Severe Liver Damage Research Articles

Glycolipidomics of Liver Flukes and Host Tissues during Fascioliasis: Insights from Mass Spectrometry Imaging.

Fascioliasis, a zoonotic disease caused by liver flukes of the genus Fasciola, poses significant health threats to both humans and livestock. While some infections remain asymptomatic, others can lead to fatal outcomes, particularly during the acute phase characterized by the migration of immature parasites causing severe liver damage. Through the combination of data acquired via high-spatial-resolution atmospheric-pressure scanning microprobe matrix-assisted laser desorption/ionization mass spectrometry imaging (AP-SMALDI MSI) and nanohydrophilic interaction chromatography tandem mass spectrometry, we investigated glycosphingolipids (GSLs) in both adult and immature parasite stages as well as the host liver and bile duct to unravel the intricacies of the host-pathogen interplay and associated pathology. Several GSLs showed characteristic distribution patterns within the parasite depending on the fatty acid composition of their ceramides, notably including GSLs carrying very long-chain fatty acids. Additionally, GSL compositions within the tegument of immature versus adult parasites varied, suggestive of tissue remodeling upon maturation. AP-SMALDI MSI further enabled the identification of GSLs potentially involved in in vivo interactions between the host and immature parasites. Moreover, our experiments unveiled alterations in other lipid classes during Fasciola infection, providing a broader understanding of lipidomic changes associated with the disease. Collectively, our findings contribute to a deeper comprehension of the molecular intricacies underlying fascioliasis, with a specific focus on GSLs.

Overexpression of SULT1E1 alleviates salt-processed Psoraleae Fructus-induced cholestatic liver damage

ObjectiveSalt-processed Psoraleae fructus (SPF) is widely used as a phytoestrogen-like agent in the treatment of osteoporosis. However, due to improper clinical use or misuse, resulting in liver damage. In this study, network pharmacology was employed to analyze the mechanism of cholestatic liver damage. An adeno-associated virus overexpressing SULT1E1 (rAAV8-SULT1E1) was constructed and the hepatotoxicity of SPF, psoralen, and isopsoralen was determined. MethodsBy utilizing three databases inclding TCMSP, TCMID, and BATMAN- TCM, the targets of the three databases were summarized, and a total of 45 psoralen compounds were included. Network pharmacology analysis was then performed. The adenoviral vectors were injected into the tail vein of C57BL6 mice to elucidate the role of SULT1E1 in SPF-induced cholestasis-mediated hepatotoxicity in vivo. SPF (10 g/kg), psoralen, and isopsoralen (50 mg/kg each) were intragastrically administered to mice for 30 d. B-ultrasound and samples were collected and examined for follow-up experiments. ResultsA total of 854 targets were predicted for 45 active components, with 151 cholestasis-mediated hepatotoxicity-related disease targets obtained for SPF. A total of 126 pathways were enriched based on KEGG pathway analysis, with the “estrogen signaling pathway” identified as one of the top 20 pathways. In terms of pathological hepatic changes, treated mice had visually swollen hepatocytes, dilated bile ducts, and elevated serum biochemical markers, which were more prominent in mice treated with isopsoralen than in those treated with other compounds. Notably, the overexpression of SULT1E1 could reverse liver damage in each treatment group. B-ultrasound was used to observe the size of the gallbladder in vivo. The size of the gallbladder was found to significantly increase on day 30 after treatment in the SPF-, psoralen-, and isopsoralen-treated groups, especially the SPF group. Compared with the expression levels in the negative control group (rAAV8-empty+con), the expression levels of FXR, Mrp2, Bsep, SULT1E1, SULT2A1, Ntcp, and Nrf2 decreased, whereas those of CYP7a1 and IL-6 increased in the SPF-, psoralen-, and isopsoralen-treated groups. ConclusionThe overexpression of SULT1E1 could alleviate the decreased or increased expression of indicators, indicating that SULT1E1 is an important target gene for SPF-induced liver damage. The severity of liver damage was significantly lower in the rAAV8-SULT1E1 groups than in the rAAV8-empty groups.

