Treatment Of Drug-induced Liver Injury Research Articles

Novel fast dissolving freeze dried sublingual baicalin tablets for enhanced hepatoprotective effect: in-vitro characterization, cell viability, and in-vivo evaluation

Baicalin (BG), a natural product, has been used in the prevention and treatment of drug-induced liver injury (DILI); however, its poor solubility and extensive liver metabolism limit its pharmacological use. The aim of the present study was the formulation of fast-dissolving freeze-dried sublingual tablets (FFSTs) to increase BG dissolution, avoid first-pass metabolism, and overcome swallowing difficulties. FFSTs were prepared following a 23 factorial design. The effect of three independent variables namely matrix former, Maltodextrin, concentration (4%, and 6%), binder concentration (2%, and 3%), and binder type (Methocel E5, and Methocel E15) on the FFSTs’ in-vitro disintegration time and percentage dissolution was studied along with other tablet characteristics. Differential scanning calorimetry, scanning electron microscopy, in-vitro HepG2 cell viability assay, and in-vivo characterization were also performed. F8 (6% Maltodextrin, 2% Mannitol, 2% Methocel E5), with desirability of 0.852, has been furtherly enhanced using 1%PEG (F10). F10 has achieved an in-vitro disintegration time of 41 secs, and 60.83% in-vitro dissolution after 2 min. Cell viability assay, in-vivo study in rats, and histopathological studies confirmed that pretreatment with F10 has achieved a significant hepatoprotective effect against acetaminophen-induced hepatotoxicity. The outcome of this study demonstrated that FFSTs may present a patient-friendly dosage form against DILI.

NIR-II luminescent nanoparticles based-Theranostic platform for drug-induced liver injury diagnoses and ameliorates

Precise diagnosis followed by prompt treatment of drug-induced liver injury (DILI) is vital to prevent its progression to other liver diseases, even liver failure. Reactive oxygen species (ROS) are recognized as an early sign in the progression of DILI. However, ROS-centric diagnosis and therapy of DILI are still unsatisfactory due to methodological limitations. In this work, a rationally designed theranostic nanoplatform was developed by integrating lanthanide-doped second near-infrared (NIR-II) luminescent nanoparticles with salvianolic acid B and Fe3+. Here, NaGdF4:3%Nd@NaGdF4 with NIR-II emission was synthesized and transferred to the aqueous solution via capping with the amphiphilic polymer, C18PMH-mPEG. Upon loading the salvianolic acid B and Fe3+ complex (Sal B/Fe) into the polymer, the NIR-II luminescence of nanoparticles was quenched through the absorption competitive-induced emission (ACIE) principle. However, ROS generated in the DILI can restore the NIR-II luminescence as the Sal B/Fe was destroyed by the ROS. On the other hand, the nanosystem could efficiently alleviate the oxidative stress of DILI via scavenging ROS thanks to the antioxidant properties of salvianolic acid B. Liver injury-related symptoms, including histopathological biochemical serological indicators, expression of SOD, GSH, and malondialdehyde were evidently mitigated.

Network meta-analysis of different liver protective drugs in the treatment of drug-induced liver injury.

Currently, drug-induced liver injury (DILI) has become one of those public issues in society, which has added a huge burden to both the individuals and the society. In the current clinical stage, there are numerous drugs developed to treat this disease, and different drug treatment measures have been proven to achieve certain clinical efficacy in the corresponding randomized controlled trials. However, there are still many therapeutic drugs that have not been directly compared and studied. Therefore, it is difficult to directly compare the effectiveness and safety of various strategies for the treatment of DILI. In this regard, the present study collected the therapeutic efficacy of diverse treatments in DILI in recent years through network meta-analysis, evaluated and screened the existing optimal clinical therapeutic plan, and helped physicians formulate clinical therapeutic plans. Databases, including the Chinese Journal Full-text Database, Wanfang Data Journal Paper Resources (Wangfang), VIP Chinese Science and Technology Journal Full-text Database, The Cochrane Library, PubMed, and EMBASE, were searched using keywords from inception to January 2023. Eligible randomized controlled trials were selected in line with eligibility criteria, and mesh meta-analysis of binary variables was carried out using Stata 16 software. In combination with alanine aminotransferase, aspartate aminotransferase, and total bilirubin, MI may be the intervention measure for minimizing alanine aminotransferase levels in patients after treatment. Besides, compound glycyrrhizin may be the intervention for minimizing aspartate aminotransferase levels in patients after treatment, and polyene phosphatidylcholine may be the intervention for minimizing total bilirubin levels in patients after treatment. Placebo is the potential intervention that has the least adverse reactions post-treatment, and RT has the second least adverse reactions. Moreover, hepatocyte growth-promoting factors may be the most effective intervention after treatment. To sum up, the present work compared the clinical effects of 13 liver protective drugs through meta-analysis and provided a systematic understanding of commonly used drugs for the treatment of DILI in clinical practice.

