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Cisplatin (cis-diaminodichloroplatinum II, CDDP), an essential chemotherapeutic agent, can cause potential hepatotoxicity, but the underlying molecular mechanisms remain unclear. In this study, the protective effects of ellagic acid (EA) on CDDP exposure-induced hepatotoxicity and the underlying molecular mechanisms were investigated in a mouse model. Mice were randomly divided into control, CDDP model, EA100 (i.e., 100 mg/kg/day), and CDDP plus 25, 50, or 100 mg/kg/day EA groups. Mice in all the CDDP-treated groups were intraperitoneally injected with 20 mg/kg/day CDDP for two days. For all EA cotreatments, the mice were orally administered EA for seven days. Our results revealed that CDDP treatment resulted in liver dysfunction, oxidative stress, and caspase activation, which were effectively attenuated by EA cotreatment in a dose-dependent manner. Furthermore, EA supplementation significantly downregulated the CDDP exposure-induced protein and mRNA expression of NF-κB, IL-1β, TNF-α, and IL-6 but further upregulated the protein and mRNA expression of Nrf2 and HO-1. Molecular docking analysis revealed strong interactions between EA and the NF-κB or Keap1 proteins. In conclusion, our results revealed that EA supplementation could ameliorate CDDP-induced liver toxicity in mice by activating the Nrf2/HO-1 signaling pathway and inhibiting the NF-kB signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Several factors contribute to post-anesthetic hepatic dysfunction, including a decrease in oxygen supply to the liver, direct physical compression of the liver, viral hepatitis, blood transfusions, preexisting hepatic dysfunction, and the use of hepatotoxic drugs. Diagnosing volatile anesthetic drug-induced liver injury (VA-DILI) involves excluding these causes. Case: The patient underwent total mastectomy under anesthesia using sevoflurane. He had diabetes, and no abnormal results were found on preoperative laboratory examinations, and surgery was uneventful. Abnormal laboratory findings were observed after surgery, including an aspartate aminotransferase level of 1,417 IU/L, an alanine aminotransferase level of 2,176 IU/L, and a total bilirubin level of 3.8 mg/dl. He presented with symptoms of mild icteric sclera, fatigue, and pruritus. After ruling out other causes of liver injury, we concluded that these results indicated VA-DILI. Conclusions: VA-DILI, though rare, we should be aware of the association between the disease and the use of halogenated anesthetics. [ABSTRACT FROM AUTHOR]

Objectives: To identify magnetic resonance imaging (MRI) features associated with injury type, severity, and liver transplantation (LT)/liver-related death (LRD) in drug-induced liver injury (DILI). Methods: The eligible DILI patients (2016 to 2020) who underwent contrast abdominal MRI within 3 months of onset were retrospectively analysed at Beijing Friendship Hospital, Capital Medical University. The MRI features independently associated with severity and prognosis were identified by backwards logistic regression. Unadjusted odds ratios (ORs) and 95% confidence intervals (CIs) are given. Results: The median age of 180 patients was 55.5 years, with 126 (70.0%) women. The injury types included hepatocellular (135 cases, 75.0%), mixed (23, 12.8%), and cholestatic (22, 12.2%). The proportion of periportal oedema in patients with hepatocellular and mixed injury was significantly higher than that in cholestatic injury (62.2%, 47.8% vs. 18.2%, p < 0.001). For severity, 157 (87.2%) patients had mild to moderate injury, and 23 (12.8%) had severe to fatal/LT. Irregularity of the liver surface (6.56 (95% CI, 1.27–22.84)), transient hepatic attenuation difference (THAD) (3.27 (95% CI, 1.14–9.36)), and splenomegaly (5.86 (95% CI, 1.96–17.53)) were independently associated with severity. Eight (4.4%) patients died/underwent LT. THAD (8.89 (95% CI, 1.35–58.43)), and ascites (64.63 (95% CI, 6.93–602.40)) were independently associated with LT/LRD. The prediction of the new model employing THAD and ascites for LT/LRD within 1 year was 0.959 (95% CI, 0.917–1.000). Conclusions: Periportal oedema was associated with the type of injury. Irregularity of the liver surface, THAD, and splenomegaly were associated with severity. THAD and ascites may have potential clinical utility in predicting LT/LRD outcomes within 1 year. Key Points: • Contrast abdominal magnetic resonance imaging features can help clinicians evaluate the type of injury, severity, and poor prognosis of drug-induced liver injury. • Transient hepatic attenuation difference and ascites have potential clinical utility in the prediction of the poor prognosis of liver transplantation/liver-related death. • The new model predicting poor prognosis has a relatively high sensitivity of 0.875 and a high specificity of 0.919. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic has revolutionized the priorities of the medical society worldwide. Although most patients infected with SARS-CoV-2 exhibit respiratory symptoms, other organs may also be involved, including the liver, often resulting in liver injury. Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world, and its prevalence is expected to increase together with the epidemics of type 2 diabetes and obesity. Data about liver injury during COVID-19 are numerous, while overviews of this infection in patients with NAFLD, both in terms of respiratory and liver, are emerging. In this review, we summarise the current research focusing on COVID-19 in NAFLD patients and discuss the association between liver injury in COVID-19 subjects and non-alcoholic fatty liver disease. [ABSTRACT FROM AUTHOR]

Objective: AcetaCalc was used to evaluate Psi’s accuracy in predicting cases that required prolonged N-acetylcysteine (NAC) therapy, as well as Psi’s optimal cut-off. Materials and Methods: This is a retrospective study of patients with acute paracetamol overdose who were treated with NAC at Siriraj Hospital between 2007 and 2016. The Psi parameter was calculated using the Acetacalc after entering paracetamol concentrations, blood sampling times, and NAC onset times. Indications for NAC continuation is in accordance with the guidelines, which recommended that NAC treatment be continued if the follow-up aminotransferase reached 50 U/L or higher. Results: We enrolled 403 patients, the proportion of NAC prolongation was 50.4 %. Psi was shown to be a significant predictor of NAC prolongation (p < 0.001) with area under the receiver operational characteristics curve 0.766 (95% confidence interval (CI) 0.719-0.813). The Psi cutoff with highest Youden index was 1.757 mM-hour. The sensitivities and specificities of the cutoff were 0.517 (95% CI 0.449-0.585) and 0.940 (95% CI 0.898-0.965), respectively. Conclusion: Psi parameter calculated through AcetaCalc is a useful tool for the prediction of cases where extension of NAC therapy beyond the standard regimen is indicated. [ABSTRACT FROM AUTHOR]

Aim: We aimed to investigate the frequency of intra-abdominal injury in posttraumatic isolated transverse process fractures (iTPF) and the factors affecting the injury, especially the effect of the size of the fracture on the injury. Materials and Methods: Patients' age, gender, trauma type determined by Computed Tomography (CT), fracture localization, separation distance of the fracture from the vertebral body, neurological status, and non-vertebral organ injury, if any, were evaluated retrospectively. Results: Intra-abdominal injury was detected in 16 of 70 patients with iTPF included in the study. The most common cause of iTPF was falls. Those with multiple TPF had a higher rate of intra-abdominal injury. Liver injury was the most common type of intra-abdominal injury. The separation distance of iTPFs from the vertebral body was mean 5.81±1.9 mm in patients with intra-abdominal injury and 3.90±1.69 mm in patients without intra-abdominal injury, and the separation distance was statistically significantly higher in patients with intra-abdominal injury (p < 0.05). Conclusion: This study showed that intra-abdominal injury may be common in cases of iTPF. The severity of the trauma, the high number of fractures, and the length of the fracture distances have caused organ damage to be seen more frequently. [ABSTRACT FROM AUTHOR]

Cereal vinegar sediment (CVS) is a natural precipitate formed during the aging process of traditional grain vinegar. It has been used as Chinese traditional medicine, while its composition and function are reported minimally. In this study, we measured CVS in terms of saccharide, protein, fat and water content, and polyphenol and flavonoid content. Furthermore, we determined the amino acids, organic acids, and other soluble metabolites in CVS using reverse-phase high-performance liquid chromatography (RP-HPLC), HPLC, and liquid chromatography with tandem mass spectrometry (LC-MS/MS) platforms. The hepatoprotective effect of CVS was evaluated in acute CCl4-induced liver injury mice. Administration of CVS for 7 days prior to the CCl4 treatment can significantly decrease liver alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and reactive oxygen species (ROS) levels, compared with those in the hepatic injury model group. The gut microbiota was changed by CCl4 administration and was partly shifted by the pretreatment of CVS, particularly the Muribaculaceae family, which was increased in CVS-treated groups compared with that in the CCl4 administration group. Moreover, the abundances of Alistipes genus and Muribaculaceae family were correlated with the liver ALT, AST, and malondialdehyde (MDA) levels. Our results illustrated the composition of CVS and its hepatoprotective effect in mice, suggested that CVS could be developed as functional food to prevent acute liver injury.

