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Intrahepatic circulation is essential for the repair of acute liver injury (ALI); however, very limited information is available concerning changes in the circulatory pathways during ALI. Therefore, multi-scale X-ray phase-contrast CT combined with three-dimensional (3D) visualization is used to quantitatively analyze the intrahepatic circulation pathway (including the hepatic vein, portal vein and hepatic sinusoid) in the mouse model via the intraperitoneal injection of carbon tetrachloride (CCl4) from acute injury to recovery. The results demonstrate that the liver still preserves some vessel-like channels accessed to the central vein when the injury causes the severe collapse of the hepatic sinusoids that cannot be observed in two-dimensional pathologic slices. Moreover, angiogenesis is observed in the terminal branches of the hepatic vein and portal vein. Additionally, we extend the two-dimensional primary lobule to a 3D model and find that the sinusoids in zone III have the most severe injury. The sinusoids in different zones also show changes in parameters such as density and mean diameter during the ALI. In conclusion, phase-contrast CT can reveal the intact vascular system within the liver lobes, thus providing critical information for studying the mechanisms involved in the evolution of circulatory structures from damage to repair. Multiscale phase-contrast CT combined with 3D visualization provides insights into the morphological mechanisms of damage, compensation and repair of blood circulation pathways within the intact liver lobe during acute liver injury in mice. [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP) overdose is a major cause of drug‐induced liver injury. Sirtuins 5 (SIRT5) has been implicated in the development of various liver diseases. However, its involvement in APAP‐induced acute liver injury (AILI) remains unclear. The present study aimed to explore the role of SIRT5 in AILI. SIRT5 expression is dramatically downregulated by APAP administration in mouse livers and AML12 hepatocytes. SIRT5 deficiency not only exacerbates liver injury and the inflammatory response, but also worsens mitochondrial oxidative stress. Conversely, the opposite pathological and biochemical changes are observed in mice with SIRT5 overexpression. Mechanistically, quantitative succinylome analysis and site mutation experiments revealed that SIRT5 desuccinylated aldehyde dehydrogenase 2 (ALDH2) at lysine 385 and maintained the enzymatic activity of ALDH2, resulting in the suppression of inflammation and mitochondrial oxidative stress. Furthermore, succinylation of ALDH2 at lysine 385 abolished its protective effect against AILI, and the protective effect of SIRT5 against AILI is dependent on the desuccinylation of ALDH2 at K385. Finally, virtual screening of natural compounds revealed that Puerarin promoted SIRT5 desuccinylase activity and further attenuated AILI. Collectively, the present study showed that the SIRT5‐ALDH2 axis plays a critical role in AILI progression and might be a strategy for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions The emergence of drug‐resistant tuberculosis has necessitated novel treatments like the pretomanid, bedaquiline and linezolid (BPaL) regimen. This study investigated the association of drug‐induced liver injury (DILI) with the BPaL regimen compared to first‐line antituberculosis drugs (isoniazid, rifampin, pyrazinamide and ethambutol [HRZE]).A retrospective pharmacovigilance analysis was conducted using data from the US Food and Drug Administration Adverse Event Reporting System database from July 2019 to June 2023. Disproportionality analysis was employed to calculate the reporting odds ratio (ROR) of DILI for each component of the BPaL regimen. Onset time and mortality rates of DILI across different regimens were also compared.We identified 1242 cases of BPaL‐related DILI. Most cases occurred in individuals under 65 years of age (63.8%), with more male patients affected than females (51.4% vs 39.5%). The association between antituberculosis drugs and DILI was stronger for the HRZE regimen (ROR = 7.99, 95% confidence interval [CI] 7.74‐8.25) than the BPaL regimen (ROR = 4.75, 95% CI 4.55‐4.97). The median onset time for DILI was significantly shorter with the BPaL regimen (8 days, interquartile range [IQR] 3‐28) compared to the HRZE regimen (20 days, IQR 6‐48) (P < .001). Additionally, the BPaL regimen was associated with a higher risk of death due to DILI compared to the HRZE regimen (14.1% vs 10.4%, P = .003).Although the BPaL regimen had a lower overall risk of DILI compared to the HRZE regimen, it was significantly associated with DILI, indicating a need for careful monitoring during treatment. [ABSTRACT FROM AUTHOR]

Near‐infrared region (NIR; 650–1700 nm) dyes offer many advantages over traditional dyes with absorption and emission in the visible region. However, developing new NIR dyes, especially organic dyes with long wavelengths, small molecular weight, and excellent stability and biocompatibility, is still quite challenging. Herein, we present a general method to enhance the absorption and emission wavelengths of traditional fluorophores by simply appending a charge separation structure, dihydropyridopyrazine. These novel NIR dyes not only exhibited greatly redshifted wavelengths compared to their parent dyes, but also displayed a small molecular weight increase together with retained stability and biocompatibility. Specifically, dye NIR‐OX, a dihydropyridopyra‐zine derivative of oxazine with a molecular mass of 386.2 Da, exhibited an absorption at 822 nm and an emission extending to 1200 nm, making it one of the smallest molecular‐weight NIR‐II emitting dyes. Thanks to its rapid metabolism and long wave‐length, NIR‐OX enabled high‐contrast bioimaging and assessment of cholestatic liver injury in vivo and also facilitated the evalua‐tion of the efficacy of liver protection medicines against cholestatic liver injury. [ABSTRACT FROM AUTHOR]

Traditional adhesive hydrogels perform well in tissue adhesion but they fail to prevent postoperative tissue adhesion. To address this challenge, a biodegradable Janus adhesive hydrogel (J-AH) was designed and fabricated by the assembly of three different functional layers including anti-adhesive layer, reinforceable layer, and wet tissue adhesive layer. Each layer of J-AH serves a specific function: the top zwitterionic polymeric anti-adhesive layer shows superior resistance to cell/protein and tissue adhesion; the middle poly(vinyl alcohol)/tannic acid reinforceable matrix layer endows the hydrogel with good mechanical toughness of ∼2.700 MJ/m3; the bottom poly(acrylic acid)/polyethyleneimine adhesive layer imparts tough adhesion (∼382.93 J/m2 of interfacial toughness) to wet tissues. In the rat liver and femoral injury models, J-AH could firmly adhere to the bleeding tissues to seal the wounds and exhibit impressive hemostatic efficiency. Moreover, in the in vivo adhesion/anti-adhesion assay of J-AH between the defected cecum and peritoneal walls, the top anti-adhesive layer can effectively inhibit undesired postoperative abdominal adhesion and inflammatory reaction. Therefore, this research may present a new strategy for the design of advanced bio-absorbable Janus adhesive hydrogels with multi-functions including tissue adhesion, anti-postoperative adhesion and biodegradation. Despite many adhesive hydrogels with tough tissue adhesion capability have been reported, their proclivity for undesired postoperative adhesion remains a serious problem. The postoperative adhesion may lead to major complications and even endanger the lives of patients. The injectable hydrogels can cover the irregular wound and suppress the formation of postoperative adhesion. However, due to the lack of adhesive properties with tissue, it is difficult for the hydrogels to maintain on the wound surface, resulting in poor anti-postoperative adhesion effect. Herein, we design a Janus adhesive hydrogel (J-AH). J-AH integrates together robust wet tissue adhesion and anti-postoperative adhesion. Therefore, this research may present a new strategy for the design of advanced bio-absorbable Janus adhesive hydrogels. [Display omitted] [ABSTRACT FROM AUTHOR]

Rationale: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) cause right ventricular dysfunction, which can impact other solid organs. However, the profiles and consequences of hepatic injury resulting from PAH and CTEPH have not been well studied. Objectives: We aimed to identify underlying patterns of liver injury in a cohort of patients with PAH and CTEPH enrolled in 15 randomized clinical trials conducted between 1998 and 2014. Methods: We used unsupervised machine learning to identify liver injury clusters in 13 trials and validated the findings in two additional trials. We then determined whether these liver injury clusters were associated with clinical outcomes or treatment effect heterogeneity. Measurements and Main Results: Our training dataset included 4,219 patients and our validation dataset included 1,756 patients with serum total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and albumin data. Using k-means clustering, we identified phenotypes with no liver injury, hepatocellular injury, cholestatic injury, and combined injury patterns. Patients in the cholestatic injury liver cluster had the shortest time to clinical worsening and the highest risk of mortality. The cholestatic injury group also experienced the greatest placebo-corrected treatment effect on 6-minute-walk distance. Randomization to the experimental arm transitioned patients to a healthier liver status. Conclusions: Liver injury was associated with adverse outcomes in patients with PAH and CTEPH. Randomization to active treatment had beneficial effects on liver health compared with placebo. The role of liver disease (often subclinical) in determining outcomes warrants prospective studies. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusions Although turmeric is commonly ingested and well tolerated, there is increasing evidence that over‐the‐counter turmeric supplements can cause drug‐induced liver injury. We sought to thoroughly characterise clinicopathological features of patients for whom liver injury was attributed clinically to turmeric supplements.We identified 11 patients via retrospective pathology archive review: 10 females (91%) and one male, with a median age of 58 years (range = 37–66 years). Six patients (55%) were asymptomatic with abnormal liver function tests, while five patients (45%) presented with malaise and/or jaundice. Ten patients (91%) showed predominant transaminase abnormalities, while one exhibited predominant alkaline phosphatase elevation. Histologically, biopsies showed acute hepatitis (eight cases, 73%, including five pan‐lobular and three zone 3‐predominant inflammation), scattered lobular aggregates of histiocytes (two; 18%) and a chronic hepatitis pattern of injury (one; 9%). Mild bile duct injury was present in five biopsies (45%). All patients stopped ingesting turmeric supplements after presenting with liver injury, and four patients additionally received steroid therapy; liver function tests normalised in all patients. Roussel Uclaf causality assessment method (RUCAM) analysis estimated the likelihood of turmeric supplement‐associated liver injury to be probable (eight cases) and possible (three).Histological features in the ‘possible’ cases were consistent with drug‐induced injury, highlighting the added benefit of histological analysis relative to RUCAM analysis isolation. This study underscores the need to obtain a full history of over‐the‐counter medications and supplements when investigating aetiologies for liver injury, including supplements purportedly containing innocuous compounds such as turmeric. [ABSTRACT FROM AUTHOR]