Metabolic and hepatic phenotypes in sarcopenic obesity and impact of bariatric surgery

Background & AimsSarcopenic obesity (SO) is associated with cardiometabolic disorders and steatotic liver disease and carries major health risks. We assessed the hepatic and metabolic clinical phenotype associated with SO in patients with obesity undergoing bariatric surgery (BS). We also evaluated whether weight-loss and metabolic improvement post-surgery differ between patients with and without SO. Methods972 consecutive patients from a single-center BS cohort who underwent whole-body dual-energy X-ray absorptiometry (DXA) and peri-operative liver biopsy were included. SO was diagnosed using the AIM-SO score, an AI-assisted unbiased clustering algorithm based on body composition. One-year post-surgery, 862 patients were reassessed for AIM-SO score changes. ResultsPre-operatively, 207 (21.3%) patients were diagnosed with SO. These patients had significantly higher prevalence of type-2 diabetes (T2D), arterial hypertension and obstructive sleep apnea (OSA) compared to patients without SO (all p≤0.003). Patients with SO had more severe liver damage: higher grades of moderate/advanced steatosis (64.2% vs. 47.3%), steatohepatitis (44.4% vs. 32.3%) and advanced fibrosis (12.1% vs. 6.0%) (all p≤0.01). One-year post-BS, 58.5% of patients had remission of SO. Patients with persistent SO exhibited less weight-loss than those with SO remission (–23.8 kg vs. –29.1 kg, p<0.001) and had lower rates of remission for T2D (41.9% vs. 69.8%), arterial hypertension (20.8% vs. 45.3%), and metabolic syndrome (47.6% vs. 75.0%) (all p≤0.009). ConclusionThe DXA-based AIM-SO score identifies patients with SO who are at greater risk of hepatic and cardiometabolic comorbidities, and predicts less favorable weight-loss and metabolic improvements post-BS.

Hepatocyte-Targeted Lipid Nanoparticle Delivery of HERC2 Plasmid Controls Drug-Induced Hepatotoxicity by Limiting β-Catenin-Regulated CYP2E1 Expression.

Understanding the molecular mechanisms that bridge hepatic inflammation and liver injury is crucial for developing effective therapeutic strategies for drug-induced liver injury (DILI) management. HECT domain and RCC1-like domain 2(HERC2) belongsto the large Herc family of ubiquitin E3 ligases, which are implicated in tissue development and inflammation. The observation reveals a pronounced HERC2 expression in specific hepatocyte subsets that proliferate in response to DILI in humans, prompting an investigation into the role of HERC2 in distinct DILI progression. Under the APAP challenge, liver-specific HERC2-deficient mice suffer more severe liver damage. Integrated single-cell RNA sequencing analysis unveils a negative correlation between HERC2 and CYP2E1, a vital metabolic enzyme for xenobiotics, in hepatocytes from APAP-challenged mice. Mechanistically, HERC2 interacts with β-catenin to promote its ubiquitination, thereby governing CYP2E1 transcriptional regulation. Targeted hepatic delivery of lipid nanoparticle-encapsulated HERC2-overexpressing plasmid markedly reduces liver damage caused by APAP overdose. Collectively, these findings elucidate a previously unrecognized protective role of HERC2 in protecting against acute liver injury associated with drug metabolism disorders, highlighting its potential as a therapeutic target in treating DILI.

Liver damage in galactosemia type I: a literary review

Galactosemia is a rare hereditary disease associated with impaired galactose metabolism, which is characterized by a wide range of clinical syndromes. Most long-term observations are devoted to the study of neurological, ophthalmological and reproductive disorders. Liver damage in galactosemia is one of the central manifestations of the disease, determining the severity and prognosis of the disease, mainly in the neonatal period. The lack of timely dietary correction in the neonatal period leads to severe liver damage with the development of cirrhosis, portal hypertension and liver failure. An information search has shown that prolonged and catamnestic studies on the condition of the liver in children with various variants of galactosemia, in particular, against the background of dietary correction, are few. Most studies show significant reversibility of hepatopathy on the background of diet (even with severe manifestation), however, the number of such publications is not large and the issue requires further research.

Hepatotoxicity Induced by Methyl Eugenol: Insights from Toxicokinetics, Metabolomics, and Gut Microbiota.

