Acute Liver Damage Research Articles

A novel immunopharmacological biocompound

The publication is devoted to topical issues of experimental study of new biocompounds, based on the creation of a consortium of biological composite compounds – biological active substances (metabiotics) produced by strains 59T and 60T of saprophytic compounds of the genus Bacillus subtilis. These strains are very promising for the creation of hepatopicts, new medicinal substances, in the creation and development of a new pharmacological class of hepatoprotectors. Previous studies have shown the safety and hepatoprotective effect of biologically active drugs. It is worth noting that the very effective compounds are the produced biologically active substances – metabolites of bacterial origin, on the basis of which it seems appropriate to create a new class of drugs – metabiotics. The absence of vegetative probiotic cells in such compounds will reduce the additional immune load on the body. The combined use of these compounds provides a potentiated pharmacological effect. In this regard, it seemed appropriate, under the conditions of modeling toxic liver damage by carbon tetrachloride, to conduct an experimental assessment of the immunotropic effect of biologically active substances (BAS) on laboratory animals in order to confirm the effect on cellular factors of immunity. The purpose of the study was to study the effect of the combined use of dietary supplements produced by Bacillus subtilis microorganisms on indicators of cellular immunity in laboratory animals with toxic liver damage. Acute toxic hepatitis was reproduced in white laboratory rats with repeated intragastric administration of carbon tetrachloride. The comparison drug was a registered hepatoprotective drug – ursosan. The immunotropic effect was assessed using factors such as: phagocytic activity of macrophages and neutrophils (FA), NBT test, quantitative assessment of antibody-forming cells, T and B lymphocytes. As a result of the studies performed, reliable data were obtained on an increase in the number of T and B lymphocytes, antibody-forming cells, as well as an increase in FA, which confirms the activation of all parts of cellular immunity in conditions of acute toxic liver damage. The data obtained allow us to recommend the studied biocompound for the creation of new drug candidates of microbiological origin, hepatoprotective agents with immunotropic effects.

A Protocol for the Isolation of Oval Cells without Preconditioning.

Oval cells (OCs) is the name of hepatic progenitor cells (HPCs) in rodents. They are a small population of cells in the liver with the remarkable ability to proliferate and regenerate hepatocytes and cholangiocytes in response to acute liver damage. Isolating OCs generally requires a pretreatment with special diets, chemicals, and/or surgery to induce hepatic damage and OC proliferation in mice. Unfortunately, these pretreatments are not only painful for the mice but also increase the cost of the assays, and the effects on the different organs as well as on various liver cells are still unclear. Therefore, the search for a protocol to obtain OCs without prior liver damage is mandatory. In our study, we present a protocol to isolate murine OCs from healthy liver (HL-OCs) and compare them with OCs isolated from mice pretreated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC-OCs). Our results demonstrated that cells derived from untreated mice exhibited similar behavior to those from treated mice in terms of surface marker expression, proliferation, and differentiation capacity. Therefore, given the impracticability of isolating human cells with prior hepatotoxic treatment, our model holds promise for enabling the isolation of progenitor cells from human tissue in the future. This advancement could prove invaluable for translational medicine in the understanding and treatment of liver diseases.

An outbreak of Galerina sulciceps-like (Galerina cf. sulciceps) mushroom poisoning

Objective Amatoxin-containing mushroom poisoning is a significant threat to public health worldwide. We report a mass poisoning of Galerina sulciceps-like mushrooms (Galerina cf. sulciceps) in Luzhou, Sichuan Province, China, aiming to offer insights for future prevention and treatment strategies. Methods We performed a retrospective survey of mass mushroom poisoning patients admitted to our hospital. The demographic data, clinical presentations, laboratory findings, therapeutic measures and prognostic information were collected and analyzed. We used the 2020 Chinese consensus on the clinical diagnosis and treatment of amatoxin-containing mushroom poisoning to assess the severity of poisoning. Mushrooms were examined through morphological analysis, molecular biology identification, and toxin detection. Results Our patient cohort consisted of nine males and six females, with mean (±SD) age of 34.9 ± 13.0 years. Gastrointestinal symptoms were the first to manifest, with mean (±SD) latency period of 13.4 ± 3.9 h. The majority of patients (86.7%) experienced nausea, vomiting, and diarrhea. Liver dysfunction was noted in 66.7% of patients, and thrombocytopenia was present in 26.7% of patients. In terms of the severity of poisoning, there were 10 mild cases and 5 severe cases. The mushrooms were provisionally labeled as Galerina cf. sulciceps, containing the toxins α-amanitin, β-amanitin, and γ-amanitin. All patients eventually recovered. Discussion We report what appears to be a new type of mushroom that is morphologically and phylogenetically similar to the known Galerina sulciceps, but further study is required to determine if it represents a distinct species. Conclusion This poisoning event was caused by unintentional ingestion of Galerina cf. sulciceps, an amatoxin-containing mushroom. Early symptoms are primarily gastrointestinal, with acute liver damage and coagulopathy being the main toxic effects. Thrombocytopenia is also prominent, particularly in severe cases. Accurate assessment and prompt, individualized, and intensive treatment are crucial for managing patients with acute Galerina cf. sulciceps poisoning effectively.

