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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]

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]

Objective: To analyze the clinical and laboratory characteristics and to identify predictors of moderate to severe anti-tuberculosis drug-induced liver injury (ATB-DILI) in patients with tuberculosis. Methods: This prospective study enrolled Tuberculosis (TB) patients treated with first-line anti-tuberculosis drugs at the Affiliated Hospital of Zunyi Medical University between May 2022 and June 2023. The occurrence of ATB-DILI was monitored, and demographic and clinical data were gathered. We analyzed risk factors for the development of moderate to severe ATB-DILI. Results: ATB-DILI was detected in 120 (10.7%) of the patients, with moderate to severe ATB-DILI occurring in 23 (2.0%) of the 1,124 patients treated with antituberculosis treatment. Multivariate cox regression analysis identified malnutrition (HR = 4.564, 95% CI: 1.029-20.251, p = 0.046) and hemoglobin levels <120 g/L (HR = 2.825, 95% CI: 1.268-11.540, p = 0.017) as independent risk factors for moderate to severe ATB-DILI. Conclusion: The incidence of moderate to severe ATB-DILI was found to be 2.0%. Malnutrition and hemoglobin levels below 120 g/L emerged as significant independent risk factors for the occurrence of moderate to severe ATB-DILI in this patient population. [ABSTRACT FROM AUTHOR]

Chronic liver disease, a long-term condition resulting from various causes such as alcohol abuse, metabolic disorders, and viral hepatitis, is becoming a significant global health challenge. Gypenosides (GPs), derived from the traditional Chinese medicine Gynostemma pentaphyllum (Thunb.) Makino, exhibited hepatoprotective properties in recent years, yet the precise therapeutic mechanism remains unclear. In this study, label-free and parallel reaction monitoring (PRM) proteomics were used to elucidate the hepatoprotective mechanism of GPs in liver injury rats. Through label-free proteomics, we identified 2104 differentially expressed proteins (DEPs) associated with liver injury, along with 1974 DEPs related to the effects of GPs. Bioinformatics analysis revealed that GPs primarily restored metabolic processes involving valine, leucine, and isoleucine degradation, as well as propanoate and butanoate metabolism, and steroid hormone biosynthesis during liver injury. Subsequently, overlapping the two groups of DEPs identified 1508 proteins reversed following GPs treatment, with key targets further validated by PRM. Eight target proteins were identified for GPs treatment of liver injury, including Lgals3, Psat1, Phgdh, Cyp3a9, Cyp2c11, Cyp4a2, Glul, and Ces1d. These findings not only elucidated the hepatoprotective mechanism of GPs, but may also serve as potential therapeutic targets of chronic liver disease. [ABSTRACT FROM AUTHOR]

Introduction: Excessive alcohol intake often results in hangovers and inflammatory liver damage, posing a significant health concern. Current treatment options for hangovers are still insufficient, highlighting the urgent need for new therapeutic approaches. Psyllium fiber (PF) is well-known for its gastrointestinal benefits, but its effect on hangovers is less explored. Methods: We utilized a mouse model with a single binge drinking (4 g/kg) to induce hangover and inflammatory liver injury. Intestine and liver injury were serologically and histologically estimated. Hangover symptoms were assessed using cylinder and footprint tests to objectively quantify hangover symptoms in mice. Results: Binge drinking significantly activated alcohol-metabolizing enzymes in the small intestine and liver, leading to inflammatory damage. Concurrently, there was a rise in alcohol metabolites such as acetaldehyde and acetone, which exhibited a positive correlation with hangover symptoms in mice. Interestingly, the oral administration of PF (100 mg/kg) alongside alcohol consumption significantly reduced the activity of these enzymes and lowered the levels of alcohol metabolites. Mice treated with PF exhibited a considerable improvement in hangover symptoms and a reduction in hepatic inflammation, compared to control groups. Furthermore, in vitro experiments using HepG2 cell lines and semipermeable membranes demonstrated that PF effectively inhibits alcohol absorption into the body. Discussion: In conclusion, PF demonstrates a potential protective effect against alcohol-induced hangover and liver injury by inhibiting the absorption of alcohol and lowering hangover-related alcohol metabolites. This study suggests that PF could serve as an effective therapeutic option for mitigating the adverse effects of excessive alcohol consumption. [ABSTRACT FROM AUTHOR]

Background: Patrinia villosa (Thunb.) Juss is one of the plant resources of the famous traditional Chinese medicine "Bai jiang cao (herba patriniae)," and it is considered to function at the liver meridian, thereby treating diseases of the liver as demonstrated by the traditional theory of TCM. Unfortunately, the therapeutic mechanism of the whole plant of PV is so far unknown. Method: UPLC QTOF-MS/MS was used to analyze the profile of PV. Male Sprague-Dawley rats were categorized into five groups, and PV groups (125 and 375mg/kg) were administered by oral gavage for seven consecutive days. The model of liver injury was induced by intraperitoneal injection of 40% CCl4 oil solution. H&E staining was performed for histological evaluation. The ELISA method was used to assess the serumlevel of ALT, AST, and T-BIL. Serum and liver bile acid (BA) profiling was analyzed by LC-MS/MS. TUNEL-stained liver sections were used to monitor apoptosis caused by CCl4. HepG2 cells were used to detect autophagy caused by CCl4. Results: A total of 16 compounds were identified from the 70% methanol extract of PV. PV (125 and 375 mg/kg) could reverse the ectopic overexpression of AST, ALT, and T-BIL caused by CCl4 administration. H&E staining indicated that PV (125 and 375 mg/kg) could reduce the infiltration of inflammatory cells and restore liver tissue and hepatocyte structures. Six bile acids, including DCA, HDCA, GCA, TCA, TCDCA, and TUDCA, were significantly altered both in the serum and liver tissue after CCl4 administration, and the level of all these six bile acids was restored by PV treatment. Moreover, PV inhibited apoptosis caused by CCl4 stimulation in liver tissue and suppressed autophagy in HepG2 cells treated with CCl4. Conclusion: The results in this paper for the first time reveal the alteration of the bile acid profile in CCl4-induced liver injury and demonstrate that inhibiting apoptosis and autophagy was involved in P. villosa-elicited liver protection, providing a scientific basis for the clinical utilization of P. villosa as a natural hepatic protective agent. [ABSTRACT FROM AUTHOR]

Effective therapy for liver fibrosis is lacking. Here, we examined whether LP340, the lead candidate of a new-generation of hydrazide-based HDAC1,2,3 inhibitors (HDACi), decreases liver fibrosis. Liver fibrosis was induced by CCl4 treatment and bile duct ligation (BDL) in mice. At 6 weeks after CCl4, serum alanine aminotransferase increased, and necrotic cell death and leukocyte infiltration occurred in the liver. Tumor necrosis factor-α and myeloperoxidase markedly increased, indicating inflammation. After 6 weeks, α-smoothmuscle actin (αSMA) and collagen-1 expression increased by 80% and 575%, respectively, indicating hepatic stellate cell (HSC) activation and fibrogenesis. Fibrosis detected by trichrome and Sirius-red staining occurred primarily in pericentral regions with some bridging fibrosis in liver sections. 4-Hydroxynonenal adducts (indicator of oxidative stress), profibrotic cytokine transforming growth factor-β (TGFβ), and TGFβ downstream signaling molecules phospho-Smad2/3 also markedly increased. LP340 attenuated indices of liver injury, inflammation, and fibrosis markedly. Moreover, Skirelated novel protein-N (SnoN), an endogenous inhibitor of TGFβ signaling, decreased, whereas SnoN expression suppressor microRNA-23a (miR23a) increased markedly. LP340 (0.05 mg/kg, ig., daily during the last 2 weeks of CCl4 treatment) decreased 4-hydroxynonenal adducts andmiR23a production, blunted SnoN decreases, and inhibited the TGFβ/Smad signaling. By contrast, LP340 had no effect on matrix metalloproteinase-9 expression. LP340 increased histone-3 acetylation but not tubulin acetylation, indicating that LP340 inhibited Class-I but not Class-II HDAC in vivo. After BDL, focal necrosis, inflammation, ductular reactions, and portal and bridging fibrosis occurred at 2 weeks, and αSMA and collagen-1 expression increased by 256% and 560%, respectively. LP340 attenuated liver injury, ductular reactions, inflammation, and liver fibrosis. LP340 also decreased 4-hydroxynonenal adducts and miR23a production, prevented SnoN decreases, and inhibited the TGFβ/Smad signaling after BDL. In vitro, LP340 inhibited immortal human hepatic stellate cells (hTERT-HSC) activation in culture (αSMA and collagen-1 expression) as well as miR23a production, demonstrating its direct inhibitory effects on HSC. In conclusions, LP340 is a promising therapy for both portal and pericentral liver fibrosis, and it works by inhibiting oxidative stress and decreasing miR23a. [ABSTRACT FROM AUTHOR]

