaluated using microPET imaging and conjunction analysis. These findings support further PET-based investigations of brain function in ALI/ALF that may inform timely therapeutic interventions.

Fibroblast growth factor 21 alleviates acetaminophen induced acute liver injury by activating Sirt1 mediated autophagy

Background and aimsAcetaminophen (APAP) is the main cause of acute liver injury (ALI) in the Western. Our previous study has shown that fenofibrate activated hepatic expression of fibroblast growth factor 21 (FGF21) can protect the liver form APAP injuries by promoting autophagy. However, the underlying mechanism involved in FGF21-mediated autophagy remains unsolved. MethodsThe ALI mice model was established by intraperitoneal injection of APAP. To investigate the influence of FGF21 on autophagy and Sirt1 expression in APAP-induced ALI, FGF21 knockout (FGF21KO) mice and exogenously supplemented mouse recombinant FGF21 protein were used. In addition, primary isolated hepatocytes and the Sirt1 inhibitor EX527 were used to observe whether FGF21 activated autophagy in APAP injury is regulated by Sirt1 at the cellular level. ResultsFGF21, Sirt1, and autophagy levels increased in mice with acute liver injury (ALI) and in primary cultured hepatocytes. Deletion of the FGF21 gene exacerbated APAP-induced liver necrosis and oxidative stress, and decreased mitochondrial potential. It also reduced the mRNA and protein levels of autophagy-related proteins such as Sirt1, LC3-II, and p62, as well as the number of autophagosomes. Replenishment of FGF21 reversed these processes. In addition, EX527 partially counteracted the protective effect of FGF21 by worsening oxidative damage, mitochondrial damage, and reducing autophagy in primary liver cells treated with APAP. ConclusionFGF21 increases autophagy by upregulating Sirt1 to alleviate APAP-induced injuries.

Overexpression of DTX1 inhibits D-GalN/TNF-α-induced pyroptosis and inflammation in hepatocytes by regulating NLRP3 ubiquitination.

Acute liver injury (ALI) is characterized by massive hepatocyte death and has high mortality and poor prognosis. Hepatocyte pyroptosis plays a key role in the pathophysiology of ALI and is involved in the inflammatory response mediated by NOD-like receptor protein 3 (NLRP3) inflammasome activation. Deltex 1 (DTX1) is a single transmembrane protein with ubiquitin E3 ligase activity and is closely involved in cell growth, differentiation, and apoptosis, as well as intracellular signal transduction. However, little is known about the influence of DTX1 on ALI. This study aimed to investigate the role of DTX1 in pyroptosis and inflammation induced by D-galactosamine (D-GalN) and tumor necrosis factoralpha (TNF-α) in human hepatocytes (LO2 cells) in vitro. Cell pyroptosis was measured by flow cytometry. The levels of DTX1, pyroptosis-associated proteins, and inflammatory cytokines were detected by quantitative real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. Immunofluorescence staining, co-immunoprecipitation, ubiquitination, and luciferase reporter and chromatin immunoprecipitation assays were performed to detect the regulation between DTX1 and NLRP3 or hepatocyte nuclear factor 4 alpha (HNF4α). Analysis of variance was performed to compare groups. We found that DTX1 was decreased in D-GalN/TNF-α-induced LO2 cells. DTX1 overexpression significantly inhibited D-GalN/TNF-α-induced cell pyroptosis and inflammation. DTX1 interacted with NLRP3 and induced NLRP3 ubiquitination and degradation. Furthermore, by targeting NLRP3, DTX1 knockdown significantly induced cell pyroptosis and inflammation. In addition, HNF4α promoted DTX1 transcription by binding with its promoter. Our study revealed that DTX1 suppressed D-GalN/TNF-α-induced hepatocyte pyroptosis and inflammation by regulating NLRP3 ubiquitination.

Differentiating Ischemic Hepatitis from Acetaminophen Overdose in Acute Liver Failure: Role of Acetaminophen Adducts-Ischemic Hepatitis vs Acetaminophen Overdose.

Acetaminophen (APAP) hepatotoxicity and ischemic hepatic injury (IH) demonstrate remarkably similar biochemical patterns. Deciding between these two etiologies in the setting of acute liver failure (ALF) can be challenging. We reviewed all cases in the Acute Liver Failure Study Group (ALFSG) registry where these diagnoses were considered, to determine reasons for, and frequency of, difficulties making these diagnoses. We hypothesized that the newly developed APAP-CYS adduct assay could help in discerning the correct diagnosis. Among 3364 patients with ALF or acute liver injury (ALI: INR ≥ 2.0 but without encephalopathy) between 1998 and 2019, 1952 (58%) received a final diagnosis of either APAP (1681) or IH (271). We utilized a review committee of senior hepatologists as well as the APAP-CYS assay (where sera were available), measuring the presence of toxic by-products of APAP injury to optimize adjudication. With these methods, a total of 575 adduct positive APAP cases included 488 recognized APAP, as well as an additional 87 patients previously diagnosed as other etiologies. Nine cases initially attributed to IH were deemed combination APAP-IH injuries. Conversely, 215 of the 280 IH subjects tested for adducts disclosed 173 confirmed as IH with adduct testing below the toxicity threshold, while 9 cases were revised from APAP to the IH-APAP combination phenotype, where both hypotension and APAP likely played a role. Discerning APAP from IH can be difficult-in rare cases, combined injury is observed (18/1952). APAP-CYS testing resulted in revising the diagnosis in 14.6% of cases.