The role of 2ʹ–5ʹ-oligoadenylate synthase-like protein (OASL1) in biliary and hepatotoxin-induced liver injury in mice

Following an injury, the liver embarks on a process that drives the accumulation and reformation of the extracellular matrix, leading to hepatic fibrosis. Type I interferons (IFNs), including IFN-α and IFN-β, play a crucial role in averting chronic liver injury through the activation of IFN-stimulated genes (ISGs), which are instrumental in sculpting adaptive immunity. The role of 2ʹ–5ʹ-oligoadenylate synthase-like protein 1 (OASL1), an antiviral ISG, in the context of liver fibrosis remains to be elucidated. To elicit liver fibrosis, a diet containing 0.1% diethoxycarbonyl-1,4-dihydrocollidine (DDC) and carbon tetrachloride (CCl4) were employed to induce cholestatic- and hepatotoxin-mediated liver fibrosis, respectively. Histological analyses of both models revealed that OASL1−/− mice exhibited reduced liver damage and, consequently, expressed lower levels of fibrotic mediators, notably α-smooth muscle actin. OASL1−/− mice demonstrated significantly elevated IFN-α and IFN-β mRNA levels, regulated by the IFN regulatory factor 7 (IRF7). Additionally, OASL1−/− ameliorated chronic liver fibrosis through the modulation of nuclear factor-κB (NF-κB) signaling. The effect of OASL1 on type I IFN production in acute liver damage was further explored and OASL1−/− mice consistently showed lower alanine transaminase levels and pro-inflammatory cytokines, but IFN-α and IFN-β mRNA levels were upregulated, leading to amelioration of acute liver injury. Additionally, the study discovered that F4/80-positive cells were observed more frequently in OASL1−/− CCl4 acutely treated mice. This implies that there is a significant synergy in the function of macrophages and OASL1 deficiency. These results demonstrate that in instances of liver injury, OASL1 inhibits the production of type I IFN by modulating the NF-κB signaling pathway, thereby worsening disease.

Curcumin delivery nanoparticles based on Maillard reaction of Haematococcus pluvialis protein/galactose for alleviating acute alcoholic liver damage

Curcumin delivery nanoparticles based on Maillard reaction of Haematococcus pluvialis protein/galactose for alleviating acute alcoholic liver damage

Role of exosomes from mesenchymal stem cell in hepatic regeneration after acute liver damage by carbon tetrachloride in adult male albino rats. Histological study

Role of exosomes from mesenchymal stem cell in hepatic regeneration after acute liver damage by carbon tetrachloride in adult male albino rats. Histological study

Extracts of the Canadian goldenrod (Solidago Canadensis L.) – promising agents with antimicrobial, anti-inflammatory and hepatoprotective activity