Background: The development and marketing of Bedaquiline (BDQ) represent significant advancements in treating tuberculosis, particularly multidrug-resistant forms. However, comprehensive research into BDQ's real-world safety remains limited. Purpose: We obtained BDQ related adverse event (AE) information from the US Food and Drug Administration's Adverse Event Reporting System (FAERS) to assess its safety and inform drug usage. Methods: The AE data for BDQ from 2012 Q4 to 2023 Q3 was collected and standardized. Disproportionality analysis, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Multi-item Gamma Poisson Shrinker (MGPS), and Bayesian Confidence Propagation Neural Network (BCPNN) was used to quantify signals of BDQ-related AEs. Logistic regression was used to analyze the individual data of hepatotoxicity and drug-induced liver injury, and multiple linear regression models were established. Additionally, network pharmacology was employed to identify the potential biological mechanisms of BDQ-induced liver injury. Results: We identified 2017 case reports directly related to BDQ. Our analysis identified 341 Preferred Terms (PTs) characterizing these AEs across 27 System Organ Classes (SOC). An important discovery was the identification of AEs associated with ear and labyrinth disorders, which had not been documented in the drug's official leaflet before. Subgroup analysis revealed a negative correlation between BDQ-related liver injury and females (OR: 0.4, 95%CI: 0.3-0.6). In addition, via network pharmacology approach, a total of 76 potential targets for BDQ related liver injury were predicted, and 11 core target genes were selected based on the characterization of protein-protein interactions. The pathway linked to BDQ-induced liver injury was identified, and it was determined that the PI3K-Akt signaling pathway contained the highest number of associated genes. Conclusion: The analysis of the FAERS database revealed adverse events linked to BDQ, prompting the use of a network pharmacology approach to study the potential molecular mechanism of BDQ-induced liver injury. These findings emphasized the significance of drug safety and offered understanding into the mechanisms behind BDQ-induced liver injury. BDQ demonstrated distinct advantages, including reduced incidence of certain adverse events compared to traditional treatments such as injectable agents and second-line drugs. However, it is important to acknowledge the limitations of this analysis, including potential underreporting and confounding factors. This study provides valuable insights into the safety of BDQ and its role in the management of MDR-TB, emphasizing the need for continued surveillance and monitoring to ensure its safe and effective use. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the protective role and potential mechanisms of Xie Zhuo Tiao Zhi decoction (XZTZ) on alcohol-associated liver disease (ALD). XZTZ significantly alleviated alcohol-induced liver dysfunction, based on histological examinations and biochemical parameters after 4-week administration. Mechanically, alcohol-stimulated hepatic oxidative stress was ameliorated by XZTZ, accompanied by the improvement of Nrf2/Keap1 expression and alcoholactivated phosphorylation of pro-inflammatory transcription factors, including JNK, P38, P65, and IαB&, were rescued by XZTZ. In conclusion, XZTZ demonstrates potential in alleviating alcohol-induced liver injury, oxidative stress, and inflammation possibly through modulation of Nrf2/Keap1 and MAPKs/NF-κB signaling pathways, suggesting its potential as a therapeutic option for patients with alcoholic liver disease. [ABSTRACT FROM AUTHOR]

Idiosyncratic drug-induced liver injury (iDILI) is a major concern in drug development because its occurrence is unpredictable. Presently, iDILI prediction is a challenge, and cell toxicity is observed only at concentrations that are much higher than the therapeutic doses in preclinical models. Applying a proprietary cell educating technology, we developed a person-dependent spheroid system that contains autologous educated immune cells that can detect iDILI risk at therapeutic concentrations. Integrating this system into a high-throughput screening platform will help pharmaceutical companies accurately detect the iDILI risk of new molecules de-risking drug development. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the potential risk of druginduced liver injury (DILI) caused by the CDK4/6 inhibitors (CDK4/6is abemaciclib, ribociclib, and palbociclib by comprehensively analyzing the FDA Adverse Event Reporting System (FAERS) database. Moreover, potential toxicological mechanisms of CDK4/6is-related liver injury were explored via drug-gene network analysis. Methods: In this retrospective observational study, we collected reports of DILI associated with CDK4/6i use from the FAERS dated January 2014 to March 2023. We conducted disproportionality analyses using the reporting odds ratio (ROR) with a 95% confidence interval (CI). Pathway enrichment analysis and drug-gene network analyses were subsequently performed to determine the potential mechanisms underlying CDK4/6i-induced liver injury. Results: We found positive signals for DILI with ribociclib (ROR = 2.60) and abemaciclib (ROR = 2.37). DILIs associated with liver-related investigations, signs, and symptoms were confirmed in all three reports of CDK4/6is. Moreover, ascites was identified as an unlisted hepatic adverse effect of palbociclib. We isolated 189 interactive target genes linking CDK4/6 inhibitors to hepatic injury. Several key genes, such as STAT3, HSP90AA1, and EP300, were revealed via proteinprotein analysis, emphasizing their central roles within the network. KEGG pathway enrichment of these genes highlighted multiple pathways. Conclusion: Our study revealed variations in hepatobiliary toxicity among the different CDK4/6 inhibitors, with ribociclib showing the highest risk of liver injury, followed by abemaciclib, while palbociclib appeared relatively safe. Our findings emphasize the need for cautious use of CDK4/6 inhibitors, and regular liver function monitoring is recommended for long-term CDK4/6 inhibitor use. [ABSTRACT FROM AUTHOR]

Background: Matrine, an alkaloid derived from the dried roots of Sophora flavescens Aiton, has been utilized for the treatment of liver diseases, but its potential hepatotoxicity raises concerns. However, the precise condition and mechanism of action of matrine on the liver remain inconclusive. Therefore, the objective of this systematic review and meta-analysis is to comprehensively evaluate both the hepatoprotective and hepatotoxic effects of matrine and provide therapeutic guidance based on the findings. Methods: The meta-analysis systematically searched relevant preclinical literature up to May 2023 from eight databases, including PubMed, Web of Science, Cochrane Library, Embase, China National Knowledge Infrastructure, WanFang Med Online, China Science and Technology Journal Database, and China Biomedical Literature Service System. The CAMARADES system assessed the quality and bias of the evidence. Statistical analysis was conducted using STATA, which included the use of 3D maps and radar charts to display the effects of matrine dosage and frequency on hepatoprotection and hepatotoxicity. Results: After a thorough screening, 24 studies involving 657 rodents were selected for inclusion. The results demonstrate that matrine has bidirectional effects on ALT and AST levels, and it also regulates SOD, MDA, serum TG, serum TC, IL-6, TNF-α, and CAT levels. Based on our comprehensive three-dimensional analysis, the optimal bidirectional effective dosage of matrine ranges from 10 to 69.1 mg/kg. However, at a dose of 20-30 mg/kg/d for 0.02-0.86 weeks, it demonstrated high liver protection and low toxicity. The molecular docking analysis revealed the interaction between MT and SERCA as well as SREBP-SCAP complexes. Matrine could alter Ca2+ homeostasis in liver injury via multiple pathways, including the SREBP1c/SCAP, Notch/RBP-J/HES1, IκK/NF-κB, and Cul3/Rbx1/Keap1/Nrf2. Conclusion: Matrine has bidirectional effects on the liver at doses ranging from 10 to 69.1 mg/kg by influencing Ca2+ homeostasis in the cytoplasm, endoplasmic reticulum, Golgi apparatus, and mitochondria. [ABSTRACT FROM AUTHOR]

Background: Under the circumstance of the increasing waiting list for liver transplantation, living donor liver transplantation (LDLT) can alleviate the shortage of liver donors to some extent. However, how to reduce both donor and graft ischemia-reperfusion injury (IRI) is still an unsolved problem in LDLT. Hypoxia-induced transcription factor 1 (HIF1) activation is considered an important mechanism of cellular adaptation to hypoxia, and early activation of HIF1 may be a new way to alleviate liver IRI. Therefore, we aimed to investigate the impact of the HIF1 stabilizer dimethyloxalylglycine (DMOG) on IRI and the survival rate of donors and recipients of rat LDLT. Methods: Seventy percent partial liver resection and 30% partial liver transplantation were used to simulate donor and recipient of clinical LDLT. Rats were treated with DMOG (40 mg/kg) or with an equivalent amount of saline. The expression of HIF1 and downstream targets was analyzed after 2 h of reperfusion. Liver function and histopathology, apoptosis and oxidative stress levels were detected 6 h after reperfusion. At the same time, the 7-day survival rate of rats was calculated. Results:DMOGpretreatment significantly reduced IR-induced injury in the donor and recipient, which was manifested by reducing liver function damage and promoting tissue recovery. Meanwhile, compared with the untreated group, the oxidative stress level and the cell apoptosis rate were decreased in the group pretreated with DMOG. In addition, the transcription and expression of HIF1 target genes in the DMOG group were significantly enhanced. Remarkably, DMOG also increased the survival rate of the recipient. Conclusion: This study provides the first evidence that DMOG pretreatment of donors significantly alleviates liver IRI in both donors and recipients and increases the survival rate of recipients in LDLT. Therefore, DMOG may be a promising strategy for improving LDLT in the future. [ABSTRACT FROM AUTHOR]

