Acute Drug-induced Liver Injury Research Articles

Risk factors related to significant hepatic inflammation in patients with acute drug-induced liver injury

BackgroundCurrently, research on biopsy-proven acute drug-induced liver injury (DILI) remains limited. This study aimed to identify clinical characteristics and risk factors for significant hepatic inflammation in patients with acute DILI. MethodsAn ambispective cohort study was conducted on biopsy-proven acute DILI patients admitted to our hospital from 2012 to 2018. Using the Scheuer scoring system, patients were categorized into G0-2 or G3-4 groups and followed up for 12 months after first admission. Clinical characteristics and outcomes were retrieved from medical records. ResultsThe median age of the 157 enrolled patients (65.6% female) was 40.4 (interquartile range (IQR), 31.9–49.1) years. The median latency and length of hospitalization were 30.0 (IQR, 5.0–60.0) and 18.0 (IQR, 12.0–26.0) days. The proportions of patients in the G0-2 and G3-4 groups were 54.8% and 45.2%, respectively. Logistic regression analysis revealed that females (odds ratio (OR): 2.623, 95% confidence interval (CI): 1.169–5.887, p ​= ​0.019), higher body mass index (OR: 1.168, 95% CI: 1.029–1.325, p ​= ​0.016), higher total bilirubin (OR: 1.004, 95% CI: 1.000–1.007, p ​= ​0.047), and lower prothrombin activity (OR: 0.976, 95% CI: 0,957–0.995, p ​= ​0.013) were associated with significant hepatic inflammation. The predominance of the hepatocellular injury pattern (60.5%) at admission transformed into a predominance of the cholestatic pattern (60.5%) at discharge. During follow-up, 23 patients (14.6%) developed chronic DILI, with nine patients (5.7%) progressing to cirrhosis. Moreover, 15 female patients (9.6%) developed autoimmunity (3cases in the G0-2 group vs 12 cases in the G3-4 group, p ​< ​0.05). ConclusionsAcute DILI patients with high-risk factors were more likely to develop significant hepatic inflammation, and females with significant inflammation were at a higher risk of developing autoimmunity during follow-up.

Treatment on Acute Liver Injury with Tian Jing Yi Xue Decoction by Repressing the PI3K/AKT/mTOR Signaling Pathway and Reducing Inflammation

The increasing incidence of drug-induced acute liver injury (ALI) has drawn global attention to this health concern. Tian Jing Yi Xue Decoction (TJYXD), an ancient formula, has shown potential clinical efficacy for ALI. However, no studies have yet confirmed its effectiveness in treating ALI. In this study, we investigate the therapeutic potential of TJYXD in H2O2-induced HepG2 cell injury and CCl4-induced liver injury in Sprague-Dawley rats. High-performance liquid chromatography-mass spectrometry was used to analyze TJYXD components. Network pharmacology was employed to predict its mechanisms and effective components for ALI treatment, followed by experimental verification. In cellular experiments, 2 mg/mL TJYXD significantly reduced the levels of alanine transaminase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). In animal experiments, TJYXD significantly decreased the levels of ALT, ALP, and malondialdehyde and increased the level of superoxide dismutase. Histopathological analysis with Hematoxylin and Eosin staining and Masson staining further confirmed the efficacy of TJYXD compared to silymarin in treating ALI. Moreover, we determined that the therapeutic effects of TJYXD in the treatment of ALI were attributed to its inhibition of the PI3K/AKT/mTOR pathway and reduction in both serum and livers levels of transforming growth factor-β 1, interleukin-6, tumor necrosis factor-α. Furthermore, quercetin, apigenin, and luteolin were speculated to be the main active constituents. In conclusion, TJYXD demonstrates remarkable efficacy both in vitro and in vivo for the treatment of ALI by enhancing immunity and suppressing inflammation. Furthermore, TJYXD holds promise as a first-line or adjunctive therapeutic agent.