S. canadensis L. and S. virgaurea L. are the most common species of Solidago L. in Europe and with a long tradition of use in medicine for various therapeutic purposes: diseases of the urinary tract, gastrointestinal tract, diabetes, allergies and antiseptic purposes. Therefore, the research of species of the Solidago genus, which have a rich content of natural BACs, and the development of new effective medicinal products of plant origin are relevant. The aim. The method of work is the phytochemical and pharmacological study of extracts of the Canadian goldenrod herb, obtained by ethanol solutions of various concentrations, for the innovative perspective of creating new medicines based on them with antimicrobial, anti-inflammatory and hepatoprotective activity. Materials and methods. The objects of the study were extracts of herb from Canadian goldenrod, obtained using purified water, 40 %, 70 % and 90 % ethanol. Phytochemical study of the extracts was performed by TLC and spectrophotometry. Study of acute toxicity, antimicrobial, anti-inflammatory and hepatoprotective activity of extracts was carried out according to standard methods. Research results. A study of the phytochemical composition and pharmacological activity of extracts of herb from Canadian goldenrod obtained with different solvents. It was established that extracts of herb from Canadian goldenrod show anti-inflammatory activity. The most pronounced antiexudative activity is shown by the extract of the Canadian goldenrod herb (extractant - 40 % ethanol), reducing the degree of swelling by 24.77 %. Herb extracts from from Canadian goldenrod in acute toxic liver damage show moderate hepatoprotective activity, which is somewhat inferior to the comparative drug "Silibor". A more intense and effective effect on the hepatobiliary system was shown by the extract of the Canadian goldenrod herb (extractant - 40 % ethanol). Conclusions. The perspective of creation based on herb of Canadian goldenrod new drugs with hepatoprotective activity. The most promising substance turned out to be an extract of herb from Canadian goldenrod obtained with a 40 % ethanol solution.

Cystathionine gamma-lyase deficiency exaggerates diethylnitrosamine-induced liver damage in mice

Cystathionine gamma-lyase (CSE) is a key enzyme in reverse transsulfuration pathway and contributes to the majority of H2S generation in liver tissues via cysteine metabolism. Dysfunction of the CSE/H2S system is linked to both chronic and acute liver damage. This study investigated the regulatory role of CSE deficiency on diethylnitrosamine (DEN)-induced liver damage in mice. A single injection of DEN was administered into 4-week-old male CSE knockout (CSE-KO) mice and wild-type (WT) littermates, and the mice were sacrificed at 28 weeks of age. Compared to age-matched WT mice, CSE-KO mice spontaneously developed steatosis with increased oxidative stress and higher expressions of inflammation and fibrosis-related genes at 28-weeks of age. Following DEN injection, CSE-KO mice experienced more severe liver damage in comparison with the WT group as reflected by elevated levels of lipid accumulation, increased activities of alanine aminotransferase and aspartate aminotransferase, higher oxidative stress and fibrosis development, and increased expressions of inflammation and fibrosis-related genes. No visible tumors were observed in both types of mice with DEN treatment. In addition, the expression levels of the three H2S-generating proteins (CSE, cystathionine beta-synthase, and 3-mercaptopyruvate sulfurtransferase) and the H2S production rate in liver tissues were unaffected by DEN. Taken together, our study demonstrates that CSE provides a significant hepatoprotective effect and deficiency of CSE exaggerates DEN-induced liver damage in mice. Based on these findings, it can be suggested that targeting the CSE/H2S signaling pathway could be a potential therapeutic target for the treatment of liver diseases.

Empagliflozin impact on experimentally induced acetaminophen toxicity: Imprint of mitochondrial dynamics, biogenesis, and cGAS/STING signal in amending liver insult.

Acetaminophen (APAP) is one of the most clinically relevant medications associated with acute liver damage. A prolific deal of research validated the hepatoprotective effect of empagliflozin (EMPA); however, its effect on APAP-induced hepatotoxicity has still not been investigated. In this study, the prospective hepatoprotective impact of EMPA against APAP-induced hepatotoxicity was investigated. Twenty-eight Balb-C mice were assigned to four groups: control, APAP, EMPA10/APAP, and EMPA25/APAP. At the end of the experiment, serum hepatotoxicity biomarkers, MDA level, and GSH content were estimated. Hepatic mitofusin-2 (MFN2), optic atrophy 1 (OPA1), dynamin-related protein 1 (Drp1), and mitochondrial fission 1 protein (FIS1) were immunoassayed. PGC-1α, cGAS, and STING mRNA expression were assessed by real-time PCR. Histopathological changes and immunohistochemistry of INF-β, p-NF-κB, and iNOS were evaluated. APAP treatment caused significant hepatic functional impairment and increased hepatic MDA levels, as well as a concomitant decrease in GSH content. Marked elevation in Drp1 and FIS1 levels, INF-ß, p-NF-κB, and iNOS immunoreactivity, and reduction in MFN2 and OPA1 levels in the APAP-injected group, PGC-1α downregulation, and high expression of cGAS and STING were also documented. EMPA effectively ameliorated APAP-generated structural and functional changes in the liver, restored redox homeostasis and mitochondrial dynamics balance, and enhanced mitochondrial biogenesis, remarkably diminished hepatic expression of cGAS and STING, and elicited a reduction in hepatic inflammation. Moreover, the computational modeling data support the interaction of APAP with antioxidant system-related proteins as well as the interactions of EMPA against Drp1, cGAS, IKKA, and iNOS proteins. Our findings demonstrated for the first time that EMPA has an ameliorative impact against APAP-induced hepatotoxicity in mice via modulation of mitochondrial dynamics, biogenesis, and cGAS/STING-dependent inflammation. Thus, this study concluded that EMPA could be a promising therapeutic modality for acute liver toxicity.