An innovative near-infrared fluorescent probe designed to track the evolution of carboxylesterase in drug-induced liver injury

Drug-induced liver injury (DILI) is a common side effect of medicines, which is a pathological process of drug-induced liver dysfunction or injury. As an important enzyme mainly existing in the human liver, carboxylesterase (CE) has been proven that the decrease or lack of its activity is related to the occurrence and severity of DILI. Therefore, detecting the change of CE level in DILI will help to understand the pathological and physiological repercussions of DILI. In this study, we designed and synthesized a novel near-infrared (NIR) fluorescent probe (MB-CE) that displayed excellent optical properties for detecting CE. The probe MB-CE featured low cytotoxicity, high sensitivity, and selectivity. Furthermore, the MB-CE was successfully utilized to detect endogenous CE in a liver injury caused by acetaminophen (APAP) and its subsequent treatment with glutathione (GSH) in cells. Notably, with the assistance of probe MB-CE, we successfully achieved realized in situ monitoring of CE decreased in the APAP-induced liver injury mouse model. These results indicate the potential clinical utility of the probe MB-CE for investigating the occurrence, progression, and treatment of DILI.

Network pharmacology integrated with molecular docking technology to reveal the potential mechanism of Shuganfang against drug-induced liver injury.

This study aimed to investigate the active composition and mechanism of the Shuganfang (SGF) in treating drug-induced liver injury (DILI) using network pharmacology and molecular docking. The potential active ingredients and targets of SGF were obtained from the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) database. DILI-related targets were queried from various databases including GEO, GeneCards, OMIM, NCBI, and DisGeNET. The STRING database was used to establish a protein-protein interaction (PPI) network. DAVID was utilized for conducting gene ontology (GO) function enrichment and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses. The data visualization and analysis of herb-ingredient-target and disease-pathway-target-ingredient networks were conducted using Cytoscape software (version 3.7.2). PyMoL and AutoDock software was used to select the best binding target for molecular docking. A total of 177 active ingredients,126 targets and 10112 disease targets were obtained, including 122 intersection targets. The identified potential active ingredients consisted of quercetin, kaempferol, luteolin, tanshinone IIa, nobiletin, isorhamnetin, beta-sitosterol and naringenin. The core targets implicated in the study were IL6, estrogen receptor 1 (ESR1), hypoxia-inducible factor alpha subunit 1 (HIF1A), MYC and vascular endothelial growth factor A (VEGFA). KEGG analysis revealed that the treatment of DILI with SGF mainly acted through apoptosis, the PI3K-Akt signaling pathway, and the tumor necrosis factor (TNF) signaling pathway. Furthermore, the binding affinities between the potential ingredients and the core targets were subsequently confirmed through molecular docking experiments. The findings indicated that the docking outcomes remained consistent and demonstrated a favorable capacity for binding. SGF exerts a therapeutic effect on DILI through multiple active ingredients, multiple targets and multiple pathways. Our findings contribute to a positive investigation and establish a theoretical basis for further extensive exploration of SGF as a potential treatment for DILI in future research.