Due to continuous application as a flavoring agent in the pesticide, pharmaceutical, and food industries, methyl eugenol (ME) persists in the environment and causes deleterious impacts including cytotoxicity, genotoxicity, and liver damage. This study utilized a comprehensive approach, integrating toxicokinetics, metabolomics, and gut microbiota analysis, to explore the mechanisms behind ME-induced hepatotoxicity in mice. The study observed significant rises in ALT and AST levels, along with significant weight loss, indicating severe liver damage. Toxicokinetic data showed delayed Tmax and plasma accumulation after 28 days of repeated ME exposure at doses of 20 mg/kg, 40 mg/kg, and 60 mg/kg. The metabolomic analysis pinpointed four critical pathways-TCA cycle; alanine, aspartate, and glutamate metabolism; arginine biosynthesis; and tyrosine metabolism-linked to 20 potential biomarkers. Gut microbiota analysis revealed that extended ME exposure led to microbial imbalance, particularly altering the populations of Akkermansia, Prevotella, and Ruminococcus, which are key to amino acid metabolism and the TCA cycle, thus contributing to hepatotoxicity. However, the causal relationship between changes in gut microbiota and liver metabolite levels still requires further in-depth research. This study underscores the significant role of liver metabolites and gut microbiota in ME-induced liver damage.

Protective Effects of Trimetazidine and Dexmedetomidine on Liver Injury in a Mesenteric Artery Ischemia-Reperfusion Rat Model via Endoplasmic Reticulum Stress.

Acute mesenteric ischemia can lead to severe liver damage due to ischemia-reperfusion (I/R) injury. This study investigated the protective effects of trimetazidine (TMZ) and dexmedetomidine (DEX) against liver damage induced by mesenteric artery I/R via endoplasmic reticulum stress (ERS) mechanisms. Twenty-four rats were divided into four groups: control, I/R, I/R+TMZ, and I/R+DEX. TMZ (20 mg/kg) was administered orally for seven days, and DEX (100 µg/kg) was given intraper-itoneally 30 min before I/R induction. Liver tissues were analyzed for creatinine, alanine ami-notransferase (ALT), aspartate aminotransferase (AST), thiobarbituric acid reactive substances (TBARS), and total thiol (TT) levels. Compared with the control group, the I/R group presented significantly increased AST, ALT, TBARS, and TT levels. TMZ notably reduced creatinine levels. I/R caused significant liver necrosis, inflammation, and congestion. TMZ and DEX treatments reduced this histopathological damage, with DEX resulting in a more significant reduction in infiltrative areas and vascular congestion. The increase in the expression of caspase-3, Bax, 8-OHdG, C/EBP homologous protein (CHOP), and glucose-regulated protein 78 (GRP78) decreased with the TMZ and DEX treatments. In addition, Bcl-2 positivity decreased both in the TMZ and DEX treatments. Both TMZ and DEX have protective effects against liver damage. These effects are likely mediated through the reduction in ERS and apoptosis, with DEX showing slightly superior protective effects compared with TMZ.

Nanozyme and bifunctional nanobody-based colorimetric-SERS dual-mode Immunosensor for microcystin-LR detection

Microcystin-LR (MC-LR), a potent cyanotoxin in freshwater, poses a risk of severe liver damage and other health issues, making its detection vital. However, the detection capabilities of conventional antibodies are constrained, which limited their use in immunoassays. In this work, we designed a new bifunctional nanobody, named A2.3-SBP (comprised of nanobody and streptavidin binding peptide), capable of binding with MC-LR and streptavidin. Based on A2.3-SBP and Fe3O4@Au-Pt nanozyme, we introduced an enzyme-free immunosensor that operated in microplate with colorimetric and surface-enhanced Raman scattering (SERS) detection modes. The dual-mode assay showed color changes and SERS intensity directly correlating to MC-LR concentrations with a range from 1.0 to 500 ng/mL and a limit of detection of 0.26 and 0.032 ng/mL, respectively. This strategy eliminated the need for complex enzymatic reactions and realized dual-signal detection of MC-LR in 96 water samples (0.03 μg/kg) within 30 min, suggesting its potential in drinking water detection.