Rutaecarpine Aggravates Acetaminophen-Induced Acute Liver Injury by Inducing CYP1A2.

In this study, we investigated whether rutaecarpine could aggravate acetaminophen-induced acute liver damage in vivo and in vitro. CCK-8 and apoptosis assays were performed to verify the cytotoxicity of acetaminophen to L02 cells with or without rutaecarpine. The expression levels of the target proteins and genes were determined using Western blotting and qRT-PCR. The liver pathological changes were evaluated with hematoxylin and eosin staining, while the aspartate aminotransferase (AST) and alanine aminotransferase (AST) levels in plasma were measured to assess the liver damage. Our results revealed that pretreatment of the cell and mice with rutaecarpine significantly aggravated the acetaminophen-induced liver damage. Mechanistically, rutaecarpine induces the CYP1A2 protein, which accelerates the metabolism of acetaminophen to produce a toxic intermediate, N-acetyl-p-benzoquinone imine (NAPQI), leading to severe liver inflammation. Rutaecarpine exacerbated the liver damage by upregulating CYP1A2 and proinflammatory factors. These findings highlight the importance of carefully considering the dosage of rutaecarpine when combined with acetaminophen in drug design and preclinical trials.

N-acetyl Cysteine Overdose Induced Acute Toxicity and Hepatic Microvesicular Steatosis by Disrupting GSH and Interfering Lipid Metabolisms in Normal Mice.

N-acetyl cysteine (NAC) is a versatile drug used in various conditions, but the limitations and toxicities are not clear. The acute toxicity and toxicological mechanisms of an intraperitoneal injection of NAC in normal mice were deciphered. The LD50 for male and female BALB/cByJNarl mice were 800 mg/kg and 933 mg/kg. The toxicological mechanisms of 800 mg/kg NAC (N800) were investigated. The serum biomarkers of hepatic and renal indices dramatically increased, followed by hepatic microvesicular steatosis, renal tubular injury and necrosis, and splenic red pulp atrophy and loss. Thus, N800 resulted in mouse mortality mainly due to acute liver, kidney, and spleen damages. The safe dose (275 mg/kg) of NAC (N275) increased hepatic antioxidant capacity by increasing glutathione levels and catalase activity. N275 elevated the hepatic gene expressions of lipid transporter, lipid synthesis, β-oxidation, and ketogenesis, suggesting a balance between lipid production and consumption, and finally, increased ATP production. In contrast, N800 increased hepatic oxidative stress by decreasing glutathione levels through suppressing Gclc, and reducing catalase activity. N800 decreased the hepatic gene expressions of lipid transporter, lipid synthesis, and interferred β-oxidation, leading to lipid accumulation and increasing Cyp2E1 expression, and finally, decreased ATP production. Therefore, NAC doses are limited for normal individuals, especially via intraperitoneal injection or similar means.

Bioinformatics study of the TNFRSF1A mechanism involved in acute liver injury in sepsis through the mTOR signaling pathway.