Drug-induced liver injury (DILI) remains an important, yet challenging diagnosis for physicians. Each year, additional drugs are implicated in DILI and this year was no different, with more than 1400 articles published on the subject. This review examines some of the most significant highlights and controversies in DILI-related research over the past year and their implications for clinical practice. Several new drugs were approved by the US Food and Drug Administration including a number of drugs implicated in causing DILI, particularly among the chemotherapeutic classes. The COVID-19 pandemic was also a major focus of attention in 2020 and we discuss some of the notable aspects of COVID-19-related liver injury and its implications for diagnosing DILI. Updates in diagnostic and causality assessments related to DILI such as the Roussel Uclaf Causality Assessment Method are included, mindful that there is still no single biomarker or diagnostic tool to unequivocally diagnose DILI. Glutamate dehydrogenase received renewed attention as being more specific than alanine aminotransferase. There were a few new reports of previously unrecognized hepatotoxins, including immune modulators and novel gene therapy drugs that we highlight. Updates and new developments of previously described hepatotoxins, such as immune checkpoint inhibitors and anti-tuberculosis drugs are reviewed. Finally, novel technologies such as organoid culture systems to better predict DILI preclinically may be coming of age and determinants of hepatocyte loss, such as calculating PALT are poised to improve our current means of estimating DILI severity and the risk of acute liver failure. [ABSTRACT FROM AUTHOR]

Hepatic fibrosis is a spontaneous wound-healing response triggered by chronic liver injury. Pien Tze Huang (PZH), a traditional Chinese herbal medicine, has been widely used to treat various hepatic diseases in Asia. We used a CCl4-induced mouse model to establish a PZH group of hepatic fibrosis mice treated with PZH and a control group of hepatic fibrosis mice without any treatment. We performed RNA-seq and mass spectrometry sequencing to investigate the mechanism of the PZH response in hepatic fibrosis and identified multiple differentially expressed transcripts (DETs) and proteins (DEPs) that may be drug targets of PZH. Liver functional indices, including serum albumin (ALB), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), were significantly decreased in the PZH treatment group (P < 0.05) in the eighth week. Hematoxylin–eosin (HE), Masson and Sirius red staining demonstrated that PZH significantly inhibited infiltration of inflammatory cells and collagen deposition. A total of 928 transcripts and 138 proteins were differentially expressed in PZH-treated mice compared to the control group. Gene Ontology (GO) enrichment analysis suggested that PZH may alleviate liver injury and fibrosis by enhancing the immune process. Taken together, our results revealed that multiple DETs and DEPs may serve as drug targets of PZH in hepatic fibrosis patient in future clinical practice. [ABSTRACT FROM AUTHOR]

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Liver injury is a common consequence of blunt abdominopelvic trauma. Contrast-enhanced CT allows for the rapid detection and evaluation of liver injury. The treatment strategy for blunt liver injury has shifted from surgical to nonoperative management, which has been widely complemented by interventional management to treat both liver injury and its complications. In this article, we review the major imaging features of liver injury and the role of interventional management for the treatment of liver injury. [ABSTRACT FROM AUTHOR]

The article presents the use of a newly marketed selective progesterone receptor modulator, ulipristal acetate (UPA). Topics include drug-induced liver injury (DILI) being one of the most common causes of withdrawal from the market of promising drugs; treatment of moderate or severe symptoms of uterine fibroids such as heavy vaginal bleeding and pelvic pain as an alternative to surgery; and antagonising the progesterone receptors without infuencing the estrogen effects in endometrial tissue.

Background and Aims: Severe acute liver injury (ALI) can lead to poor outcomes without timely management. Comparatively worse outcomes in various severe, emergent conditions have been attributed to reduced hospital resources experienced by patient weekend admissions, a phenomenon termed "weekend effect." To date, a weekend effect has not been studied in severe ALI, an emergency also necessitating timely management. We aimed to evaluate such an effect in this condition by analyzing a large national inpatient database in the United States. Methods: We analyzed the Nationwide/National Inpatient Sample (NIS) 2000 to 2014, the largest inpatient, all‐payer database in the United States (US), containing sociodemographic, clinical, patient‐, and hospital‐level data. We identified severe ALI using International Classification of Disease, 9th Revision diagnosis codes for acute/subacute hepatic necrosis (570) with encephalopathy (572.2). Our primary outcome was in‐hospital mortality. Using a full‐model approach for covariate selection, we performed multiple logistic regression modeling to assess for weekend effect and identify predictors of in‐hospital mortality. Results: We identified 15 762 eligible hospitalizations, with 12 182 (77.3%) having complete covariate data. This sample comprised 53.3% males, 69.3% White race, and had an average (± SD) age of 55.0 ± 14.1 years. We utilized a full‐model approach for covariate inclusion but did not include patient transfer data due to limited availability. We observed no significant mortality differences in weekend admissions (OR = 1.06, 95% CI: 0.97‐1.15, P = 0.02). However, significantly higher mortality was associated with male sex, older age, Black or Hispanic race, Northeast US hospitalization, urban teaching status, and larger hospital size. Sensitivity analyses using multiple imputation datasets and transfer covariates did not change our results. Conclusion: We did not observe a weekend effect of in‐hospital mortality for weekend admissions for severe ALI, but our overall diagnosis ascertainment yield was low—indicating that lack of accurate documentation for the etiology of severe ALI may be masking an effect. Additionally, our findings suggest that racial differences and hospital‐level characteristics in the context of severe ALI may be associated with varying outcomes, regardless of admission day, which warrants further research. [ABSTRACT FROM AUTHOR]

In the present study, the hepatoprotective activity of the unsaponifiable matter (UNSAP) of olive oil, linseed, and sesame oils against CCl4-induced liver toxicity in rats was investigated. In a preliminary antioxidant study, UNSAP showed pronounced DPPH radical scavenging activity (IC50 6.2-10.8 mg/mL). The constituents of UNSAP were determined by GC-MS. The subcutaneous administration of CCl4, caused liver injury. The hepatoprotective effect of UNSAP was comparable to that of a-tocopherol, a standard antioxidant agent. The co-administration of the investigated UNSAP normalized the activities of serum marker enzymes, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Furthermore, the serum alkaline phosphatase (ALP) activity and hepatic malondialdehyde (MDA) level were found to be alleviated by pre-treatment with the UNSAP. A histopathological evaluation showed marked improvement in the liver of UNSAP- and a-Tocopheroltreated animals. The hepatoprotective effect could be attributed to the antioxidant characteristics of UNSAP. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are thought to have great potential in the therapy of acute liver injury. It is possible that these cells may be regulated by the stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor-4 (CXCR4) signaling axis, which has been shown to promote stem cells migration in the inflammation-associated diseases. However, the effects of SDF-1/CXCR4 axis on the MSCs-transplantation-based treatment for acute liver injury and the underlying mechanisms are largely unknown. In this study, we sought to determine whether SDF-1/CXCR4 would augment the therapeutic effect of bone marrow mesenchymal stem cells (BMSCs) by promoting their migration, which may result from activating the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, in a rat acute liver injury model induced by lipopolysaccharide (LPS). We found that BMSCs transplantation markedly attenuated liver injury and improved the survival of LPS-treated rats. Of interest, overexpression of CXCR4 in BMSCs could substantially promote their migration both in vitro and in vivo, and result in even better therapeutic effects. This might be attributed to the activation of PI3K/Akt signaling pathway in BMSCs that is downstream of CXCR4, as demonstrated by the use of the CXCR4 antagonist AMD3100 and PI3K pathway inhibitor LY294002 assays in vitro and in vivo. Together, our results unraveled a novel molecular mechanism for the therapeutic effect of BMSCs for the treatment of acute liver injury, which may shed a new light on the clinical application of BMSCs for acute liver failure. [ABSTRACT FROM AUTHOR]