Polycomb repressive complex 2 (PRC2) is an evolutionarily conserved epigenetic modifier responsible for tri-methylation of lysine 27 on histone H3 (H3K27me3). Previous studies have linked PRC2 to invariant natural killer T (iNKT) cell development, but its physiological and precise role remained unclear. To address this,we conditionally deleted Eed, a core subunit of PRC2, inmouse T cells. The results showed that Eed-deficient mice exhibited a severe reduction in iNKT cell numbers, particularly NKT1 and NKT17 cells, while conventional T cells andNKT2 cells remained intact. Deletion of Eed disrupted iNKT cell differentiation, leading to increased cell death, which was accompanied by a severe reduction in H3K27me3 levels and abnormal expression of Zbtb16, Cdkn2a, and Cdkn1a. Interestingly, Eed-deficient mice were highly susceptible to acetaminophen-induced liver injury and inflammation in an iNKT cell-dependent manner, highlighting the critical role of Eed-mediated H3K27me3 marks in liver-resident iNKT cells. These findings provide further insight into the epigenetic orchestration of iNKT cell-specific transcriptional programs. [ABSTRACT FROM AUTHOR]

Background and Aims: Acetaminophen (APAP) hepatotoxicity and ischemic hepatic injury (IH) demonstrate remarkably similar biochemical patterns. Deciding between these two etiologies in the setting of acute liver failure (ALF) can be challenging. We reviewed all cases in the Acute Liver Failure Study Group (ALFSG) registry where these diagnoses were considered, to determine reasons for, and frequency of, difficulties making these diagnoses. We hypothesized that the newly developed APAP-CYS adduct assay could help in discerning the correct diagnosis. Methods: Among 3364 patients with ALF or acute liver injury (ALI: INR ≥ 2.0 but without encephalopathy) between 1998 and 2019, 1952 (58%) received a final diagnosis of either APAP (1681) or IH (271). We utilized a review committee of senior hepatologists as well as the APAP-CYS assay (where sera were available), measuring the presence of toxic by-products of APAP injury to optimize adjudication. Results: With these methods, a total of 575 adduct positive APAP cases included 488 recognized APAP, as well as an additional 87 patients previously diagnosed as other etiologies. Nine cases initially attributed to IH were deemed combination APAP-IH injuries. Conversely, 215 of the 280 IH subjects tested for adducts disclosed 173 confirmed as IH with adduct testing below the toxicity threshold, while 9 cases were revised from APAP to the IH-APAP combination phenotype, where both hypotension and APAP likely played a role. Conclusions: Discerning APAP from IH can be difficult—in rare cases, combined injury is observed (18/1952). APAP-CYS testing resulted in revising the diagnosis in 14.6% of cases. [ABSTRACT FROM AUTHOR]

Primary liver cancer is an increasing problem worldwide and is associated with significant mortality. A popular method of modeling liver cancer in mice is plasmid hydrodynamic tail vein injection (HTVI). However, plasmid-HTVI models rarely recapitulate the chronic liver injury which precedes the development of most human liver cancer. We sought to investigate how liver injury using thioacetamide contributes to the pathogenesis and progression of liver cancer in two oncogenic plasmid-HTVI-induced mouse liver cancer models. Fourteen-week-old male mice received double-oncogene plasmid-HTVI (SB/AKT/c-Met and SB/AKT/NRas) and then twice-weekly intraperitoneal injections of thioacetamide for 6 weeks. Liver tissue was examined for histopathological changes, including fibrosis and steatosis. Further characterization of fibrosis and inflammation was performed with immunostaining and real-time quantitative PCR. RNA sequencing with pathway analysis was used to explore novel pathways altered in the cancer models. Hepatocellular and cholangiocellular tumors were observed in mice injected with double-oncogene plasmid-HTVI models (SB/AKT/c-Met and SB/AKT/NRas). Thioacetamide induced mild fibrosis and increased alpha smooth muscle actin-expressing cells. However, the combination of plasmids and thioacetamide did not significantly increase tumor size, but increased multiplicity of small neoplastic lesions. Cancer and/or liver injury up-regulated profibrotic and proinflammatory genes while metabolic pathway genes were mostly down-regulated. We conclude that the liver injury microenvironment can interact with liver cancer and alter its presentation. However, the effects on cancer development vary depending on the genetic drivers with differing active oncogenic pathways. Therefore, the choice of plasmid-HTVI model and injury agent may influence the extent to which injury promotes liver cancer development. [ABSTRACT FROM AUTHOR]

Simple Summary: Lipopolysaccharide (LPS), an endotoxin derived from the outer membrane of Gram-negative bacteria, is one of the causes of acute liver injury. Cordyceps militaris extract (CME) contains many bioactive compounds, mainly cordycepin (CPN). This study aimed to investigate the possible mechanisms underlying the amelioration of LPS-induced acute liver injury in piglets by CME or CPN supplementation using transcriptomic and metabolomic analyses. We found that CPN or CME supplementation significantly decreased the C-reactive protein level and improved liver tissue pathology after LPS injection. Transcriptomic and metabolomic results showed that CME or CPN supplementation could attenuate liver injury by downregulating LPS-induced liver inflammation-related pathways and by modulating the levels of immune response-related metabolites. The present study reveals the immunomodulatory effects of CPN and CME against LPS-induced liver injury. Cordyceps militaris extract (CME) contains many bioactive compounds, mainly cordycepin (CPN). This study aimed to investigate the possible mechanisms underlying the amelioration of LPS-induced acute liver injury in piglets by CME or CPN supplementation using multi-omics analysis. Twenty-four weaned piglets were randomly distributed into 4 groups (n = 6): the control and LPS groups were fed basal diets; the CPN + LPS (CPN-LPS) and CME + LPS (CME-LPS) groups were fed the basal diets supplemented with CME or CPN. The results showed that CPN or CME supplementation significantly decreased the C-reactive protein level (p < 0.05) and improved liver tissue pathology to prevent acute liver injury after LPS treatment. Compared with LPS, the transcriptomic analysis indicated that CPN supplementation significantly downregulated cell adhesion molecules, while CME supplementation significantly downregulated inflammatory mediator regulation of TRP channels, complement and coagulation cascades and cytokine-cytokine receptor interaction. The metabolomic results showed that CPN or CME supplementation significantly reduced disease biomarker of bicyclo-prostaglandin E2, and increased levels of deoxyinosine and 3-hydroxyanthranilic acid (p < 0.05). The combined transcriptome and metabolome helped identify two metabolites PC 34:2 and PC 36:0, which may be associated with the restoration of liver cell morphology. In conclusion, CPN and CME could attenuate LPS-induced acute liver injury by regulating immune-related genes and metabolites. This study elucidates the potential protective mechanism of CPN or CME supplementation against acute liver injury. [ABSTRACT FROM AUTHOR]