In this current study, we explored the preventive capacity of the aqueous extract of Orobanche foetida (OF), a root holoparasite, against CCl4 prompt hepatotoxicity in rats. LC-MS/MS profiling revealed the existence of 32 compounds belonging to organic acids, benzoic acid derivatives, and hydroxycinnamic acids along with their glycosides and derivatives as well as several flavonoids. In vitro, OF demonstrated substantial antioxidant potential at DPPH and ABTS assays. Results showed that the pretreatment with OF for 6 weeks at the doses (25 mg/kg bw) and (50 mg/kg bw) countered the CCl4-induced liver injury by restoring liver injuries indicators (ALT, AST, LDH, ALP, GGT and bilirubin), normalizing lipid profile (TC, TG, LDL-C, and HDL-C), as well as, impeding DNA fragmentation. Furthermore, OF blocked the hepatic oxidative stress spurred by CCl4 administration through boosting antioxidant enzymes (GSH, CAT, and SOD) responsible of diminishing lipid peroxidation. exhibited an anti-inflammatory effect by downregulating TNF-α and IL-6 levels. OF suppressive effect on proinflammatory cytokines is further exerted by its capacity to modulate the expression of the NF-κB gene. In silico investigation revealed that among the 32 identified compounds, vanillic acid glucoside and dihydroxybenzoic acid glucoside have strong and stable bindings with the active sites of three key inflammatory proteins (PARP-1, TNF-α, IL-6), which could highlight the antioxidant and anti-inflammatory capacity of. Overall, this research provides a preliminary pharmacological support for the medicinal applications of Orobanche foetida for addressing inflammatory and hepato-pathological conditions. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) is one of the serious adverse drug reactions (ADRs), which belongs to immune-mediated adverse drug reactions (IM-ADRs). As an essential health drug, albendazole has rarely been reported to cause serious liver damage. A young man in his 30 s developed severe jaundice, abnormal transaminases, and poor blood coagulation mechanism after taking albendazole, and eventually developed into severe liver failure. The patient was found heterozygous of HLA-B*15:02 and HLA-B*13:01 through HLA-targeted sequencing, which may have a pathogenic role in the disease. This case report summarizes his presentation, treatment, and prognosis. A useful summary of the diagnosis and associated genetic variant information is provided. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to assess the alleviative effect of quercetagetin (QG) on zearalenone (ZEN)-induced liver injury in rabbits. Methods: Ninety 41-day-old healthy Hyla rabbits were randomly assigned into three groups, including a control (fed with basic diet), ZEN addition group (fed with basic diet + 600 µg/kg ZEN), and ZEN + QG addition group (fed with basic diet + 600 µg/kg ZEN + 100 mg/kg QG), with 30 rabbits per group. The duration of the experiment was 28 days. Results: The results revealed no significant differences in the average daily gain, average daily feed intake, the gain to feed ratio and the liver, kidney and spleen organ indexes (p > 0.05) between the rabbits across the three groups. However, the sacculus rotundus index of the rabbits in the control group was significantly higher than that in the ZEN + QG group (p < 0.05). The intake of ZEN-contaminated diet also significantly increased the activities or levels of alanine transaminase, alkaline phosphatase, total bile acid (TBA), total bilirubin, malondialdehyde, and interleukin-4 (IL-4) and enhanced the abundance of kelch-like ECH-associated protein 1 (Keap1), heat shock protein 70 (HSP70) and cysteine-aspartic acid protease-3 (Caspase-3) mRNA in the blood or liver tissue in ZEN group, compared to the control group (p < 0.05). On the contrary, the activities or levels of immunoglobulin A, complement 3, total antioxidant capacity, glutathione peroxidase (GSH-Px), superoxide dismutase, interleukin-10, and the abundance of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) mRNA were significantly decreased (p < 0.05). Supplementing the diet with QG still maintained significantly higher levels of TBA and IL-4, and the abundance of GSH-Px, HSP70, IL-4, and Caspase-3 mRNA in the blood and liver of rabbits in the ZEN + QG group than in the control group (p < 0.05). At the same time, the other indicators were restored to levels in the control group (p > 0.05). Discussion: In conclusion, QG alleviated the ZEN-induced oxidative damage and liver injury caused by inflammatory reaction through the Keap1-Nrf2-antioxidant response element (ARE) signal pathway, which protected the liver. This study revealed the alleviative effect of QG on the hepatotoxicity of ZEN in rabbits for the first time, providing a new perspective for applying QG and developing a ZEN antidote. [ABSTRACT FROM AUTHOR]

Objective: Yinchen Sini decoction (YCSND), a traditional Chinese medicine (TCM) formula, plays a crucial role in the treatment of liver disease. However, the bioactive constituents and pharmacological mechanisms of action remain unclear. The present study aimed to reveal the molecular mechanism of YCSND in the treatment of acute liver injury (ALI) using integrated network analysis and metabolomics. Methods: Ultra-high-performance liquid chromatography coupled with Q-Exactive focus mass spectrum (UHPLC-QE-MS) was utilized to identify metabolites in YCSND, and high-performance liquid chromatography (HPLC) was applied to evaluate the quality of four botanical drugs in YCSND. Cell damage and ALI models in mice were established using CCl4. 1 H-NMR metabolomics approach, along with histopathological observation using hematoxylin and eosin (H&E), biochemical measurements, and reverse transcription quantitative real-time PCR (RT-qPCR), was applied to evaluate the effect of YCSND on CCl4- induced ALI. Network analysis was conducted to predict the potential targets of YCSND in ALI. Result: Our results showed that 89 metabolites in YCSND were identified using UHPLC-QE-MS. YCSND protected against ALI by reducing the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and malondialdehyde (MDA) contents and increasing those of superoxide dismutase (SOD), and glutathione (GSH) both in vivo and in vitro. The 1 H-NMRmetabolic pattern revealed that YCSND reversed CCl4-induced metabolic abnormalities in the liver. Additionally, the Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analysis identified five pathways related to liver injury, including the PI3K-AKT, MAPK, HIF-1, apoptosis, and TNF signaling pathways. Moreover, RT-qPCR showed YCSND regulated the inflammatory response (Tlr4, Il6, Tnfα, Nfκb1, Ptgs2, and Mmp9) and apoptosis (Bcl2, Caspase3, Bax, and Mapk3), and inhibited PI3K-AKT signaling pathway (Pi3k and Akt1). Combined network analysis and metabolomics showed a link between the key targets (Tlr4, Ptgs2, and Mmp9) and vital metabolites (choline, xanthine, lactate, and 3-hydroxybutyric acid) of YCSND in ALI.Conclusion: Overall, the results contribute to the understanding of the therapeutic effects of YCSND on ALI, and indicate that the integrated network analysis and metabolomics could be a powerful strategy to reveal the pharmacological effects of TCM. [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP) overdose is a significant cause of drug-induced liver injury and acute liver failure. The diagnosis, screening, and management of APAP induced liver injury (AILI) is challenging because of the complex mechanisms involved. Starting from the current studies on the mechanisms of AILI, this review focuses on novel findings in the field of diagnosis, screening, and management of AILI. It highlights the current issues that need to be addressed. This review is supposed to summarize the recent research progress and make recommendations for future research. [ABSTRACT FROM AUTHOR]

The study aimed to investigate the protective effects and biological mechanisms of glycyrrhizin arginine salt (Gly-Arg) against cisplatin (Cis)-induced liver injury. Our data showed that Gly-Arg improved Cis-induced liver injury. Further study showed that BECN1 (beclin1) and LC3-II/LC3-I protein expression was significantly increased in primary hepatocytes and mouse liver tissues after Cis treatment, but Gly-Arg reduced the protein levels of BECN1 and LC3-II/LC3-I in primary hepatocytes and mouse liver tissues. Also, Gly-Arg improved indicators related to Cis-induced ferroptosis. Furthermore, Cis increased colocalization of lysosomal membrane-associated protein 1A (LAMP1) with ferritin heavy chain 1 (FTH1) in primary mouse hepatocytes, while Gly-Arg intervention attenuated this colocalization in primary hepatocytes. More improtantly, Cis enhanced the formation of the BECN1-xCT complex, thus inhibiting solute carrier family 7 member 11 (SLC7A11, xCT) and glutathione peroxidase-4 (GPX4) activity. In contrast, Gly-Arg intervention disrupted the formation of this complex. However, Gly-Arg alleviated Cis-induced liver injury in mice by preventing autophagic death and ferroptosis through the inhibition of BECN1-xCT complex formation. [ABSTRACT FROM AUTHOR]