The article offers information on the treatment with efruxifermin in cirrhotic patients with metabolic dysfunction-associated steatohepatitis (MASH), showing "clinically meaningful" but not yet statistically significant benefits at 36 weeks. Topics include the background of FGF21 and efruxifermin, the SYMMETRY study design and patient population, and the study results showing improvements in fibrosis without worsening MASH, resolution of MASH, and improvements in liver injury.

INTRODUCTION: The aim of this study is to investigate the effects of obstructive jaundice on the liver and effectivity of alpha-lipoic acid on liver damage and oxidative stress. MATERIALS AND METHODS: Thirty-six male Sprague-Dawley rats were divided into 3 groups per 12 animals, namely into Group I (control group): the bile duct was only mobilized by laparotomy, Group II (bile duct ligation group - BDL): the common bile duct was closed with clips and OJ was caused after laparotomy, and Group III (bile duct ligation and alpha-lipoic acid group - BDL+LA): after closing the common bile duct, LA was administered in an intramuscular dose of 50 mg/kg for 10 days. On the 10th day, malondialdehyde, glutathione and superoxide dismutase levels were measured in liver and histopathological evaluation was performed. RESULTS: AST (U/L)/ALT(U/L) in groups I, II and III were 155.33/51.83, 445.28/165.89, 380.78/173.33, respectively (p < 0.005). Superoxide dismutase and glutathione levels were lower in patient groups than in the control group (0.31 μl/g vs 0.36 μl/g; p < 0.05). After the lipoic acid treatment, none of the biochemical markers of liver improved. Only the increase in superoxide dismutase (0.31 μl/g and 0.34 μl/g in groups II and III, respectively) and glutathione levels (0.16 μl/g and 0.22 μl/g in groups II and III, respectively) was statistically significant (p < 0.05). CONCLUSIONS: Histopathological damage was statistically significantly decreased and antioxidant levels were statistically significantly increased after LA treatment (Tab. 1, Fig. 6, Ref. 23). [ABSTRACT FROM AUTHOR]

Here we have explored the effect of neoagarotetraose (NAT) on liver injury caused by intense exercise. Our results showed that NAT treatment obviously decreased liver weight (p < 0.01), improved the liver morphological structure, decreased ALT level (p < 0.05) and endotoxin (LPS) (p < 0.01). In addition, NAT could regulate bile acid profiles in feces and serum of mice, which indicated the potential of liver function, suggesting that NAT was effective to relieve intense exercise-induced liver injury. NAT could regulate the expression of colon genes. NAT tended to alter the microbial composition of mice under intense exercise. We uncovered the network interactions between liver traits and microbial communities in NAT treatment mice. Interestingly, our data indicated that intense exercise-induced liver injury may be related to Clostridiales. In summary, these results demonstrated that NAT relieved liver injury induced by intense exercise may be related to gut microbiota. NAT can effectively relieve liver injury induced by intense exercise. We uncovered the network interactions between liver traits and microbial communities in NAT treatment mice. [ABSTRACT FROM AUTHOR]

Abstract Background Current researches show that N,N-dimethylformamide (DMF) exposure is associated with liver injury, but it is debatable whether PNPLA3, GCKR, COL13A1 and TM6SF2 gene polymorphisms are associated with liver injury. Our objective was to examine the relationship among DMF exposure, PNPLA3 rs738409, GCKR rs780094, COL13A1 rs1227756, TM6SF2 rs58542926 and liver injury. Methods The cohort consisted of 461 workers exposed above the DMF threshold limit value (TLV) and 211 exposed below the DMF TLV in China, who were followed for 5 years. The relationship between the measured dose of DMF and the relative risk (RR) of liver injury was also investigated by Poisson analysis. Logistic regression models were used to examine the association between measured dose of DMF, gene locus, and RR for liver injury. All workers had a annual physical examinations were conducted at certified physical examination centers in Taicang CDC, including liver serum transaminase assessment and abdominal ultrasound. Genomic DNA was extracted from peripheral blood leukocytes using a genomic DNA extraction kit. Results The incidence of liver injury in the above DMF TLV group was significantly higher than in the below DMF TLV group. GCKR rs780094 was associated with liver injury. The interaction among the GCKR rs780094, DMF exposure and liver injury showed no significant association. Conclusions Our data indicated that in DMF exposure, GCKR rs780094 may contribute to the risk of liver injury. Our results suggest that GCKR rs780094 is a useful genetic marker to help identify liver injury. Highlights • It is the first to analyze the interaction between the four SNPs and exposure to DMF on liver injury. • Exposure above the DMF threshold limit value significantly increased prevalence of liver injury. • The presence of GG genotypes (rs780094) was associated with increased risk of liver injury. • The interaction among the GCKR rs780094, DMF exposure and liver injury showed no significant association. [ABSTRACT FROM AUTHOR]

Abstract Liver fibrosis occurs in most types of chronic liver diseases. The understanding of the pathogenesis of liver fibrosis has grown considerably, but the effective treatments are still lacking. Alogliptin, a classical Dipeptidyl peptidase-4 (DPP4) inhibitor with great effects on type 2 diabetes, has shown the potential to protect liver, but its effects on the progression of liver fibrosis have not been clarified. Herein, we explored the anti-fibrosis effects of alogliptin. In vitro , we demonstrated that alogliptin suppressed the activation of LX-2 upon transforming growth factor-β (TGF-β) challenge. In vivo , chronic treatment with alogliptin alleviated hepatic steatosis and protected from the liver injury in ob/ob mice, which delayed the progression of liver fibrosis. Furthermore, alogliptin significantly relieved the hepatic fibrosis in CCl4-induced liver fibrosis mouse model. In conclusion, our results demonstrate that negatively modulation of alogliptin on hepatic stellate cell (HSC) activation might contribute to liver fibrosis alleviation. Our research provides the potential possibility of alogliptin on the application for liver fibrosis therapy and suggests that DPP4 may be a novel target for liver fibrosis therapy. Highlights • Alogliptin suppresses the activation of hepatic stellate cell. • Alogliptin ameliorates the progression of liver fibrosis. • DPP4 may be a potential target for liver fibrosis therapy. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury remains a frequent reason for drug withdrawal. Accordingly, more predictive and translational models are required to assess human hepatotoxicity risk. This study presents a comprehensive evaluation of two promising models to assess mechanistic hepatotoxicity, microengineered Organ-Chips and 3D hepatic spheroids, which have enhanced liver phenotype, metabolic activity and stability in culture not attainable with conventional 2D models. Sensitivity of the models to two hepatotoxins, acetaminophen (APAP) and fialuridine (FIAU), was assessed across a range of cytotoxicity biomarkers (ATP, albumin, miR-122, α-GST) as well as their metabolic functionality by quantifying APAP, FIAU and CYP probe substrate metabolites. APAP and FIAU produced dose- and time-dependent increases in miR-122 and α-GST release as well as decreases in albumin secretion in both Liver-Chips and hepatic spheroids. Metabolic turnover of CYP probe substrates, APAP and FIAU, was maintained over the 10-day exposure period at concentrations where no cytotoxicity was detected and APAP turnover decreased at concentrations where cytotoxicity was detected. With APAP, the most sensitive biomarkers were albumin in the Liver-Chips (EC50 5.6 mM, day 1) and miR-122 and ATP in the liver spheroids (14-fold and EC50 2.9 mM, respectively, day 3). With FIAU, the most sensitive biomarkers were albumin in the Liver-Chip (EC50 126 µM) and miR-122 (15-fold) in the liver spheroids, both on day 7. In conclusion, both models exhibited integrated toxicity and metabolism, and broadly similar sensitivity to the hepatotoxicants at relevant clinical concentrations, demonstrating the utility of these models for improved hepatotoxicity risk assessment. [ABSTRACT FROM AUTHOR]

