Development Of Acute Liver Injury Research Articles

Protein 4.1R regulates M1 macrophages polarization via glycolysis, alleviating sepsis-induced liver injury in mice

Acute liver injury (ALI) is a common clinical disease caused by sepsis, metabolic syndrome, hepatitis virus. Macrophage plays an important role in the development of ALI, which is characterized by polarization and inflammatory regulation. The polarization process of macrophages is related to membrane binding proteins and adaptors. Protein 4.1R acts as an adaptor, linking membrane proteins to the cytoskeleton, and is involved in cell activation and cytokine secretion. However, whether protein 4.1R is involved in regulating macrophage polarization and inflammation-induced liver injury remains unknown. In this study, protein 4.1R is identified with the special effect on macrophage M1 polarization. And it is further demonstrated that protein 4.1R deficiency significantly enhance glycolytic metabolism. Mechanistically, the regulation of protein 4.1R on pyruvate kinase M2 (PKM2) plays a key role in glycolysis metabolism. In addition, we found that protein 4.1R directly interacts with toll-like receptor 4 (TLR4), inhibits the activation of the AKT/HIF-1α signaling pathway. In conclusion, protein 4.1R targets HIF-1α mediated glycolysis regulates M1 macrophage polarization, indicating that protein 4.1R is a candidate for regulating macrophage mediated inflammatory response. In conclusion, we have revealed a novel function of protein 4.1R in macrophage polarization and ALI, providing important insights into the metabolic reprogramming, which is important for ALI therapy. We have revealed a novel function of protein 4.1R in macrophage polarization and ALI, providing important insights into the metabolic reprogramming, which is important for ALI therapy.

Hesperetin derivative 2a inhibits lipopolysaccharide-induced acute liver injury in mice via downregulation of circDcbld2.

Acute liver injury (ALI) is a complex, life-threatening inflammatory liver disease, and persistent liver damage leads to rapid decline and even failure of liver function. However, the pathogenesis of ALI is still not fully understood, and no effective treatment has been discovered. Recent evidence shows that many circular RNAs (circRNAs) are associated with the occurrence of liver diseases. In this study we investigated the mechanisms of occurrence and development of ALI in lipopolysaccharide (LPS)-induced ALI mice. We found that expression of the circular RNA circDcbld2 was significantly elevated in the liver tissues of ALI mice and LPS-treated RAW264.7 cells. Knockdown of circDcbld2 markedly alleviates LPS-induced inflammatory responses in ALI mice and RAW264.7 cells. We designed and synthesized a series of hesperidin derivatives for circDcbld2, and found that hesperetin derivative 2a (HD-2a) at the concentrations of 2, 4, 8 μM effectively inhibited circDcbld2 expression in RAW264.7 cells. Administration of HD-2a (50, 100, 200 mg/kg. i.g., once 24 h in advance) effectively relieved LPS-induced liver dysfunction and inflammatory responses. RNA sequencing analysis revealed that the anti-inflammatory and hepatoprotective effects of HD-2a were mediated through downregulating circDcbld2 and suppressing the JAK2/STAT3 pathway. We conclude that HD-2a downregulates circDcbld2 to inhibit the JAK2/STAT3 pathway, thereby inhibiting the inflammatory responses in ALI. The results suggest that circDcbld2 may be a potential target for the prevention and treatment of ALI, and HD-2a may have potential as a drug for the treatment of ALI.

The Outcome Relevance of Pre-ECMO Liver Impairment in Adults with Acute Respiratory Distress Syndrome.

We hypothesize that (1) a significant pre-ECMO liver impairment, which is evident in the presence of pre-ECMO acute liver injury and a higher pre-ECMO MELD (model for end-stage liver disease) score, is associated with increased mortality; and (2) the requirement of veno-veno-arterial (V-VA) ECMO support is linked to a higher prevalence of pre-ECMO acute liver injury, a higher pre-ECMO MELD score, and increased mortality. We analyze 187 ECMO runs (42 V-VA and 145 veno-venous (V-V) ECMO) between January 2017 and December 2020. The SAPS II score is calculated at ICU admission; hepatic function and MELD score are assessed at ECMO initiation (pre-ECMO) and during the first five days on ECMO. SOFA, PRESERVE and RESP scores are calculated at ECMO initiation. Pre-ECMO cardiac failure, acute liver injury, ECMO type, SAPS II and MELD, SOFA, PRESERVE, and RESP scores are associated with mortality. However, only the pre-ECMO MELD score independently predicts mortality (p = 0.04). In patients with a pre-ECMO MELD score > 16, V-VA ECMO is associated with a higher mortality risk (p = 0.0003). The requirement of V-VA ECMO is associated with the development of acute liver injury during ECMO support, a higher pre-ECMO MELD score, and increased mortality.