Background: Considering the genetic characteristics of people with antituberculosis (TB)-drug-induced liver injury (ATDILI), genetic factors and their consequences for treatment need to be studied. Objective: The correlation between N-acetyltransferase 2 (NAT2) genetic polymorphisms and ATDILI was analysed. Methods: In this study, the liver and coagulation functions of 120 patients with TB were monitored dynamically for at least 3 months. The genetic polymorphisms of patients were detected by pyrosequencing, and the acetylation types of liver damage and the distribution of NAT2 genetic polymorphisms were compared and analysed. Results: The results showed that there were significant differences in the distribution of alleles and acetylation types among different groups (p < 0.05). In patients with grade 4 liver injury (liver failure), any two alleles were included, i.e., *6 and *7. Specifically, patients with fast acetylation genotypes accounted for 42.4% (14/33), those with intermediate acetylated genotypes accounted for 55.2% (32/58), and patients with slow acetylation genotypes accounted for 65.5% (19/29). Conclusion: Patients with slow acetylation genotypes had higher rates of liver failure and liver injury than those with intermediate and fast acetylation genotypes, and patients with slow acetylation genotypes containing any two alleles (*6 and *7) had a higher rate of liver failure than those with other alleles. In summary, the time of liver injury in patients with slow acetylation genotypes was earlier than the total average time, and the time of liver function recovery in patients with fast acetylation genotypes was shorter than the total average time. [ABSTRACT FROM AUTHOR]

Background: There have been individual case reports of aripiprazole in recent years, both domestically and internationally, but no analysis of the characteristics of the occurrence of adverse reactions/events of drug-induced liver injury with aripiprazole using spontaneous reports has been seen. Methods: Using a retrospective study approach, the 452 adverse reaction/event reports of aripiprazole-induced liver injury collected by the China Adverse Drug Reaction Monitoring System from 1 January 2012 to 31 December 2016 were analyzed and evaluated, and exploring it's the clinical characteristics and related risk factors for liver injury occurrence. Results: Among 452 cases of aripiprazole-induced liver injury ADR/ADE reports, there were 121 cases classified as serious, accounting for 26.8% of the total. There were 250 male and 202 female patients, with a male-to-female ratio of 1.24:1. The age of patients ranged from 11 to 77 years old, with an average age of (34.56 ± 12.81) years old, and a high proportion of young adults in the total population. Some patients had used the drug off-label or at a higher than recommended dosage. The onset of liver injury was generally within 15-90 days after continuous use, while some patients are also accompanied by nausea, vomiting, and weight gain. 70% of the combined drug instructions listed that may cause liver injury. Conclusion: In clinical practice, healthcare professionals should pay closely attention to the adverse reactions and risk factors of liver injury caused by aripiprazole. If there are potential risk factors for liver injury, early and regular monitoring of liver function should be carried out to reduce the occurrence of adverse reactions. [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 TFPAR1 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 in mice 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 druginduced liver injury. [ABSTRACT FROM AUTHOR]

Background: Natural killer (NK) cells showed an anti-fibrotic effect; however, their function is thought to be impaired in advanced liver injury. In the current study, we aimed to assess the immune and metabolic impact of testosterone on mice models of liver injury. Methods: Carbon-tetrachloride induced liver fibrosis male mice models was i.p injected for 2 weeks (acute) and 4 weeks (chronic) (n = 36). Testosterone (4 mg/kg mouse body weight) was injected i.p. following the first week of the acute model of CCl4 and following the second week of the chronic model of CCl4. At the end of the experiments, mice were sacrificed, and serum was collected for assessing liver enzymes of ALT and AST, as well as inflammatory markers of IL-6, metabolic makers of C-peptide levels, and lipid and glucose profiles. Livers were harvested and used for histological assessments for inflammation and fibrosis. Fibrosis profiles from liver extracts, αSMA and Collagen III, were assessed by RT-PCR. Moreover, liver tissue-resident NK cells were isolated and evaluated for their activity by assessing INF-γ and IL-6 receptors using ELISA and flow cytometry, respectively. Results: Serum ALT, AST, and IL-6, as well as metabolic assessments of cholesterol, triglyceride, C-peptide, fasting blood sugar, and fibrotic profiles, were linearly correlated with disease progressions. Histological characterization of the liver was worsened in the chronic model of liver injury. Testosterone-treated mice exhibit a significant reduction in collagen depositions with less dense fibrosis tissue associated with reduced liver injury enzymes and metabolic markers in both the acute and chronic CCl4 mice models in favor of the latter one (p < 0.05). Moreover, testosterone treatments displayed a significant decrease in serum IL-6 of 2.4-fold (p = 0.0001) and 2.3-fold (p = 0.0003) in the acute and chronic models, respectively (p = 0.002), and data showed an increase in INF-γ release from NK associated with a reduction in their IL-6 receptor expressions (p < 0.05). Conclusion: Our results indicated effects of testosterone on mediating a decreased expressions of NK IL-6 receptors and consequently inducing their activation; which in part, could explain the amelioration of liver injury. Our data suggest an anti-inflammatory and anti-fibrotic treatment approach of using testosterone for delaying disease progressions. [ABSTRACT FROM AUTHOR]

Background: Liver injury is a severe liver lesion caused by various etiologies and is one of the main areas of medical research. Panax ginseng C.A. Meyer has traditionally been used as medicine to treat diseases and regulate body functions. Ginsenosides are the main active components of ginseng, and their effects on liver injury have been extensively reported. Methods: Preclinical studies meeting the inclusion criteria were retrieved from PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), and Wan Fang Data Knowledge Service Platforms. The Stata 17.0 was used to perform the meta-analysis, meta-regression, and subgroup analysis. Results: This meta-analysis included ginsenosides Rb1, Rg1, Rg3, and compound K (CK), in 43 articles. The overall results showed that multiple ginsenosides significantly reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST), affected oxidative stress-related indicators, such as superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase (GSH-Px), and catalase (CAT), and reduced levels of inflammatory factor, such as factor-a (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6). Additionally, there was a large amount of heterogeneity in the meta-analysis results. Our predefined subgroup analysis shows that the animal species, the type of liver injury model, the duration of treatment, and the administration route may be the sources of some of the heterogeneity. Conclusion: In a word, ginsenosides have good efficacy against liver injury, and their potential mechanisms of action target antioxidant, anti-inflammatory and apoptotic-related pathways. However, the overall methodological quality of our current included studies was low, and more high-quality studies are needed to confirm their effects and mechanisms further. [ABSTRACT FROM AUTHOR]

Background: Cholestasis is a common pathological process in a variety of liver diseases that may lead to liver fibrosis, cirrhosis, and even liver failure. Cholestasis relief has been regarded as a principal target in the management of multiple chronic cholestasis liver diseases like primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) at present. However, complicated pathogenesis and limited acknowledgments fettered therapeutic development. Therefore, this study aimed to systematically analyze miRNA-mRNA regulatory networks in cholestatic liver injury in order to provide new treatment strategies. Methods: Gene Expression Omnibus (GEO) database (GSE159676) was used to screen differentially expressed hepatic miRNAs and mRNAs in the PSC vs. control comparison and the PBC vs. control comparison, respectively. MiRWalk 2.0 tool was used to predict miRNA-mRNA pairs. Subsequently, functional analysis and immune cell infiltration analysis were performed to explore the pivotal functions of the target genes. RT-PCR was used to verify the result. Results: In total, a miRNA-mRNA network including 6 miRNAs (miR-122, miR-30e, let-7c, miR-107, miR-503, and miR-192) and 8 hub genes (PTPRC, TYROBP, LCP2, RAC2, SYK, TLR2, CD53, and LAPTM5) was constructed in cholestasis. Functional analysis revealed that these genes were mainly involved in the regulation of the immune system. Further analysis revealed that resting memory CD4 T cells and monocytes could potentially participate in cholestatic liver injury. The expressions of DEMis and eight hub genes were verified in ANIT-induced and BDL-induced cholestatic mouse models. Furthermore, SYK was found to have an impact on the response to UDCA, and its mechanism was possibly associated with complement activation and monocyte reduction. Conclusion: In the present study, a miRNA-mRNA regulatory network was constructed in cholestatic liver injury, which mostly mediated immune-related pathways. Moreover, the targeted gene SYK and monocytes were found to be related to UDCA response in PBC. [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP) is a widely used analgesic and antipyretic over-the-counter medicine worldwide. Hepatotoxicity caused by APAP overdose is one of the leading causes of acute liver failure (ALF) in the US and in some parts of Europe, limiting its clinical application. Excessive APAP metabolism depletes glutathione and increases N-acetyl-p-benzoquinoneimide (NAPQI) levels, leading to oxidative stress, DNA damage, and cell necrosis in the liver, which in turn leads to liver damage. Studies have shown that natural products such as polyphenols, terpenes, anthraquinones, and sulforaphane can activate the hepatocyte antioxidant defense system with Nrf2 as the core player, reduce oxidative stress damage, and protect the liver. As the key enzyme metabolizing APAP into NAPQI, cytochrome P450 enzymes are also considered to be intriguing target for the treatment of APAP-induced liver injury. Here, we systematically review the hepatoprotective activity and molecular mechanisms of the natural products that are found to counteract the hepatotoxicity caused by APAP, providing reference information for future preclinical and clinical trials of such natural products. [ABSTRACT FROM AUTHOR]