Background and Aims: Distinctive gut microbial profiles have been observed between patients with Wilson disease (WD) and healthy individuals. Despite this, the exact relationship and influence of gut microbiota on the advancement of WD‐related liver damage remain ambiguous. This research seeks to clarify the gut microbiota characteristics in both human patients and mouse models of WD, as well as their impact on liver injury. Methods: Gut microbial features in healthy individuals, patients with WD, healthy mice and mice with early‐ and late‐stage WD were analysed using 16S rRNA gene sequencing. Additionally, WD‐afflicted mice underwent treatment with either an antibiotic cocktail (with normal saline as a control) or healthy microbiota (using disease microbiota as a control). The study assessed gut microbiota composition, hepatic transcriptome profiles, liver copper concentrations and hepatic pathological injuries. Results: Patients with hepatic WD and mice with WD‐related liver injury displayed altered gut microbiota composition, notably with a significant reduction in Lactobacillus abundance. Additionally, the abundances of several gut genera, including Lactobacillus, Veillonella and Eubacterium coprostanoligenes, showed significant correlations with the severity of liver injury in patients with WD. In WD mice, antibiotic treatment or transplantation of healthy microbiota altered the gut microbial structure, increased Lactobacillus abundance and modified the hepatic transcriptional profile. These interventions resulted in reduced hepatic copper concentration and alleviation of WD‐related liver injury. Conclusions: Individuals and mice with pronounced WD‐related liver injury exhibited shifts in gut microbial composition. Regulating gut microbiota through healthy microbiota transplantation emerges as a promising therapeutic approach for treating WD‐related liver injury. [ABSTRACT FROM AUTHOR]

T-cell immunoglobulin and mucin domain-containing molecule 4 (Tim-4) is an immune checkpoint molecule, which involves in numerous inflammatory diseases. Tim-4 is mainly expressed on antigen-presenting cells. However, increasing evidence has shown that Tim-4 is also expressed on natural killer T (NKT) cells. The role of Tim-4 in maintaining NKT cell homeostasis and function remains unknown. In this study, we explored the effect of Tim-4 on NKT cells in acute liver injury. This study found that Tim-4 expression on hepatic NKT cells was elevated during acute liver injury. Tim-4 deficiency enhanced IFN-γ, TNF-α expression while impaired IL-4 production in NKT cells. Loss of Tim-4 drove NKT-cell effector lineages to be skewed to NKT1 subset. Furthermore, Tim-4 KO mice were more susceptible to α-Galactosylceramide (α-GalCer) challenge. In conclusion, our findings indicate that Tim-4 plays an important role in regulating homeostasis and function of NKT cells in acute liver injury. Therefore, Tim-4 might become a new regulator of NKT cells and a potential target for the therapy of acute hepatitis. This study highlights the role of Tim-4 in modulating the homeostasis and function of NKT cells during acute liver injury. Tim-4 deficiency enhances IFN-γ, TNF-α expression while impaired IL-4 production in NKT cells and aggravates α-GalCer-inducedliver injury. This study might shed light on the novel role of Tim-4 on NKT cells and identifies Tim-4 as a promising therapeutic target for acute liver inflammatory diseases. Graphical Abstract [ABSTRACT FROM AUTHOR]

BACKGROUND: Maslinic acid (MA), a pentacyclic triterpene acid, is widely distributed in natural plants and mainly found in the fruit and leaves of olives and hawthorn. MA has been reported as having many health‐promoting functions, such as anticancer, anti‐inflammation and neuroprotective activities. According to previous study, hawthorn extract has certain hepatoprotective effects. However, the detailed mechanism is still unclear, especially the effect of MA on gut microbiota. RESULTS: Our study reveals that MA effectively counteracts alcohol‐induced liver injury and oxidative stress. It mitigates alcohol‐induced intestinal barrier damage, reverses increased permeability and reduces translocation of lipopolysaccharide (LPS). This prevents LPS/Toll‐like receptor 4 activation, leading to decreased TNF‐α and IL‐1β production. Furthermore, MA rebalances gut microbiota by reversing harmful bacterial abundance and enhancing beneficial bacteria post‐alcohol consumption. CONCLUSION: MA, through modulation of gut microbiota, alleviates alcohol‐induced liver injury via the gut–liver axis. These findings support the potential use of MA as a functional food ingredient for preventing or treating alcoholic liver disease. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Sulforaphane‐loaded nanoparticles (NP‐SF) were prepared in this study to improve their biological effects. Based on propylene glycol alginate and zein as wall materials and anthocyanin and CaCl2 as crosslinking agents, the NPs were encapsulated by the crosslinking method and freeze‐dried. With the increasing contents of anthocyanin and Ca2+, the encapsulation efficiency and loading capacity of NP‐SF were both increased. In vitro simulated digestion experiments showed controlled release of SF from the NPs. The pharmacokinetics confirmed that NP‐SF exerted a slower release effect in rats, with improved SF bioavailability and protective effects on liver injury induced by N‐diethylnitrosamine in mice. NP‐SF reduced serum indicators of liver injury, increased the activities of antioxidant enzymes and GSH levels, and reduced malondialdehyde levels in the liver. In addition, SF activated the Keap1/Nrf2 signaling pathway and upregulated the expression of the Nrf2 downstream genes NQO1 and heme oxidase 1. High doses of NP‐SF, in particular, had a higher therapeutic effect. In conclusion, encapsulation enhanced the biological activity of SF and promoted physiological function. [ABSTRACT FROM AUTHOR]

Background: Acetaminophen toxicity remains one of the most common causes of liver failure and is treated with a course of n-acetylcysteine (NAC). This exceptionally effective medication is traditionally administered using a complicated three-bag protocol that is prone to administration errors. Objective: We aimed to assess whether switching to a novel two-bag protocol (150 mg/kg over 1 h followed by 150 mg/kg over 20 h) reduced administration errors while not increasing liver injury or anaphylactoid reactions. Methods: This was a retrospective chart review of hospital encounters for patients with acetaminophen toxicity, comparing outcomes before and after the change from a three-bag protocol to a two-bag protocol at two affiliated institutions. The primary outcome was incidence of medication errors with secondary outcomes including acute liver injury (ALI) and incidence of non-anaphylactoid allergic reactions (NAAR). The study was approved by the health system's Institutional Review Board. Results: 483 encounters were included for analysis (239 in the three-bag and 244 in the two-bag groups). NAAR were identified in 11 patients with no difference seen between groups. Similarly, no differences were seen in ALI. Medication administration errors were observed significantly less often in the two-bag group (OR 0.24) after adjusting for confounders. Conclusion: Transitioning to a novel two-bag NAC regimen decreased administration errors. This adds to the literature that two-bag NAC regimens are not only safe but also may have significant benefits over the traditional NAC protocol. [ABSTRACT FROM AUTHOR]

Objective(s): This study was conducted to explore the impact of 1, 8-cineole (eucalyptol) on the biochemical, molecular, and histological changes caused by lead acetate in the liver of adult male Wistar rats. The research also investigated the potential involvement of the TLR4 signaling pathway in this effect. Materials and Methods: Rats were orally administered lead acetate (25 mg/kg-day) for 14 consecutive days and received 1, 8-cineole (100 mg/kg-day) during the same period. Results: 1, 8-cineole prevented an increase in the malondialdehyde level, a decrease in the glutathione level, and a decrease in the activity of superoxide dismutase and glutathione peroxidase enzymes in the liver of rats treated with lead acetate. This monoterpene also prevented an increase in the expression of pro-inflammatory cytokines and significantly reduced the infiltration of inflammatory cells in the liver parenchyma. Additionally, 1, 8-cineole discouraged the increase in toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), and nuclear factor kappa B (NF-κB) expression in the liver and stopped a rise in serum AST and ALT enzymes. Conclusion: 1, 8-cineole can prevent liver damage caused by lead acetate by reducing oxidative stress and inflammation. This hepatoprotection is probably achieved by inhibiting TLR4/MyD88/NF-κB signaling. [ABSTRACT FROM AUTHOR]

We report a case of a 17 year old lady who presented with severe abdominal pain for 4 days. Patient developed fulminant hepatitis and disseminated intravascular coagulation during her hospital stay. History of Ratol (3% yellow phosphorus) ingestion was revealed on the second day of admission. She was managed with NAC infusion for 3 days along with supportive treatment and was discharged on the 10th day of admission. Accidental ingestion of Ratol is common in rural India. Early diagnosis and management of yellow phosphorus can improve the outcome of the patient. It is important to identify predictors of outcome of patients with toxin-induced liver injury. [ABSTRACT FROM AUTHOR]

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AbstractPleuropterus multiflorus root (PMR, Polygoni Multiflori Radix) is an herbal medicine widely used in East Asia, particularly China. However, the potential hepatotoxicity has hindered its rational and safe application of PMR in clinical practice. Recently, the hepatotoxic study of PMR have made great progress, especially drug metabolism and transport-mediated liver injury. In this review, we summarized the advancement of drug metabolism and transport regluated hepatic injury of PMR, pointed out the key role of drug metabolizing enzymes and transporters in regulating hepatic injury of PMR, and emphasized the main hepatotoxic substances, toxicity promoter, and hepatic toxic substance-toxicity promoter interactions in PMR. On this basis, the clinical prospect of preventing and treating hepatic injury of PMR from the perspective of metabolism and transporter was discussed, to provide a useful reference and theoretical basis for the prevention and treatment of hepatic injury of PMR. [ABSTRACT FROM AUTHOR]