Lyciumbarbarum polysaccharides ameliorate canine acute liver injury by reducing oxidative stress, protecting mitochondrial function, and regulating metabolic pathways.

The development of acute liver injury can result in liver cirrhosis, liver failure, and even liver cancer, yet there is currently no effective therapy for it. The purpose of this study was to investigate the protective effect and therapeutic mechanism of Lyciumbarbarum polysaccharides (LBPs) on acute liver injury induced by carbon tetrachloride (CCl4). To create a model of acute liver injury, experimental canines received an intraperitoneal injection of 1 mL/kg of CCl4 solution. The experimental canines in the therapy group were then fed LBPs (20 mg/kg). CCl4-induced liver structural damage, excessive fibrosis, and reduced mitochondrial density were all improved by LBPs, according to microstructure data. By suppressing Kelch-like epichlorohydrin (ECH)-associated protein 1 (Keap1), promoting the production of sequestosome 1 (SQSTM1)/p62, nuclear factor erythroid 2-related factor 2 (Nrf2), and phase II detoxification genes and proteins downstream of Nrf2, and restoring the activity of anti-oxidant enzymes like catalase (CAT), LBPs can restore and increase the antioxidant capacity of liver. To lessen mitochondrial damage, LBPs can also enhance mitochondrial respiration, raise tissue adenosine triphosphate (ATP) levels, and reactivate the respiratory chain complexes I‒V. According to serum metabolomics, the therapeutic impact of LBPs on acute liver damage is accomplished mostly by controlling the pathways to lipid metabolism. 9-Hydroxyoctadecadienoic acid (9-HODE), lysophosphatidylcholine (LysoPC/LPC), and phosphatidylethanolamine (PE) may be potential indicators of acute liver injury. This study confirmed that LBPs, an effective hepatoprotective drug, may cure acute liver injury by lowering oxidative stress, repairing mitochondrial damage, and regulating metabolic pathways.

Prediction of the development of acute liver injury in mushroom poisoning by hemogram parameters

Prediction of the development of acute liver injury in mushroom poisoning by hemogram parameters

Blocking cGAS/STING signaling protects against sepsis-associated acute liver injury

Sepsis-associated acute liver injury (ALI) contributes to the pathogenesis of multiple organ dysfunction syndrome and thus increases mortality. Nevertheless, specific therapeutics for sepsis-associated ALI are scant so far. The cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, is implicated in a series of inflammatory diseases. However, whether cGAS functions in the pathogenesis of ALI is still unclear. We herein investigated the role of cGAS in the development of ALI, and if any, by which mechanism cGAS is involved. After a challenge using cecum ligation and puncture (CLP) or lipopolysaccharide (LPS) plus d-galactosamine (GalN) in WT and gene-modified mice, we found that cGAS signaling was activated, and cGAS deficiency significantly attenuated CLP- or LPS/GalN-induced liver injury, liver dysfunction and so-caused mice death. In addition, CLP or LPS/GalN augmented type I interferon signaling—the downstream of cGAS pathway. Recombinant interferon-β (rIFNβ) enhanced LPS/GalN-induced hepatocyte death and partly reversed the protection induced by cGAS depletion. Besides of inflammation, cGAS deletion was capable of preventing LPS/GalN-induced hepatocyte death. Hepatocyte-specific deletion of STING, the downstream of cGAS activation, showed a significant protection against ALI, which could be phenocopied by pharmacological inhibition of cGAS or STING via RU.521 or H-151 respectively. Taken together, cGAS/STING signaling promotes ALI by both type I IFN responses and hepatocyte death. Inhibition of cGAS/STING signaling would be a promising strategy for preventing ALI in sepsis.

