Acute Hepatic Injury Research Articles

The Relationship Between COVID-19 Related Coagulopathy with Organ Damage and Prognosis

Objective: Coagulopathy and thromboembolic complications are frequently seen in COVID-19. We aimed to evaluate the relationship of coagulopathy with organ dysfunction and mortality in COVID-19.
 Methods: COVID-19 patients requiring intensive care for treatment and follow-up were retrospectively analyzed. In the definition of coagulopathy, the International Society on Thrombosis and Hemostasis (ISTH) overt disseminated intravascular coagulation (DIC) scoring system was used. Patients were divided into three groups according to the ISTH scores as follows; patients with no coagulopathy (ISTH score 2) and mechanical ventilation requirement, acute kidney injury (AKI), acute hepatic injury (AHI) and mortality rates were compared between these groups.
 Results: One hundred fifty-five critically ill adult patients with COVID-19 were included in the study. An abnormal coagulation profile developed in 94 (60.6%) patients; of those, 56 (36.1%) patients had non-evident abnormal coagulation, and 38 (24.5%) had evident abnormal coagulation. While there was a significant difference between the groups regarding coagulopathy and development of AKI, requirement for mechanical ventilation, and mortality, no significant difference was found in AHI and length of stay in the intensive care unit. Both mortality and development of AKI increased in correlation with the severity of coagulopathy. ISTH score and development of AKI and AHI were risk factors for both mortality and mechanical ventilation requirement.
 Conclusion: COVID-19-related coagulopathy, as determined by the ISTH overt DIC scoring system, is a predictor of organ damage and mortality.

RCsHscB Derived from Clonorchis sinensis: A Carcinogenic Liver Fluke Ameliorates LPS-Induced Acute Hepatic Injury by Repression of Inflammation.

Sepsis-associated acute liver injury caused by spillovers of bacteria and endotoxins (lipopolysaccharide, LPS) into the liver remains a public health issue due to the lack of specific therapeutic approaches. Previous studies showed that the recombinant protein HscB (rCsHscB) of Clonorchis sinensis, a carcinogenic liver fluke, had an anti-inflammatory effect and could alleviate inflammatory diseases such as enteritis; however, whether it can prevent sepsis-associated acute liver injury induced by LPS is still unknown. In our current study, the therapeutic effects and the potential mechanisms of rCsHscB on LPS-induced acute liver injury were investigated both in vivo and in vitro. The data showed that rCsHscB prevented LPS-induced liver damage, as demonstrated by histopathological observation and hepatic damage markers (the activities of serum ALT and AST) in a murine model of sepsis-associated acute liver injury. rCsHscB also significantly reversed the high levels of serum IL-6 and MCP-1 induced by LPS. In addition, rCsHscB attenuated the production of LPS-induced proinflammatory cytokines, including IL-6 and TNF-α, in a macrophage cell line-RAW264.7, through possible mediation by the MAPK signaling pathway in vitro. In conclusion, the present study demonstrates that rCsHscB derived from a fluke C. sinensis protects against sepsis-associated acute liver injury induced by LPS, which may be attributed to the inhibition of the MAPK signaling pathway. Our present study provides a potential therapeutic strategy for sepsis-associated acute liver injury.

Ameliorative Effects of Oyster Protein Hydrolysates on Cadmium-Induced Hepatic Injury in Mice.

Cadmium (Cd) is a widespread environmental toxicant that can cause severe hepatic injury. Oyster protein hydrolysates (OPs) have potential effects on preventing liver disease. In this study, thirty mice were randomly divided into five groups: the control, Cd, Cd + ethylenediaminetetraacetic acid (EDTA, 100 mg/kg), and low/high dose of OPs-treatment groups (100 mg/kg or 300 mg/kg). After continuous administration for 7 days, the ameliorative effect of OPs on Cd-induced acute hepatic injury in Cd-exposed mice was assessed. The results showed that OPs significantly improved the liver function profiles (serum ALT, AST, LDH, and ALP) in Cd-exposed mice. Histopathological analysis showed that OPs decreased apoptotic bodies, hemorrhage, lymphocyte accumulation, and inflammatory cell infiltration around central veins. OPs significantly retained the activities of SOD, CAT, and GSH-Px, and decreased the elevated hepatic MDA content in Cd-exposed mice. In addition, OPs exhibited a reductive effect on the inflammatory responses (IL-1β, IL-6, and TNF-α) and inhibitory effects on the expression of inflammation-related proteins (MIP-2 and COX-2) and the ERK/NF-κB signaling pathway. OPs suppressed the development of hepatocyte apoptosis (Bax, caspase-3, and Blc-2) and the activation of the PI3K/AKT signaling pathway in Cd-exposed mice. In conclusion, OPs ameliorated the Cd-induced hepatic injury by inhibiting oxidative damage and inflammatory responses, as well as the development of hepatocyte apoptosis via regulating the ERK/NF-κB and PI3K/AKT-related signaling pathways.