CRISPR/Cas9-Mediated fech Knockout Zebrafish: Unraveling the Pathogenesis of Erythropoietic Protoporphyria and Facilitating Drug Screening

Erythropoietic protoporphyria (EPP1) results in painful photosensitivity and severe liver damage in humans due to the accumulation of fluorescent protoporphyrin IX (PPIX). While zebrafish (Danio rerio) models for porphyria exist, the utility of ferrochelatase (fech) knockout zebrafish, which exhibit EPP, for therapeutic screening and biological studies remains unexplored. This study investigated the use of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated fech-knockout zebrafish larvae as a model of EPP1 for drug screening. CRISPR/Cas9 was employed to generate fech-knockout zebrafish larvae exhibiting morphological defects without lethality prior to 9 days post-fertilization (dpf). To assess the suitability of this model for drug screening, ursodeoxycholic acid (UDCA), a common treatment for cholestatic liver disease, was employed. This treatment significantly reduced PPIX fluorescence and enhanced bile-secretion-related gene expression (abcb11a and abcc2), indicating the release of PPIX. Acridine orange staining and quantitative reverse transcription polymerase chain reaction analysis of the bax/bcl2 ratio revealed apoptosis in fech−/− larvae, and this was reduced by UDCA treatment, indicating suppression of the intrinsic apoptosis pathway. Neutral red and Sudan black staining revealed increased macrophage and neutrophil production, potentially in response to PPIX-induced cell damage. UDCA treatment effectively reduced macrophage and neutrophil production, suggesting its potential to alleviate cell damage and liver injury in EPP1. In conclusion, CRISPR/Cas9-mediated fech−/− zebrafish larvae represent a promising model for screening drugs against EPP1.

Liver Fibrosis Is Enhanced by a Higher Egg Burden in Younger Mice Infected with S. mansoni.

Schistosomiasis affects over 250 million people worldwide, with the highest prevalence at the age of 10-14 years. The influence of the host's age on the severity of liver damage is unclear. We infected male 8, 14, and 20-week-old mice with S. mansoni. Hepatic damage, inflammation, fibrosis, and metabolism were analyzed by RT-qPCR, Western blotting, ELISA, immunohistochemistry, and mechanistic transwell chamber experiments using S. mansoni eggs and human hepatic stellate cells (HSCs) or primary mouse hepatocytes. Major results were validated in human biopsies. We found that hepatosplenomegaly, granuloma size, egg load, inflammation, fibrosis, and glycogen stores all improved with the increasing age of the host. However, serum alanine transaminase (ALT) levels were lowest in young mice infected with S. mansoni. Hepatic carbohydrate exploitation was characterized by a shift towards Warburg-like glycolysis in S. mansoni-infected animals. Notably, S. mansoni eggs stimulated hepatic stellate cells to an alternatively activated phenotype (GFAP+/desmin+/αSMA-) that secretes IL-6 and MCP-1. The reduction of fibrosis in older age likely depends on the fine-tuning of regulatory and inflammatory cytokines, alternative HSC activation, and the age-dependent preservation of hepatic energy stores. The current results emphasize the significance of investigations on the clinical relevance of host age-dependent liver damage in patients with schistosomiasis.

Metabolic and genetic basis of liver damage in mechanical jaundice of non-tumor genesis in obstractive cholangitis or biliary pancreatitis