Rare data reported tacrolimus-induced liver injury (tac-DILI) in real world. We performed a nested case-control analysis of 1,010 renal transplant recipients. Recipients with tac-DILI were randomly matched at a ratio of 1:4 by the year of admission to the remaining recipients without tac-DILI to explore risk factors. The incidence of tac-DILI was 8.9% (95% CI = 7.2–10.7%). The most common type was cholestatic pattern (6.7%, 95% CI = 5.2–8.3%), followed by hepatocellular (1.6%, 95% CI = 0.8–2.4%) and mixed patterns (0.6%, 95% CI = 0.1–1.1%). 98.9% of recipients with tac-DILI have mild severity. The latency period were 42.0 (range, 21.5–99.8 days), 14.0 (range, 9.0–80.3 days), 16.0 (range, 11.5–24.5 days), and 49.0 days (range, 28.0–105.6 days) for total, hepatocellular, mixed, and cholestatic patterns, respectively. Baseline ALP level (OR = 1.015, 95% CI = 1.006–1.025, p = 0.002), age (OR = 0.971, 95% CI = 0.949–0.994, p = 0.006), and body weight (OR = 0.960, 95% CI = 0.940–0.982, p < 0.001) were independent risk factors. In conclusion, cholestatic pattern represents the most frequent type of tac-DILI. Young age, low body weight and abnormal baseline ALP level were risk factors. [ABSTRACT FROM AUTHOR]

As a traditional Chinese medicine, rhubarb has been used in a variety of liver diseases and it is widely used in clinic to prevent and treat acute liver injury. Anthraquinone, as the main medicinal component of rhubarb, can reverse the further development of liver fibrosis caused by acute liver injury. In this study, metabonomics was used to explore the mechanism of different doses of rhubarb anthraquinone on acute liver injury in rats. Rhubarb anthraquinone was administered intragastric to rats at doses of 3.9, 7.8 and 15.6 mg/kg, respectively, for 7 days, and then 30% CCl4 was injected intraperitoneally at the dose of 1 ml/kg to replicate the acute liver injury model. The biochemical indicators content of ALT, AST, ALP, γ-GT, TG, TC, LDL, HDL in serumand GSH, Hyp, SOD, TNF-α, IL-6 and IL-8 in liver tissue extract were tested respectively, and liver tissue was histopathologically analysis. At the same time, UPLC-Q-TOF-MS combined with non-targeted metabolomics were used to study the metabolites and metabolic pathways of rhubarb anthraquinone in treating acute liver injury. Compared with normal rats, the contents of ALT, AST, ALP, TG, TC, LDL, γ-GT in serumandHyp, MDA, IL-6, IL-8, TNF-α in the liver tissue extract were significantly increased inmodel rats (p < 0.05, p < 0.01), and the content of HDL in the serum was significantly decreased (p < 0.05); the activities of GSH and SOD in liver tissue extract were also significantly decreased (p < 0.05). After administration of rhubarb anthraquinone, compared with the model group, with the increase of dosage, some biochemical indexes showed opposite changes, and gradually approached to normal rats. 12 different metabolites were identified by metabonomics, and the biosynthesis and metabolism of phenylalanine, tyrosine and tryptophan, the metabolism of amino sugars, nucleotide sugars and pyrimidines metabolism, and the biosynthesis of steroid hormone were identified based on the biomarker analysis. Based on the biochemical analysis and metabonomics analysis of rats with acute liver injury treated with different doses of rhubarb anthraquinone, combined with histopathological observation, the results show that the protective effect of rhubarb anthraquinone on acute liver injury is related to the dosage; Meanwhile, the metabolic pathway analysis suggested that rhubarb anthraquinone alleviate acute liver injury by regulating inflammation, oxidative stress and fibrosis disorders. This study explained the therapeutic effect of rhubarb anthraquinone on acute liver injury from both material basis and action pathway, and provided safe and effective research ideas for clinical application of rhubarb. [ABSTRACT FROM AUTHOR]

Acetaminophen (N-acetyl-p-aminophenol, APAP) is a common antipyretic agent and analgesic. An overdose of APAP can result in acute liver injury (ALI). Oxidative stress and inflammation are central to liver injury. N-acetylcysteine (NAC), a precursor of glutathione, is used commonly in clinical settings. However, the window of NAC treatment is limited, and more efficacious alternatives must be found. Endogenous cytokines such as fibroblast growth factor (FGF) 21 can improve mitochondrial function while decreasing intracellular oxidative stress and inflammatory responses, thereby exhibiting antioxidant-like effects. In this study, self-assembled nanoparticles comprising chitosan and heparin (CH) were developed to deliver FGF21 (CH-FGF21) to achieve the sustained release of FGF21 and optimize the in vivo distribution of FGF21. CH-FGF21 attenuated the oxidative damage and intracellular inflammation caused by APAP to hepatocytes effectively. In a murine model of APAP-induced hepatotoxicity, CH-FGF21 could alleviate ALI progression and promote the recovery of liver function. These findings demonstrated that a simple assembly of CH nanoparticles carrying FGF21 could be applied for the treatment of liver diseases. [ABSTRACT FROM AUTHOR]

Objectives: Changes in serum levels of cytokines have been proposed as possible biological markers of tissue damage, including drug-induced liver injury (DILI). Here, we aimed to screen cytokine markers that have guiding significance for the degree of inflammation of DILI. Patients and methods: 54 patients with DILI were retrospectively analyzed as the experimental group, and 14 healthy subjects were randomly selected as the control group. A total of 20 cytokines were detected by using a cytokine protein antibody chip, and differentially expressed proteins were screened. Results: There were significant differences in serum cytokines between DILI patients and healthy controls. Compared with the control group, the DILI group expressed 11 differential proteins. IL-8, TNF RII, TNFα, TNF RI, MIP-1β, MIP-1α, and IL-1β were differentially expressed in DILI patients with different degrees of inflammation from G1 to G4. MIG, IL-12p40, and IL-10 were differentially expressed in the higher degree of inflammation groups (G2, G3, and G4 groups). Tissue inhibitor of metalloproteinases-1 (TIMP-1) was differentially expressed in the group with the highest inflammation degree (G4 group). Chemokine C-C motif ligand 1 (I-309) was only differentially expressed in the lowest inflammation group (G1 group). Conclusion: The changes and differential expression of specific cytokine levels were helpful for evaluating different degrees of inflammation of DILI. [ABSTRACT FROM AUTHOR]

Valproic acid (VPA) is widely used as a major drug in the treatment of epilepsy. Despite the undisputed pharmacological importance and effectiveness of VPA, its potential hepatotoxicity is still a major concern. Being a simple fatty acid, the hepatotoxicity induced by VPA has long been considered to be due primarily to its interference with fatty acid β-oxidation (β-FAO). The aim of this study was to investigate the biomarkers for VPA-induced abnormal liver function in epileptic children and to determine potential mechanisms of its liver injury. Targeted metabolomics analysis of acylcarnitines (ACs) was performed in children's serum. Metabolomic analysis revealed that VPA-induced abnormal liver function resulted in the accumulation of serum long-chain acylcarnitines (LCACs), and the reduced expression of β-FAO relevant genes (Carnitine palmitoyltrans-ferase (CPT)1, CPT2 and Long-chain acyl-CoA dehydrogenase (LCAD)), indicating the disruption of β-FAO. As direct peroxisome proliferator-activated receptor a (PPARα)- regulated genes, CPT1A, CPT2 and LCAD were up-regulated after treatment with PPARα agonist, fenofibrate (Feno), indicating the improvement of β-FAO. Feno significantly ameliorated the accumulation of various lipids in the plasma of VPA-induced hepatotoxic mice by activating PPARα, significantly reduced the plasma ACs concentration, and attenuated VPA-induced hepatic steatosis. Enhanced oxidative stress and induced by VPA exposure were significantly recovered using Feno treatment. In conclusion, this study indicates VPA-induced β-FAO disruption might lead to liver injury, and a significant Feno protective effect against VPA -induced hepatotoxicity through reversing fatty acid metabolism. [ABSTRACT FROM AUTHOR]