Paracetamol Dosing Errors in People Aged 12 Years and Over: An Analysis of Over 14,000 Cases Reported to an Australian Poisons Information Centre.

Paracetamol dosing errors can cause acute liver injury, with potentially toxic doses only slightly above the therapeutic range. This study aimed to characterise unintentional paracetamol overdose reported to an Australian poisons centre, including time trends, demographics, types of dosing errors, and outcomes. Records regarding paracetamol dosing errors for individuals aged ≥12 years were extracted from the New South Wales Poisons Information Centre database, January 2017 to June 2023. Data from 2021 underwent an in-depth screening of free text case notes to examine: dose, duration, products involved, reasons for ingestion and outcomes including hospitalisation, treatment, liver transplantations and deaths. Where possible, complete outcome data were obtained from medical records of New South Wales hospitalised cases in 2021. There were 14,380 exposures due to paracetamol dosing errors (predominantly self-administered, median age 43 years, 62.6% female), with an average yearly increase of 2.5% (95% CI 1.6-3.8%; p < 0.0001). The in-depth analysis of exposures recorded during 2021 revealed 1899 exposures (median age 46 years, 63.4% female) with 26.8% requiring hospitalisation. Immediate- and modified-release formulations were highly implicated. Multiple paracetamol-containing products were ingested in approximately 20% of exposures. Hospitalised exposures were associated with paracetamol use for dental pain and ingested higher doses for longer durations. Over half of those hospitalised (52%) were treated with the antidote (N-acetylcysteine), and 6% of exposures developed hepatotoxicity. Paracetamol dosing errors continue to occur, with relatively high rates of hospitalisation and liver injury. Many hospitalisations involved use for dental pain. Possible preventative measures include ingredient name prominence and increased education on appropriate dosing.

Tirzepatide-Related Acute Liver Injury.

Tirzepatide should be used cautiously, with regular monitoring of liver function tests.If patients develop severe gastrointestinal symptoms or worsening abdominal pain, immediate hospital admission is necessary for further work-up, including a CT abdomen.Daily liver function tests, renal function tests and international normalised ratio (INR) tests should be conducted to identify and manage potential complications.

“Parvovirus B19–related Acute Hepatitis: Clinical Spectrum and Outcome in Children”

Acute liver injury is a common manifestation of parvovirus B19 (PVB19) infection in immunocompromised patients. However, literature in immunocompetent children is scarce. We aimed to study the clinicolaboratory features and outcome of hepatic involvement by PVB19 infection in hospitalized children. We retrospectively analyzed our prospectively kept database of all children (<18 years old) admitted with acute viral hepatitis (AVH), acute liver failure (ALF) or acute-on-chronic liver failure (ACLF), and PVB19 infection between January 2010 and December 2023. Clinical features, laboratory parameters, and complications were evaluated. Poor outcome was defined as death or liver transplantation. A total of 35 children (19 boys [54%], median age: 7.25 [interquartile range: 4-10.8] years) with PVB19-related hepatitis were studied (28 [80%] isolated PVB19 infection and 7 [20%] coinfections [3 with Epstein-Barr virus, 2 with hepatitis A, and 1 each with hepatitis-E and cytomegalovirus]). AVH (17, 49%) was the most common presentation, followed by ALF (13, 37%) and acute insult in ACLF (5, 14%). Patients with coinfection had significantly higher bilirubin (14.6 [9.4-21.5] vs 6.8 [4.3-10.9] mg/dl; P=0.004) and transaminases (ALT: 697 [428-1296] vs. 277 [157-478] U/L; P=0.02) but similar mortality (1/7 vs 6/23; P=1.0) than PVB19 alone. Nine cases (25.7%) had extrahepatic complications (hemophagocytic lymphohistiocytosis [HLH]: 3, acute kidney injury: 3, aplastic anemia: 2, and myocarditis: 1). Poor outcome occurred in 38% (5/13) ALF, 11.7% (2/17) AVH (HLH: 1, myocarditis: 1), and none (0/5) of the ACLF cases. PVB19 should be considered in children presenting with indeterminate acute liver injury, especially in younger children or those with complications such as aplastic anemia, HLH, or myocarditis.