This study analyzed potential key genes involved in the mechanism of acute liver injury induced by sepsis through bioinformatics techniques, aiming to provide novel insights for the identification of early-stage sepsis-induced acute liver injury and its diagnosis. Gene chip data sets containing samples from acute liver injury induced by sepsis and control groups (GSE22009 and GSE60088) were selected from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) with |log fold change| >1 and p<0.05 were screened with the GEO2R tool, which was also used for the selection of upregulated DEGs in the chips with p<0.05. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, Gene Ontology, and protein-protein interaction (PPI) analyses were then conducted. Results were visualized using R language packages, including volcano plots, Venn diagrams, and boxplots. The intersection of candidate genes with relevant genes in the Comparative Toxicogenomics Database (CTD) was performed, and the clinical significance of these genes was explored through a literature review. A rat model of acute liver injury was developed by inducing sepsis with the cecum ligation and puncture method. Real-time PCR was performed to determine the gene expression in rat liver tissues. A total of 646 upregulated DEGs were determined in GSE22009 and 146 in GSE60088. A Venn diagram was used to find the intersection of the upregulated DEGs between the two data sets, and 67 DEGs associated with sepsis-mediated acute liver damage were obtained. Enrichment analysis from the KEGG pathway showed that DEG upregulation was primarily associated with various pathways: TNF, NF-κB, IL-17, ferroptosis, mTOR, and JAK-STAT signaling pathways. DEGs resulted in three clusters and 15 candidate genes, as revealed by the PPI network and module analyses. Intersection with sepsis-induced acute liver injury-related genes in the CTD resulted in the identification of three significant differentially co-expressed genes: CXCL1, ICAM1, and TNFRSF1A. Sepsis-induced liver tissue indicated the overexpression of CXCL1, ICAM1, and TNFRSF1A mRNA, as compared with the control group (p<0.05). The key genes identified and related signaling pathways provided insights into the molecular mechanisms of sepsis-induced acute liver injury. In vivo studies revealed the overexpression of CXCL1, ICAM1, and TNFRSF1A mRNA in sepsis-mediated injured liver tissues, providing a theoretical basis for early diagnosis and targeted treatment research.

Pathophysiological features of acute liver failure caused by cholestasis [

Acute liver failure is a syndrome that occurs in 20-59% of patients with liver pathology and is one of the main causes of death in 40% of patients with mechanical jaundice of benign origin and in more than 70% of cases of tumor obstruction of the biliary tract and cancer of caput pancreas. In most cases, the syndrome is a consequence of acute liver damage (viral or drug-induced). Still, it can occur with longterm obstructive jaundice, be the first manifestation of Wilson’s disease, autoimmune chronic hepatitis, or superinfection of the hepatitis D virus against the background of chronic hepatitis B. The aim of the work was to study the pathophysiological features of the development of acute liver failure in patients with bile outflow disorders. The pathogenesis of acute liver failure caused by cholestasis is based on the damage and death of hepatocytes due to impaired blood circulation in the liver, as well as the toxic effect on the parenchyma of both the etiological factors themselves and their metabolites. The first week from the onset of symptoms is very important and usually accompanied by a systemic inflammatory response syndrome with significant consequences. At the same time, the main factors influencing the results of treatment of patients at different points in time are the combination of the critical functional reserve of the liver and the nature and severity of liver damage. In the case of the development of a systemic inflammatory response syndrome, there is a further increase in inflammation, which has a systemic nature and leads to the failure of other organs. Under these circumstances, understanding the pathophysiological features of the course of acute liver failure makes it possible to carry out the necessary diagnostic measures on time and offer appropriate therapy.

Structural characterization of Aspalatus linearis polysaccharide and its improving effect on acute alcoholic liver injury.

Polysaccharides from natural sources can regulate the composition of intestinal flora through the "gut-liver axis" pathway, potentially ameliorating alcoholic liver injury. Aspalathus linearis, also known as rooibos, is one such natural product that has shown promise in this regard. This study looked at the structural properties of A. linearis polysaccharide (ALP) and how well it would work to treat acute alcoholic liver impairment. This study looks at the composition of monosaccharides, functional groups, and molecular weight (Mw) of a newly discovered water-soluble polysaccharide, named ALP. The polysaccharide is composed of pyranose rings, amide groups, and sulfate groups linked by β-glycosidic linkage. It has a relative Mw of 4.30×103kDa and is composed of glucose, rhamnose, and some other monosaccharides. The study found that treating mice with the model of acute alcoholic liver disease with ALP could alleviate pathological symptoms, inhibit the release of inflammatory cytokines, and suppress indicators of oxidative stress. Experiments have shown that different doses of ALP can activate the P4502E1/Keap1-Nrf2-HO-1 signaling pathway. The regulation of inflammatory factors and downstream antioxidant enzymes occurs as a result. Based on these data, it is likely that ALP protects the liver via the "gut-liver axis" pathway by reducing oxidative stress-related damage, inflammation, and alcohol-related alterations to the gut microbiome. The results indicate that ALP mitigates injury caused by oxidative stress, inflammatory responses, and changes in the gut microbiota induced by alcohol through the "gut-liver axis" pathway, which provides protection to the liver. This provides preliminary evidence for the development of related drugs. PRACTICAL APPLICATION: Researchers extracted a polysaccharide from fresh leaves of Auricularia auricula. The polysaccharide was purified and determined to have a predominantly homogeneous molecular weight. An acute alcoholic liver damage mouse model was established, and it was concluded that the polysaccharide could ameliorate liver injury in mice through the "gut-liver axis" pathway. This novel polysaccharide can be used as an additive to develop functional foods with beneficial effects, which can positively impact the daily maintenance of consumers.