Abstract In our study, the ameliorative effect of salidroside (SAL) from Rhodiola Rosea L. on the intestinal microflora subject to furan-induced liver injury in a mouse model was investigated by 16 S rDNA, oxidative indexes, LPS and cytokine levels. The results demonstrated that SAL alleviated hepatic oxidative injury by inhibiting the activities of AST, ALT and the content of MDA, and promoting the activities of SOD, GSH and GST, compared to the furan-treated group. SAL significantly modified the intestinal microbial diversity and downregulated the circulating levels of serum LPS, IL-6, and TNF-α, as well as enhanced the content of IL-10. Importantly, SAL dramatically increased LPS-suppressing bacteria genera Akkermansia, and decreased LPS-producing bacteria phyla Proteobacteria. Our results indicate that SAL supplement restrains intestinal microbial dysbiosis and systemic low-grade inflammation induced by furan. Hopefully, SAL is a potential therapeutical and prophylactic compound in medicament for hepatic diseases. Graphical abstract SAL play an ameliorative role to improve liver diseases by affecting gut microbiota in furan-induced mice using 16 S rDNA sequencing. Image 1 Highlights • The ameliorative effect of SAL on gut microflora subject to furan-induced liver injury was investigated by 16 S rDNA. • SAL dramatically increased LPS-suppressing bacteria Akkermansia , and decreased LPS-producing bacteria Proteobacteria. • SAL supplement restrained intestinal microbial dysbiosis and systemic low-grade inflammation induced by furan. [ABSTRACT FROM AUTHOR]

Antifungal therapy is used to treat sporotrichosis. However, there are several limitations in this therapy, such as development of drug resistance and potential health risks including liver injury. The purpose of our study was to evaluate the antifungal efficacy of antibody against the hybrid phage nanofibers displaying KPVQHALLTPLGLDR (phage-KR) in a fungal-infected mouse model. In this study, we extracte an antibody against hybrid phage nanofibers (phage-KR) from immunized mice and passively inoculate Sporothrix globosa (S. globosa) infected mice. The study shows that the antibody exhibits efficient inhibition efficacy of the S. globosa infection, including reduction of the progressive fungi colonizing, increase of animal survival rate and relief of organ inflammation in the mice. The results indicate that antibody against phage-KR may act as a potential strategy for safe and efficient treatment of S. globosa infections. [ABSTRACT FROM AUTHOR]

Abstract Introduction Acetaminophen (APAP) intoxication is a major cause of acute liver failure. Alginate, an anionic polysaccharide, was previously shown as a macroporous scaffold, to reduce liver inflammation and sustain hepatic synthetic function, when implanted on liver remnant after extended partial hepatectomy. In the recent study we wanted to examine in a model of APAP intoxication the potential of a specially formulated alginate solution to prevent APAP toxicity. Methods Three alginate solutions from low (30–50 kDa, VLVG), medium (100 kDa, LVG54) and high (150 kDa, LVG150) molecular weights were examined. Mice were orally administered with the alginate solution before, with and after APAP administration and were compared to control mice which received vehicle only. All mice were euthanized 24 h after APAP administration. Liver enzyme, blood APAP, IL-6 and liver histology including Ki-67 proliferation, IgG necrosis and nitrotyrosine staining were studied. Results VLVG- treated mice presented low ALT levels while 20–40 fold increase was demonstrated in control mice. The effect of LVG solutions was marginal. Accordingly, liver histology was normal with no hepatocytes proliferation in the VLVG group while massive centrilobular necrosis, increased nitrotyrosine staining and high proliferation appeared in livers of control mice. APAP blood levels were comparable in the two groups. Treatment with VLVG was associated with prevention of increase of IL-6 serum levels. Conclusion VLVG, a novel alginate solution, alleviated the liver toxicity and inhibited oncotic necrosis and related immune-mediated damage. VLVG may serve as a novel hepato-protector and prevent drug induced liver injury. Highlights • A novel alginate formulation prevented acetaminophen-induced liver injury in mice. • Oral treatment greatly alleviated liver enzymes and inhibited oncotic necrosis. • Acetaminophen blood levels were comparable in alginate-treated and control groups. • Treatment was associated with suppressed of serum IL-6 levels. [ABSTRACT FROM AUTHOR]

Abstract In our previous studies, vitamin C (VC) exerts potent pharmacological activities against liver injury (LI). Therefore, this report was designed to use network pharmacology-based strategy to predict therapeutic targets of VC against LI, and further to investigate the pharmacological molecular mechanisms. Pathological targets of LI were identified, followed by acquisition of verified targets of VC. After constructing target-functional protein interaction network of VC against LI, the core therapeutic targets of VC against LI were obtained. Further, biological function and pathway enrichment analyses were performed on core therapeutic targets to evaluate the biological processes and key signaling pathways of VC against LI. As revealed in network pharmacology assays, 6 key therapeutic targets for VC against LI were identified, showing tumor necrosis factor (TNF), nuclear factor-kappa-B p65 (RELA), nuclear factor-kappa-B p105 (NFKB1), TNF receptor-associated factor 2 (TRAF2), interleukin 6 (IL-6) and interleukin 1 beta (IL1B). On the basis of data analyses from DAVID database and omicshare cloud platform, bio-functional enrichment assays showed that the therapeutic effects of VC against LI were closely associated with regulating inflammatory reaction and apoptosis. Further, pathway enrichment analysis indicated the anti-LI benefits of VC were principally implicated in regulating the top 20 signaling pathways, such as inflammation-associated TNF signaling pathway, NF-κB signaling pathway. Taken together, the bioinformatics data elucidate that anti-LI pharmacological activities of VC may be predominantly related to inhibition of inflammatory stress, contributing to suppression of LI development. These resultant findings highlight the predicted therapeutic targets may be potential biomarkers for anti-LI. Highlights • Pathological targets of LI are identified before mapping. • Biological targets of VC are verified before mapping. • Top 6 key therapeutic targets of VC-exerted anti-LI are identified. • VC against LI is closely linked to regulating development of inflammation. • Predicted targets of VC may be potential biomarkers for anti-LI. [ABSTRACT FROM AUTHOR]