Study based on the acetaldehyde dehydrogenase 2 gene polymorphism and acetaminophen-induced liver injury

Objective: To explore the association between aldehyde dehydrogenase 2 (ALDH2) gene polymorphisms and abnormal liver function-induced by acetaminophen (APAP) drugs. Methods: An ALDH2 gene knockout mouse model was constructed using CRISPR/Cas9 gene editing technology. The obtained heterozygous mice were mated with opposite sex of heterozygotes. Genomic DNA was extracted from the tail of the offspring mouse. The polymerase chain reaction (PCR) method was used to determine the ALDH2 genotype. APAP was further used to induce acute drug-induced liver injury models in wild-type and ALDH2 knockout mice. Blood and liver tissues of mice were collected for liver function index, HE staining, F4/80 immunohistochemistry, and other detections. The intergroup mean was compared using a one-way ANOVA. The LSD- t test was used for pairwise comparison. Results: ALDH2 knockout mice were bred successfully. The genotyping of the offspring was segregated into the wild-type (ALDH2(+/+)), heterozygous mutant (ALDH2(+/-)), and homozygous mutant (ALDH2(-/-)), respectively. Biochemical and histological results after APAP modeling showed that the level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBil) was not significantly increased in the blank control group (P < 0.05), while the ALT, AST,ALP, and TBil were all elevated in the APAP experimental group. The levels of ALT (P = 0.004), AST (P = 0.002), and TBil (P = 0.012) were significantly elevated among the mutant group compared to those in the wild-type group, and the expression levels of these indicators were also significantly elevated among the homozygous mutant group compared to those in the heterozygous mutant group (P = 0.003, 0 and 0.006). In addition, the ALP levels were higher in the heterozygous mutation group than those in the homozygous mutant group (P = 0.085) and wild-type group mice, but the difference was only statistically significant compared to wild-type mice (P = 0.002). HE staining results showed that mice in the APAP experimental group had hepatocyte degeneration, necrosis, and increased inflammatory cell infiltration, which was mostly evident in mutant mice. Simultaneously, the F4/80 immunohistochemical staining results showed that brown granules were visible in the liver tissue of APAP experimental group mice, and its expression levels were significantly enhanced compared to the blank control group. Conclusion: APAP-induced liver function abnormalities were associated with the ALDH2 gene polymorphism. The liver injury symptoms were increased in ALDH2 mutant mice following APAP modeling, and the ALDH2 gene defect may alleviate, to some extent, APAP-induced liver function abnormalities.

Efficacy and safety of bicyclol for treating patients with antituberculosis drug-induced liver injury.

BACKGROUND: Bicyclol was used for treating idiosyncratic acute drug-induced liver injury (DILI) in a phase II trial. This study was aimed at evaluating the efficacy and safety of bicyclol 25 and 50 mg thrice a day (TID) for treating acute DILI caused by anti-TB drugs in the light of the trial results.METHODS: We analysed clinical data of patients with TB drug-induced DILI in the trial database. The primary endpoint was reduction in serum alanine aminotransferase (ALT) levels after 4 weeks of treatment compared to baseline.RESULTS: Overall, 148 patients were included, with respectively 48, 52 and 48 patients included in the control (456 mg polyene phosphatidylcholine TID), high-dose (50 mg bicyclol TID) and low-dose (25 mg bicyclol TID) groups. ALT levels decreased by respectively â-"149.0 (IQR â-"299.3 to â-"98.3 (), â-"225.5 (IQR â-"309.3 to â-"181.8 ) and â-"242.5 (IQR â-"364.8 to â-"153.8) U/L in the control, high-dose and low-dose groups (P < 0.001). The ALT normalisation rates at weeks 1, 2, 4, 6 and 8 were higher in the high- and low-dose groups, while adverse events and serious adverse events were similar across groups.CONCLUSIONS: Bicyclol (25 and 50 mg TID) is effective and safe in treating anti-TB DILI, and bicyclol 50 mg TID showed higher efficacy.