PREVALENCE OF HEPATITIS B IN LOCAL AREA OF DISTRICT SIALKOT, PAKISTAN

Hepatitis B virus (HBV), a small encapsulated DNA virus, predominantly infects hepatocytes, causing acute and chronic liver damage. Objective: This study aimed to assess the incidence of HBV among the population of the local area of district Sialkot. Methods: A hospital-based study was conducted at Tehsil Headquarters Hospital Daska between January 2022 and May 2022. Sixty participants were registered for the study, including males and females aged 7 to 68. Data collection was performed using a standardised questionnaire. Each participant provided 5 ml of blood for an immunochromatography test. Descriptive statistics were used to analyse the data. Results: Out of the 60 participants, 20 tested reactive for HBV, with 18 males and 2 females. Most of the reactive participants were males aged between 20 and 40, and most were married. Conclusion: The findings indicate a significant incidence of HBV among males, particularly those aged 20-40 years in the district of Sialkot. These results can inform public health initiatives to prevent HBV and promote precautionary measures.

Pericopsis laxiflora (Baker) stem bark extract is protective against carbon tetrachloride-induced acute liver damage by modulation of oxidative stress and inflammation

The present study aimed to investigate the hepatoprotective activity of the hydroethanolic (HSE) and methanolic extracts (MSE) of Pericopsis laxiflora stem bark on carbon tetrachloride-induced hepatotoxicity in rats. The stem bark of P. laxiflora was extracted with 50% ethanol and methanol. Hepatoprotective activities were assessed using the CCl4 model and tested against extracts at 100, 250, and 500 mg/kg bwt. Biochemical, antioxidant enzymes and proinflammatory cytokines in liver homogenate were assayed. Treatment with HSE and MSE resulted in a significant increase in SOD, CAT, and GSH levels and a significant decrease in MDA and MPO levels in livers of CCl4 treated rats. There was also restoration of liver biomarkers and pro-inflammatory cytokines to near-normal levels. The present investigation suggests P. laxiflora extracts possess good hepatoprotective properties. This could be attributed in part to the inhibitory effect of the extracts on oxidative stress and the suppression of proinflammatory cytokines.

IRG1/itaconate alleviates acute liver injury in septic mice by suppressing NLRP3 expression and its mediated macrophage pyroptosis via regulation of the Nrf2 pathway

Sepsis, a systemic inflammatory response triggered by infection, has a considerably high mortality rate. However, effective prevention and intervention measures against sepsis remain insufficient. Therefore, this study aimed to investigate the mechanisms underlying the protective properties of immune response gene-1 (IRG1) and 4-Octyl itaconate (OI) during acute liver damage in mice with sepsis.A sepsis mouse model was established to compare wild-type and IRG1-/- groups. The impact of IRG1/Itaconate on pro- and anti-inflammatory cytokines was evaluated using J774A.1 cells. IRG1/Itaconate substantially reduced pro-inflammatory cytokines and increased the release of anti-inflammatory cytokines. It reduced pathological damage to liver tissues, preserved normal liver function, decreased the release of reactive oxygen species (ROS) and LDH, and enhanced the GSH/GSSG ratio. Moreover, IRG1 and itaconic acid activated the Nrf2 signaling pathway, regulating the expression of its downstream antioxidative stress-related proteins. Additionally, they inhibited the activity of NLRP3 inflammatory vesicles to suppress the expression of macrophage-associated pyroptosis signaling molecules.Our findings demonstrate that IRG1/OI inhibits NLRP3 inflammatory vesicle activation and macrophage pyroptosis by modulating the Nrf2 signaling pathway, thereby attenuating acute liver injury in mice with sepsis. These findings could facilitate the clinical application of IRG1/Itaconate to prevent sepsis-induced acute liver injury.