Abstract Methyl helicterate (MH) has been reported to have protective effects against CCl 4 -induced hepatic injury and fibrosis in rats, but its protective mechanism, especially on hepatic stallete cells (HSCs), remains unclear. Recently, our pilot experiment showed that MH could inhibit miR-21 expression in HSC-T6 cells, suggesting that miR-21 may be one of the targets of MH to intervene liver fibrosis. To verify the hypothesis, the present study would focus on the regulatory effect of MH on the miR-21-mediated ERK and TGF-β1/Smads pathways. Briefly, rats were intraperitoneally injected with 0.5 ml porcine serum (PS) twice a week for 24 weeks to induce liver fibrosis, and meanwhile, the rats were treated with MH from weeks 16 to 24. In vitro experiment, miR-21 expression in HSC-T6 cells was up- or down-regulated using lentiviral transfection assay. Collagen accumulation, inflammatory cytokines, cell apoptosis, miR-21 expression, and activation of the ERK and TGF-β1/smad2/3 pathways were then assessed. The results showed that MH treatment markedly alleviated PS-induced liver injury, as evidenced by the attenuation of histopathological changes and the decrease in serum alanine and aspartate aminotransferases activity. MH significantly decreased the content of inflammatory cytokines and recruited the anti-oxidative defense system. Moreover, MH treatment significantly decreased miR-21 expression and inhibited the activation of the ERK and TGF-β1/smad2/3 pathways in liver tissues. In vitro experiments showed that MH strongly inhibited HSC-T6 cell activation and reduced collagen accumulation. Interestingly, miR-21 overexpression significantly promoted HSC-T6 cell proliferation, reduced HSC apoptosis, and increased collagenation, while these abnormal changes induced by miR-21overexpression were significantly reversed by MH treatment. Furthermore, miR-21 overexpression notably activated the ERK and TGF-β1/Smads pathways via repressing SPRY2 and Smad7 expression respectively, however, these effects were largely abolished by MH treatment. In conclusion, our study demonstrates that MH significantly alleviates PS-induced liver injury and fibrosis by inhibiting miR-21-mediated ERK and TGF-β1/Smads pathways. Highlights • Methyl helicterte (MH) alleviates porcine serum (PS)-induced liver fibrosis. • MH blocks the ERK signaling pathway via regulating miR-21 expression. • MH inhibits the TGF-β1/Smads pathway via regulating miR-21 expression. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the hepatoprotective effects of blue honeysuckle (BH) on carbon tetrachloride (CCl4)‐induced acute hepatic damage in mice. The experiment used a total of 60 ICR mice, which were divided into six groups. Except for the intact control groups, all groups received a single intraperitoneal injection of CCl4 after a 7 day pre‐treatment period with distilled water, BH extracts, or silymarin. Twenty‐four hours after the CCl4 injection, the following observations, representative of classical oxidative stress‐mediated centrolobular necrotic acute liver injuries, were observed: decreased body weight; small nodule formation and enlargement on the gross inspections with related liver weight increase; elevation of serum AST and ALT, increases in hepatic lipid peroxidation and related depletion of endogenous antioxidants and antioxidative enzymes; centrolobular necrosis; increases in apoptotic markers, lipid peroxidation markers, and oxidative stress markers. However, liver damage was significantly inhibited by the pre‐treatment with BH extracts. The present study demonstrated that oral administration of BH extracts prior to exposure to CCl4 conferred favorable hepatoprotective effects. These results demonstrated that BHe possessed suitable properties for use as a potent hepatoprotective medicinal food. BHe 200 mg/kg showed more favorable hepatoprotective effects compared with those of silymarin 100 mg/kg on CCl4‐induced acute liver damage in mice. [ABSTRACT FROM AUTHOR]

Neuronal voltage‐gated potassium channels KV7.2/KV7.3 are sensitive to small‐molecule drugs such as flupirtine, even though physiological response occurs in the absence of ligands. Clinically, prolonged use of flupirtine as a pain medication is associated with rare cases of drug‐induced liver injury. Thus, safety concerns prevent a broader use of this non‐opioid and non‐steroidal analgesic in therapeutic areas with unmet medical needs such as hyperactive bladder or neonatal seizures. With the goal of studying influences of chemical structure on activity and toxicity of flupirtine, we explored modifications of the benzylamino bridge and the substitution pattern in both rings of flupirtine. Among twelve derivatives, four novel thioether derivatives showed the desired activity in cellular assays and may serve as leads for safer KV channel openers. Bridge reconstructed! Exchange of an aminoalkyl‐group of analgesic flupirtine for a sulfide bridge maintains activity at voltage‐gated potassium channels but excludes toxification via azaquinone‐diimine formation. Thio‐analogues such as 9 g could serve as leads for next generation potassium channel openers to treat pain or epilepsy. [ABSTRACT FROM AUTHOR]

Abstract Liver injury is an important cause of serious liver disease and is characterized by inflammatory and oxidative responses. Esculin, a coumarinic derivative found in Aesculus hippocastanum L. , has been shown to exhibit anti-inflammatory and anti-oxidative effects. Here, we investigated the effects and molecular mechanism of esculin on Lipopolysaccharide/D-Galactosamine (LPS/D-Gal)-induced acute liver injury. A mouse model for acute liver injury was induced by intraperitoneal injection with D-Gal and LPS, and was assessed by histology, and serum transaminase analyses. The results showed that esculin significantly reduced the pathological symptoms of acute liver injury, as well as serum AST and ALT levels. LPS/D-Gal-induced liver myeloperoxidase (MPO) activity and malondialdehyde (MDA) content were also suppressed by esculin. Furthermore, LPS/D-Gal-induced liver tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) production were attenuated by esculin. Our data demonstrate that esculin can inhibit nuclear factor kappa B (NF-κB) activation as well as increase nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression. In conclusion, this paper demonstrates that esculin protects liver injury induced by LPS/D-Gal via inhibiting inflammatory and oxidative responses. Highlights • Esculin significantly reduced the pathological symptoms of acute liver injury, serum AST and ALT levels. • LPS/D-Gal-induced liver MPO activity and MDA content were also suppressed by esculin. • Furthermore, LPS/D-Gal-induced liver TNF-α and IL-1β production were attenuated by esculin. • Esculin could inhibit NF-κB signaling pathway and activate Nrf2 signaling pathway. [ABSTRACT FROM AUTHOR]

In the present study, the capacity of the aqueous extracts of Senna singueana (SS), Nymphaea lotus (NL), Cochlospermum planchoni (CP) and Acacia nilotica (AN) as antitoxicants to protect against aspirin and carbon tetrachloride (CCl4) induced hepatotoxicity in rats was investigated. Ten groups containing three replicates each were used. Biochemical parameters including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), direct bilirubin (DB), total bilirubin (TB), total protein (TP) and albumin (ALB) were assayed. SS, NL, CP and AN extracts (250 mg/kg) were given daily by gavage to the animals in the groups V to X for fourteen consecutive days to explore the protective effects against aspirin and CCl4-induced hepatotoxicity. Animals of negative and standard controls (group I and II) respectively received vehicle and vehicle with 2 mL/kg olive oil by subcutaneous injections twice a week for a period of two weeks. Animals of the CCl4-treated group (group III) and the aspirin-treated group (group IV) respectively received vehicle with 2 mL/kg CCl4 in olive oil by subcutaneous injections and vehicle with 1 mL/kg aspirin orally twice a week for a period of two weeks. The results obtained were statistically evaluated using One-Way ANOVA followed by Least Significant Difference (LSD) for the parameters found to be statistically significant at a = 0.05. Mean serum AST, ALT and ALP, DB and TB levels/activities of the groups III and IV were statistically (p < 0.05) higher than those of the controls. DB and TB levels were slightly (p > 0.05) higher when compared with the controls, in contrast with the mean serum TP and ALB levels of the groups III and IV that were found to differ statistically (p < 0.05) being lower than those of controls. Conversely, mean serum AST, ALT and ALP, DB and TB levels/activities of the groups V to X differ statistically (p < 0.05) being lower than those of the groups III and IV except for DB and TB levels that were slightly lower (p > 0.05) when compared with the groups III and IV. Mean serum TP and ALB levels of the groups V to X and the controls were found to differ statistically (p < 0.05) being higher than those of the groups III and IV. Taken together, the results of this study showed that the SS or NL extracts were found effective as hepatoprotective agents, and the mixture of SS and CP or the mixture of NL and AN extracts significantly antagonized aspirin and CCl4-induced liver damage in rats in comparison with control values, as evidenced by the biochemical parameters. [ABSTRACT FROM AUTHOR]