Inhibition of cGAS-STING pathway by stress granules after activation of M2 macrophages by human mesenchymal stem cells against drug induced liver injury

ObjectiveCells can produce stress granules (SGs) to protect itself from damage under stress. The cGAS-STING pathway is one of the important pattern recognition pathways in the natural immune system. This study was investigated whether human mesenchymal stem cells (hMSCs) could protect the liver by inducing M2 macrophages to produce SGs during acute drug induced liver injury (DILI) induced by acetaminophen (APAP). MethodsAfter intragastric administration of APAP in vivo to induce DILI mice model, hMSCs were injected into the tail vein. The co-culture system of hMSCs and M2 macrophages was established in vitro. It was further use SGs inhibitor anisomicin to intervene M2 macrophages. The liver histopathology, liver function, reactive oxygen species (ROS) level, apoptosis pathway, endoplasmic reticulum stress (ERS) level, SGs markers (G3BP1/TIA-1), cGAS-STING pathway, TNF-α, IL-6, IL-1β mRNA levels in liver tissue and M2 macrophages were observed. ResultsIn vivo experiments, it showed that hMSCs could alleviate liver injury, inhibite the level of ROS, apoptosis and ERS, protect liver function in DILI mice. The mount of M2 was increased in the liver. hMSCs could also induce the production of SGs, inhibit the cGAS-STING pathway and reduce TNF-α, IL-6, IL-1β mRNA expression. The results in vitro showed that hMSCs could induce the production of SGs in macrophages, inhibit the cGAS-STING pathway, promote the secretion of IL-4 and IL-13, and reduce TNF-α, IL-6, IL-1β mRNA level in cells. In the process of IL-4 inducing M2 macrophage activation, anisomycin could inhibit the production of SGs, activate the cGAS-STING pathway, and promote the inflammatory factor TNF-α, IL-6, IL-1β mRNA expression in cells. ConclusionsHMSCs had a protective effect on acute DILI in mice induced by APAP. Its mechanism might involve in activating M2 type macrophages, promoting the production of SGs, inhibiting the cGAS-STING pathway, and reducing the expression of pro-inflammatory factors in macrophages, to reduce hepatocytes damage.

2′-Hydroxycinnamaldehyde mitigates acetaminophen-induced acute liver injury by inhibiting the Warburg effect-mediated pyroptosis via the PKM2-NLRP3 axis

Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver injury. However, the underlying mechanisms appear to be multifaceted and there are few effective treatments. In this study, we used the 2′-Hydroxycinnamaldehyde (HCA), an active ingredient extracted from cinnamon stem bark to evaluate the therapeutic effect against APAP-induced ALI. The results indicated that pyruvate kinase M2 (PKM2)-mediated aerobic glycolysis may activate NLRP3 inflammasome in APAP-induced ALI, However, this process was prevented by HCA. Additionally, overexpression of PKM2 by adeno-associated virus (AAV9-PKM2) in vivo and plasmid (PKM2-OE) in vitro reversed the inhibition of NLRP3 inflammasome by HCA. Intriguingly, the HCA-triggered repressive pyroptosis was mediated through dephosphorylation and nuclear translocation of PKM2. Furthermore, the therapeutic effect of HCA on APAP-induced ALI was achieved by partially stimulating the Akt-mTOR signaling pathway, thus inhibiting the PKM2-NLRP3 axis. These findings elucidate that a potential drug to the clinical treatment of APAP overdose by HCA.

Near-infrared molecular sensor for visualizing and tracking ONOO- during the process of anti-tuberculosis drug-induced liver damage.