Currently liver transplantation is the only treatment option for liver disease, but organ availability cannot meet patient demand. Alternative regenerative therapies, including cell transplantation, aim to modulate the injured microenvironment from inflammation and scarring towards regeneration. The complexity of the liver injury response makes it challenging to identify suitable therapeutic targets when relying on experimental approaches alone. Therefore, we adopted a combined in vivo-in silico approach and developed an ordinary differential equation model of acute liver disease able to predict the host response to injury and potential interventions. The Mdm2fl/fl mouse model of senescence-driven liver injury was used to generate a quantitative dynamic characterisation of the key cellular players (macrophages, endothelial cells, myofibroblasts) and extra cellular matrix involved in liver injury. This was qualitatively captured by the mathematical model. The mathematical model was then used to predict injury outcomes in response to milder and more severe levels of senescence-induced liver injury and validated with experimental in vivo data. In silico experiments using the validated model were then performed to interrogate potential approaches to enhance regeneration. These predicted that increasing the rate of macrophage phenotypic switch or increasing the number of pro-regenerative macrophages in the system will accelerate the rate of senescent cell clearance and resolution. These results showcase the potential benefits of mechanistic mathematical modelling for capturing the dynamics of complex biological systems and identifying therapeutic interventions that may enhance our understanding of injury-repair mechanisms and reduce translational bottlenecks. [ABSTRACT FROM AUTHOR]

Summary Background and Aims Methods Results Conclusions While immune checkpoint inhibitors (ICIs) are revolutionising cancer therapy, checkpoint inhibitor‐induced liver injury is a significant immune‐related side effect of this immunotherapy. This study focuses on the severity classifications and characteristics of patients with checkpoint inhibitor‐induced hepatitis.A retrospective analysis of patients with severe Checkpoint Inhibitor‐induced hepatitis grade 3 and 4 according to the recommended Common Terminology Criteria for Adverse Events (CTCAE) classification was conducted. Data on clinicobiological characteristics, treatment and outcomes were collected from 3 university hospitals, and causality was assessed by using the updated Roussel Uclaf Causality Assessment Method. The severity of hepatitis was assessed using the Model for End‐stage Liver Disease score, the Drug‐Induced Liver Injury Network, and the Drug‐Induced Liver Injury International Expert Working Group classifications.We retrospectively included 100 patients presenting various hepatitis patterns with a median time to onset of 20 days after checkpoint inhibitors. Severity grading varied significantly among the classifications used. A lower incidence of severe cases was observed when using the Drug‐Induced Liver Injury classifications instead of the recommended CCTCAE classification, and this was correlated with outcomes.This retrospective study challenges the efficacy of the CTCAE classification in defining the severity of Checkpoint Inhibitor‐induced hepatitis and suggests that the traditional hepatology‐focused scores may be more relevant. The CTCAE classification is inconsistent and gives equal weight to jaundice and elevated transaminases, which leads to steroid overtreatment and limits the rechallenge of ICIs. [ABSTRACT FROM AUTHOR]

The accumulation of protoporphyrin IX in the liver caused by isoniazid and rifampicin through the disorder of heme biosynthesis was considered an important mechanism of anti‐tuberculosis drug‐induced liver injury (ATLI). Alanine synthase 1 (ALAS1) is a rate‐limiting enzyme in the process of heme synthesis. This study aimed to investigate the association between ALAS1 gene polymorphism, serum ALAS1 level, and the risk of ATLI. This study was a case‐control study including 58 ATLI cases and 192 controls. Four single nucleotide polymorphisms (SNPs) of the ALAS1 gene were selected for genotyping and serum ALAS1 concentrations were detected using ELISA kits. There was no significant difference in the genotype distribution of four SNPs between the ATLI cases and the controls under different genetic models. Patients carrying the GG genotype of SNP rs352163 in controls had higher baseline ALAS1 levels than those in ATLI cases (243.6 vs 290.2 ng/L, P = .034), and patients with baseline ALAS1 < 337.85 ng/L had a higher risk of ATLI than those with ALAS1 ≥ 337.85 ng/L (HR = 2.679, 95% CI: 1.360‐5.278, P = .004). Our findings indicated that the serum ALAS1 concentrations in the ATLI cases were lower than those in the controls, and the lower baseline ALAS1 levels can be associated with higher ATLI risk. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Normothermic machine perfusion (NMP) aims to reduce ischemia–reperfusion injury in donor livers and its clinical manifestation, early allograft dysfunction (EAD) by maintaining perfusion and oxygenation. However, there is limited data on which NMP perfusate biomarkers might be associated with such EAD and the role of perfusate hemoglobin has not been assessed.We performed a pilot retrospective analysis of adult donor livers undergoing NMP between 2020 and 2022 at our center. NMP was commenced at the recipient hospital after initial static cold storage. All NMP circuits were primed in the same manner according to the manufacturer's instructions. Livers were stratified by initial perfusate hemoglobin below (≤5.2 mmol/L) or above (>5.2 mmol/L) the median. The association between hemoglobin levels and EAD or recipient peak transaminase levels was assessed.Among 23 livers, eight were considered unsuitable for transplantation, leaving 15 livers for assessment. Higher initial hemoglobin was associated with a lower risk of EAD (0% vs. 55.6%, p = 0.04). Perfusate hemoglobin decreased after NMP initiation (p = 0.003) and negatively correlated with recipient peak transaminase levels (ALT: ρ = −0.72, p = 0.002; AST: ρ = −0.79, p < 0.001). Consistently, higher hemoglobin livers also demonstrated lower perfusate liver enzymes.Perfusate hemoglobin levels decreased during NMP, and lower perfusate hemoglobin levels were associated with a higher incidence of EAD and higher levels of liver injury markers. Maintaining higher hemoglobin levels during NMP may help reduce ischemia–reperfusion injury and prevent or attenuate EAD. Larger prospective studies are needed to validate the findings of this pilot study. [ABSTRACT FROM AUTHOR]

Summary: Background: Azithromycin (AZ) is a widely used antibiotic. The aim of this study was to characterise the clinical features, outcomes, and HLA association in patients with drug‐induced liver injury (DILI) due to AZ. Methods: The clinical characteristics of individuals with definite, highly likely, or probable AZ‐DILI enrolled in the US Drug‐Induced Liver Injury Network (DILIN) were reviewed. HLA typing was performed using an Illumina MiSeq platform. The allele frequency (AF) of AZ‐DILI cases was compared to population controls, other DILI cases, and other antibiotic‐associated DILI cases. Results: Thirty cases (4 definite, 14 highly likely, 12 probable) of AZ‐DILI were enrolled between 2004 and 2022 with a median age of 46 years, 83% white, and 60% female. Median duration of AZ treatment was 5 days. Latency was 18.5 days. 73% were jaundiced at presentation. The injury pattern was hepatocellular in 60%, cholestatic in 27%, and mixed in 3%. Ten cases (33%) were severe or fatal; 90% of these were hepatocellular. Two patients required liver transplantation. One patient with chronic liver disease died of hepatic failure. Chronic liver injury developed in 17%, of which 80% had hepatocellular injury at onset. HLA‐DQA1*03:01 was significantly more common in AZ‐DILI versus population controls and amoxicillin‐clavulanate DILI cases (AF: 0.29 vs. 0.11, p = 0.001 and 0.002, respectively). Conclusion: Azithromycin therapy can lead to rapid onset of severe hepatic morbidity and mortality in adult and paediatric populations. Hepatocellular injury and younger age were associated with worse outcomes. HLA‐DQA1*03:01 was significantly more common in AZ cases compared to controls. [ABSTRACT FROM AUTHOR]

The synthesis of H2O2-activatable small molecules in the second near-infrared (NIR-II) window remains challenging. We present the NIR-II probe Z-1065 for real-time detection of H2O2. Z-1065 demonstrates high sensitivity and selectivity towards H2O2in vitro and effectively monitors H2O2 generation in drug-induced liver injury (DILI) mouse models. [ABSTRACT FROM AUTHOR]

Drug‐induced liver injury (DILI) presents unique challenges in clinical practice. While some types of DILI are mild and resolve quickly after removing the drug, other situations are more complex, with competing aetiologies or underlying liver disease. Guidelines from professional societies agree that the liver biopsy retains a role in understanding and managing DILI in certain situations. Liver biopsy allows characterization of the histological pattern of injury as well as assessment of severity. Inflammatory infiltrates, bile duct injury or loss and vascular injury are all revealed by liver biopsy. Communication between the hepatopathologist and clinical team with clinicopathological correlation of the findings is necessary for the best determination of causality and differentiation from other diseases of exclusion, like autoimmune hepatitis and graft‐versus‐host disease. This review highlights important aspects of the role of liver biopsy in DILI evaluation. [ABSTRACT FROM AUTHOR]