Clinical evidence suggests that most idiosyncratic drug-induced liver injury (IDILI) is immune-mediated. The danger hypothesis suggests that liver injury and inflammation would increase the risk of an immune response leading to IDILI. Therefore, a reasonable hypothesis would be that an underlying chronic liver disease such as non-alcoholic steatohepatitis (NASH) would increase the risk of developing IDILI due to inflammation and release of danger signals from damaged cells. In order to test this hypothesis, mice were fed a methionine-/choline-deficient (MCD) diet that produces a consistent NASH phenotype, along with amodiaquine (AQ) - a drug known to cause IDILI in humans. This study employed both wild-type C57BL/6 mice and PD-1−/− mice co-treated with anti-CTLA-4 antibodies. The PD-1−/− + anti-CTLA-4 model produces an immune-mediated liver injury very similar to the idiosyncratic liver injury observed in humans. The liver injury observed in the present experiment was dominated by the injury caused by the MCD diet; there was no significant difference between mice treated with the MCD diet alone and those also treated with AQ, whether in wild-type mice of the PD-1−/− model. Therefore, the MCD diet, which results in a state that mimics NASH, did not appear to increase the liver injury associated with AQ treatment. Ultimately, an animal model is just that - only a model, and cannot provide a definitive answer to clinical questions. However, given the difficulty of performing clinical studies with appropriate control populations, the present results provide important evidence to support a general clinical finding that underlying liver injury does not usually increase the risk of IDILI. [ABSTRACT FROM AUTHOR]

Recently, there has been a great deal of interest in the use of the medicinal plants with high antioxidant compounds for curing liver injuries induced by hepatoxcitic agents. This study was to assess the protective effect of Carum carvi L. essential oil (E.O) on the hepatoxitic rats induced by overdose of iron oxide nanoparticles (NPs). The rats were distributed to 4 groups. In negative control group (NC), the rats received normal saline and DMSO daily for 3 days. In control group (C), iron oxide nanoparticles (Fe2O3) (200 mg/kg b.w) was injected daily for 3 days. In the treatment groups, iron oxide nanoparticles plus E.O at 100 & 200 mg/kg b.w were injected daily for 3 days. In following, cytochrome P450 (CYP450), glutathione S-transferase (GST), glutathione (GSH), aspartate transaminase (AST), alkaline phosphatase (ALP) and alanine transaminase (ALT) were estimated at 72 h after NP-treatment. The administration of the E.O could return considerably the decrease of the GST and GSH levels as well as the increase of the level of AST induced by iron oxide NPs. These results are in agreement with histopathological results. The data indicated that E.O provided an efficient prevention against iron oxide NPs-induced hepatotoxicity in rats. [ABSTRACT FROM AUTHOR]

AKAP12 belongs to A-kinase anchoring protein (AKAP) family of scaffold proteins and is known as a tumor suppressor in several human cancer types. Its role as a tumor suppressor in hepatocellular carcinoma (HCC) was proposed due to its downregulation and epigenetic modification in human HCC; however, the effect of its deficiency on liver injuries, such as liver fibrosis and cancer has been poorly studied. By analyzing tumor and non-tumor tissues of 15 patients with HCC, it was confirmed that AKAP12 expression was downregulated in human HCC as compared with adjacent non-tumor tissues. Immunohistochemical staining of mouse liver tissue for AKAP12 revealed that its sinusoidal expression was diminished in capillarized endothelium after 8 weeks of thioacetamide (TAA) administration. AKAP12 deficiency resulted in the promotion of ductular response of biliary epithelial cells, whereas overall fibrosis and myofibroblast activation were comparable between genotypes after short-term TAA treatment. The mRNA expressions of some fibrosis-related genes such as those encoding epithelial cell adhesion molecule, collagen type 1 α1 and elastin were upregulated in liver tissues of AKAP12-knockout mice. Long-term administration of TAA for 26 weeks led to the development of liver tumors; the incidence of tumor development was higher in AKAP12-deficient mice than in wild-type littermates. Together, these results suggest that AKAP12 functions as a tumor suppressor in liver cancer and is associated with the regulation of hepatic non-parenchymal cells. [ABSTRACT FROM AUTHOR]

Abstract Acute liver injury (ALI) is highly lethal acute liver failure caused by different etiologies. Transforming growth factor β (TGF-β) is a multifunctional cytokine and a well-recognized inducer of apoptotic and necrotic cell death in hepatocytes. Latent TGF-β is activated partly through proteolytic cleavage by a serine protease plasma kallikrein (PLK) between the R58 and L59 residues of its propeptide region. Recently, we developed a specific monoclonal antibody to detect the N-terminal side LAP degradation products ending at residue R58 (R58 LAP-DPs) that reflect PLK-dependent TGF-β activation. This study aimed to explore the potential roles of PLK-dependent TGF-β activation in the pathogenesis of ALI. We established a mouse ALI model via the injection of anti-Fas antibodies (Jo2) and observed increases in the TGF-β1 mRNA level, Smad3 phosphorylation, TUNEL-positive apoptotic hepatocytes and R58-positive cells in the liver tissues of Jo2-treated mice. The R58 LAP-DPs were observed in/around F4/80-positive macrophages, while macrophage depletion with clodronate liposomes partly alleviated the Jo2-induced liver injury. Blocking PLK-dependent TGF-β activation using either the serine proteinase inhibitor FOY305 or the selective PLK inhibitor PKSI-527 or blocking the TGF-β receptor-mediated signaling pathway using SB431542 significantly prevented Jo2-induced hepatic apoptosis and mortality. Furthermore, similar phenomena were observed in the mouse model of ALI with the administration of acetaminophen (APAP). In summary, R58 LAP-DPs reflecting PLK-dependent TGF-β activation may serve as a biomarker for ALI, and targeting PLK-dependent TGF-β activation has potential as a therapeutic strategy for ALI. Highlights • TGF-β contributes to the pathogenesis of acute liver injury (ALI). • PLK-dependent TGF-β activation occurs in/around macrophages in ALI mice. • R58 latency associated protein-degradation products serve as an indicator for ALI. • Inhibiting PLK suppresses apoptosis and improves survival rate of ALI mice. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: Chronic liver disease presents a major global public health challenge. Stratification of asymptomatic, at‐risk patients in primary care using non‐invasive methods has the potential to address this by identifying those likely to progress. We, therefore, evaluated variant alleles at loci associated with non‐alcoholic fatty liver disease as genetic determinants of substantial liver injury in patients with disease risk factors. Methods: Levels of serum procollagen III (PIIINP), an established fibrosis and steatohepatitis marker, were determined in 467 people who had type 2 diabetes and/or BMI > 27.3 (identified from registration with general practitioners) in this observational cross‐sectional study. Patients were genotyped for characterised risk alleles in PNPLA3 (rs738409), GCKR (rs1260326) and TM6SF2 (rs58542926) and associations with PIIINP assessed. Results: The risk alleles in PNPLA3, GCKR or TM6SF2 were not found to be individually associated with the presence of a disease risk factor and were not significantly more common in patients with raised serum PIIINP. The prevalence of possession of both PNPLA3 and GCKR variant alleles combined was significantly higher in at‐risk patients with clinically significant liver disease indicated by serum PIIINP above 11 ng/mL (P = .014). Conclusions: Genotyping, therefore, has limited value for predicting severe liver disease in at‐risk individuals identified in a community setting. [ABSTRACT FROM AUTHOR]

Drug induced liver injury (DILI) is the prime cause of liver disfunction which may lead to mild non-specific symptoms to more severe signs like hepatitis, cholestasis, cirrhosis and jaundice. Not only the prescription medications, but the consumption of herbs and health supplements have also been reported to cause these adverse reactions resulting into high mortality rates and post marketing withdrawal of drugs. Due to the continuously increasing DILI incidences in recent years, robust prediction methods with high accuracy, specificity and sensitivity are of priority. Bioinformatics is the emerging field of science that has been used in the past few years to explore the mechanisms of DILI. The major emphasis of this review is the recent advances of in silico tools for the diagnostic and therapeutic interventions of DILI. These tools have been developed and widely used in the past few years for the prediction of pathways induced from both hepatotoxic as well as hepatoprotective Chinese drugs and for the identification of DILI specific biomarkers for prognostic purpose. In addition to this, advanced machine learning models have been developed for the classification of drugs into DILI causing and non-DILI causing. Moreover, development of 3 class models over 2 class offers better understanding of multi-class DILI risks and at the same time providing authentic prediction of toxicity during drug designing before clinical trials. [ABSTRACT FROM AUTHOR]