Isoniazid (INH) and pyrazinamide (PZA) are both the first-line anti-tuberculosis drugs in clinical treatment. It is notable that there are serious side effects of the drugs along with upregulation of reactive nitrogen species, mainly including peripheral neuritis, gastrointestinal reactions, and acute drug-induced liver injury (DILI). Among them, DILI is the most common clinical symptom as well as the basic reason of treatment interruption, protocol change, and drug resistance. As vital reactive nitrogen species (RNS), peroxynitrite (ONOO-) has been demonstrated as a biomarker for evaluation and pre-diagnosis of drug-induced liver injury (DILI). In this work, we developed a red-emitting D-π-A type fluorescence probe DIC-NP which was based on 4'-hydroxy-4-biphenylcarbonitrile modified with dicyanoisophorone as a fluorescent reporter and diphenyl phosphinic chloride group as the reaction site for highly selective and sensitive sensing ONOO-. Probe DIC-NP displayed a low detection limit (14.9 nM)and 60-fold fluorescent enhancement at 669 nm in the sensing of ONOO-. Probe DIC-NP was successfully applied to monitor exogenous and endogenous ONOO- in living HeLa cells and zebrafish. Furthermore, we verified the toxicity of isoniazid (INH) and pyrazinamide (PZA) by taking the oxidative stress induced by APAP as a reference, and successfully imaged anti-tuberculosis drug-induced endogenous ONOO- in HepG2 cells. More importantly, we developed a series of mice models of liver injury and investigated the hepatotoxicity caused by the treatment of anti-tuberculosis drugs. At the same time, H&E of mice organs (heart, liver, spleen, lung, kidney) further confirmed thecompetence of probe DIC-NP for estimating the degree of drug-induced liver injury, which laid a solid foundation for medical research.

Hepatocyte DDX3X protects against drug-induced acute liver injury via controlling stress granule formation and oxidative stress

Drug-induced liver injury (DILI) is the leading cause of acute liver failure (ALF). Continuous and prolonged hepatic cellular oxidative stress and liver inflammatory stimuli are key signatures of DILI. DEAD-box helicase 3, X-linked (DDX3X) is a central regulator in pro-survival stress granule (SG) assembly in response to stress signals. However, the role of DDX3X in DILI remains unknown. Herein, we characterized the hepatocyte-specific role of DDX3X in DILI. Human liver tissues of DILI patients and control subjects were used to evaluate DDX3X expression. APAP, CCl4 and TAA models of DILI were established and compared between hepatocyte-specific DDX3X knockout (DDX3XΔhep) and wild-type control (DDX3Xfl/fl) mice. Hepatic expression of DDX3X was significantly decreased in the pathogenesis of DILI compared with controls in human and mice. Compared to DDX3Xfl/fl mice, DDX3XΔhep mice developed significant liver injury in multiple DILI models. DDX3X deficiency aggravates APAP induced oxidative stress and hepatocyte death by affecting the pro-survival stress granule (SG) assembly. Moreover, DDX3X deficiency induces inflammatory responses and causes pronounced macrophage infiltration. The use of targeted DDX3X drug maybe promising for the treatment of DILI in human.

An Extracellular miRNA‐Responsive Artificial Receptor via Dynamic DNA Nano‐assembly for Biomarker‐Driven Therapy

AbstractMicroRNAs (miRNAs) have emerged as promising diagnostic biomarkers and therapeutic targets in various diseases. However, there is currently a lack of molecular strategies that can effectively use disease‐associated extracellular miRNAs as input signals to drive therapeutic functions. Herein, we present a modular and programmable miRNA‐responsive chimeric DNA receptor (miRNA‐CDR) capable of biomarker‐driven therapy. By grafting a miRNA‐responsive DNA nanodevice on a natural membrane receptor via aptamer anchoring, miRNA‐CDR can sense extracellular miRNA levels and autonomously induce dimerization‐mediated receptor activation via the complementary‐mediated strand displacement reaction‐induced dynamic DNA assembly. The sequence programmability of miRNA‐CDR allows it to sense and respond to a user‐defined miRNA with tunable sensitivity. Moreover, the miRNA‐CDR is versatile and customizable to reprogram desirable signaling output via adapting a designated receptor, such as MET and FGFR1. Using a mouse model of drug‐induced acute liver injury (DILI), we demonstrate the functionality of a designer miRNA‐CDR in rewiring the recognition of the DILI‐elevated miR‐122 to promote MET signaling of hepatocytes for biomarker‐driven in situ repair and liver function restoration. Our synthetic miRNA‐CDR platform provides a novel molecular device enabling biomarker‐driven therapeutic cellular response, potentially paving the way for improving the precision of cell therapy in regenerative medicine.