Background: Anti-tuberculosis drug-induced liver injury (ATB-DILI) is an adverse reaction with a high incidence and the greatest impact on tuberculosis treatment. However, there is a lack of effective biomarkers for the early prediction of ATB-DILI. Herein, this study uses UPLC-MS/MS to reveal the plasma metabolic profile and lipid profile of ATB-DILI patients before drug administration and screen new biomarkers for predicting ATB-DILI. Methods: A total of 60 TB patients were enrolled, and plasma was collected before antituberculosis drug administration. The untargeted metabolomics and lipidomics analyses were performed using UPLC-MS/MS, and the highresolution mass spectrometer Q Exactive was used for data acquisition in both positive and negative ion modes. The random forest package of R software was used for data screening and model building. Results: A total of 60 TB patients, including 30 ATB-DILI patients and 30 non-ATB-DILI subjects, were enrolled. There were no significant differences between the ATB-DILI and control groups in age, sex, smoking, drinking or body mass index (p > 0.05). Twenty-two differential metabolites were selected. According to KEGG pathway analysis, 9 significantly enriched metabolic pathways were found, and both drug metabolism-other enzymes and niacin and nicotinamide metabolic pathways were found in both positive and negative ion models. A total of 7 differential lipid molecules were identified between the two groups. Ferroptosis and biosynthesis of unsaturated fatty acids were involved in the occurrence of ATB-DILI. Random forest analysis showed that the model built with the top 30 important variables had an area under the ROC curve of 0.79 (0.65-0.93) for the training set and 0.79 (0.55-1.00) for the validation set. Conclusion: This study demonstrated that potential markers for the early prediction of ATB-DILI can be found through plasma metabolomics and lipidomics. The random forest model showed good clinical predictive value for ATB-DILI. [ABSTRACT FROM AUTHOR]

Patrinia villosa (Thunb.) Juss (P.V) is widely used in the treatment of chronic diseases, such as appendicitis, enteritis and gynecological inflammation. Modern research indicated that the herb has pharmacological effect on liver injury caused by inflammation, but the metabolomics mechanism is not clear. For the purpose of discovering the therapeutic effect and metabolomic mechanism of P.V on liver injury, 40 Sprague-Dawley (SD) rats were divided into normal group, model group, and P.V groups (0.98,1.97, and 2.96 g/kg). The model group and P.V groups were injected intraperitoneally with 40% CCl4 (v/v, olive oil) to establish liver injury model. After administration of P.V for seven consecutive days. Therapeutic effect of P.V on liver injury rats were analyzed. P.V could decrease serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels of liver injury rats as a dose-dependent manner. Compared with the model group, the pathological analysis of liver tissue of P.V groups exhibit significant decrease tendency of hepatic tissue structure destruction, cytoplasmic vacuolation, cellular swelling, and inflammatory cell infiltration as a dose-dependent manner. 82 endogenous metabolites in rat serum and liver were analyzed by Ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). 14 metabolites in serum and 26 metabolites in liver were significantly different between the P.V group (2.96 g/kg) and the model group. Metabolic pathway analysis revealed that the main pathway including alanine, aspartate and glutamate metabolism, and TCA cycle were significantly altered. It is suggested that P.V can alleviate CCl4 induced liver injury, and its effect on metabolites may be an important mechanism of action. [ABSTRACT FROM AUTHOR]

Rifampicin is a first-line antituberculosis drug. Hepatocyte toxicity caused by rifampicin is a significant clinical problem. However, the specific mechanism by which rifampicin causes liver injury is still poorly understood. Endoplasmic reticulum (ER) stress can have both protective and proapoptotic effects on an organism, depending on the environmental state of the organism. While causing cholestasis and oxidative stress in the liver, rifampicin also activates ER stress in different ways, including bile acid accumulation and cytochrome p450 (CYP) enzyme-induced toxic drug metabolites via pregnane X receptor (PXR). The short-term stress response helps the organism resist toxicity, but when persisting, the response aggravates liver damage. Therefore, ER stress may be closely related to the "adaptive" mechanism and the apoptotic toxicity of rifampicin. This article reviews the functional characteristics of ER stress and its potentially pathogenic role in liver injury caused by rifampicin. [ABSTRACT FROM AUTHOR]

We aimed to investigate the preventive effect of high mobility group box 1 (HMGB1)-A box and the mechanism by which it alleviates inflammatory injury in acute liver failure (ALF) by inhibiting the extracellular release of HMGB1. BALB/c mice were intraperitoneally (i.p.) administered LPS/D-GalN to establish an ALF mouse model. HMGB1-A box was administered (i.p.) 1 h before establishing the ALF mouse model. The levels of extracellularly released HMGB1, TLR-4/NF-κB signaling molecules, the proinflammatory cytokines TNF-α, IL-1β, and IL-6 and COX-2 were measured in the liver tissue and/or serum by Immunohistochemistry, Western blotting and Enzyme-linked immunosorbent assay (ELISA). The levels of extracellularly released HMGB1, TLR-4/NF-κB signaling molecules and proinflammatory cytokines were measured in Huh7 cells as well as LPS- and/or HMGB1-A box treatment by confocal microscopy, Western blotting and ELISA. In the ALF mouse model, the levels of HMGB1 were significantly increased both in the liver and serum, TLR-4/ NF-κB signaling molecules and proinflammatory cytokines also was upregulated. Notably, HMGB1-A box could reverse these changes. HMGB1-A box could also cause these changes in LPS-induced Huh7 cells. HMGB1-A box played a protective role by inhibiting inflammatory liver injury via the regulation of HMGB1/TLR-4/NF-κB signaling in the LPS/D-GaIN-induced ALF mouse model, which may be related to inhibiting the extracellular release of HMGB1. [ABSTRACT FROM AUTHOR]

Traditional medicines have greatly contributed to people's health worldwide. However, in recent years, the frequent occurrence of herb-induced liver injury (HILI) has raised public concerns regarding the safety of herbs. HILI not only severely impacts public health, thus increasing its medical burden, but also consumes medical resources. However, the pharmacoepidemiology and risk factors of HILI are still unclear due to the complexity of herbs (medication theory, drug composition, dual properties of drugs and food, etc.). China is the country with the most extensive use of herbs and cases of HILI worldwide. The safety profile of herbs (especially with respect to HILI) has also affected the use of herbs internationally. Therefore, this review focuses on the epidemic situation of HILI in mainland China to compile its characteristics, while focusing on the three main aspects of patients, drugs, and unreasonable prescriptions to explore the potential risk factors. Our objective was to provide a reference for HILI pharmacovigilance and risk prevention and control and contribute to Chinese knowledge of the realisation of the "Medication without Harm" global safe medication strategic goal of the World Health Organization. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) is a serious clinical disease associated with reactive oxygen species (ROS) burst and subsequent inflammatory responses. However, traditional treatments were limited by low efficacy and serious side effects due to the special liver structure. Here, we developed a molybdenum (Mo)-based nanoparticles, EGM NPs, after overall consideration of the pathophysiology of DILI and the advantages of nanodrugs. It demonstrated that EGM NPs treated acetaminophen (APAP)-induced DILI by scavenging ROS and inhibiting inflammation. EGM NPs effectively scavenged various ROS and reduced cell apoptosis at the cellular level. More importantly, EGM NPs can treat APAP-induced DILI in vivo, reducing the levels of liver function indicators in mice with liver injury, scaling down the area of hepatocyte necrosis and successfully inhibiting endoplasmic reticulum (ER) stress in the liver. EGM NPs also showed a certain anti-inflammatory effect by reducing infiltration of macrophages, decreasing pro-inflammatory factors and inhibiting the expression levels of inducible nitric oxide synthase (NOS2) and myeloperoxidase (MPO). Collectively, our findings suggest that EGM NPs- based nanotherapeutic is a novel strategy for the treatment of DILI. [ABSTRACT FROM AUTHOR]

Polygoni Multiflori Radix (PMR) is a commonly used traditional Chinese medicine in clinical practice, while adverse effects of hepatotoxicity related to PMR have been frequently reported. The clinical case reports indicated that PMR hepatotoxicity could occur under both overdose medication/long-term exposure and low doses with short-duration (idiosyncratic) conditions. The combination treatment with emodin and 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucopyranoside (TSG), two major PMR components, was reported to contribute to PMR hepatotoxicity after long-term treatment. However, the role of the combination treatment of these two components in PMR-induced idiosyncratic liver injury has not been clearly clarified. In this study, the LPS-mediated inflammatory stress model rats were adopted to explore the idiosyncratic liver injury induced by the bolus combination treatment with emodin and TSG. After a bolus oral administration with TSG (165 mg/kg), emodin (5 mg/kg) or their combination in both normal and LPS-mediated inflammatory stress model rats, the systemic/hepatic concentrations of emodin, emodin glucuronides and bile acids were determined; the hepatotoxicity assessments were conducted via monitoring histopathological changes and liver injury biomarkers (ALT and AST). Moreover, the protein expressions of bile acid homeostasis- and apoptosis-related proteins were examined. No liver damage was observed in the normal rats after a bolus dose with the individual or combination treatment, while the bolus combination treatment with emodin and TSG induced liver injury in the LPS-mediated inflammatory stress model rats, evidenced by the elevated plasma levels of alanine aminotransferase (~66%) and aspartate aminotransferase (~72%) accompanied by severe inflammatory cell infiltration and apoptotic hepatocytes in liver tissue. Moreover, such combination treatment at a bolus dose in the LPS-mediated inflammatory stress model rats could significantly elevate the hepatic TBA levels by about 45% via up-regulating the hepatic protein expression levels of bile acid synthesis enzymes and inhibiting that of bile acid efflux transporters and the expression levels of apoptosis-related proteins. Our study for the first time proved the major contribution of the combination treatment with emodin and TSG in PMR-induced idiosyncratic liver injury. [ABSTRACT FROM AUTHOR]