Background: Steatohepatitis is a morphological pattern of liver injury that, in non-alcoholic patients, may represent a form of chronic liver disease currently known as non-alcoholic steatohepatitis (NASH). Probiotics, Lactobacillus sp. and Bifidobacterium sp., have been proposed to prevent and treat different inflammatory conditions of the gastrointestinal tract. Objective: To examine the effect of Lactobacillus plantarum (L. plantarum) on the liver damage of non-alcoholic steatohepatitis (NASH) rats. Materials and Methods: Male Sprague-Dawley rats were randomly divided into three groups. Group 1 (control, n = 8) was fed with phosphate-buffered saline (PBS) 1 mL/rat. Group 2 (NASH, n = 8) was fed with 100% fat diet for 6 weeks. Group 3 (NASH + L. plantarum, n = 8) was fed with 100% fat diet plus L. plantarum 1.8 × 109 colony-forming unit/mL was suspended in PBS by gavage twice a day at an interval of 4 h for 6 weeks. All rats were sacrificed to collect blood and liver samples at the end of the treatment period. Results: The levels of hepatic malondialdehyde (MDA) and tumor necrosis factor alpha (TNF-α) were increased while the expression of peroxisome proliferator activated receptors gamma (PPAR-γ) was decreased significantly in the NASH group as compared with the control group. Histopathology from the NASH group showed macrovesicular steatosis, hepatocyte ballooning, and lobular inflammation. The NASH + L. plantarum group had attenuated the levels of MDA and TNF-α, enhanced PPAR-γ expression, and improved the histopathology. Conclusion: L. plantarum treatment can attenuate oxidative stress, inflammation, and improvement of histopathology in rats with NASH. Abbreviations used: NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis; TNF-α: Tumor necrosis factor-alpha; MDA: Malondialdehyde; PPARγ: Peroxisome proliferator-activated receptor gamma; TBARS: Thiobarbituric acid-reactive substances; ELISA: Enzyme-linked immunosorbent assay. [ABSTRACT FROM AUTHOR]

Overdose of acetaminophen (APAP) induces acute liver injury due in part to destruction of mitochondria and resulted oxidative stress. Recently, FGF21 has been demonstrated to be an endocrine factor to protect liver from oxidative stress. The aim of present study is to explore the role of fibroblast growth factor 21 (FGF21) in the protective effect of fenofibrate, an agonist of peroxisome proliferator-activated receptor alpha (PPARα), against acetaminophen (APAP)-induced liver injury. Mice and primary cultured hepatocytes were used to test the potential hepatoprotective effect of fenofibrate against APAP-induced hepatotoxicity. FGF21 deficient mice were used to evaluate the role of FGF21 in fenofibrate against APAP-induced acute liver injury. Post-treatment with fenofibrate significantly inhibits APAP-induced hepatotoxicity, as evidenced by decreased serum ALT and AST levels and hepatic necrosis in liver tissue as well as increased the surviving rate in response to APAP overdose, whereas this protective effect of fenofibrate is largely attenuated in FGF21 KO mice. Interestingly, administration of fenofibrate efficiently increases autophagy, which was companied with alleviating hepatotoxicity in APAP-treated WT mice. However, such effect is significantly attenuated in APAP-treated FGF21 KO mice. In conclusion, our findings suggest that fenofibrate against APAP-induced hepatotoxicity is at least in part mediated by up-regulating the expression of FGF21, which in turn promotes autophagy-mediated hepatoprotective effects. [ABSTRACT FROM AUTHOR]

Valproic acid (VPA) is a commonly used agent in the management of seizures and psychiatric disorders. Hyperammonemia is a common complication of VPA with 27.8% of patients having elevated levels - that is unrelated to hepatotoxicity and normal transaminases. Common side effects include obesity, insulin resistance, metabolic disorder and severe forms of hepatotoxicity. Other rare and idiosyncratic reactions have been reported, one of which is presented in our case. A 27-year old patient presented with hyperammonemia and encephalopathy as a consequence of idiosyncratic VPA reaction causing drug-induced liver injury (DILI) with severely elevated transaminases. DILI is commonly overlooked when investigating encephalopathy in the setting of VPA. Physicians should consider DILI in the context of hyperammonemia and transaminitis. [ABSTRACT FROM AUTHOR]

Drug‐induced liver injury (DILI) occurs in a small fraction of individuals exposed to drugs, herbs or dietary supplements and is a relatively rare diagnosis compared with other liver disorders. DILI can be serious, resulting in hospitalization and even life‐threatening liver failure, death or need for liver transplantation. Toxic liver damage usually presents as an acute hepatitis viral‐like syndrome or as an acute cholestasis that resolves upon drug discontinuation. However, un‐resolving chronic outcome after acute DILI can ensue in some subjects, the mechanisms and risk factors for this particular evolution being yet scarcely known. Furthermore, the definition of chronicity after acute DILI is controversial, regarding both the time frame of liver injury persistence and the magnitude of the abnormalities required. Besides this, in some instances the phenotypes and pathological manifestations are those of chronic liver disease at the time of DILI diagnosis. These include non‐alcoholic fatty liver disease, vascular lesions, drug‐induced autoimmune hepatitis, chronic cholestasis leading to vanishing bile duct syndrome and even cirrhosis, and some drugs such as amiodarone or methotrexate have been frequently implicated in some of these forms of chronic DILI. In addition, all of these DILI phenotypes can be indistinguishable from those related to other etiologies, making the diagnosis particularly challenging. In this manuscript we have critically reviewed the more recent data on chronicity in DILI with a particular focus on the epidemiology, mechanisms and risk factors of atypical chronic DILI phenotypes. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury is one of the most significant adverse drugs reactions and, in severe cases, could be a potentially life-threatening condition. It can be classified in intrinsic and idiosyncratic reactions and, anti-tuberculous drugs are known to induce the later one. In some cases, it might develop some autoimmune features which represent a challenge for both diagnosis and treatment. We report a 37-year-old woman who was admitted to our hospital with signs of severe acute liver injury. She was diagnosed with autoimmune-like drug-induced liver injury by antituberculous drugs and was treated with corticosteroids, N-Acetylcysteine and Ursodesoxycholic acid. Indeed, based on this case a review of the literature is presented. [ABSTRACT FROM AUTHOR]