Acute Hepatic Injury Associated with Acute Administration of Synthetic Cannabinoid XLR-11 in Mouse Animal Model

The widespread recreational use of synthetic cannabinoids (SCs) has become a serious health issue. Reports of life-threatening intoxications related to SC consumption have markedly increased in recent years, including neurotoxicity, cardiotoxicity, nephrotoxicity, and hepatotoxicity. We investigated the impact of acute administration of the synthetic cannabinoid XLR-11 (3 mg/kg, i.p. for 5 consecutive days) on the liver in BALB/c mouse animal model. Using real-time quantitative RT-PCR, MDA assay, and TUNEL assay, we found consistent up-regulation of a variety of genes involved in oxidative stress (NOX2, NOX4, and iNOS), inflammation (TNF-α, IL-1β, IL-6), and apoptosis (Bax) in the liver of XLR-11 treated mice compared to control mice. These finding were supported with an elevation of MDA levels and TUNEL positive cells in the liver of XLR-11 treated mice which further confirm increased oxidative stress and apoptosis, respectively. Histopathological analysis of the liver of XLR-11 treated mice confirmed pronounced hepatic necrosis associated with inflammatory cell infiltration. Furthermore, elevated ALT and AST serum levels were also identified in XLR-11 treated mice indicating possible liver damage. Overall, SC-induced hepatotoxicity seems to be mainly mediated by activated oxidative stress and inflammatory processes in the liver, but the specific mechanisms involved require further investigations. However, the present study shed light on the potential deleterious role of acute administration of SCs in the progression to acute hepatic injury which enhances our understanding of the adverse effect of SC consumption.

Anti-Inflammatory and Chondro-Protective Effects of Acidic Polysaccharide from Enteromorpha Prolifera in Experimental Models of Osteoarthritis In-Vitro and In-Vivo.

Osteoarthritis (OA) progression has been shown to increase the expression of inflammatory cytokines in joints, leading to the destruction of cartilage matrix. Interleukin (IL)-1β is a potent inflammatory cytokine associated with osteoarthritic synovial fluid. The protective effects of polysaccharides from Enteromorpha prolifera against acute hepatic injury was reported. In this study, we examined the effects of Enteromorpha polysaccharide extracts (EPEs) in the treatment of OA. The effects of the EPEs were assessed using an IL-1β-stimulated SW1353 and SW982 cells. The expression levels of specific mRNA and proteins were evaluated using semi-quantitative reverse transcription polymerase chain reaction (sqRT-PCR) and western immunoblotting. An OA animal study involving C57BL/6J mice was also conducted to assess the effects on tactile sensitivity and anterior cruciate ligament transection (ACLT). Acidic polysaccharide extract (APE) was shown to significantly reduce cytokine and chemokine mRNA levels in IL-1β-stimulated SW1353 and SW982 cells and attenuate the expression of proinflammatory cytokines and p38/AP-1 in SW1353 cells. APE was also shown to minimize the effect of osteolytic lesions in the knee joints of ACLT-induced osteoarthritic mice. APE is a potent inhibitor of joint degeneration associated with OA.

Mechanisms of Ardisia japonica in the Treatment of Hepatic Injury in Rats Based on LC-MS Metabolomics.