An Extracellular miRNA-Responsive Artificial Receptor via Dynamic DNA Nano-assembly for Biomarker-Driven Therapy.

MicroRNAs (miRNAs) have emerged as promising diagnostic biomarkers and therapeutic targets in various diseases. However, there is currently a lack of molecular strategies that can effectively use disease-associated extracellular miRNAs as input signals to drive therapeutic functions. Herein, we present a modular and programmable miRNA-responsive chimeric DNA receptor (miRNA-CDR) capable of biomarker-driven therapy. By grafting a miRNA-responsive DNA nanodevice on a natural membrane receptor via aptamer anchoring, miRNA-CDR can sense extracellular miRNA levels and autonomously induce dimerization-mediated receptor activation via the complementary-mediated strand displacement reaction-induced dynamic DNA assembly. The sequence programmability of miRNA-CDR allows it to sense and respond to a user-defined miRNA with tunable sensitivity. Moreover, the miRNA-CDR is versatile and customizable to reprogram desirable signaling output via adapting a designated receptor, such as MET and FGFR1. Using a mouse model of drug-induced acute liver injury (DILI), we demonstrate the functionality of a designer miRNA-CDR in rewiring the recognition of the DILI-elevated miR-122 to promote MET signaling of hepatocytes for biomarker-driven in situ repair and liver function restoration. Our synthetic miRNA-CDR platform provides a novel molecular device enabling biomarker-driven therapeutic cellular response, potentially paving the way for improving the precision of cell therapy in regenerative medicine.

Geometric Isomer of Guanabenz Confers Hepatoprotection to a Murine Model of Acetaminophen Toxicity.

Overdose of acetaminophen, a widely used antipyretic and analgesic drug, is one of the leading causes of drug-induced acute liver injury in the United States and worldwide. Phase-I metabolism of acetaminophen generates the toxic N-acetyl-p-benzoquinone imine (NAPQI) intermediate. Reactions of NAPQI with a wide range of biomolecules cause increased oxidative stress, endoplasmic reticulum (ER) stress, inflammation, and mitochondrial dysfunction, some of the cellular events contributing toward liver toxicity. Previously, we evaluated the potential of an FDA-approved, ER stress-modulating antihypertensive drug, Wytensin (trans-guanabenz, E-GA), as an antidote for acetaminophen hepatotoxicity. E-GA prevented elevation of the liver enzyme alanine aminotransferase (ALT), even when administered up to 6 h after acetaminophen overdose, and exhibited synergistic analgesic interactions. However, the commercially available guanabenz exists solely as a trans-isomer and suffers from sedative side effects resulting from the inhibition of central α2A-adrenergic receptors in locus coeruleus. Here, we studied the utility of the relatively unexplored cis-isomer of guanabenz as a treatment option for acetaminophen-induced liver toxicity. cis(Z)-Guanabenz acetate (Z-GA) lacks interaction with α2A-adrenoreceptors and is thus devoid of sedative, blood-pressure-lowering side effects of E-GA. Treatment of mice with Z-GA (10 mg/kg) before acetaminophen overdose and up to 6 h post APAP administration prevented liver injury and suppressed the elevation of serum ALT levels. Mechanistically, hepatoprotective effects of both isomers are similar and partly attributed to attenuation of the ER stress and oxidative stress in the liver. The results of this study suggest that Z-GA may be a safer, effective antidote for the clinical management of acute liver injury resulting from acetaminophen overdose. It also raises a tantalizing possibility of a prophylactic combination of the geometric isomer of the approved drug guanabenz with acetaminophen in a clinical setting.