Introduction and aim. Salidroside and curcumin (SC) formula could alleviate lipid deposition in high fat diet-induced nonalcoholic fatty liver disease (NAFLD). However, the mechanisms are still unknown, and the magnitude of potential therapeutic benefit remains understudied. Material and methods. The rats were treated with high fat diet for 14 weeks to induce NAFLD. The experiment was divided into control, model (NAFLD), SC formula and rosiglitazone groups (n = 7 in each group). Hematoxylin-eosin (H&E) staining was applied to detect liver morphological changes. Biochemical, metabolic indices and inflammation factors in liver tissue and serum were detected. Additionally, the activities of related enzymes were detected by enzyme-linked immunosorbent assay. Results. In the established rat model, typical lipid deposition and liver steatosis were observed. Liver triglyceride, free fatty acids, sera alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, fasting insulin, fasting blood glucose and homeostasis model assessment of insulin resistance were elevated in model group. Liver malondialdehyde was significantly elevated, while superoxide dismutase was significantly decreased in model group, compared with control. Moreover, tumor necrosis factor-α and Interleukin-1 were significantly produced in model group, compared with control. As a mechanism, high fat diet decreased tissue AMP-activated protein kinase (AMPK), phosphorylated AMPK, carnitine palmitoyltransferase 1 and increased inacetyl-CoA carboxylase (ACCase), phosphorylated ACCase. Importantly, these abnormal changes caused by high fat diet were reduced by SC formula administration. Conclusion. SC formula could ameliorate the injury caused by high fat diet. The effect was likely mediated via its influence on insulin resistance, lipid peroxidation injury and AMPK signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Acarbose has been deemed contraindicated in diabetic patients with chronic kidney disease (CKD) or end-stage renal disease (ESRD), but such use is not uncommon. We tested whether this concept hold true in this population with different background hepatic diseases. Methods: All incident diabetic patients (n = 2,036,531) with stage 5 CKD/ESRD were enrolled from Taiwan between 2017 and 2013 and divided into those without chronic liver disease (CLD), with CLD but without cirrhosis, and those with cirrhosis. Among each group, acarbose users, defined as cumulative use >30 days within the preceding year, were propensity-score matched 1:2 to non-users. Our main outcome was the development of liver injury events during follow-up. Results: Acarbose users did not exhibit an increased incidence of liver injury during follow-up compared to non-users (hazard ratio and 95% confidence interval, 1.04 [0.88–1.25], 0.97 [0.61–1.56], and 0.71 [0.33–1.54] among those without CLD, with CLD but without cirrhosis, and those with cirrhosis, respectively), after adjusting for demographic profiles, comorbidities, potentially hepatotoxic medication use, and diabetic severity. Conclusions: The incidence of liver injury did not increase significantly among diabetic acarbose users with severe renal insufficiency than non-users, regardless of the presence or absence of chronic liver disease. Our findings support the renaissance of acarbose as a useful adjunct in diabetic patients with stage 5 and 5D chronic kidney disease. [ABSTRACT FROM AUTHOR]

Trichloroethylene (TCE) is able to induce trichloroethylene hypersensitivity syndrome (THS) with multi-system immune injuries. In our previous study, we found kallikrein-kinin system (KKS) activation, including the bradykinin B1 receptor (B1R), which contributed to immune organ injury in TCE sensitized mice. However, the mechanism of B1R mediating immune dysfunction is not clarified. The present study initiates to investigate the potential mechanism of B1R on liver injury. We establish a TCE sensitized BALB/c mouse model to explore the mechanism with or without a B1R inhibitor R715. We found B1R expression was increased in TCE sensitization-positive mice. As expect, hepatocyte intracellular organelles and mitochondria disappeared, glycogen particles reduced significantly as well in TCE sensitization-positive mice via the transmission electron microscopic examination, meanwhile, R715 alleviated the deteriorate above. The blockade of B1R resulted in a significant decreased p-ERK1/2 and increased p-AKT expression. The expression of CD68 kupffer cell and its relative cytokine, including IL-6 and TNF-α, increased in TCE sensitization-positive mice and decreased in R715 pretreatment TCE sensitization-positive mice. Together, the results demonstrate B1R plays a key role in ERK/MAPK and PI3K/AKT signal pathway activation and inflammation cytokine expression in immune liver injury induced by TCE. B1R exerts a pivotal role in the development of TCE induced liver injury. [ABSTRACT FROM AUTHOR]

[Objectives] This study was conducted to elucidate the mechanism of action of total glucosides of paeony (TGP) against the liver injury induced by isoniazid (INH) and rifampicin (RFP), and to provide experimental evidence for rational use of anti-tuberculosis drugs. [Methods] Liver injury in mice was induced by the combination of INH and RFP in mice. After the mice were given different doses of Total Glucosides of White Paeony Capsules (TGP) for 10 d, the hepatosomatic index, biochemical indices in serum and liver homogenate were measured, and histopathological changes in liver tissue were observed. Glucurolactone was used as the positive control, and 0.9% sodium chloride was used as the negative control in the experiment. [Results] TGP reduced the activities of alanine transaminase (ALT) and aspartate transferase (AST) in serum and the level of malondialdehyde (MDA) in liver tissue, and increased the level of glutathione (GSH) and the activity of superoxidase dismutase (SOD) in liver tissue. [Conclusions] TAP has a protective effect against the liver injury induced by INH and RFP. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) has not been previously reported as a complication of treatment with everolimus. A 56-year-old Caucasian male liver transplant recipient developed DILI after receiving everolimus. Elevations in transaminase levels occurred within a week of starting everolimus and an upward trend in the transaminase levels continued with supporting histopathologic changes confirmed by liver biopsy. Within one week of drug discontinuation, his liver enzymes normalized to baseline. This report includes a brief review of the pharmacokinetic properties of everolimus, a review of the relevant literature, and an analysis using the RUCAM and Naranjo algorithms. [ABSTRACT FROM AUTHOR]

Autoimmune liver diseases are a group of chronic liver injuries mediated by abnormal autoimmunity and mainly include autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis. With the continuous improvement in people’s understanding of these diseases and the level of diagnosis and treatment, the incidence of autoimmune liver diseases is constantly increasing and such diseases have been taken more and more seriously by hepatologists. In 2017, new achievements have been made in the basic and clinical research on AIH and PBC, and this article reviews the research advances in these two diseases in 2017. [ABSTRACT FROM AUTHOR]

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Acetaminophen (APAP) overdose can induce acute liver injury (ALI) with significant morbidity and mortality. Propacetamol is an APAP prodrug, which is clinically bioequivalent to APAP. Kaempferol, a dietary flavonoid, has antioxidant, anti-inflammatory, and anti-apoptotic effects. In this study, we investigated the protective effect of kaempferol on propacetamol-induced ALI and its underlying mechanism in mice. Kaempferol pretreatment (125 mg/kg) before propacetamol injection significantly decreased propacetamol-induced serum ALT and AST activities, and DNA fragmentation. Kaempferol administration also reduced propacetamol-induced oxidative stress by inhibiting thiobarbituric acid reactive substances (TBARS) and 3-nitrotyrosine (3-NT) formation partly through downregulation of cytochrome P450 2E1 (CYP2E1) expression, upregulation of UDP glucuronosyltransferase family 1 member A1 (UGT1A1) expression, restoration of the activities of antioxidant enzymes including SOD, GPx and catalase toward normal, recovery of propacetamol-suppressed Nrf2 and GCLC expressions, and maintenance of normal glutathione level. Furthermore, kaempferol markedly attenuated APAP-induced serum TNF-α and IL-6 productions, downregulated APAP-induced phosphorylations of JNK and ERK, and decreased early hepatic apoptosis via decreasing Bax/Bcl-2 ratio and caspase 3 activation. Furthermore, administration of N-acetylcysteine (NAC) and kaempferol significantly rescued more mice than a low dose of NAC only did when a lethal dose of propacetamol injected and therapized at a delayed time point. These data suggested that kaempferol protects the liver against propacetamol-induced injury through anti-oxidative, anti-inflammatory and anti-apoptotic activities. [ABSTRACT FROM AUTHOR]

As a phenylpropanoid and dibenzylbutyrolactone lignan present in medical plants, such as those used in traditional Chinese herbal medicine, including Arctium lappa (Niubang), arctigenin exhibits antimicrobial, anti-inflammatory, and anticancer activities. In this study, we investigated the protective role of arctigenin in Concanavalin A (ConA)-induced acute hepatitis in mice. Arctigenin remarkably reduced the congestion and necroinflammation of livers, and improved hepatic function (ALT and AST) in ConA-induced acute hepatitis in vivo. The infiltration of CD4 T, NKT and macrophages into the livers was found to be reduced with arctigenin treatment. Arctigenin suppressed ConA-induced T lymphocyte proliferations that might have resulted from enhanced IL-10 production by macrophages and CD4 T cells. These results suggested that arctigenin could be a powerful drug candidate for acute hepatitis through immune suppression. [ABSTRACT FROM AUTHOR]