Acute Liver Injury and Bilateral Pulmonary Artery Thrombosis Due to Hypereosinophilic Syndrome.

A 46-year-old Japanese man was referred to our hospital because of a marked increase in his eosinophil count (22,870/μL) and elevated liver enzyme levels. Computed tomography (CT) showed thrombi measuring approximately 8 cm in both femoral veins. A liver biopsy revealed eosinophilic infiltration, hepatocyte necrosis, fibrosis, and multiple thrombi. We suspected acute liver injury and deep vein thrombosis associated with hypereosinophilic syndrome and initiated steroids and heparin treatment. Four days after starting treatment, the patient experienced sudden chest pain and cardiopulmonary arrest. CT revealed bilateral pulmonary artery thrombosis, and despite administration of a tissue plasminogen activator, the patient died.

Cisplatin induces acute liver injury by triggering caspase-3/GSDME-mediated cell pyroptosis

BackgroundCisplatin triggers Gasdermin E (GSDME) cleavage, causing membrane bubble formation, content release, and inflammation. Caspase-3 activation initiates GSDME cleavage, and thus inhibiting this pathway mitigates cisplatin-induced pyroptosis in hepatocytes. This study aimed to delve into how cisplatin induces liver injury via pyroptosis. MethodsFor animal experiments, C57BL/6J mice were divided into three groups: control, liver injury model group, and Ac-DMLD-CMK (caspase-3 inhibitor) intervention group. The liver histology was evaluated by hematoxylin and eosin staining, immunohistochemistry, immunofluorescence and TUNEL staining. The mRNA and protein levels were detected by real-time polymerase chain reaction (PCR) and Western blot analysis. For in vitro experiments, HL-7702 cells were treated with cisplatin or GSDME siRNA. Cell pyroptosis was determined via cellular morphology, cytotoxicity and viability detection, flow cytometric assay, and Western blot detection for the expression of pyroptosis-related proteins. ResultsCisplatin-induced distinct liver morphological changes, hepatocellular injury, and inflammation in mice, along with elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and increased pro-inflammatory cytokine expression. Heightened macrophage infiltration and hepatocellular death indicated cisplatin-induced hepatotoxicity. Cisplatin upregulated GSDME activation, along with Bax-mediated caspase-3 cleavage both in vivo and in vitro, implicating caspase-3/GSDME-dependent pyroptosis in liver injury. Treatment with Ac-DMLD-CMK ameliorated cisplatin-induced liver injury, reducing hepatocellular lesions, serum ALT and AST levels, cytokine expression, macrophage infiltration, and hepatocyte death. Ac-DMLD-CMK also attenuated GSDME-dependent pyroptosis post-cisplatin induction, as evidenced by decreased GSDME expression, Bax upregulation, and cleaved caspase-3 activation. For HL-7702 cells, GSDME siRNA transfection reduced GSDME expression, attenuated typical signs of cisplatin-induced pyroptosis, partially restored cell viability, and significantly inhibited cytotoxicity and a decrease in the proportion of propidium iodide-positive cells, indicating protection against cisplatin-induced hepatocyte pyroptosis. ConclusionOur study underscores the role of the caspase-3/GSDME signaling pathway in mediating cisplatin-induced hepatotoxicity, particularly in cases of excessive or cumulative cisplatin exposure. These findings suggest that targeting GSDME could represent a promising therapeutic approach to mitigate cisplatin-induced liver damage.

LP-46 Leaky gut causes inflammatory stress: a determinant of acute liver injury induced by coadministration of rhein and LPS

LP-46 Leaky gut causes inflammatory stress: a determinant of acute liver injury induced by coadministration of rhein and LPS

Ethylene Glycol Poisoning with Acute Liver Injury Due to Delayed Diagnosis: An Autopsy Case Report and Literature Review

Ethylene glycol (EG), commonly used as antifreeze, is frequently ingested accidentally or in suicides, and causes acute renal failure. We report an unusual case of EG poisoning with acute liver injury. After vomiting and loss of consciousness, a 48-year-old male was admitted to the emergency room. Despite prompt conservative treatment for metabolic acidosis, kidney function deteriorated, necessitating the continuous renal replacement therapy. Blood toxicology results, showing EG levels of 510 mg/L, arrived 10 hours after admission. Oral ethyl alcohol therapy commenced 16 hours post-admission. By 36 hours, liver function tests indicated significant liver damage, and the patient died 45 hours upon admission. On autopsy, histological findings were hepatic centrilobular necrosis, cerebral perivascular neutrophilic and lymphocytic infiltration with calcium oxalate deposition, and renal tubular necrosis with calcium oxalate deposition. EG concentrations in the blood and gastric contents were 18.7 mg/L and 45.0 mg/L, respectively. Glycolic acid and oxalic acid, metabolites of EG produced by alcohol dehydrogenase in the liver, cause metabolic acidosis, renal tubular calcium oxalate deposition, and acute renal failure, leading to death. Generally, because fomepizole or ethyl alcohol block alcohol dehydrogenase in the liver, acute liver injury by EG poisoning is rare. To the best of authors’ knowledge, only one relevant report was found in the literature described a case in which EG caused centrilobular necrosis in liver. In the current case, delays in diagnosis and antidote therapy without gastric lavage allowed continued metabolism of EG which led to acute liver injury and acute renal failure.