Recently we have shown that protein disulfide isomerase (PDI or PDIA1) is involved in mediating chemically-induced, glutathione (GSH) depletion-associated ferroptotic cell death through NOS activation (dimerization) and NO accumulation. The present study aims to determine the role of PDI in mediating chemically-induced hepatocyte injury in vitro and in vivo and whether PDI inhibitors can effectively protect against chemically-induced hepatocyte injury. We show that during the development of erastin-induced ferroptotic cell death, accumulation of cellular NO, ROS and lipid-ROS follows a sequential order, i.e., cellular NO accumulation first, followed by accumulation of cellular ROS, and lastly cellular lipid-ROS. Cellular NO, ROS and lipid-ROS each play a crucial role in mediating erastin-induced ferroptosis in cultured hepatocytes. In addition, it is shown that PDI is an important upstream mediator of erastin-induced ferroptosis through PDI-mediated conversion of NOS monomer to its dimer, which then leads to accumulation of cellular NO, ROS and lipid-ROS, and ultimately ferroptotic cell death. Genetic manipulation of PDI expression or pharmacological inhibition of PDI function each can effectively abrogate erastin-induced ferroptosis. Lastly, evidence is presented to show that PDI is also involved in mediating acetaminophen-induced liver injury in vivo using both wild-type C57BL/6J mice and hepatocyte-specific PDI conditional knockout (PDIfl/fl Alb-cre) mice. Together, our work demonstrates that PDI is an important upstream mediator of chemically-induced, GSH depletion-associated hepatocyte ferroptosis, and inhibition of PDI can effectively prevent this injury. [ABSTRACT FROM AUTHOR]

There is increasing evidence that cannabidiol (CBD) use is associated with clinically significant liver enzyme (LE) elevations and drug‐induced liver injury (DILI). The proportion of LE elevations and DILI events reported in the literature meet the Council for International Organizations of Medical Sciences' (CIOMS) classification of a common adverse drug reaction. However, these potential adverse events are unknown to many clinicians and may be overlooked. The increasing use of CBD for both medical and non‐medical use necessitates clear direction in the diagnosis and management of CBD‐associated hepatotoxicity. To our knowledge, no such clinical guidance currently exists. For people presenting with elevated LEs, CBD use should be screened for and be considered in the differential diagnosis. This narrative review will provide clinicians with guidance in the prevention, detection, and management of CBD‐related hepatotoxicity. [ABSTRACT FROM AUTHOR]

Introduction While the 44-mm clay penetration criterion was developed in the 1970s for soft body armor applications, and the researchers acknowledged the need to conduct additional tests, the same behind the armor blunt trauma displacement limit is used for both soft and hard body armor evaluations and design considerations. Because the human thoraco-abdominal contents are heterogeneous, have different skeletal coverage, and have different functional requirements, the same level of penetration limit does not imply the same level of protection. It is important to determine the regional responses of different thoraco-abdominal organs to better describe human tolerance and improve the current behind armor blunt trauma standard. The purpose of this study was to report on the methods, procedures, and data collected from swine. Materials and Methods Live swine tests were conducted after obtaining approvals from the local institution and the Army Care and Use Review Office of the U.S. Department of Defense. Trachea tubes and an intravenous line were introduced before administering anesthesia. Pressure transducers were inserted into the lungs and aorta. An indenter simulating the backface deformation profiles produced by body armor from military-relevant ballistics to human cadavers was used to deliver impact loading to the liver region. A triaxial accelerometer was included in the indenter design. The animals were monitored for 6 hours, necropsies were performed, and injuries were identified. Biomechanical data of the energy, velocity, deflection, viscous criterion, force, and impulse variables were obtained for each test. Results Peak accelerations, velocities, deflections, forces, impulse, and energies ranged from 897 to 5,808 g, 21 to 59 m/s, 1.96 to 8.87 cm, 2.3 to 13.1 kN, 1.1 to 7.1 Ns, and 58 to 387 J, respectively. The peak viscous criterion ranged from 0.8 to 5.8 m/s. All animals survived the 6-hour survival period. Three animals responded with liver lacerations while the remaining 4 did not have any injuries. Conclusion The experimental design based on parallel tests with whole body human cadavers and cadaver swine was found to be successful in delivering controlled impacts to the liver region of live swine and reproducing liver injuries. Previously used biomechanical measures as potential candidates for injury criteria development were obtained. Using this proven model, tests with additional samples are needed to develop injury risk curves for liver impacts and obtain regional (liver) injury criteria. [ABSTRACT FROM AUTHOR]

Introduction Battlefield trauma necessitates prompt hemostatic intervention to mitigate fatalities resulting from critical blood loss. Insights from Operation Enduring Freedom and Operation Iraqi Freedom emphasize the limitations of conventional methods, such as tourniquets, especially in noncompressible torso hemorrhage. Despite advancements in hemostatic agents, the evolving dynamics of multidomain operations necessitate novel, lightweight strategies for hemorrhage control. This study investigates the Silicone-Based Polymer (SBP) Universal Combat Matrix (UCM) by SiOxMed, a multimodal matrix exhibiting efficacy in lethal hemorrhage models. The study evaluates UCM's multiday hemostatic capabilities in a noncompressible torso hemorrhage model, offering pivotal insights for potential deployment in battlefield trauma. Materials and Methods This research was performed under Institutional Animal Care and Use Committee approval and was designed to replicate austere conditions in an off-site enclosed facility. Yorkshire Hampshire swine underwent baseline assessments and anesthesia induction (n  = 3). A Grade IV liver injury was made by incising X-shaped lesions, each measuring 4 cm × 2.5 cm, into the diaphragmatic surface of the left and right middle lobes using a scalpel blade, resulting in a lesion region of approximately 3 cm × 6 cm × 3 cm, followed by 30 seconds of uncontrolled bleeding. The injuries were then treated with SBP. Intensive care unit monitoring for 1 hour ensured sustained hemostasis, followed by 48 hours of postanesthesia monitoring and then a return to the operating table to visualize sustained hemostasis. Posteuthanasia, liver tissue underwent histological assessments to evaluate the hemorrhagic interface and liver tissue reactivity. Results The average time to hemostatic control was 247.3 ± 71.3 seconds. Stable heart rate (81.3 ± 10.0) and respiratory rate (31.7 ± 16.5) were maintained during intensive care unit monitoring. All swine survived the 1-hour anesthesia monitoring period and the subsequent 48-hour monitoring (average survival time, 48.0 hours ± 0.0, n  = 3). Visualization of the abdominal cavity at 48 hours revealed no hemorrhage. Histological assessment demonstrated aligned red blood cells and stratified layers of fibrin at the hemorrhagic interface. Masson's Trichrome analysis demonstrated a reactive and regenerative scenario 48 hours postinjury, with a collagen membrane demarcating uninjured and exposed liver regions, along with a comprehensive stromal response. Conclusions In conclusion, our investigation into the SBP UCM hemostatic efficacy in a grade IV liver laceration model demonstrates its rapid and reliable action in controlling bleeding, showcasing practicality with an average mass of 4.0 ± 1.0 g. Silicone-Based Polymer sustained hemostasis without adverse physiological effects, as evidenced by stable parameters and the survival of all swine during and after anesthesia. Macroscopic examination at 48 hours revealed durable adherence with no indications of hemorrhage. Histological evaluations highlighted SBP's role in stable clot formation, fibrinogenesis, and tissue regeneration, indicating its potential as a multimodal wound dressing. Although promising, the study has limitations, emphasizing the need for future research with larger samples and controls. This work sets the stage for exploring SBP's clinical implications, particularly in scenarios where lightweight, multimodal technologies are crucial for addressing traumatic injuries and enhancing military medical capabilities. [ABSTRACT FROM AUTHOR]

Background: Chemicalsmay lead to acute liver injuries, posing a serious threat to human health. Achieving the precise safety profile of a compound is challenging due to the complex and expensive testing procedures. In silico approaches will aid in identifying the potential risk of drug candidates in the initial stage of drug development and thus mitigating the developmental cost. Methods: In current studies, QSAR models were developed for hepatotoxicity predictions using the ensemble strategy to integrate machine learning (ML) and deep learning (DL) algorithms using various molecular features. A large dataset of 2588 chemicals and drugswas randomly divided into training (80%) and test (20%) sets, followed by the training of individual base models using diverse machine learning or deep learning based on three different kinds of descriptors and fingerprints. Feature selection approaches were employed to proceed with model optimizations based on the model performance. Hybrid ensemble approaches were further utilized to determine the method with the best performance. Results: The voting ensemble classifier emerged as the optimal model, achieving an excellent prediction accuracy of 80.26%, AUC of 82.84%, and recall of over 93% followed by bagging and stacking ensemble classifiers method. The model was further verified by an external test set, internal 10-fold cross-validation, and rigorous benchmark training, exhibiting much better reliability than the published models. Conclusion: The proposed ensemble model offers a dependable assessment with a good performance for the prediction regarding the risk of chemicals and drugs to induce liver damage. [ABSTRACT FROM AUTHOR]