Acute liver injury progression is associated with dynamic enteric eubiosis alteration in mice

Liver health has long been linked to the homeostasis of gut microbiota. Although some studies have shown that alterations in the species and function of gut microbiota contribute to the initiation and development of acute liver injury (ALI), studies investigating the effects of ALI on gut microbial dynamic composition changes are still limited. To observe whether liver damage can alter the composition of gut microbiota dynamically, we established three chemical models (e.g., acetaminophen, carbon tetrachloride, lipopolysaccharide) of ALI. Using these models, multiple time points of liver injury and intestinal microbiome were analyzed through plasma biochemical analysis and 16S rRNA gene sequencing. We assessed α-diversity, Unifrac principal coordinates analysis (PCoA), and linear discriminant analysis effect size (LEfSe) in the injury and control groups. The composition of the gut microbiota underwent dramatic shifts with liver injury and recovery in each model. Additionally, specific microbial abundance was significantly correlated with the level of plasma alanine transaminase and aspartate transaminase. These data provide new evidence that liver dysfunction and restoration is dynamically linked with the changes in the intestinal microbiome.

Ethanol and its Nonoxidative Metabolites Promote Acute Liver Injury by Inducing ER Stress, Adipocyte Death, and Lipolysis

Binge drinking in patients with metabolic syndrome accelerates the development of alcohol-associated liver disease. However, the underlying mechanisms remain elusive. We investigated if oxidative and nonoxidative alcohol metabolism pathways, diet-induced obesity, and adipose tissues influenced the development of acute liver injury in a single ethanol binge model. A single ethanol binge was administered to chow-fed or high-fat diet (HFD)-fed wild-type and genetically modified mice. Oral administration of a single dose of ethanol induced acute liver injury and hepatic endoplasmic reticulum (ER) stress in chow- or HFD-fed mice. Disruption of the Adh1 gene increased blood ethanol concentration and exacerbated acute ethanol-induced ER stress and liver injury in both chow-fed and HFD-fed mice, while disruption of the Aldh2 gene did not affect such hepatic injury despite high blood acetaldehyde levels. Mechanistic studies showed that alcohol, not acetaldehyde, promoted hepatic ER stress, fatty acid synthesis, and increased adipocyte death and lipolysis, contributing to acute liver injury. Increased serum fatty acid ethyl esters (FAEEs), which are formed by an enzyme-mediated esterification of ethanol with fatty acids, were detected in mice after ethanol gavage, with higher levels in Adh1 knockout mice than in wild-type mice. Deletion of the Ces1d gene in mice markedly reduced the acute ethanol-induced increase of blood FAEE levels with a slight but significant reduction of serum aminotransferase levels. Ethanol and its nonoxidative metabolites, FAEEs, not acetaldehyde, promoted acute alcohol-induced liver injury by inducing ER stress, adipocyte death, and lipolysis.

Intestinal Microbiomics and Metabolomics Insights into the Hepatoprotective Effects of Lactobacillus paracasei CCFM1222 Against the Acute Liver Injury in Mice.

In recent years, acute liver injury (ALI) has received wide-range attention in the world due to its relatively high morbidity and mortality. This study aimed to explore the hepatoprotective effect of Lactobacillus paracasei CCFM1222 against lipopolysaccharide (LPS)-induced ALI mice and further elaborate its mechanism of action from the perspective of intestinal microbiomics and metabolomics. The results displayed that L. paracasei CCFM1222 pretreatment significantly decreased the serum ALT, and AST levels, inhibited the releases of hepatic TNF-α, IL-1β, and IL-6 levels, and activated the SOD, CAT, and GSH-Px activities in LPS-treated mice. The cecal short-chain fatty acid (SCFAs) levels were increased in LPS-treated mice with L. paracasei CCFM1222 pretreatment. In addition, L. paracasei CCFM1222 pretreatment remarkably shifted the intestinal microbiota composition, including the higher abundance of Faecalibaculum, Bifidobacterium, and lower abundance of the Prevotellaceae NK3B31 group, which is positively associated with the cecal propionic, butyric, valeric, isobutyric, and isovaleric acids. The metabolomics based on UPLC-QTOF/MS revealed that L. paracasei CCFM1222 pretreatment significantly regulated the composition of feces metabolites in LPS-treated mice, especially the potential biomarker-related butanoate metabolism, vitamin B6 metabolism, D-glutamine and D-glutamate metabolism, tryptophan metabolism, caffeine metabolism, arginine biosynthesis, arginine, and proline metabolism. Moreover, L. paracasei CCFM1222 pretreatment remarkably regulated the expression of gene-associated ALI (including Tlr4, Myd88, Nf-kβ, iNOS, Cox2, Iκ-Bα, Nrf2, and Sirt-1). In conclusion, these results suggest the possibility that L. paracasei CCFM1222 supplementation has beneficial effects on preventing the occurrence and development of ALI by inhibiting the inflammatory responses and altering intestinal microbiota composition and their metabolites.