The mechanism of action of Ardisia japonica in the treatment of immune liver injury was systematically analyzed from the perspective of the biological metabolic network by using non-targeted metabolomics combined with biological network analysis tools. A rat model of acute immune hepatic injury was established by Concanavalin A (Con A) and the efficacy of the treatment of acute immune liver injury was judged by gavage of A. japonica. Liquid chromatography-mass spectrometry (LC-MS)-based plasma metabolomics was used to identify the key metabolites and metabolic pathways for the hepatoprotective effects of A. japonica. The results demonstrated that A. japonica reduced the levels of inflammatory parameters, decreased hepatic malondialdehyde levels, and enhanced hepatic antioxidant enzyme activity in animal experiments. The clustering of metabolomic samples showed significant separation in principal component analysis plots and the three groups in PLS-DA and OPLS-DA models could be clearly distinguished in multivariate statistical analysis. Among the 937 total metabolites, 445 metabolites were significantly different between the control and model groups, while 144 metabolites were identified as metabolites with differences between the model and administration groups, and a total of 39 differential metabolites were identified to affect the metabolic levels of the three groups. The differential metabolites were principally involved in the citric acid cycle, glutathione metabolism, vitamin B6 metabolism, and steroid hormone biosynthesis. This study found that A. japonica can significantly inhibit acute liver injury in rats, and exert a hepatoprotective effect through anti-inflammatory effect, inhibition of lipid peroxidation, improvement of the antioxidant defense system, and regulation of metabolites and related metabolic pathways. This study will provide a theoretical basis for the application of A. japonica in the treatment of the liver injury.

A Case of Ecstasy-Induced Acute Hepatic Injury

The recreational use of a drug such as 3,4-methylenedioxymethamphetamine (MDMA), also known as "ecstasy," may be associated with significant side effects. Although liver failure with ecstasy is rare, the use of the drug should be investigated in all patients with severe hepatitis of unknown origin. Early diagnosis and intervention can prevent patients from ending up in liver transplantation. Here, we present a case of a 27-year-old female who developed acute liver injury secondary to recreational intoxication with ecstasy.

Transplantation of adipose-derived mesenchymal stem cells ameliorates acute hepatic injury caused by nonsteroidal anti-inflammatory drug diclofenac sodium in female rats

BackgroundAlthough the beneficial role of adipose-derived mesenchymal stem cells (AD-MSCs) in acute liver injury has been addressed by numerous studies employing different liver injury inducers, the role of rat AD-MSCs (rAD-MSCs) in diclofenac sodium (DIC) – induced acute liver injury has not yet been clarified. ObjectiveThis study aimed to investigate whether rat adipose- rAD-MSCs injected intraperitoneal could restore the DIC-induced hepatoxicity. MethodsHepatotoxicity was induced by DIC in a dose-based manner, after which intraperitoneal injection of rAD-MSCs was performed. ResultsHere, the transplanted cells migrated to the injured liver, and this was evidenced by detecting the specific SRY in the liver samples. After administering DIC, a significant decrease in body weight, survival rate, serum proteins, antioxidants, anti-apoptotic gene expression, and certain growth factors, whereas hepatic-specific markers, pro-inflammatory mediators, and oxidative, pro-apoptotic, and ER-stress markers were elevated. These adverse effects were significantly recovered after engraftment with rAD-MSCs. This was evidenced by enhanced survival and body weight, improved globulin and albumin values, increased expression of SOD, GPx, BCL-2, VEGF, and FGF-basic expression, and decreased serum ALT, AST, ALP, and total bilirubin. rAD-MSCs also reduced liver cell damage by suppressing the expression of MDA, IL-1B, IL-6, BAX, JNK, GRP78/BiP, CHOP, XBP-1, and cleaved caspase 3/7. Degenerative hepatic changes and multifocal areas of fatty change within liver cells were observed in DIC-received groups. These changes were improved with the transplantation of rAD-MSCs. ConclusionsWe could conclude that targeted AD-MSCs could be applied to reduce hepatic toxicity caused by NSAIDs (DIC).