Hydroxymethylglutaryl-CoA reductase activity is essential for mitochondrial β-oxidation of fatty acids to prevent lethal accumulation of long-chain acylcarnitines in the mouse liver.

Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR), and exert adverse effects on mitochondrial function, although the mechanisms underlying these effects remain unclear. We used a tamoxifen-induced Hmgcr-knockout (KO) mouse model, a multi-omics approach and mitochondrial function assessments to investigate whether decreased HMGCR activity impacts key liver energy metabolism pathways. We established a new mouse strain using the Cre/loxP system, which enabled whole-body deletion of Hmgcr expression. These mice were crossed with Rosa26Cre mice and treated with tamoxifen to delete Hmgcr in all cells. We performed transcriptomic and metabolomic analyses and thus evaluated time-dependent changes in metabolic functions to identify the pathways leading to cell death in Hmgcr-KO mice. Lack of Hmgcr expression resulted in lethality, due to acute liver damage caused by rapid disruption of mitochondrial fatty acid β-oxidation and very high accumulation of long-chain (LC) acylcarnitines in both male and female mice. Gene expression and KO-related phenotype changes were not observed in other tissues. The progression to liver failure was driven by diminished peroxisome formation, which resulted in impaired mitochondrial and peroxisomal fatty acid metabolism, enhanced glucose utilization and whole-body hypoglycaemia. Our findings suggest that HMGCR is crucial for maintaining energy metabolism balance, and its activity is necessary for functional mitochondrial β-oxidation. Moreover, statin-induced adverse reactions might be rescued by the prevention of LC acylcarnitine accumulation.

Soybean meal peptide Gly-Thr-Tyr-Trp could protect mice from acute alcoholic liver damage: A study of protein-protein interaction and proteomic analysis

Alcoholic liver disease (ALD) is a serious health threat. Soybean meal peptide (SMP) supplementation may protect against this damage; however, the potential mechanism underlying the specific sequence of SMPs is unclear. Protein-protein interaction and proteomic analyses are effective methods for studying functional ingredients in diseases. This study aimed to investigate the potential mechanism of action of the peptide Gly-Thr-Tyr-Trp (GTYW) on ALD using protein-protein interaction and proteomic analyses. These results demonstrate that GTYW influenced the targets of glutathione metabolism (glutathione-disulfide reductase, glutathione S-transferase pi 1, and glutathione S-transferase mu 2). It also regulated the expression of targets related to energy metabolism and amino acid conversion (trypsin-2, cysteine dioxygenase type-1, and F6SJM7). Amino acid and lipid metabolisms were identified based on Gene Ontology annotation. These results indicate that GTYW might affect alcohol-related liver disease signaling pathways. This study provides evidence of the protective and nutritional benefits of SMPs in ALD treatment.

De Ritis Ratio to Predict Clinical Outcomes of Intermediate- and High-Risk Pulmonary Embolisms.

Background: Abnormal liver function tests can identify severe cardiopulmonary failure. The aspartate transaminase/alanine transaminase (AST/ALT) ratio, or the De Ritis ratio, is commonly used to evaluate acute liver damage. However, its prognostic value in pulmonary embolism (PE) is unknown. Methods: Two cohorts, including patients with intermediate- and high-risk PEs, were established: one with an abnormal baseline AST/ALT ratio (>1) and another with a normal baseline AST/ALT ratio (<1). The primary outcome was a 60-day mortality. Secondary outcomes included peak N-terminal pro-brain-natriuretic-peptide (NT-proBNP) levels, complications, and the need for critical care treatment. To assess the effect of abnormal AST/ALT ratios, inverse probability weighted (IPW) analyses were performed. Results: In total, 230 patients were included in the analysis, and 52 (23%) had an abnormal AST/ALT ratio. After the IPW correction, patients with an abnormal AST/ALT ratio had a significantly higher mortality rate and peak NT-proBNP levels. The relative risks of 60-day mortality, shock development, use of inotropes/vasopressors, mechanical ventilation, and extracorporeal life support were 9.2 (95% confidence interval: 3.3-25.3), 10.1 (4.3-24), 2.7 (1.4-5.2), 2.3 (1.4-3.7), and 5.7 (1.4-23.1), respectively. Conclusions: The baseline AST/ALT ratio can be a predictor of shock, multiorgan failure, and mortality in patients with a pulmonary embolism.