Hyaluronan synthase 2, a target of miR-200c, promotes carbon tetrachloride-induced acute and chronic liver inflammation via regulation of CCL3 and CCL4

Liver fibrosis occurs during wound healing after repeated liver injury and is characterized by extensive extracellular matrix deposition. We previously identified hyaluronan synthase 2 (HAS2) as a driver of liver fibrosis and hepatic stellate cell (HSC) activation. Developing strategies to suppress HSC activation is key to alleviating liver fibrosis, and HAS2 is an attractive candidate for intervention. To gain insight into the molecular function of HAS2, we investigated its posttranscriptional regulation. We found that miR-200c directly targets the 3’ untranslated regions of HAS2. Moreover, miR-200c and HAS2 were inversely expressed in fibrotic human and mouse livers. After establishing the direct interaction between miR-200c and HAS2, we investigated the functional outcome of regulating HAS2 expression in three murine models: CCl4-induced acute liver injury, CCl4-induced chronic liver fibrosis, and bile duct ligation-induced liver fibrosis. Hepatic Has2 expression was induced by acute and chronic CCl4 treatment. In contrast, miR-200c expression was decreased after CCl4 treatment. HSC-specific Has2 deletion reduced the expression of inflammatory markers and infiltration of macrophages in the models. Importantly, hyaluronidase-2 (HYAL2) but not HYAL1 was overexpressed in fibrotic human and murine livers. HYAL2 is an enzyme that can cleave the extracellular matrix component hyaluronan. We found that low-molecular-weight hyaluronan stimulated the expression of inflammatory genes. Treatment with the HA synthesis inhibitor 4-methylumbelliferone alleviated bile duct ligation-induced expression of these inflammatory markers. Collectively, our results suggest that HAS2 is negatively regulated by miR-200c and contributes to the development of acute liver injury and chronic liver inflammation via hyaluronan-mediated immune signaling.

ATRA-mediated-crosstalk between stellate cells and Kupffer cells inhibits autophagy and promotes NLRP3 activation in acute liver injury

The crosstalk between hepatic stellate cells (HSCs) and Kupffer cells (KCs) is involved in acute liver injury (ALI). Meanwhile, the change of lipid droplet in HSCs predicts the development of ALI. However, it is not clear whether all trans retinoic acid (ATRA), as one of the important products of lipid droplet metabolism from HSC, regulate the activation of KCs. Firstly, our results confirmed that ATRA release and IL-1β production were significantly increased in a CCl4-induced model of ALI. In addition, we observed that ATRA could induce KCs to produce IL-1β through retinoic acid receptor (RAR) in vitro. Further mechanism studies confirmed that RAR could promote priming of NLRP3 inflammasome through transcriptional activation. ATRA also blocked autophagic flow by activating the AKT/mTOR pathway, leading to an excessive accumulation of ROS, which further activated the NLRP3 inflammasome. Activated NLRP3 inflammasome caused pyroptosis of macrophages and explosive release of IL-1β. In conclusion, we have uncovered a novel crosstalk pattern between HSCs and KCs, and ATRA-mediated-crosstalk between HSCs and KCs inhibits autophagy and promotes NLRP3 activation to aggravate acute liver injury.