S3094 Leptospirosis-Induced Acute Liver Injury

Introduction: Weil’s disease (Leptospirosis) is a relatively common worldwide zoonotic infection due to Leptospira spp. However, leptospirosis is underreported due to its low incidence in the United States and its variable presentation. Furthermore, leptospirosis-induced acute hepatic injury is extremely rare. The purpose of this case report to enlighten urban practitioners to consider testing for leptospirosis in patients with acute liver injury. We are reporting a rare case of leptospirosis induced acute liver injury. Case Description/Methods: A 38 year-old-male with no past medical history presented with 6-day history of fever, abdominal pain, N/V, fatigue and myalgia. On presentation patient was vitally stable, physical exam, ill appearing man with icterus sclera, mild tenderness in RUQ abdomen. Labs: WBC 14.16, ALT 181, AST 232, Bilirubin 7.5 (direct bilirubin 6.2), platelets 41, INR 1.13, aPTT 19.7, BUN 33, Cr 3.41, GFR 21.6, CT abdomen revealed hepatic steatosis and hepatomegaly. Extensive hepatic and sepsis work up sent and patient was started on vancomycin, piperacillin/tazobactam. For next 4 days, WBC 25.22, Bilirubin 18, (direct bilirubin >10.0) with more yellow skin, however, ALT 68, AST 54, platelets 93 improved. Renal function worsened to BUN 58, Cr 4.05, GFR 17.5. All the extensive work up came back unremarkable, Leptospira IgM antibody was sent on day 5. The patient was transferred to the intensive care unit on day 6 for multi-organ failure. On day 8 leptospira IgM antibody came back positive and antibiotics were de-escalated to IV penicillin G. On day 12, patient had significant clinical and labs improvement, WBC 10.16, Platelets 347, ALT 59, AST 44, Bilirubin 4.2, (direct bilirubin 2.6), BUN 20, Cr 1.22, GFR >60. 2 weeks after hospital discharge, patient was feeling much better and his hepatic and renal function returned to baseline. Discussion: Leptospirosis-induced acute liver injury is exceedingly rare in United States; hence, a high index of suspicion is required to make the diagnosis due to its variable clinical course. Most cases are mild, while some are severe and potentially fatal. In urban areas, the disease is mainly transmitted via rodent urine contamination of water and soil. With the increase use of various types of cycles, riders of these devices, as well as sewer workers and joggers, risk greater exposure to the disease. Providers, especially in urban settings, should have a high index of suspicion, and evaluate patients with acute liver injury for leptospirosis.

Nilotinib alleviated acetaminophen-induced acute hepatic injury in mice through inhibiting HIF-1alpha/VEGF-signaling pathway

The current study inspects the impact of nilotinib (Nil) on liver damage caused by acetaminophen (APAP). Adult male mice were pre-treated with nilotinib (Nil,5 and 10 mg/kg) orally once daily for 7 days followed by a single intraperitoneal administration of acetaminophen (APAP, 200 mg/kg) on the 7th day.The results indicated that nilotinib significantly decreased APAP-induced elevation of biochemical markers (ALT, AST, ALP, LDH, ɤ GT, and total bilirubin). Additionally, nilotinib significantly increased hepatic GSH and SOD content, while decreased MDA content. Nil significantly suppressed the expression of HIF-1α and VEGF. Histopathological examination of hepatic tissue from Nil-treated mice revealed that Nil reduced acetaminophen-induced necrosis.

Hepatoprotection of Paederia scandens (Lour.) Merr. on Acetaminophen-Related Hepatic Injury Rats by 1H-NMR-Based Metabonomics Coupled with Network Pharmacology.

Background Acetaminophen-related hepatic injury (ARHI) is a kind of acute hepatic injury caused by overdosing acetaminophen, which is mainly related to toxic metabolite production, oxidative stress, and mitochondrial dysfunction. The extract of Paederia scandens (Lour.) Merr. (PSM) has the abilities of anti-inflammatory, antivirus, and antioxidation. Research studies showed that PSM could improve acute or chronic hepatic injury, while the mechanism of which is still indistinct. Methods Here, the authors applied the approach based on serum metabonomics combined with network pharmacology to study the protection of PSM on ARHI rats. Results 10 serum potential biomarkers were found to be closely related to ARHI by metabonomics, while 3 compounds (L-ascorbyl 2,6-dipalmitate, squalene, and tributyl O-acetylcitrate) and 3 targets (NOS2, MAOB, and PDE3A) were found that might be the potential active components and active site of PSM on treating ARHI by network pharmacology analysis. Furthermore, molecular biology strategy was performed to validate whether iNOS/NF-κB signaling pathway is the potential mechanism of PSM treating ARHI. Conclusions This study indicated that PSM could ameliorate ARHI by iNOS/NF-κB signaling pathway. During ARHI treatment by PSM, L-ascorbyl 2, 6-dipalmitate, squalene, and tributyl O-acetylcitrate might be the potential active components, while the possible active site might be NOS2, MAOB, and PDE3A.

Design for a Multicentre Prospective Cohort for the Assessment of Platelet Function in Patients with Hepatitis-B-Virus-Related Acute-on-Chronic Liver Failure.