Moxifloxacin is the most widely prescribed antibiotics due to its excellent oral bioavailability and broad-spectrum antibacterial effect. Despite of its popularity, the rare and severe liver injury induced by moxifloxacin is a big concern that cannot be ignored in clinical practice. However, the early warning and related metabolic disturbances of moxifloxacin induced hepatoxicity were rarely reported. In this study, the dose- and time-dependent manners of moxifloxacin induced liver injury were investigated by a targeted metabolomics method. In dose-dependent experiment, three different dosages of moxifloxacin were administered to the rats, including 36 mg kg-1 d-1, 72mgkg-1 d-1, and 108 mg kg-1 d-1. In time-dependent experiment, moxifloxacin was orally administered to the rats for 3, 7 or 14 consecutive days. Pathological analysis showed that moxifloxacin caused obvious transient hepatotoxicity, with the most serious liver injury occurred in the 7 days continuous administration group. The transient liver injury can be automatically restored over time. Serum levels of liver function related biochemical indicators, including ALT, AST, TBIL, alkaline phosphatase, superoxide dismutase, and malondialdehyde, were also measured for the evaluation of liver injury. However, these indicators can hardly be used for the early warning of hepatotoxicity caused by moxifloxacin due to their limited sensitivity and significant hysteresis. Targeted metabolomics study demonstrated that serum concentrations of fatty acyl carnitines, fatty acids and dehydroepiandrosterone can change dynamically with the severity of moxifloxacin related liver injury. The elevated serum levels of fatty acyl carnitine, fatty acid and dehydroepiandrosterone were promising in predicting the hepatotoxicity induced by moxifloxacin. [ABSTRACT FROM AUTHOR]

Acute liver failure (ALF) is an unfavorable condition characterized by the rapid loss of liver function and high mortality. Chrysophanol-8-O-glucoside (CPOG) is an anthraquinone derivative isolated from rhubarb. This study aims to evaluate the protective effect of CPOG on lipopolysaccharide (LPS)/D-GalN-induced ALF and its underlying mechanisms. LPS/D-GalN-induced mice ALF model and LPS treatment model in RAW 264.7 and LX2 cells were established. It was found that CPOG ameliorated LPS/D-GalN-induced liver injury and improved mortality as indicated by Hematoxylin-eosin (H&E) staining. Molecularly, qPCR and ELISA results showed that CPOG alleviated LPS/D-GalN-induced release of alanine aminotransferase and aspartate transaminase and the secretion of TNF-a and IL-1ß in vivo. LPS/D-GalN-induced intracellular ROS production was also attenuated by CPOG in liver tissue. Further, CPOG attenuated ROS generation and inhibited the expression of p-IB and p-p65 as well as the expression of TNF-a and IL-1ß stimulated by LPS in RAW 264.7 cells. In addition, CPOG alleviated LPS-induced up-regulation of LC3B, p62, ATG5 and Beclin1 by attenuating ROS production and inhibiting MAPK signaling in LX2 cells. Taken together, our data indicated that the CPOG protected against LPS/D-GalN-induced ALF by inhibiting oxidative stress, inflammation response and autophagy. These findings suggest that CPOG could be potential drug for the treatment of ALF in clinic. [ABSTRACT FROM AUTHOR]

Objective: To investigate how Hydroxysafflor yellow A (HSYA) effects acute liver injury (ALI) and what transcriptional regulatory mechanisms it may employ. Methods: Rats were randomly divided into five groups (n = 10): Control, Model, HSYA-L, HSYA-M, and HSYA-H. In the control and model groups, rats were intraperitoneally injected with equivalent normal saline, while in the HSYA groups, they were also injected with different amounts of HSYA (10, 20, and 40 mg/kg/day) once daily for eight consecutive days. One hour following the last injection, the control group was injected into the abdominal cavity with 0.1 ml/100 g of peanut oil, and the other four groups got the same amount of a peanut oil solution containing 50% CCl4. Liver indexes were detected in rats after dissection, and hematoxylin and eosin (HE) dyeing was utilized to determine HSYA's impact on the liver of model rats. In addition, with RNASequencing (RNA-Seq) technology and quantitative real-time PCR (qRT-PCR), differentially expressed genes (DEGs) were discovered and validated. Furthermore, we detected the contents of anti-superoxide anion (anti-O2 -) and hydrogen peroxide (H2O2), and verified three inflammatory genes (Icam1, Bcl2a1, and Ptgs2) in the NF-kB pathway by qRT-PCR. Results: Relative to the control and HSYA groups, in the model group, we found 1111 DEGs that were up-/down-regulated, six of these genes were verified by qRT-PCR, including Tymp, Fabp7, Serpina3c, Gpnmb, Il1r1, and Creld2, indicated that these genes were obviously involved in the regulation of HSYA in ALI model. Membrane rafts, membrane microdomains, inflammatory response, regulation of cytokine production, monooxygenase activity, and iron ion binding were significantly enriched in GO analysis. KEGG analysis revealed that DEGs were primarily enriched for PPAR, retinol metabolism, NF-kB signaling pathways, etc. Last but not least, compared with the control group, the anti-O2 - content was substantially decreased, the H2O2 content and inflammatory genes (Icam1, Bcl2a1, and Ptgs2) levels were considerably elevated in the model group. Compared with the model group, the anti-O2 - content was substantially increased, the H2O2 content and inflammatory genes (Icam1, Bcl2a1, and Ptgs2) levels were substantially decreased in the HSYA group (p < 0.05). Conclusion: HSYA could improve liver function, inhibit oxidative stress and inflammation, and improve the degree of liver tissue damage. The RNA-Seq results further verified that HSYA has the typical characteristics of numerous targets and multiple pathway. Protecting the liver from damage by regulating the expression of Tymp, Fabp7, Serpina3c, Gpnmb, Il1r1, Creld2, and the PPAR, retinol metabolism, NF-kappa B signaling pathways. [ABSTRACT FROM AUTHOR]

Fucosylation is a common glycan terminal modification, which has been reported to be inhibited by 2-fluorofucose (2FF) both in vivo and in vitro. The present study aimed to investigate the effect of 2FF on acetaminophen (APAP)-induced acute liver injury, and further clarified the possible mechanisms. In the present study, inhibition of fucosylation by 2FF relieved APAP-induced acute liver injury in vivo. Pretreatment with 2FF remarkably suppressed APAP-induced oxidative stress and mitochondria damage. 2FF markedly enhanced the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and simultaneously promoted the expression of downstream proteins including HO-1 and NQO1. Furthermore, pretreatment with 2FF significantly suppressed the expression of inflammation-associated proteins, such as COX2 and iNOS. The data from lectin blot assay revealed that the alteration of α1,6-fucosylation was involved in APAP-induced acute liver injury. The second part of this study further confirmed that the enhancements to antioxidant capacity of 2FF pretreatment and α1,6-fucose deficiency were related to Nrf2/keap1 and NF-κB signaling pathways in HepG2 cells. Taken together, the current study suggested that 2FF might have a potential therapeutic effect for APAP-induced acute liver injury. [ABSTRACT FROM AUTHOR]

Background: Xiao-Yao-San (XYS) is a traditional Chinese prescription that regulates gastrointestinal function, improves mental and psychological abnormalities, and enhances liver function. However, the underlying mechanism of XYS for relieving anti-tuberculosis (AT) drug-induced liver injury is not clear. Objective: The current study examined whether XYS alleviated the symptoms of AT drug-induced liver injury in mice via the mitochondrial oxidative stress pathway. Methods: BALB/c male mice were randomly divided into four groups of 12 animals, including a control group, a model group, a 0.32 g/kg XYS group, and a 0.64 g/kg XYS group. The effect of XYS on the degree of liver injury was observed using haematoxylin and eosin staining (HE) and oil red O staining of pathological sections, biochemical parameters, and reactive oxygen species (ROS) levels. The protein expression of mitochondrial synthesis-related proteins and ferroptosis-related proteins was examined using Western blotting. Results: XYS improved the pathological changes in liver tissue and reduced the level of oxidative stress in liver-injured mice. XYS increased the expression of mitochondrial synthesis-related proteins and reversed the expression of ferroptosis-related proteins. Knockdown of G-rich RNA sequence binding factor 1 (Grsf1) expression with Grsf1 shRNA blocked the protective effects of XYS in liver injury. Conclusion: Our findings suggest that XYS alleviates AT drug-induced liver injury by mediating Grsf1 in the mitochondrial oxidative stress pathway. [ABSTRACT FROM AUTHOR]