The Benevolent Bile: Bile Acids as Stimulants of Liver Regeneration

The Benevolent Bile: Bile Acids as Stimulants of Liver Regeneration

Comparing development of liver injury using the two versus three bag acetylcysteine regimen despite early treatment in paracetamol overdose

Introduction Some studies have reported that early administration of acetylcysteine using a 3-bag regimen may not fully prevent development of liver injury in some patients. We compared the incidence of acute liver injury (ALI) in patients receiving acetylcysteine within eight hours of ingestion between the two-bag acetylcysteine regimen (200 mg/kg over four hours, 100 mg/kg over 16 h) and the three-bag regimen (150 mg/kg over 1 h, 50 mg/kg over 4 h, 100 mg/kg over 16 h). Method This was a retrospective cohort study of the two-bag and three-bag acetylcysteine regimens from Monash Health, Victoria, Australia (2009–2020), compared to the three-bag acetylcysteine regimen data from the Canadian Acetaminophen Overdose Study (CAOS) database (1980–2005). The inclusion criteria included patients with an acute single ingestion of paracetamol; normal aminotransferases on presentation and acetylcysteine administered within eight hours post-overdose. The primary outcome was development of ALI (defined as: peak aminotransferase >150 IU/L). Results At Monash Health, 191 patients were treated with the two-bag acetylcysteine regimen, and 180 patients with the three-bag regimen. The CAOS cohort provided 515 patients treated with the three-bag regimen. ALI developed in 1.6% (3/191) of the two-bag Monash Health group, 2.2% (4/180) of the three-bag Monash Health group (difference −0.6%, p 0.7), and 2.9% (15/515) of the three-bag CAOS group (difference compared to two-bag −1.3%, p 0.4). Hepatotoxicity (ALT >1000) developed in 0.5% (1/191) of patients treated with the two-bag regimen, 1.7% (3/180) in the Monash Health three-bag regimen and 1% (5/515) of the three-bag CAOS group. There were no statistically significant differences between groups. Conclusions ALI and hepatotoxicity were observed in a small, comparable percentage of patients despite early acetylcysteine administration using the two-bag and three-bag regimens. Repeating blood tests at the end of acetylcysteine treatment will identify these patients and indicate those requiring continuation of acetylcysteine.

Effects of proprotein convertase subtilisin/kexin type-9 inhibitors on fatty liver.

BACKGROUNDMany studies have investigated the progression of nonalcoholic fatty liver disease (NAFLD) and its predisposing risk factors, but the conclusions from these studies have been conflicting. More challenging is the fact that no effective treatment is currently available for NAFLD.AIMTo determine the effects of proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors on fatty infiltration of the liver.METHODSThis retrospective, chart review-based study was conducted on patients, 18-year-old and above, who were currently on PCSK9 inhibitor drug therapy. Patients were excluded from the study according to missing pre- or post-treatment imaging or laboratory values, presence of cirrhosis or rhabdomyolysis, or development of acute liver injury during the PCSK9 inhibitor treatment period; the latter being due to false elevation of liver function markers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Radiographic improvement was assessed by a single radiologist, who read both the pre- and post-treatment images to minimize reading bias. Fatty infiltration of the liver was also assessed by changes in ALT and AST, with pre- and post-treatment levels compared by paired t-test (alpha criterion: 0.05).RESULTSOf the 29 patients included in the study, 8 were male (27.6%) and 21 were female (72.4%). Essential hypertension was present in 25 (86.2%) of the patients, diabetes mellitus in 18 (62.1%) and obesity in 15 (51.7%). In all, patients were on PCSK9 inhibitors for a mean duration of 23.69 ± 11.18 mo until the most recent ALT and AST measures were obtained. Of the 11 patients who received the radiologic diagnosis of hepatic steatosis, 8 (72.73%) achieved complete radiologic resolution upon use of PCSK9 inhibitors (mean duration of 17.6 mo). On average, the ALT level (IU/L) decreased from 21.83 ± 11.89 at pretreatment to 17.69 ± 8.00 at post-treatment (2-tailed P = 0.042) and AST level (IU/L) decreased from 22.48 ± 9.00 pretreatment to 20.59 ± 5.47 post-treatment (2-tailed P = 0.201).CONCLUSIONPCSK9 inhibitors can slow down or even completely resolve NAFLD.