BackgroundAcute-on-chronic liver failure (ACLF) has high short-term mortality and lacks sufficient medical therapy. Available algorithms are unable to precisely predict short-term outcomes or safely stratify patients with ACLF as emergent liver transplantation candidates. Therefore, a personalized prognostic tool is urgently needed.PurposePlatelet function and its clinical significance in ACLF patients with chronic hepatitis B virus (HBV) infection have not been investigated. This study aimed to assess changes in platelet function using thromboelastography (TEG) and platelet mapping (TEG-PM) in HBV-related ACLF patients.MethodsChronic liver disease patients with acute decompensation or acute hepatic injury were recruited. The derivation cohort enrolled HBV-related patients at Nanfang Hospital. HBV-related and non-HBV-related patients were both enrolled in internal and external validation cohorts at seven university hospitals. TEG and TEG-PM were performed at baseline in the derivation cohort and baseline, day 7, and day 14 in the validation cohorts. The primary outcome was all-cause 28-day mortality. Status check and new-onset complications were recorded during the 3-month follow-up, but status check will extend to 5 years.Conclusion and Future PlansIn this study, 586 participants were enrolled, including 100 in derivation cohort, 133 in internal validation cohort, and 353 in external validation cohort. Biomaterials, including plasma, serum, urine, and some explanted liver tissues, were collected from these patients. A 3-month follow-up with survival status was completed. The baseline characteristics indicated that 51% of the patients had adenosine diphosphate (ADP)-hyporesponsive circulating platelets. The prognostic potential of platelet function will be explored in the derivation cohort (HBV-related ACLF patients) and further substantiated in the validation cohorts (HBV-related and non-HBV-related ACLF patients). Biosamples are currently used to explore the underlying mechanisms related to ADP-hyporesponsive platelets. The ongoing proteomic and metabolic analyses will provide new insights into the pathogenesis of extrahepatic organ failures in ACLF patients.

Artificial Intelligence-Assisted Image Analysis of Acetaminophen-Induced Acute Hepatic Injury in Sprague-Dawley Rats.

Although drug-induced liver injury (DILI) is a major target of the pharmaceutical industry, we currently lack an efficient model for evaluating liver toxicity in the early stage of its development. Recent progress in artificial intelligence-based deep learning technology promises to improve the accuracy and robustness of current toxicity prediction models. Mask region-based CNN (Mask R-CNN) is a detection-based segmentation model that has been used for developing algorithms. In the present study, we applied a Mask R-CNN algorithm to detect and predict acute hepatic injury lesions induced by acetaminophen (APAP) in Sprague-Dawley rats. To accomplish this, we trained, validated, and tested the model for various hepatic lesions, including necrosis, inflammation, infiltration, and portal triad. We confirmed the model performance at the whole-slide image (WSI) level. The training, validating, and testing processes, which were performed using tile images, yielded an overall model accuracy of 96.44%. For confirmation, we compared the model’s predictions for 25 WSIs at 20× magnification with annotated lesion areas determined by an accredited toxicologic pathologist. In individual WSIs, the expert-annotated lesion areas of necrosis, inflammation, and infiltration tended to be comparable with the values predicted by the algorithm. The overall predictions showed a high correlation with the annotated area. The R square values were 0.9953, 0.9610, and 0.9445 for necrosis, inflammation plus infiltration, and portal triad, respectively. The present study shows that the Mask R-CNN algorithm is a useful tool for detecting and predicting hepatic lesions in non-clinical studies. This new algorithm might be widely useful for predicting liver lesions in non-clinical and clinical settings.

Strategic application of liposomal system to R-α-lipoic acid for the improvement of nutraceutical properties