Anti-TLR4 IgG2 Prevents Acetaminophen-induced Acute Liver Injury through the Toll-like Receptor 4/MAPKs Signaling Pathway in Mice.

Acetaminophen (APAP) is a widely used antipyretic and analgesic. If taken in excess, it can cause severe drug-induced acute liver injury. The purpose of this study was to investigate the effects of anti-TLR4 IgG2 on APAP-induced liver injury and its underlying mechanisms. We injected APAP into the abdominal cavity of mice to establish a liver injury model. Mice were divided into the control group, APAP group, and APAP + anti-TLR4 IgG2 group. In order to verify the implication of the toll-like receptor4 and mitogen-activated protein kinases activation (TLR4/MAPKs) signaling pathway, mice were intraperitoneally injected with a TLR4 / MAPKs inhibitor anti-TLR4 IgG2. We evaluated the effects of TLR4 IgG2 on the antioxidant, anti-apoptotic, anti-inflammatory, and liver histopathology of APAP mice. In addition, the expression of the TLR4 / MAPKs signaling pathway was detected by Western blot. Our study showed that APAP mouse models were successfully established; however, pretreatment with anti-TLR4 IgG2 alleviated APAP-induced hepatic injury, as evidenced by the 24-h survival rate. Meanwhile, anti-TLR4 IgG2 prevented the elevation of serum biochemical parameters and lipid profile. Furthermore, compared with the APAP group, hepatic antioxidants, including 3- Nitrotyrosine, high mobility group protein B1, superoxide dismutase, catalase, and glutathione, were increased in APAP + anti-TLR4 IgG2 group. In contrast, a significant decrease was observed in the levels of the malondialdehyde, which is a lipid peroxidation product. Moreover, the western blotting analysis showed that anti-TLR4 IgG2 treatment inhibited the activation of the apoptotic pathway by increasing Bcl-2 and decreasing Bax, P53, and cleaving caspase-3 / caspase-3 protein expression. These results were further validated by TUNEL staining and immunohistochemical. Histopathological observation also revealed that pretreat-ment with anti-TLR4 IgG2 could significantly reverse hepatocyte inflammatory infiltration, congestion, and necrosis in liver tissues by APAP. Importantly, anti-TLR4 IgG2 effectively alleviated APAP-induced liver injury by inhibiting tolllike receptor4 and mitogen-activated protein kinases activation signaling pathways (TLR4/MAPKs). The results clearly suggest that the underlying molecular mechanisms in the hepatoprotection of anti-TLR4 IgG2 in APAP-induced hepatotoxicity may be due to its antioxidation, anti-apoptosis, and anti-inflammation effects through inhibition of the TLR4/MAPKs signaling axis.

Microphysiological Models for Mechanistic-Based Prediction of Idiosyncratic DILI.

Drug-induced liver injury (DILI) is a major contributor to high attrition rates among candidate and market drugs and a key regulatory, industry, and global health concern. While acute and dose-dependent DILI, namely, intrinsic DILI, is predictable and often reproducible in preclinical models, the nature of idiosyncratic DILI (iDILI) limits its mechanistic understanding due to the complex disease pathogenesis, and recapitulation using in vitro and in vivo models is extremely challenging. However, hepatic inflammation is a key feature of iDILI primarily orchestrated by the innate and adaptive immune system. This review summarizes the in vitro co-culture models that exploit the role of the immune system to investigate iDILI. Particularly, this review focuses on advancements in human-based 3D multicellular models attempting to supplement in vivo models that often lack predictability and display interspecies variations. Exploiting the immune-mediated mechanisms of iDILI, the inclusion of non-parenchymal cells in these hepatoxicity models, namely, Kupffer cells, stellate cells, dendritic cells, and liver sinusoidal endothelial cells, introduces heterotypic cell-cell interactions and mimics the hepatic microenvironment. Additionally, drugs recalled from the market in the US between 1996-2010 that were studies in these various models highlight the necessity for further harmonization and comparison of model characteristics. Challenges regarding disease-related endpoints, mimicking 3D architecture with different cell-cell contact, cell source, and the underlying multi-cellular and multi-stage mechanisms are described. It is our belief that progressing our understanding of the underlying pathogenesis of iDILI will provide mechanistic clues and a method for drug safety screening to better predict liver injury in clinical trials and post-marketing.