Exacerbated LPS/GalN-Induced Liver Injury in the Stress-Sensitive Wistar Kyoto Rat Is Associated with Changes in the Endocannabinoid System.

Acute liver injury (ALI) is a highly destructive and potentially life-threatening condition, exacerbated by physical and psychological stress. The endocannabinoid system plays a key role in modulating stress and hepatic function. The aim of this study was to examine the development of acute liver injury in the genetically susceptible stress-sensitive Wistar-Kyoto (WKY) rat compared with normo-stress-sensitive Sprague Dawley (SD) rats, and associated changes in the endocannabinoid system. Administration of the hepatotoxin lipopolysaccharide/D-Galactosamine (LPS/GalN) resulted in marked liver injury in WKY, but not SD rats, with increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH) plasma levels, significant histopathological changes, increased hepatic pro-inflammatory cytokine expression and caspase-3 activity and expression and reduced Glutathione (GSH) activity. Furthermore, compared to SD controls, WKY rats display increased anandamide and 2-Arachidonoylglycerol levels concurrent with decreased expression of their metabolic enzymes and a decrease in cannabinoid (CB)1 receptor expression following LPS/GalN. CB1 antagonism with AM6545 or CB2 agonism with JWH133 did not alter LPS/GalN-induced liver injury in SD or WKY rats. These findings demonstrate exacerbation of acute liver injury induced by LPS/GalN in a stress-sensitive rat strain, with effects associated with alterations in the hepatic endocannabinoid system. Further studies are required to determine if the endocannabinoid system mediates or modulates the exacerbation of liver injury in this stress-sensitive rat strain.

Neutralization of interleukin-6 alleviates acute liver injury in mice

Objective: To study the role of interleukin 6 (IL-6) in the occurrence and development of acute liver injury. Methods: Twelve C57BL/6 male mice without specific pathogens were randomly divided into a control group and an acute liver injury model group, with six mice in each group. Control and model group were injected with an equal volume (dosage of 10 mg/kg) of phosphate-buffered saline (PBS) and concanavalin A (ConA) into the tail vein, respectively. Samples were collected at 6 h for liver HE staining. Transaminase assay was used to determine the success of the induction model. The expression of IL-6, IL-17, IL-1β, interferon (IFN) γ and tumor necrosis factor α were screened by quantitative fluorescence PCR (qPCR). The expressional condition of IL-6 and IFNγ were measured by enzyme-linked immunosorbent assay (ELISA). Subsequently, three control groups and three IL-6 neutralizing antibody groups were established for acute liver injury, respectively. Equal volumes of PBS or IL-6 neutralizing antibody (100 μg/body) were injected prior 30 minutes, followed by injection of ConA (10 mg/kg) into the tail vein. Blood sampled from eye and liver tissue were fetched at 6 h. Liver tissues were stained with HE and serum alanine aminotransferase (ALT) was determined. An independent sample T-test was used for data comparison. Results: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) of the model group was significantly higher than control group [ALT: (2 618.99 ± 188.08) U/L and (43.34 ± 5.02) U/L, t = -13.69, P = 0.001; AST: (942.48 ± 150.44) U/L and (57.80 ± 4.84) U/L, t = -5.878, P = 0.01]. Liver HE staining showed that the structure of hepatocyte cord was disordered, the cytoplasm of hepatocyte was lightly stained, and large necrotic foci were gradually formed, accompanied by lymphocyte infiltration, and then a mouse model of acute liver injury was successfully established. Protein levels of IL-6 and IFN, and mRNA of the model group were significantly up-regulated, as compared to control group. IL-6 mRNA expression of the model group was increased 73.7 times that of the control group (t =-6.218, P < 0.001), and the serum IL-6 expression level was also higher than that of the control group (18 537.02 ± 92.57) pg/ml (t = -199.782, P < 0.001). IFNγ mRNA was 108.4 times higher than that of the control the group (t = -4.413, P = 0.003), and serum IFNγ concentration of the model group was also higher than the control group (12 068.30 ± 288.43) pg/ml (t = -41.748, P < 0.001). Among them, IL-6 level was obviously increased, suggesting that it could participate in the occurrence and development of liver injury. IL-6 neutralizing antibody was injected into the tail vein. ALT level of IL-6 neutralizing antibody was significantly lower than acute liver injury control group [(167.41 ± 47.80) U/L and (1 520.34 ± 190.21) U/L, t = 6.899, P = 0.015]. Liver tissue HE staining showed that hepatocyte necrosis and the number of necrotic foci was significantly alleviated after blocking serum IL-6.Immunohistochemical results showed that the expression of activated caspase3 and hepatocyte apoptosis in the IL-6 neutralizing antibody group was decreased. Conclusion: Neutralizing IL-6 can significantly reduce acute liver injury caused by concanavalin A.