The utility of pharmacist consultation for drug-induced liver injury (DILI) management has not been explored. This retrospective cohort study evaluated the impact of a pharmacist active consultation (PAC) service on the management and outcome in patients with DILI. Consecutive patients meeting clinical biochemical criteria for DILI were enrolled at a tertiary teaching hospital between 1 January 2020 and 30 April 2022. The Roussel Uclaf Causality Assessment Method was used to assess causality between drug use and liver injury for each suspected DILI patient. Included patients were grouped according to whether they received PAC, and a proportional hazard model with multivariate risk adjustment, inverse probability of treatment weighting (IPTW), and propensity score matching (PSM) was used to assess DILI recovery. In the PSM cohort, the quality of medical care was compared between PAC and no PAC groups. A total of 224 patients with DILI (108 who received PAC and 116 who did not) were included in the analysis. Of these patients, 11 (10%) were classified as highly probable, 58 (54%) as probable, and 39 (36%) as possible DILI in the PAC group, while six patients (5%) were classified as highly probable, 53 (46%) as probable, and 57 (49%) as possible DILI in the no PAC group (p = 0.089). During patient recovery, PAC was associated with a ~10% increase in the cumulative 180-day recovery rate. The PAC group had a crude hazard ratio (HR) of 1.73 [95% confidence interval (CI): 1.23-2.43, p = 0.001] for DILI 180-day recovery, which remained stable after multivariate risk adjustment (HR = 1.74, 95% CI: 1.21-2.49, p = 0.003), IPTW (HR = 1.72, 95% CI: 1.19-2.47, p = 0.003), and PSM (HR = 1.49, 95% CI: 1.01-2.23, p = 0.046). In the PSM cohort, PAC was more likely to identify suspect drugs (90% vs. 60%, p < 0.001) and lead to timely withdrawal of the medication (89% vs. 57%, p < 0.001). Thus, PAC is associated with a better quality of medical care for patients with DILI and can improve patient outcomes. [ABSTRACT FROM AUTHOR]

Paeoniflorin (PF) is the main active component in Paeonia lactiflora Pall, and it has multiple effects. However, the precise mechanism of PF in hypercholesterolemia is unclear. In this study, rats were either fed a highcholesterol diet (HCD) for 4 weeks to establish the hypercholesterolemic model or administered normal saline or PF (20 mg/kg/day). PF significantly reduced liver weight and the liver index. PF reduced hepatic lipid deposition and inflammation, improved serum lipid metabolism, and significantly inhibited serum and hepatic oxidative stress and the inflammatory response. PF treatment caused a marked decrease in the phosphorylated myosin phosphatase target subunit (p-MYPT)-1, nuclear sterol regulatory elementbinding protein-1c (SREBP-1c), fatty acid synthase (FAS) levels, and an increase in the low-density lipoprotein receptor (LDLR) and phosphorylated- AMP-activated protein kinase (p-AMPK). Thus, PF could alleviate liver injury in hypercholesterolemic rats, and the specific mechanism may be related to the antioxidant, anti-inflammatory properties, and ROCK/AMPK/SREBP-1c signaling pathway. [ABSTRACT FROM AUTHOR]

Multiple types of liver diseases, particularly cholestatic liver diseases (CSLDs) and biliary diseases, can disturb bile acid (BA) secretion; however, BA accumulation is currently seen as an important incentive of various types of liver diseases’ progression. Da-Chai-Hu decoction (DCHD) has long been used for treating cholestatic liver diseases; however, the exact mechanisms remain unclear. Currently, our study indicates that the liver damage and cholestasis status of the α-naphthylisothiocyanate (ANIT)-induced intrahepatic cholestasis and bile duct ligation (BDL)-induced extrahepatic cholestasis, following DCHD treatment, were improved; the changes of BA metabolism post-DCHD treatment were investigated by targeted metabolomics profiling by UPLCMS/ MS. DCHD treatment severely downregulated serum biochemical levels and relieved inflammation and the corresponding pathological changes including necrosis, inflammatory infiltration, ductular proliferation, and periductal fibrosis in liver tissue. The experimental results suggested that DCHD treatment altered the size, composition, and distribution of the BAs pool, led the BAs pool of the serum and liver to sharply shrink, especially TCA and TMCA, and enhanced BA secretion into the gallbladder and the excretion of BAs by the urinary and fecal pathway; the levels of BAs synthesized by the alternative pathway were increased in the liver, and the conjugation of BAs and the pathway of BA synthesis were actually affected. In conclusion, DCHD ameliorated ANIT- and BDL-induced cholestatic liver injury by reversing the disorder of BAs profile. [ABSTRACT FROM AUTHOR]

Potassium para-aminobenzoate (POTABA) is used to treat Peyronie's disease by decreasing fibrosis and plaque size progression. Among potential side effects, drug-induced liver injury (DILI) attributed to POTABA administration has been reported in a few cases and inferred to immune hypersensitivity. In the present case, we investigated clinical, biochemical, and serological features as well as searched for non-drug-related causes, and applied the updated Roussel Uclaf Causality Assessment Method (RUCAM) confirming a highly probable causality of POTABA-induced liver injury. Moreover, we here observed specific activated CD3+ T lymphocytes during the acute phase of liver injury by monitoring of human leukocyte antigen receptor (HLA-DR) expression. Furthermore, improvement of biochemical markers of liver injury after POTABA withdrawal was associated with a rapid decline of CD3+ HLA-DR+ immune cells. In contrast, CD14+ monocytes expressing HLA-DR remained stable during recovery from liver injury. These observations implicate a specific involvement of activated T lymphocytes in liver injury mediated by POTABA. Clinicians should be aware of POTABA-induced liver injury, and measurement of activated immune cells by assessment of HLA-DR could provide pathomechanistic insights enabling biomonitoring of recovery from DILI. [ABSTRACT FROM AUTHOR]

Chemical liver injury is closely related to gut microbiota and its metabolites. In this study, we combined 16S rRNA gene sequencing, 1 H NMR-based fecal metabolomics and GC-MS to evaluate the changes in gut microbiota, fecal metabolites and Short-chain fatty acids (SCFAs) in CCl4-induced liver injury in Sprague-Dawley rats, and the therapeutic effect of Shaoyao Gancao Decoction (SGD). The results showed that CCl4-induced liver injury overexpressed CYP2E1, enhanced oxidative stress, decreased antioxidant enzymes (SOD, GSH), increased peroxidative products MDA and inflammatory responses (IL6, TNF-α), which were ameliorated by SGD treatment. H&E staining showed that SGD could alleviate liver tissue lesions, which was confirmed by the recovered liver index, ALT and AST. Correlation network analysis indicated that liver injury led to a decrease in microbiota correlation, while SGD helped restore it. In addition, fecal metabolomic confirmed the PICRUSt results that liver injury caused disturbances in amino acid metabolism, which were modulated by SGD. Spearman's analysis showed that liver injury disrupted ammonia transport, urea cycle, intestinal barrier and energy metabolism. Moreover, the levels of SCFAs were also decreased, and the abundance of Lachnoclostridium, Blautia, Lachnospiraceae_NK4A136_group, UCG-005 and Turicibacter associated with SCFAs were altered. However, all this can be alleviated by SGD. More importantly, pseudo germ-free rats demonstrated that the absence of gut microbiota aggravated liver injury and affected the efficacy of SGD. Taken together, we speculate that the gut microbiota has a protective role in the pathogenesis of liver injury, and has a positive significance for the efficacy of SGD. Moreover, SGD can treat liver injury by modulating gut microbiota and its metabolites and SCFAs. This provides useful evidence for the study of the pathogenesis of liver injury and the clinical application of SGD. [ABSTRACT FROM AUTHOR]

Aims: N-Acetylcysteine (NAC) is used as an antidote in acetaminophen (APAP) overdose to prevent and mitigate drug-induced liver injury (DILI). Our objective was to systematically review evidence of the use of NAC as a therapeutic option for APAP overdose and APAPrelated DILI in order to define the optimal treatment schedule and timing to start treatment. Methods: Bibliographic databases (PubMed, Web of Science, Embase, and MEDLINE) were searched for retrospective and prospective cohort studies, case series, and clinical trials. The prespecified primary outcomes were DILI-related mortality, hepatotoxicity, and adverse events (AEs). Results: In total, 34 studies of NAC usage in APAP-related DILI cases with 19,580 patients were identified, of which 2,376 patients developed hepatotoxicities. The mortality rate across different studies ranged from 0 to 52%. Large variability of NAC regimens was found, i.e., intravenous (I.V.) (100-150 mg/kg) and oral (70-140 mg/kg), and length of treatment varied--12, 24, or 48 h for I.V. regimen and 72 h for oral administration. The timing of initiation of NAC treatment showed different results in terms of occurrence of hepatotoxicity and mortality; if started within 8 h and no more than 24 h from APAP overdose, either intravenously or orally, NAC administration was efficacious in terms of mortality. The most frequent AEs reported were anaphylactic reactions, followed by cutaneous AEs for the IV route and intestinal AEs for the oral one. Conclusion: NAC improves hepatotoxicity and reduces mortality. Timing of treatment, ranging from 8 to 24 h from APAP overdose, regardless of the regimen or route of administration, is important to prevent or minimize liver damage, particularly in children and in elderly and obese patients. [ABSTRACT FROM AUTHOR]