Aim. Establishment of versatile mechanisms behind liver damage in mechanical jaundice of non-tumor genesis combined with acute obstructive cholangitis or acute biliary pancreatitis.Materials and methods. In total, 64 cases of mechanical jaundice developed against the background of cholelithiasis were studied. Group 1 included 30 patients with mechanical jaundice combined with cholangitis; group 2 included 34 patients with acute biliary pancreatitis. Bile duct reconstruction was performed by an open method followed by standardized treatment. The intensity of membrane lipid peroxidation was determined by the level of diene conjugates, malonic dialdehyde, superoxide dismutase activity, and the activity of phospholipase A2. The severity of endotoxemia was estimated; a molecular-genetic test of the polymorphism of antioxidant system genes was performed.Results. The significance of the gene polymorphism of antioxidant enzymes in the formation of systemic alterative phenomena and severity of liver damage in mechanical jaundice complicated by cholangitis or acute pancreatitis was determined by allocation of patient subgroups depending on the presence of mutant allele T in the gene of superoxide dismutase SOD2 (C1147T). The groups of patients with the presence of such polymorphism, regardless of the combined diseases, demonstrated more pronounced and prolonged liver functional disorders and homeostasis disorders after restoration of biliary tract patency.Conclusion. The presence of mutant alleles of the SOD2 gene (C47T) in patients with non-tumor mechanical jaundice combined with acute cholangitis or pancreatitis is associated with an increase in the intensity of damage mechanisms at the systemic level, primarily with membrane lipid peroxidation, which correlates with the severity of liver damage (r = 0.834–0.967; p &lt; 0.05).

Graphene oxide functionalized with silatrane as probe for electrochemical recognition of acetaminophen in pharmaceuticals tablets

Acetaminophen, commonly known as paracetamol, is a widely used analgesic and antipyretic drug that is frequently found in over-the-counter and prescription medications. Due to its extensive use, precise monitoring of acetaminophen levels is crucial for ensuring patient safety, especially to prevent accidental overdoses which can lead to severe liver damage. In this study, a novel electrochemical sensor based on graphene oxide (GO) functionalized with silatrane was developed for the detection of acetaminophen. The hybrid material was synthesized and electrodeposited on a glassy carbon electrode, providing a highly selective, sensitive, and reproducible platform for acetaminophen detection. The sensor exhibited a linear detection range from 2.5 to 100 μM with a limit of detection of 84.8 nM. The effectiveness of this GO-based sensing platform was demonstrated through the successful quantification of acetaminophen in pharmaceutical tablets such as Dolo 650, Paracip, and Crocin. The results highlight the potential application of this sensor in quality control and safety monitoring of pharmaceutical formulations, ensuring accurate determination of acetaminophen content.

Hepsin as a potential therapeutic target for alleviating acetaminophen-induced hepatotoxicity via gap-junction regulation and oxidative stress modulation

Acetaminophen (APAP) overdose is a leading cause of drug-induced liver damage, highlighting the limitations of current emergency treatments that primarily involve administering the glutathione precursor N-acetylcysteine and supportive therapy. This study highlights the essential protective role of the type II transmembrane serine protease (TTSP), hepsin, in mitigating acetaminophen-induced liver injury, particularly through its regulation of gap junction (GJ) abundance in response to reactive oxygen stress in the liver. We previously reported that reduced levels of activated hepatocyte growth factor and the c-Met receptor tyrosine kinase—both of which are vital for maintaining cellular redox balance—combined with increased expression of GJ proteins in hepsin-deficient mice. Here, we show that hepsin deficiency in mice exacerbates acetaminophen toxicity compared to wild-type mice, leading to more severe liver pathology, elevated oxidative stress, and greater mortality within 6 h after exposure. Administering hepsin had a protective effect in both mouse models, reducing hepatotoxicity by modulating GJ abundance. Additionally, transcriptome analysis and a functional GJ inhibitor have highlighted hepsin's mechanism for managing oxidative stress. Combining hepsin with relatively low doses of N-acetylcysteine had a synergistic effect that was more efficacious than high-dose N-acetylcysteine alone. Our results illustrate the crucial role of hepsin in modulating the abundance of hepatic GJs and reducing oxidative stress, thereby offering early protection against acetaminophen-induced hepatotoxicity and a new, combination approach. Emerging as a promising therapeutic target, hepsin holds potential for combination therapy with N-acetylcysteine, paving the way for novel approaches in managing drug-induced liver injury.Graphical 1. Hepsin−/− mice exhibit exacerbated APAP toxicity, resulting in more severe liver damage, elevated oxidative stress, and higher mortality.2. Hepsin is crucial in protecting against APAP-induced liver injury by regulating gap junctions and reducing oxidative stress.3. Combining hepsin with low doses of N-acetylcysteine provides greater protection against APAP-induced hepatotoxicity than high-dose NAC alone.

Molecular Epidemiology of Hepatitis D Virus in the North-East Region of Romania.