Combined Use of Febuxostat and Colchicine Does Not Increase Acute Hepatotoxicity in Patients with Gout: A Retrospective Study.

Colchicine has been effectively used to prevent acute flares in patients with gout, but drug-related adverse events have frequently occurred. We investigated whether colchicine therapy with febuxostat is associated with hepatotoxicity in gout patients. Gout patients treated with (n = 121) or without (n = 57) colchicine were enrolled upon initiating febuxostat as a urate-lowering treatment, and clinical and laboratory data at diagnosis were compared. Logistic regression analysis was performed to evaluate the risk factors related to hepatotoxicity. Median age of the with-colchicine and without-colchicine groups was 51.0 (37.0–62.0) and 56.0 (43.5–68.5) years, respectively. During the three months of febuxostat prescription, the prevalence of hepatotoxicity was 13/121 (10.9%) in the with-colchicine group and 4/57 (7.0%) in the without-colchicine group, without statistical significance. The rate of colchicine use was not different between the study subjects with or without hepatotoxicity (76.5% vs. 67.1%, p = 0.587). Pre-existing liver disease was significantly associated with increased risk of hepatotoxicity after febuxostat treatment (odds ratio, 4.083; 95% confidence interval, 1.326–12.577; p = 0.014). Colchicine may be safely used as a prophylactic agent for gout patients with febuxostat. However, upon initiating febuxostat, it is recommended to monitor the development of acute liver injury in gout patients with underlying liver disease.

The Role of Sirtuin 3 in Radiation-Induced Long-Term Persistent Liver Injury.

In patients with abdominal region cancers, ionizing radiation (IR)-induced long-term liver injury is a major limiting factor in the use of radiotherapy. Previously, the major mitochondrial deacetylase, sirtuin 3 (SIRT3), has been implicated to play an important role in the development of acute liver injury after total body irradiation but no studies to date have examined the role of SIRT3 in liver’s chronic response to radiation. In the current study, ten-month-old Sirt3−/− and Sirt3+/+ male mice received 24 Gy radiation targeted to liver. Six months after exposure, irradiated Sirt3−/− mice livers demonstrated histopathological elevations in inflammatory infiltration, the loss of mature bile ducts and higher DNA damage (TUNEL) as well as protein oxidation (3-nitrotyrosine). In addition, increased expression of inflammatory chemokines (IL-6, IL-1β, TGF-β) and fibrotic factors (Procollagen 1, α-SMA) were also measured in Sirt3−/− mice following 24 Gy IR. The alterations measured in enzymatic activities of catalase, glutathione peroxidase, and glutathione reductase in the livers of irradiated Sirt3−/− mice also implied that hydrogen peroxide and hydroperoxide sensitive signaling cascades in the absence of SIRT3 might contribute to the IR-induced long-term liver injury.

Opposite effects of the FXR agonist obeticholic acid on Mafg and Nrf2 mediate the development of acute liver injury in rodent models of cholestasis