R-α-lipoic acid (RLA) and dihydrolipoic acid (DHLA), a reduced form of RLA, are potent endogenous antioxidants that can reduce oxidative damage. Despite their numerous nutraceutical potentials, clinical applications of RLA are still limited due to its poor solubility and stability problems. This study aimed to develop an RLA-loaded liposome (LIP/RLA) for the improvement of nutraceutical properties. LIP/RLA was developed by a typical solvent injection method. Uniform liposomes of LIP/RLA were observed by transmission electron microscopy, and the mean particle size was calculated to be ∼150 nm from the data of dynamic light scattering. LIP/RLA could prevent the degradation of RLA even under acidic conditions (pH 1.2) possibly due to the encapsulation of RLA into the liposomal structure. In the release test under pH6.8 with lipase, LIP/RLA showed relatively rapid release of RLA, possibly due to the lipolysis of phospholipids by lipase. After the oral administration of LIP/RLA (10 mg-RLA/kg, p.o.) in rats, the systemic exposures of RLA and DHLA increased by 2.8- and 5.8-fold, respectively. In a rat model of acute hepatic injury induced by carbon tetrachloride (CCl4) (0.7 mL-CCl4/kg, p.o.), orally dosed LIP/RLA (3 mg-RLA/kg, p.o.) resulted in 78.7% and 86.4% reductions of plasma alanine aminotransferase, and aspartate aminotransferase, respectively; however, RLA was found to be less effective possibly due to the poor oral absorption. The RLA-loaded liposomal system might be a promising carrier for poorly water-soluble materials with poor stability under acidic conditions, as well as RLA, to improve their oral absorption and nutraceutical properties.

Role of Stem Cells and Erythropoietin on Experimental Acute Hepatic Injury in Rats

Role of Stem Cells and Erythropoietin on Experimental Acute Hepatic Injury in Rats

Perioperative Complications and Postoperative Mortality in Patients of Acute Stanford Type a Aortic Dissection with Cardiac Tamponade

Objective The aim of the study was to analyze perioperative complications and postoperative mortality in patients of acute Stanford type A aortic dissection(ATAAD)combined with cardiac tamponade (TMP). Methods In this study, we identified a total of 242 ATAAD patients who underwent surgery from January 2016 to December 2020. Of the 242 patients, 44(18.2%) patients were combined with TMP and 198(81.8%) patients without TMP. We compared perioperative complications and postoperative mortality between the two groups. Results The postoperative mortality was significantly higher in patients with TMP (29.5% vs 14.1%, p = 0.014). The incidence of postoperative acute kidney injury (75.0% vs 51.5%, p = 0.005), acute hepatic injury (45.5% vs 20.7%, p = 0.001), cerebral infarction (27.3% vs 13.1%, p = 0.020), low cardiac output syndrome (50.0% vs 33.3%, p = 0.038) and respiratory failure (36.4% vs 22.2%, p = 0.049) in patients with TMP was significantly higher than those without TMP. Binary logistic regression analysis showed that age [odds ratio(OR) 1.063, 95% confidence interval (CI) 1.023∼1.105; p = 0.002], surgical time[odds ratio(OR)1.393, 95% confidence interval (CI) 1.006∼1.929; p = 0.046], cardiac tamponade[odds ratio(OR)3.010, 95% confidence interval (CI) 1.166∼7.767; p = 0.023], circulatory arrest time[odds ratio(OR)1.044, 95% confidence interval (CI) 1.001∼1.088; p = 0.045] were independent risk factors for postoperative mortality in ATAAD patients. Conclusions Cardiac tamponade increases the difficulty of perioperative management in ATAAD patients, the incidence of postoperative complications and postoperative mortality, which requires the cooperation of anesthesiologists, intensivists and surgeons to save and improve patients’ lives.

Role of Glycogen Synthase Kinase-3 in Interferon-γ-Mediated Immune Hepatitis.

Glycogen synthase kinase-3 (GSK-3), a serine/threonine kinase, is a vital glycogen synthase regulator controlling glycogen synthesis, glucose metabolism, and insulin signaling. GSK-3 is widely expressed in different types of cells, and its abundant roles in cellular bioregulation have been speculated. Abnormal GSK-3 activation and inactivation may affect its original bioactivity. Moreover, active and inactive GSK-3 can regulate several cytosolic factors and modulate their diverse cellular functional roles. Studies in experimental liver disease models have illustrated the possible pathological role of GSK-3 in facilitating acute hepatic injury. Pharmacologically targeting GSK-3 is therefore suggested as a therapeutic strategy for liver protection. Furthermore, while the signaling transduction of GSK-3 facilitates proinflammatory interferon (IFN)-γ in vitro and in vivo, the blockade of GSK-3 can be protective, as shown by an IFN-γ-induced immune hepatitis model. In this study, we explored the possible regulation of GSK-3 and the potential relevance of GSK-3 blockade in IFN-γ-mediated immune hepatitis.