Objective • To analyze the manifestations of infectious mononucleosis and its impact on liver function in children. Methods • This retrospective study analyzed clinical data from 695 children with infectious mononucleosis (IM) who were hospitalized at the Department of Pediatrics, Chengdu First People’s Hospital between January 1, 2017, and December 31, 2022. They were analyzed into two groups according to whether their ALT was greater than 40 U/L. Demographic variables, clinical features, and laboratory findings were collected from medical records. Statistical analyses were performed using the Statistic Package for Social Science (SPSS) 26. Results • A total of 695 children with infectious mononucleosis (IM)(409 males and 286 females) were included in the study. The age distribution was 161 infants (<3 years), 357 preschoolers (3-7 years), and 177 school-aged children (≥7 years). After clinical recovery, 61 cases had elevated liver enzymes. Asynchronous changes in AST and ALT were present in 18 children. The highest proportion of fever onset (75.2%) occurred in infancy (P = .00). Elevated AST, lymphocyte percentage and WBCs, age in school age, uncomplicated myocardial injury these were the risk factors for the development of liver injury in children with infectious mononucleosis. P values were .00, .048, .021, .000 and .002, respectively. 95% CIs were 65., 2-315.52, 1.01-3.48, 1.18- 7.37, 2.57-13.52 and 1.79-13.35, respectively. Conclusions • The clinical features vary with sex and age. Children with IM who are school-aged, without myocardial injury, and have elevated WBC, lymphocyte percentage, and AST should be monitored for potential liver damage. Careful evaluation is necessary following clinical recovery to determine if vaccination is appropriate. [ABSTRACT FROM AUTHOR]

Background: Acute liver injury (ALI) is a serious syndrome with a high mortality rate due to viral infection, toxic exposure, and autoimmunity, and its severity can range from mildly elevated liver enzymes to severe liver failure. Activation of the nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is closely associated with the development of ALI, and the search for an inhibitor targeting this pathway may be a novel therapeutic option. Anoectochilus roxburghii polysaccharide (ARP) is a biologically active ingredient extracted from Anoectochilus roxburghii with immunomodulatory, antioxidant, and anti-inflammatory bioactivities and pharmacological effects. In this study, we focused on D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced acute liver injury by ARP through inhibition of NLRP3 inflammasome. Methods: An inflammasome activation model was established in bone marrow-derived macrophages (BMDMs) to investigate the effects of ARP on caspase-1 cleavage, IL-1β secretion, and ASC oligomerization in inflammasomes under different agonists. We used the D-GalN/LPS-induced acute liver injury model in mice, intraperitoneally injected ARP or MCC950, and collected liver tissues, serum, and intraperitoneal lavage fluid for pathological and biochemical indexes. Results: ARP effectively inhibited the activation of the NLRP3 inflammasome and had an inhibitory effect on non-classical NLRP3, AIM2, and NLRC4 inflammasomes. It also effectively inhibited the oligomerization of apoptosis-associated speck-like protein (ASC) from a variety of inflammatory vesicles. Meanwhile, ARP has good therapeutic effects on acute liver injury induced by D-GaIN/LPS. Conclusion: The inhibitory effect of ARP on a wide range of inflammasomes, as well as its excellent protection against acute liver injury, suggests that ARP may be a candidate for acute liver injury. [ABSTRACT FROM AUTHOR]

Acute liver injury is an increasing global health problem. It is a widespread side effect of cisplatin treatment in the clinic and can lead to liver failure if not treated promptly. Previous studies have revealed that green tea can protect some organs from treatments. However, the potential of white tea to prevent the negative effects of acute liver injury has not been addressed so far. The purpose of this study was to investigate the reduction in cisplatin-induced liver injury in rats receiving white tea. Female Sprague Dawley rats with similar weight were selected in this study. Twenty-four rats were divided into three groups of eight animals each and ad libitum nutrition was provided. The control and cisplatin groups were given tap water only, while the white tea + cisplatin group received white tea at a 0.5% weight/volume concentration for four weeks. At the end of the fourth week, the white tea + cisplatin group and the cisplatin group received a single dose of cisplatin (7 mg/kg) via the intraperitoneal route. Five days after that procedure, the rats were anesthetized. Liver tissues and blood samples were collected, which were used for biochemical and histopathological analyses. According to biochemical results, liver tissue MDA and GSH, serum ALT, and AST levels significantly increased in the cisplatin group compared to the control group. Compared with the cisplatin group, although MDA, AST, ALT, and GSH levels were lower in the white tea + cisplatin group, only GSH levels were statistically different. The examination of histopathological and immunohistochemical findings revealed apoptotic cells, vascular congestion, and sinusoidal dilatation in the cisplatin group compared to the control group. This adverse event decreased in the white tea + cisplatin group compared to the cisplatin group. In conclusion, white tea exhibits an ameliorating effect on cisplatin-induced liver injury. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the protective effect of echinacoside (Ech) on carbon tetrachloride (CCL4)‐induced chronic liver injury in rats and its potential mechanisms. Thirty Sprague–Dawley (SD) rats were randomly divided into five groups: the Control group, the CCL4 group, the CCL4 + Ech 25 mg/kg group, the CCL4 + Ech 50 mg/kg group, and the CCL4 + Ech 100 mg/kg group. The rats were injected intraperitoneally with CCL4 solution twice a week to induce chronic liver injury, and Ech intervention lasted for 4 weeks. After the intervention, the liver and blood samples from rats were collected for subsequent analysis. Ech effectively reduced the levels of serum liver injury markers (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, alkaline phosphatase, and total bilirubin), attenuated the hepatocyte degeneration and necrosis, improved the severity of liver fibrosis, and inhibited the local inflammatory response of the liver in a dose‐dependent manner. Ech effectively mitigated CCL4‐induced chronic liver injury in rats by downregulating the NF‐κB/NLRP3 inflammasome pathway. [ABSTRACT FROM AUTHOR]

Shaoyao Gancao Decoction (SGD), a traditional Chinese medicine, has been proven to have a good liver protection effect, but the mechanism and pharmacodynamic substances of SGD in the treatment of acute liver injury are still unclear. In this study, an ultra‐high‐performance liquid chromatography‐quadrupole‐time‐of‐flight mass spectrometry (UHPLC‐Q‐TOF‐MS) method was established to characterize 107 chemical components of SGD and 12 compounds absorbed in rat plasma samples after oral administration of SGD. Network pharmacology was applied to construct a component‐target‐pathway network to screen the possible effective components of SGD in acute liver injury. Using lipidomics based on UHPLC‐Q‐TOF‐MS coupled with a variety of statistical analyses, 20 lipid biomarkers were screened and identified, suggesting that the improvement of acute liver injury by SGD was involved in cholesterol metabolism, glycerol‐phospholipid metabolism, sphingolipid signaling pathways and fatty acid biosynthesis. In addition, the UHPLC‐tandem MS method was established for pharmacokinetics analysis, and 10 potential active components were determined simultaneously within 12 min through the optimization of 0.1% formic acid water and acetonitrile as a mobile phase system. A Pharmacokinetics study showed that paeoniflorin, albiflorin, oxypaeoniflorin, liquiritigenin, isoliquiritigenin, liquiritin, ononin, formononetin, glycyrrhizic acid, and glycyrrhetinic acid as the potential active compounds of SGD curing acute liver injury. [ABSTRACT FROM AUTHOR]

Background Serum level of microRNA-122 (miR-122) has been reported as a sensitive diagnostic biomarker for detecting liver injury, comparable to the aminotransferases. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities are increased in other conditions, such as acute skeletal muscle injury (ASMI). We determined whether miR-122 is nonspecifically increased in patients suffering from ASMI. Methods We measured ALT, AST, creatine kinase (CK), and miR-122 in 3 groups: healthy controls (n = 24), patients with ASMI (total n = 29, 11 with recreational drug use and 18 without recreational drug use), and patients with acute liver injury (ALI; n = 14). Results Levels of ALT, AST, and CK increased 83%, 97%, and 100% for patients with ASMI and 100% for all 3 enzymes in ALI patients. In contrast, miR-122 increased in 34% of patients with ASMI (44.4% with recreational drug use and 18.2% without recreational drug use) and 100% of ALI patients. In 2 drug-induced liver injury cases, miR-122 increased about 12-24 hours before ALT and AST. Conclusion Recreational drug misuse is associated with both rhabdomyolysis and drug-induced liver injury (DILI). The traditional liver function markers AST and ALT were nonspecifically increased in the majority of patients with ASMI. miR-122 is only increased in patients at risk for DILI and demonstrates superior specificity for liver injury. [ABSTRACT FROM AUTHOR]