The farnesoid-X-receptor (FXR) is validated target in the cholestatic disorders treatment. Obeticholic acid (OCA), the first in class of FXR agonist approved for clinical use, causes side effects including acute liver decompensation when administered to cirrhotic patients with primary biliary cholangitis at higher than recommended doses. The V-Maf avian-musculoaponeurotic-fibrosarcoma-oncogene-homolog-G (Mafg) and nuclear factor-erythroid-2-related-factor-2 (Nrf2) mediates some of the downstream effects of FXR. In the present study we have investigated the role of FXR/MafG/NRF2 pathway in the development of liver toxicity caused by OCA in rodent models of cholestasis. Cholestasis was induced by bile duct ligation (BDL) or administration of α-naphtyl-isothiocyanate (ANIT) to male Wistar rats and FXR−/− and FXR+/+ mice. Treating BDL and ANIT rats with OCA exacerbated the severity of cholestasis, hepatocytes injury and severely downregulated the expression of basolateral transporters. In mice, genetic ablation FXR or its pharmacological inhibition by 3-(naphthalen-2-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazole rescued from negative regulation of MRP4 and protected against liver injury caused by ANIT. By RNAseq analysis we found that FXR antagonism effectively reversed the transcription of over 2100 genes modulated by OCA/ANIT treatment, including Mafg and Nrf2 and their target genes Cyp7a1, Cyp8b1, Mat1a, Mat2a, Gss. Genetic and pharmacological Mafg inhibition by liver delivery of siRNA antisense or S-adenosylmethionine effectively rescued from damage caused by ANIT/OCA. In contrast, Nrf2 induction by sulforaphane was protective. ConclusionsLiver injury caused by FXR agonism in cholestasis is FXR-dependent and is reversed by FXR and Mafg antagonism or Nrf2 induction.

Efficacy of a two bag acetylcysteine regimen to treat paracetamol overdose (2NAC study)

BackgroundPrevious studies of paracetamol overdose treatment show that a 2-bag, 20-h intravenous (IV) acetylcysteine regimen decreased the incidence of non-allergic anaphylactic reactions compared to the 3-bag, 21 h IV regimen, but have not examined efficacy of the 20-h 2 bag regimen. MethodsThis was a multi-centre observational study of paracetamol overdose presentations treated with a 2-bag IV acetylcysteine regimen (200 mg/kg over 4 h, 100 mg/kg over 16 h) compared to a 3-bag regimen, performed from 2009 to 2019. Patients were referred from the emergency department to the inpatient toxicology units for continued management. For the primary non-inferiority analysis: subjects had single, acute ingestions, a serum paracetamol-concentration performed 4 to 8-h post-ingestion. The primary outcome was development of acute liver injury (ALI), defined as peak ALT>150 U/L; and > double admission baseline ALT (for presentations within 24 h post-overdose). Secondary outcomes included adverse reactions to acetylcysteine (cutaneous and systemic). FindingOut of 6419 paracetamol overdoses, 2763 received acetylcysteine. For the primary analysis, 1003 received the 2-bag and 783 the 3-bag acetylcysteine regimen. When presentation bloods were performed 4 to 8-h post-overdose, 21 (3.1%) developed ALI with the 2-bag regimen vs 16 (2.9%) with the 3-bag regimen (Difference: 0.2%, 95%CI:-1.6 to 2.2). The incidence of hepatotoxicity was: 1.2% (n = 8) with the two-bag regimen and 1.6% (n = 9) with the three-bag regimen (Difference -0.4%, 95%CI -1.75, 0.91). When presentation bloods were performed 8 to 24-h post-overdose, 70 (21%) developed ALI with the 2-bag regimen vs 46 (23%) with the 3-bag regimen (Difference: -2%, 95%CI -9.12 to 5.36). There were significantly less cutaneous and systemic non-allergic anaphylactic reactions recorded after treatment with the two-bag than the three-bag regimen (1.3% [n = 17] and 7.1% [n = 65], Difference: -5.8%, 95%CI -7.6 to -4.0, p < 0.0001), respectively. InterpretationA two-bag intravenous acetylcysteine regimen was found to be non-inferior to the three-bag regimen with regards to efficacy in preventing acute liver injury for early presentations of paracetamol overdose. No important differences were seen for any other presentations. The two-bag regimen also decreased the incidence of both non-allergic anaphylactic reactions and gastrointestinal adverse events from acetylcysteine treatment. FundingAW is funded by a National Health and Medical Research Council (NHMRC) Early Career Fellowship ID 1159907. GI is funded by a NHMRC Senior Research Fellowship ID 1061041. The NHMRC had no role in the design, writing of this manuscript. The corresponding author (AW) had full access to all the data in the study and final responsibility for the decision to submit the manuscript for publication.