Drug-Induced Liver Injury with Commonly Used Antibiotics in the All of Us Research Program.

Antibiotics are a known cause of idiosyncratic drug-induced liver injury (DILI). According to the Centers for Disease Control and Prevention, the five most commonly prescribed antibiotics in the United States are azithromycin, ciprofloxacin, cephalexin, amoxicillin, and amoxicillin-clavulanate. We quantified the frequency of acute DILI for these common antibiotics in the All of Us Research Program, one of the largest electronic health record (EHR)-linked research cohorts in the United States. Retrospective analyses were conducted applying a standardized phenotyping algorithm to de-identified clinical data available in the All of Us database for 318,598 study participants. Between February 1984 and December 2022, more than 30% of All of Us participants (n = 119,812 individuals) had been exposed to at least 1 of our 5 study drugs. Initial screening identified 591 potential case patients that met our preselected laboratory-based phenotyping criteria. Because DILI is a diagnosis of exclusion, we then used phenome scanning to narrow the case counts by (i) scanning all EHRs to identify all alternative diagnostic explanations for the laboratory abnormalities, and (ii) leveraging International Classification of Disease 9th revision (ICD)-9 and ICD 10th revision (ICD)-10 codes as exclusion criteria to eliminate misclassification. Our final case counts were 30 DILI cases with amoxicillin-clavulanate, 24 cases with azithromycin, 24 cases with ciprofloxacin, 22 cases with amoxicillin alone, and < 20 cases with cephalexin. These findings demonstrate that data from EHR-linked research cohorts can be efficiently mined to identify DILI cases related to the use of common antibiotics.

Synthesis of Chitosan Oligosaccharide-Loaded Glycyrrhetinic Acid Functionalized Mesoporous Silica Nanoparticles and In Vitro Verification of the Treatment of APAP-Induced Liver Injury.

the study was to find a suitable treatment for acute drug-induced liver injury. The use of nanocarriers can improve the therapeutic effect of natural drugs by targeting hepatocytes and higher loads. firstly, uniformly dispersed three-dimensional dendritic mesoporous silica nanospheres (MSNs) were synthesized. Glycyrrhetinic acid (GA) was covalently modified on MSN surfaces through amide bond and then loaded with COSM to form drug-loaded nanoparticles (COSM@MSN-NH2-GA). The constructed drug-loaded nano-delivery system was determined by characterization analysis. Finally, the effect of nano-drug particles on cell viability was evaluated and the cell uptake in vitro was observed. GA was successfully modified to obtain the spherical nano-carrier MSN-NH2-GA (≤200 nm). The neutral surface charge improves its biocompatibility. MSN-NH2-GA has high drug loading (28.36% ± 1.00) because of its suitable specific surface area and pore volume. In vitro cell experiments showed that COSM@MSN-NH2-GA significantly enhanced the uptake of liver cells (LO2) and decreased the AST and ALT indexes. this study demonstrated for the first time that formulation and delivery schemes using natural drug COSM and nanocarrier MSN have a protective effect on APAP-induced hepatocyte injury. This result provides a potential nano-delivery scheme for the targeted therapy of acute drug-induced liver injury.

Holistic Metabolomic Profiling of Chronic versus Acute Drug-induced Liver Injury

Background and ObjectivesDrug-induced liver injury (DILI) can present as a chronic phenotype or acute course. However, there is a lack of research on the underlying mechanisms of chronic DILI as well as the definition of cut-off point. We aimed to profile holistic metabolic characteristics of chronic DILI and provide evidence for the cut-off point by serum metabolomics.