A comprehensive strategy of lipidomics and pharmacokinetics based on ultra-high-performance liquid chromatography-mass spectrometry of Shaoyao Gancao Decoction.

Shaoyao Gancao Decoction (SGD), a traditional Chinese medicine, has been proven to have a good liver protection effect, but the mechanism and pharmacodynamic substances of SGD in the treatment of acute liver injury are still unclear. In this study, an ultra-high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) method was established to characterize 107 chemical components of SGD and 12 compounds absorbed in rat plasma samples after oral administration of SGD. Network pharmacology was applied to construct a component-target-pathway network to screen the possible effective components of SGD in acute liver injury. Using lipidomics based on UHPLC-Q-TOF-MS coupled with a variety of statistical analyses, 20 lipid biomarkers were screened and identified, suggesting that the improvement of acute liver injury by SGD was involved in cholesterol metabolism, glycerol-phospholipid metabolism, sphingolipid signaling pathways and fatty acid biosynthesis. In addition, the UHPLC-tandem MS method was established for pharmacokinetics analysis, and 10 potential active components were determined simultaneously within 12 min through the optimization of 0.1% formic acid water and acetonitrile as a mobile phase system. A Pharmacokinetics study showed that paeoniflorin, albiflorin, oxypaeoniflorin, liquiritigenin, isoliquiritigenin, liquiritin, ononin, formononetin, glycyrrhizic acid, and glycyrrhetinic acid as the potential active compounds of SGD curing acute liver injury.

Infection, inflammation and hepatic encephalopathy from a clinical perspective.

Hepatic encephalopathy (HE) is a syndrome that is associated with both acute and chronic liver injury. It manifests as a wide spectrum of neuropsychological abnormalities, ranging from subtle impairments in executive higher functions observed in cirrhosis, through to coma in acute liver failure. In acute liver failure, the central role of ammonia in the development of brain oedema has remained undisputed for 130 years. It latterly became apparent that infection and inflammation were profound determinants for the development of severe hepatic encephalopathy, associated with the development of cerebral oedema and intracranial hypertension. The relationship of the development of hepatic encephalopathy with blood ammonia levels in cirrhosis is less clear cut and the synergistic interplay of inflammation and infection with ammonia has been identified as being fundamental in the development and progression of hepatic encephalopathy. A perturbed gut microbiome and the presence of an impaired gut epithelial barrier that facilitates translocation of bacteria and bacterial degradation products into the systemic circulation, inducing systemic inflammation and innate and adaptive immune dysfunction, has now become the focus of therapies that treat hepatic encephalopathy in cirrhosis, and may explain why the prebiotic lactulose and rifaximin are efficacious. This review summarises the current clinical perspective on the roles of inflammation and infection in hepatic encephalopathy and presents the evidence base for existing therapies and those in development in the setting of acute and chronic liver failure.

A Butyrate-Yielding Dietary Supplement Prevents Acute Alcoholic Liver Injury by Modulating Nrf2-Mediated Hepatic Oxidative Stress and Gut Microbiota.

Alcoholic liver disease (ALD) is a globally prevalent form of liver disease for which there is no effective treatment. Recent studies have found that a significant decrease in butyrate was closely associated with ALD development. Given the low compliance and delivery efficiency associated with oral-route butyrate administration, a highly effective butyrate-yielding dietary supplement, butyrylated high-amylose maize starch (HAMSB), is a good alternative approach. Here, we synthesized HAMSB, evaluated the effect of HAMSB on acute ALD in mice, compared its effect with that of oral administration of butyrate, and further studied the potential mechanism of action. The results showed HAMSB alleviated acute ALD in mice, as evidenced by the inhibition of hepatic-function impairment and the improvement in liver steatosis and lipid metabolism; in these respects, HAMSB supplementation was superior to oral sodium butyrate administration. These improvements can be attributed to the reduction of oxidative stress though the regulation of Nrf2-mediated antioxidant signaling in the liver and the improvement in the composition and function of microbiota in the intestine. In conclusion, HAMSB is a safe and effective dietary supplement for preventing acute ALD that could be useful as a disease-modifying functional food or candidate medicine.