The hepatitis D virus (HDV) superinfection of individuals with chronic hepatitis B virus (HBV) infection causes severe liver damage and the poorest long-term prognosis among viral hepatitis. This is attributed to the unique pathogenic mechanisms of HDV characterized by a direct cytopathic effect on hepatocytes and a significant impairment of the host immune response. The HDV genotype largely influences the extent of the pathogenic mechanisms with consequences on disease progression towards cirrhosis, liver decompensation, or hepatocellular carcinoma. In this context, identifying the circulating HDV genotypes in European regions with high prevalence, such as Romania, is crucial for effectively managing the long-term liver health. Here, we report the first comprehensive HDV study in Romania that clinically characterizes 82 patients and performs HDV genotyping by combining the nested-PCR reaction with sequencing analysis in 49 samples with an HDV-RNA load higher than 5000 IU/mL. While all isolates in our study belong to the HDV-1 genotype, the phylogenetic analysis based on sequence data from GenBank reveals the presence of the following potential three groups: (i) Italy and France; (ii) Spain; and (iii) Turkey, Iran, Pakistan, and Germany. This broad clustering highlights the recent surge in migration to and from Western Europe and the Middle East. Equally important, no differences in viral markers, clinical and paraclinical parameters, or treatment options were observed between these identified clusters. Nevertheless, this study considerably advances the understanding of hepatitis D epidemiology and clinical aspects in Romania.

Arsenic-induced mtDNA release promotes inflammatory responses through cGAS-STING signaling in chicken hepatocytes

Arsenic is a toxic element that can cause severe liver damage in humans and animals. Arsenic-based inorganic pesticides, such as lead arsenate, copper arsenate, and calcium arsenate, are widely used for insect control and can eventually affect human health through accumulation in the food chain. However, the relationship between arsenic trioxide (ATO)-induced hepatotoxicity and the cGAS-STING signaling pathway has not been reported. The aim of this study was to investigate the potential role of inflammatory response in ATO-induced hepatotoxicity in chickens. In this study, we found that ATO exposure resulted in mtDNA leakage into the cytoplasm of chicken hepatocytes, which activated the cGAS-STING pathway and significantly increased the cGAS, STING, TBK1, and IRF7 mRNA and protein expression levels. Moreover, type I interferon response was activated. Concurrently, STING triggered the activation of the traditional NF-κB signaling pathway and promoted the expression of pro-inflammatory cytokine genes, including TNF-α, IL-6, and IL-1β. Subsequently, we found that both mtDNA clearance with EtBr and inhibition of the cGAS-STING pathway with H-151 reversed the ATO-induced innate immune and inflammatory responses. In summary, the above findings indicate that chicken hepatocytes can induce innate immune responses and inflammatory responses via mtDNA-cGAS-STING under ATO-exposure conditions, which is of great significance for further studies on the toxicity mechanism of ATO.

Investigating the Protective Effects of Ascorbic Acid Against Paracetamol-induced Liver Toxicity in Wistar Rats

Paracetamol is one of the most widely used analgesics and antipyretics but can cause severe liver damage at high doses. This study explores the potential protective effects of ascorbic acid (vitamin C) against paracetamol-induced hepatotoxicity in Wistar rats. For this experimental study, 25 mature male Wistar rats, weighing 140–180g, were divided into five groups: Group 1 stands for the Normal Control. Group 2 received 25 mg of PCM for 21 days, whereas Group 3 received 500 mg of ascorbic acid. Furthermore, after PCM was given, rats in groups 4 and 5 were given 500 mg and 1000 mg of ascorbic acid, respectively. Following PCM and Ascorbic acid treatment, biochemical parameters and histoarchitectural studies were examined. Histopathological examination of liver tissue was performed to evaluate cellular architecture and damage. Results indicated that treatment with ascorbic acid significantly mitigated the elevation of liver enzymes and histopathological changes compared to the paracetamol-only group. In conclusion, the research underscores the potential role of ascorbic acid in safeguarding liver function.

Characteristics of initiation timing and anticoagulation of continuous renal replacement therapy in patients following cardiac surgery: A retrospective analysis of 28 patients.