Objective Community-acquired pneumonia with abnormal liver function is not uncommon. There is no systematic study on the clinical characteristics of liver dysfunction in children with community-acquired pneumonia. We aimed to evaluate the characteristics and prognosis of liver dysfunction in children with community-acquired pneumonia. Methods This study was a multicenter prospective study involving 26 hospitals in Sichuan Province from June 2020 to June 2021. The characteristics of liver dysfunction in children with community-acquired pneumonia were recorded and analyzed according to different factors such as age, medical condition, level of transaminase in liver function, and time for liver function recovery. Results A total of 4,623 hospitalized children with pneumonia were included. Among them, 592 children had liver dysfunction, accounting for the 12.8% (592/4,623). The degree of liver function injury was more obvious in infants and in children of severe pneumonia group (average ranks were 288.95 and 319.34). The liver lesion was more serious in the group of children less than 1 year old (p = 0.000). The median time to recovery of liver function was 8 days (interquartile range: 6–15.5 days), whereas the fastest recovery was 3 days, and the longest recovery period was 162 days. Conclusion Community-acquired pneumonia with abnormal liver function is very common. Young age and severe pneumonia are risk factors for liver dysfunction. The recovery time of liver enzymes is not short. Infants and children with severe pneumonia need closer follow-up. [ABSTRACT FROM AUTHOR]

Cyclosporine-A (CsA) is currently used to treat immune rejection after organ transplantation as a commonly used immunosuppressant. Liver injury is one of the most common adverse effects of CsA, whose precise mechanism has not been fully elucidated. Pregnane X receptor (PXR) plays a critical role in mediating drug-induced liver injury as a key regulator of drug and xenobiotic clearance. As a nuclear receptor, PXR transcriptionally upregulates the expression of drug-metabolizing enzymes and drug transporters, including cytochrome P4503A (CPY3A) and multidrug resistance-associated protein 2 (MRP2). Our study established CsA-induced cytotoxic hepatocytes in an in vitro model, demonstrating that CsA dose-dependently increased the aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) level secreted in the HepG2 cell supernatant, as well as viability and oxidative stress of HepG2 cells. CsA also dose-dependently decreased the PXR, CYP3A4, CPY3A5, and MRP2 levels of HepG2 cells. Mechanistically, altering the expression of PXR, CYP3A4, CYP3A5, and MRP2 affected the impact of CsA on AST and LDH levels. Moreover, altering the expression of PXR also changed the level of CYP3A4, CPY3A5, and MRP2 of HepG2 cells treated by CsA. Our presented findings provide experimental evidence that CsA-induced liver injury is PXR tightly related. We suggest that PXR represents an attractive target for therapy of liver injury due to its central role in the regulation of the metabolizing enzymes CYP3A and MRP2-mediated bile acid transport and detoxification. [ABSTRACT FROM AUTHOR]

• Repeated-measure design in workers exposed to chromate was conducted. • Blood chromium was positively correlated with liver enzyme levels and bilirubin levels, suggesting that chromate exposure may cause liver injury. • Blood chromium was positively correlated with systemic inflammatory markers PLT and PLR, suggesting that chromate exposure may lead to increased systemic inflammation. • Systemic inflammatory markers PLT and PLR mediate the increase of liver enzymes and bilirubin induced by chromium exposure, with the mediating ratio ranging from 8.26% to 15.58%. Hexavalent chromium and its compounds are prevalent pollutants, especially in the work environment, pose a significant risk for multisystem toxicity and cancers. While it is known that chromium accumulation in the liver can cause damage, the dose-response relationship between blood chromium (Cr) and liver injury, as well as the possible potential toxic mechanisms involved, remains poorly understood. To address this, we conducted a follow-up study of 590 visits from 305 participants to investigate the associations of blood Cr with biomarkers for liver injury, including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), and direct bilirubin (DBIL), and to evaluate the mediating effects of systemic inflammation. Platelet (PLT) and the platelet-to-lymphocyte ratio (PLR) were utilized as biomarkers of systemic inflammation. In the linear mixed-effects analyses, each 1-unit increase in blood Cr level was associated with estimated effect percentage increases of 0.82% (0.11%, 1.53%) in TBIL, 1.67% (0.06%, 3.28%) in DBIL, 0.73% (0.04%, 1.43%) in ALT and 2.08% (0.29%, 3.87%) in AST, respectively. Furthermore, PLT mediated 10.04%, 11.35%, and 10.77% increases in TBIL, DBIL, and ALT levels induced by chromate, respectively. In addition, PLR mediated 8.26% and 15.58% of the association between blood Cr and TBIL or ALT. These findings shed light on the mechanisms underlying blood Cr-induced liver injury, which is partly due to worsening systemic inflammation. [Display omitted] [ABSTRACT FROM AUTHOR]

Ferroptosis is a form of iron-dependent cell death that has attracted significant attention for its potential role in numerous diseases. Targeted inhibition of ferroptosis could be of potential use in treating diseases: such as drug induced liver injury (DILI). Ferroptosis can be antagonized by the xCT/GSH/GPX4, FSP1/CoQ 10 , DHODH/CoQ 10 , GCH1/BH 4 , and NRF2 pathways. Identifying novel anti-ferroptosis pathways will further promote our understanding of the biological nature of ferroptosis and help discover new drugs targeting ferroptosis related human diseases. In this study, we identified the clinically used drug mifepristone (RU486) as a novel ferroptosis inhibitor. Mechanistically, RU486 inhibits ferroptosis by inducing GSH synthesis pathway, which supplies GSH for glutathione-S-transferase (GST) mediated 4-HNE detoxification. Furthermore, RU486 induced RLIP76 and MRP1 export 4-HNE conjugate contributes to its anti-ferroptosis activity. Interestingly, RU486 induced GSH/GSTs/RLIP76&MRP1 anti-ferroptosis pathway acts independent of classic anti-ferroptosis systems: including xCT/GSH/GPX4, FSP1, DHODH, GCH1, SCD1 and FTH1. Moreover, NRF2 was identified to be important for RU486's anti-ferroptosis activity by inducing downstream gene expression. Importantly, in mouse model, RU486 showed strong protection effect on acetaminophen (APAP)-induced acute liver injury, evidenced by decreased ALT, AST level and histological recovery after APAP treatment. Interestingly, RU486 also decreased oxidative markers, including 4-HNE and MDA, and induced NRF2 activation as well as GSTs, MRP1 expression. Together, these data suggest NRF2/GSH/GST/RLIP76&MRP1 mediated detoxification pathway as an important independent anti-ferroptosis pathway act both in vitro and in vivo. • Mifepristone is a novel ferroptosis inhibitor that independent of the major pathways. • Mifepristone (RU486) promotes 4-HNE detoxification to antagonize ferroptosis. • RU486 increases GSH and upregulates GST activity to promote detoxification of 4-HNE. • RU486 boosts export of 4-HNE conjugate by activating NRF2, enhancing RLIP76 and MRP1. • RU486 shields the liver from APAP injury, echoing in vitro mechanisms. [ABSTRACT FROM AUTHOR]

Background and Aims: Cyclooxygenase‐2 (COX‐2) is involved in different liver diseases, but little is known about the significance of COX‐2 in cholestatic injury. This study was designed to elucidate the role of COX‐2 expression in hepatocytes during the pathogenesis of obstructive cholestasis. Methods: We used genetically modified mice constitutively expressing human COX‐2 in hepatocytes. Transgenic mice (hCOX‐2‐Tg) and their wild‐type (Wt) littermates were either subjected to a mid‐abdominal laparotomy or common bile duct ligation (BDL) for 2 or 5 days. Then, we explored the mechanisms underlying the role of COX‐2 and its derived prostaglandins in liver function, and the synthesis and excretion of bile acids (BA) in response to cholestatic liver injury. Results: After BDL, hCOX‐2‐Tg mice showed lower grades of hepatic necrosis and inflammation than Wt mice, in part by a reduced hepatic neutrophil recruitment associated with lower mRNA levels of pro‐inflammatory cytokines. Furthermore, hCOX‐2‐Tg mice displayed a differential metabolic pattern of BA synthesis that led to an improved clearance after BDL‐induced accumulation. In addition, an enhanced response to the BDL‐induced oxidative stress and hepatic apoptosis was observed. In vitro experiments using hepatic cells that stably express hCOX‐2 confirmed the cytoprotective role of prostaglandin E2 against BA toxicity. Conclusions: Taken together, our data indicate that constitutive expression of COX‐2 in hepatocytes ameliorates cholestatic liver injury in mice by reducing inflammation and cell damage and by modulating BA metabolism, pointing to a role for COX‐2 as a defensive response against cholestasis‐derived BA accumulation and injury. [ABSTRACT FROM AUTHOR]