Patterns of acute kidney and hepatic injury and association with adverse outcomes in infants undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy.

To describe patterns of renal and hepatic injury in infants with hypoxic ischemic encephalopathy (HIE). Retrospective cohort of infants receiving therapeutic hypothermia for HIE was classified into groups based on organ injury: neither acute kidney injury (AKI) nor acute hepatic injury (AHI), isolated AKI, isolated AHI, or both AKI/AHI. Biomarkers and outcomes were described and analyzed. Among 188 infants, 55% had no AKI nor AHI, 7% had only AKI, 22% had only AHI and 16% had both AKI and AHI. Infants with both AKI/AHI had the highest mortality (47%) and worse outcomes, compared to other injury groups, although AKI/AHI was not significantly associated with mortality (hazard ratio 2.5; 95% CI 0.9-6.9), after accounting for severity of HIE. For surviving infants, biomarkers of organ injury, on average, normalized by discharge. Infants with HIE with both AKI/AHI have worse outcomes than infants with AKI or AHI alone.

SERP1 reduces inchoate acute hepatic injury through regulation of endoplasmic reticulum stress via the GSK3β/β‑catenin/TCF/LEF signaling pathway.

The liver is a crucial digestive organ of humans and in charge of detoxification. Acute hepatic injury is an aggressive type of hepatic disease and its harmful effect cannot be ignored. The present study examined the role and mechanism of stress-associated endoplasmic reticulum protein 1 (SERP1) in acute hepatic injury. Mice were injected intraperitoneally with D-galactosamine/lipopolysaccharide (LPS) and rat hepatocytes were induced by LPS to establish an acute hepatic injury model. Tissue lesions were observed by H&E staining, and biomarkers of hepatic injury in the serum were examined. Western blotting, immunohistochemistry and reverse transcription-quantitative PCR were performed to assess SERP1 expression in tissues and hepatocytes. A SERP1 overexpression plasmid was constructed to evaluate the role of SERP1 in inflammation, apoptosis, endoplasmic reticulum stress (ERS) and the GSK3β/β-catenin/T-cell factor (TCF)/lymphoid enhancing factor (LEF) signaling pathway. In addition, a GSK3β overexpression plasmid was constructed to investigate the role of GSK3β/β-catenin signal activation. Additionally, the present study investigated whether SERP1 regulated the endoplasmic reticulum via this pathway. In the present study, reliable animal and cellular hepatic injury models were established and verified. SERP1 overexpression reduced the expression of inflammatory factors, apoptosis-related proteins and ERS-related proteins, as well as the expression of proteins related to GSK3β/β-catenin/TCF/LEF signaling pathways. A GSK3β overexpression plasmid was constructed and it was revealed that GSK3β overexpression could reverse the effects of SERP1 overexpression in aforementioned aspects. This suggested that the activation of the GSK3β/β-catenin/TCF/LEF signaling pathway may be required for the regulation of SERP1. In conclusion, SERP1 regulated ERS via the GSK3β/β-catenin/TCF/LEF signaling pathway, thereby reducing inchoate acute hepatic injury.

Therapeutic potential of macrophage colony-stimulating factor in chronic liver disease.

ABSTRACTResident and recruited macrophages control the development and proliferation of the liver. We have previously shown in multiple species that treatment with a macrophage colony stimulating factor (CSF1)-Fc fusion protein initiated hepatocyte proliferation and promoted repair in models of acute hepatic injury in mice. Here, we investigated the impact of CSF1-Fc on resolution of advanced fibrosis and liver regeneration, using a non-resolving toxin-induced model of chronic liver injury and fibrosis in C57BL/6J mice. Co-administration of CSF1-Fc with exposure to thioacetamide (TAA) exacerbated inflammation consistent with monocyte contributions to initiation of pathology. After removal of TAA, either acute or chronic CSF1-Fc treatment promoted liver growth, prevented progression and promoted resolution of fibrosis. Acute CSF1-Fc treatment was also anti-fibrotic and pro-regenerative in a model of partial hepatectomy in mice with established fibrosis. The beneficial impacts of CSF1-Fc treatment were associated with monocyte-macrophage recruitment and increased expression of remodelling enzymes and growth factors. These studies indicate that CSF1-dependent macrophages contribute to both initiation and resolution of fibrotic injury and that CSF1-Fc has therapeutic potential in human liver disease.