Continuous renal replacement therapy (CRRT) used in cardiac surgery-associated acute kidney injury (CSA-AKI) may have different characteristics from other diseases. We reviewed the medical records of patients with CSA-AKI requiring CRRT who underwent cardiac surgery from January 2020 to September 2021. Patients with AKI caused by other reasons who received CRRT during the same period were also evaluated. A total of 28 patients with CSA-AKI and 12 patients with AKI caused by other reasons were enrolled in this study. Compared with AKI patients caused by other reasons, patients with CSA-AKI were found to have lower mean arterial pressure, higher level of bilirubin, higher vasoactive-inotropic score, and larger daily diuretic dosage. The patients with CSA-AKI were prescribed CRRT earlier than the patients with AKI caused by other reasons. There was a significant difference in the CRRT anticoagulation method between patients with CSA-AKI and patients with AKI caused by other reasons. Six patients with CSA-AKI were treated with regional citrate anticoagulation (RCA), and the other 22 patients were treated with low molecular weight heparin or without anticoagulants. The timing of CRRT initiation in patients with CSA-AKI is earlier than that in patients with AKI caused by other reasons. Although RCA is recommended as the preferred anticoagulant for patients without contraindications, patients with CSA-AKI often have circulatory dysfunction and severe liver damage, so the risk of citrate accumulation is greater, whether to use RCA should be determined according to the individual condition of the patient.

Cocaine-derived hippuric acid activates mtDNA-STING signaling in alcoholic liver disease: Implications for alcohol and cocaine co-abuse

The simultaneous abuse of alcohol-cocaine is known to cause stronger and more unpredictable cellular damage in the liver, heart, and brain. However, the mechanistic crosstalk between cocaine and alcohol in liver injury remains unclear. The findings revealed cocaine-induced liver injury and inflammation in both marmosets and mice. Of note, co-administration of cocaine and ethanol in mice causes more severe liver damage than individual treatment. The metabolomic analysis confirmed that hippuric acid (HA) is the most abundant metabolite in marmoset serum after cocaine consumption and that is formed in primary marmoset hepatocytes. HA, a metabolite of cocaine, increases mitochondrial DNA leakage and subsequently increases the production of proinflammatory factors via STING signaling in Kupffer cells (KCs). In addition, conditioned media of cocaine-treated KC induced hepatocellular necrosis via alcohol-induced TNFR1. Finally, disruption of STING signaling in vivo ameliorated co-administration of alcohol- and cocaine-induced liver damage and inflammation. These findings postulate intervention of HA-STING-TNFR1 axis as a novel strategy for treatment of alcohol- and cocaine-induced excessive liver damage.Graphical

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.

Safety evaluation of Indocalamus Iatifolius McClure leaves based on acute toxicity, harmful metals, and 9 organochlorine residue determination

To investigate the safety of Indocalamu Iatifolius McClur leaves sold in the market, a study was conducted using Indocalamu Iatifolius McClur leaves randomly collected from an online store and a large supermarket. Acute toxicity experiments were performed on mice, and their body weight was monitored for 14 days after administration. After the observation period, blood samples were collected for biochemical analysis, and organ pathology was examined. Then, the content of copper (Cu), lead (Pb), cadmium (Cd), mercury (Hg), arsenic (As), and the residues of nine organochlorine pesticides in Indocalamu Iatifolius McClur leaves were measured according to the National Food Safety Standard (GB/T5009-2003) and the pesticide residue determination methods in the 2020 edition of the Chinese Pharmacopoeia. The results showed that the mice in the Indocalamu Iatifolius McClur leaves (online store) group experienced mortality and severe liver and lung damage. The levels of lead, cadmium, mercury, arsenic, and the nine organochlorine pesticides met the relevant standards and regulations. However, the copper content in the Indocalamu Iatifolius McClur leaves (online store) group was nearly 80 times higher than that in the supermarket group. Mice in the Indocalamu Iatifolius McClur leaves (supermarket) group remained healthy without any abnormalities, and the levels of harmful metals and organochlorine pesticides complied with the standards and regulations. The study suggests the need for regulatory policies and safety standards for the sale of Indocalamu Iatifolius McClur leaves.