Understanding the endogenous mechanism of adaptive response to drug‐induced liver injury (arDILI) may discover innovative strategies to manage DILI. To gain mechanistic insight into arDILI, we investigated exosomal miRNAs in the adaptive response to toosendanin‐induced liver injury (TILI) of mice. Exosomal miR‐106b‐5p was identified as a specific regulator of arDILI by comprehensive miRNA profiling. Outstandingly, miR‐106b‐5p agomir treatment alleviated TILI and other DILI by inhibiting apoptosis and promoting hepatocyte proliferation. Conversely, antagomir treatments had opposite effects, indicating that miR‐106b‐5p protects mice from liver injury. Injured hepatocytes released miR‐106b‐5p‐enriched exosomes taken up by surrounding hepatocytes. Vim (encodes vimentin) was identified as an important target of miR‐106b‐5p by dual luciferase reporter and siRNA assays. Furthermore, single‐cell RNA‐sequencing analysis of toosendanin‐injured mouse liver revealed a cluster of Vim+ hepatocytes; nonetheless declined following miR‐106b‐5p cotreatment. More importantly, Vim knockout protected mice from acetaminophen poisoning and TILI. In the clinic, serum miR‐106b‐5p expression levels correlated with the severity of DILI. Indeed, liver biopsies of clinical cases exposed to different DILI causing drugs revealed marked vimentin expression among harmed hepatocytes, confirming clinical relevance. Together, we report mechanisms of arDILI whereby miR‐106b‐5p safeguards restorative tissue repair by targeting vimentin. [ABSTRACT FROM AUTHOR]

We investigated the role and mechanism of ginsenoside RD (GRD) in acute liver injury. Network pharmacology was used to analyze the correlations among GRD‐liver injury‐pyroptosis targets. A mouse model of acute liver injury was established by lipopolysaccharide + d‐galactose（LPS + d/Gal). After pretreatment with GRD, the changes in mouse liver function were detected. The histopathological changes were assayed by hematoxylin and eosin and Masson staining, the tissue expressions of inflammatory cytokines were detected by enzyme‐linked immunosorbent assay, and the protein expressions were assayed by immunohistochemical staining and Western blotting. Meanwhile, mechanism research was conducted using STAT3‐knockout transgenic mice and STAT3‐IN13, a STAT3 inhibitor. GRD inhibited liver injury, mitigated tissue inflammation, and suppressed STAT3‐mediated pyroptosis in mice. After applying STAT3‐knockout mouse model or STAT3‐IN13, GRD did not further inhibit the liver injury. GRD can resist liver injury by inhibiting the STAT3‐mediated pyroptosis, which is one of the hepatoprotective mechanisms of GRD. [ABSTRACT FROM AUTHOR]

Background and Objectives: Liver injury is a rare complication of cardiopulmonary resuscitation. Correct and early diagnosis and treatment are essential. The clinical signs of injury may be masked by the cardiac arrest. We present a single-centre retrospective observational study of traumatic liver injury after cardiopulmonary resuscitation. Materials and Methods: A retrospective analysis of the patients treated for liver injury after cardiopulmonary resuscitation was conducted. Demographic data, the cause of resuscitation, the duration of restoration of spontaneous circulation (ROSC), and the surgical approach were analysed. Results: We have treated nine patients with severe liver injury after cardiopulmonary resuscitation. The diagnosis was made on the basis of cardiopulmonary instability, a fall in the erythrocyte count in eight cases, and was confirmed by CT or ultrasound examination. The last one was diagnosed accidentally on MR. Surgery, in cases of unstable patients, was followed immediately after a diagnosis. We combined liver sutures and intra-abdominal packing with a planned second-look surgery. Five of the nine patients survived. Conclusions: Liver injury after cardiopulmonary resuscitation is rare and is associated with high mortality. The recurrence of cardiopulmonary instability and/or a low or falling red blood cell count are the main signs of this injury. Bedside ultrasound and CT scans are the most important methods to confirm the diagnosis. The rule of surgical repair is the same as in all liver injuries, regardless of aetiology. The key factors for survival include early diagnosis, together with the length of restoration of spontaneous circulation (ROSC). [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are increasingly being considered essential diagnostic biomarkers and therapeutic targets for multiple diseases. In recent years, researchers have emphasized the need to develop probes that can harness extracellular miRNAs as input signals for disease diagnostics. In this study, we introduce a novel miRNA-responsive biosensor (miR-RBS) designed to achieve highly sensitive and specific detection of miRNAs, with a particular focus on targeted organ-specific visualization. The miR-RBS employs a Y-structured triple-stranded DNA probe (Y-TSDP) that exhibits a fluorescence-quenched state under normal physiological conditions. The probe switches to an activated state with fluorescence signals in the presence of high miRNA concentrations, enabling rapid and accurate disease reporting. Moreover, the miR-RBS probe had a modular design, with a fluorescence-labeled strand equipped with a functional module that facilitates specific binding to organs that express high levels of the target receptors. This allowed the customization of miRNA detection and cell targeting using aptameric anchors. In a drug-induced liver injury model, the results demonstrate that the miR-RBS probe effectively visualized miR-122 levels, suggesting it has good potential for disease diagnosis and organ-specific imaging. Together, this innovative biosensor provides a versatile tool for the early detection and monitoring of diseases through miRNA-based biomarkers. [ABSTRACT FROM AUTHOR]

Ferroptosis, an iron‐dependent form of cell death, plays a crucial role in the progression of liver injury in Wilson's disease (WD). Gandouling (GDL) has emerged as a potential therapeutic agent for preventing and treating liver injury in WD. However, the precise mechanisms by which GDL mitigates ferroptosis in WD liver injury remain unclear. In this study, we discovered that treating Toxic Milk (TX) mice with GDL effectively decreased liver copper content, corrected iron homeostasis imbalances, and lowered lipid peroxidation levels, thereby preventing ferroptosis and improving liver injury. Bioinformatics analysis and machine learning algorithms identified Hspb1 as a pivotal regulator of ferroptosis. GDL treatment significantly upregulated the expression of HSPB1 and its upstream regulatory factor HSF1, thereby activating the HSF1/HSPB1 pathway. Importantly, inhibition of this pathway by NXP800 reversed the protective effects of GDL on ferroptosis in the liver of TX mice. In conclusion, GDL shows promise in alleviating liver injury in WD by inhibiting ferroptosis through modulation of the HSF1/HSPB1 pathway, suggesting its potential as a novel therapeutic agent for treating liver ferroptosis in WD. [ABSTRACT FROM AUTHOR]

Background and Objective: The complex risk factors of liver injury have prevented the establishment of causal relationships. This study aimed to explore the effects of antidepressant class, cumulative days of medication exposure, presence of comorbidities, and the use of confounding drugs on the risk of antidepressant-induced liver injury. Methods: The population-based case–control study sample included individuals registered on the Taiwan National Health Insurance Database between 2000 and 2018. Hospitalized patients with suspected drug-induced liver injury were considered as cases, while control subjects were matched 1:1 by age, gender, and index date (the first observed diagnosis of liver injury). Multivariable regression models were performed to evaluate the association between antidepressants and liver injury. Results: The findings showed that antidepressant users exhibited a higher risk of liver injury (adjusted odds ratio [aOR] 1.16, 95% confidence interval [CI] 1.12–1.20), particularly those prescribed non-selective serotonin reuptake inhibitors (NSRIs; aOR 1.05; 95% CI 1.01–1.10), selective serotonin reuptake inhibitors (SSRIs; aOR 1.22; 95% CI 1.16–1.29), serotonin-norepinephrine reuptake inhibitors (SNRIs; aOR 1.18; 95% CI 1.13–1.24), and others (aOR 1.27; 95% CI 1.14–1.42). Moreover, cases exhibited a more significant proportion of antidepressant usage and longer durations of treatment compared with controls. The risk of liver injury was higher in the first 30 days of use across all classes of antidepressants (aOR 1.24; 95% CI 1.18–1.29). Conclusion: SSRIs or SNRIs are commonly used to treat depression and other psychological disorders, and consideration of their potential effects on the liver is essential. [ABSTRACT FROM AUTHOR]

Background: The inflammatory factor YKL-40 is associated with various inflammatory diseases and is key to remodeling inflammatory cells and tissues. YKL-40 (Chi3l1) promotes the activation of tissue factor (TF), leading to intrahepatic vascular coagulation (IAOC) and liver injury. TF is a key promoter of the exogenous coagulation cascade and is also involved in several signaling involving cell proliferation, apoptosis, charring,migration and inflammatory diseases pathways. However, the effect of YKL-40-induced TF- PAR1 pathway on the expression of downstream chemokines remains unknown. Methods: We established a liver injury model using Concanavalin A (ConA) in C57 BL/6 mice. By adopting various experimental techniques, the effect of YKL-40 induced TF-PAR1 pathway on the expression of downstream chemokine ligand 2 (CCL2) and IP-10 was verified. Results: We found that overexpression of YKL-40 increased the expression of TF, protease-activated receptor 1 (PAR1), CCL2 and IP-10 inmice and exacerbated the severity of liver injury. However, blocking the expression of TF significantly reversed the extent of liver injury. Conclusion: We found that YKL-40 promotes the expression of downstream chemokines ligand 2 (CCL2) and IP-10 by activating the TF-PAR1 pathway, leading to increased recruitment of inflammatory cells and exacerbating the progression of liver injury. This provides a new approach for the clinical treatment of drug- induced liver injury. [ABSTRACT FROM AUTHOR]