Abstract 3993: In vivo efficacy of an anti-human IL11RA antibody in B-hIL11RA mice with APAP-induced liver damage

Abstract Acetaminophen (N-acetyl-p-aminophenol; APAP) overdose is a common cause of drug-induced acute liver injury, thereby making APAP administration a frequently used experimental model due to its highly reproducible and dose-dependent hepatoxicity. APAP-induced liver injury (AILI) mouse models exhibited upregulated IL11 expression, indicating that targeting IL11 or its cognate receptor, IL11RA, could have therapeutic potential. To evaluate the in vivo efficacy of anti-human IL11RA antibodies in AILI mouse models, we first generated a human IL11RA knock-in mouse model (B-hIL11RA), in which human IL11RA replaced murine Il11ra, in situ. Human IL11RA mRNA and protein levels were detected in B-hIL11RA mice. We next examined whether therapeutic inhibition of IL11 signaling was effective in reducing AILI following administration of an anti-human IL11RA antibody. In vivo efficacy data showed that anti-human IL11RA antibody inhibited all aspects of AILI, including hepatocyte death (ALT, AST and TUNEL) and centrilobular necrosis. These data suggest that B-hIL11RA mice are an effective tool for preclinical in vivo efficacy evaluation of therapeutic anti-human IL11RA antibodies. Citation Format: Fang He, Rufeng Zhang, Mari Kuraguchi, Lei Zhao, Zhaoxue Yu. In vivo efficacy of an anti-human IL11RA antibody in B-hIL11RA mice with APAP-induced liver damage. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3993.

Design and synthesis of photoacoustic probe for in situ imaging of hydrogen polysulfides in organs in vivo

Hydrogen polysulfide (H2Sn), the oxidation product of H2S, plays a critical role in driving the signal regulation of ion channels and tumor suppressors, and the homeostatic imbalance of H2Sn is closely related to various diseases. However, the fluorescence imaging probe for the currently developed H2Sn cannot realize in situ real-time monitoring of H2Sn in living organs in vivo because of limited imaging depth. This study reports on the first rational design, synthesis, and evaluation of an H2Sn-activated photoacoustic (PA) probe (AP-Sn), which enables in situ visual tracking of changes in H2Sn levels in living organs in mice via H2Sn-activated PA imaging. After an AP-Sn solution was administered to the mouse via tail-vein injection, AP-Sn probe responses to H2Sn in the liver area allowed quick imaging of H2Sn in the near-infrared window. Changes in H2Sn levels in the liver attributed to lipopolysaccharides (LPS)-induced overexpression of CSE mRNA were used to monitor the pathological progression of drug-induced acute liver injury (ALI) in inflammatory mice. ALI can be dynamically evaluated in vivo at very high resolutions owing to enhanced depths and low scattering of tissues in the PA image.

γ-Glutamyltransferase-Activatable Fluoro-Photoacoustic Reporter for Highly Sensitive Diagnosis of Acute Liver Injury and Tumor.

γ-Glutamyltransferase (GGT) has been recognized as an important clinical biomarker that is closely related to many diseases. Visualizing the GGT fluctuation facilitates early disease-related diagnosis and therapy. Herein, an activated probe (NIR-GGT) for the imaging of GGT activity was prepared. The probe consists of a stable NIR fluorophore with the tunable amino group decorated with the γ-glutamate group as a GGT-sensing unit linked by a self-elimination group. NIR-GGT can sensitively recognize GGT and cause a strong turn-on fluorescent and photoacoustic signal. The up-regulation of the GGT expression in acetaminophen-induced acute liver injury was imaged using NIR-GGT. The probe can track changes in the GGT level in the early stages of drug-induced acute liver injury (DIALI) and its remedy process by fluorescent and photoacoustic dual-modality imaging with a high temporal-spatial resolution. NIR-GGT can also be used to differentiate between tumor and para-carcinowa tissues in vivo. The probe may be a potential tool for the diagnosis of early-stage DIALI and accurate tumor resection in the clinical field.

Self-assembled FGF21 nanoparticles alleviate drug-induced acute liver injury.

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.