Protective effect of Tibetan medicine Qiwei Tiexie pills on liver injury induced by acetaminophen overdose: an integrated strategy of network pharmacology, metabolomics and transcriptomics

BackgroundDrug-induced liver injury, particularly from acetaminophen (APAP), has emerged as a significant public health concern. Unfortunately, there is currently no effective treatment strategy available. Qiwei Tiexie pills (QWTX), a traditional Tibetan medicine, have demonstrated considerable clinical efficacy in treating various liver diseases. Nevertheless, the protective effect of QWTX against drug-induced liver injury and its underlying mechanism remains poorly understood. PurposeThis study aimed to assess the therapeutic potential of QWTX, a Tibetan medicine, in an animal model of APAP-induced liver injury. Additionally, we sought to investigate the molecular mechanism through which QWTX exerts its effects. MethodsWe employed LC-MS and network pharmacology to predict the potential targets of QWTX in drug-induced liver injury. Subsequently, we employed HE staining, transcriptomics, metabolomics, and qRT-PCR to analyze the mechanism underlying QWTX treatment in drug-induced liver injury. ResultsNetwork pharmacology analysis revealed that the active components of QWTX are involved in inflammatory and drug metabolism-related pathways. In mouse models, pretreatment with QWTX effectively mitigated the elevated levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and inflammatory factors (IL-1β, IL-6, and TNF-α) induced by APAP overdose. Moreover, APAP inhibited 1459 differentially expressed genes (DEGs) and 874 differential accumulation metabolites (DAMs), while QWTX promoted their expression. Conversely, APAP promoted 874 genes and 119 metabolites, which were inhibited by QWTX. Further analysis demonstrated that QWTX ameliorated the metabolic disorders induced by APAP overdose and potentially exerted a protective effect by inhibiting the expression of critical genes in crucial inflammatory pathways. QWTX also up-regulated antioxidant enzymes, thereby mitigating the oxidative stress resulting from APAP overdose. ConclusionQWTX treatment effectively protects against APAP-induced liver damage in mice. Transcriptomic and metabolomic analyses further revealed that QWTX ameliorated hepatic metabolic disorders induced by APAP overdose while significantly suppressing the inflammatory response and oxidative stress associated with drug-induced liver injury. This study provides a new insight into the treatment of drug-induced liver injury by the TCM system and provides a basis for the development of new therapies for drug-induced liver injury by QWTX and its active ingredients.

YKL-40 promotes chemokine expression following drug-induced liver injury via TF-PAR1 pathway in mice.

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 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 drug-induced liver injury.

Schisandrol A, a bioactive constituent from Schisandrae Chinensis Fructus, alleviates drug-induced liver injury by autophagy activation via exosomes

ObjectiveTo investigate the bioactive compounds of Schisandrae Chinensis Fructus (SCF) and their mechanisms of action in the treatment of drug-induced liver injury (DILI), specifically Acetaminophen (APAP)-induced DILI. MethodChemical components in SCF were identified using the UPLC-Q-TOF-MS method. Active components were then screened using HotMap, combined with SCF efficacy results concerning the prevention and treatment of drug-induced liver injury. Its direct target was elucidated using a comprehensive chemical-pharmacodynamic-exosome approach. ResultWe identified Schisandrol A, is a lignan component, as a key active compound that improved the symptoms DILI in mouse liver tissue; specifically, reducing oxidative stress and thereby the inflammatory response. To further understand the biological function of miRNAs in mouse liver exosomes, we used TargetScan (v5.0) and Miranda (v3.3a) to predict the target genes of MicroRNAs (miRNAs), where changes in the expression of mmu-let-7 family miRNAs were closely related to autophagy. This revealed differential miRNA target genes that were involved in 20 Kyoto Encyclopedia of Genes and Genomes pathways, including glycerol phosphate metabolism, inositol phosphate metabolism, phospholipase D signaling pathway, Rap1 signaling pathway, and Ras signaling pathway. ConclusionSchisandrol A alleviated the symptoms of DILI in mice by inhibiting oxidative stress and inflammation, whereas, it alleviated DILI by activating autophagy in the exosomes.

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.

Integrated metabolomics, network pharmacology, and molecular docking to reveal the mechanisms of Isodon excisoides against drug-induced liver injury.

Isodon excisoides (Y.Z.Sun ex C.H.Hu) H. Hara has been often used to treat liver diseases in folk medicine. However, the potential hepatoprotective mechanism of I.excisoides remains unclear. In this study, the mechanism of I.excisoides in alleviating drug-induced liver injury (DILI) was explored using a strategy combining metabolomics with network pharmacology for the first time. First, serum metabolomics was applied to identify differential metabolites and enrich metabolic pathways. The potential targets of I.excisoides for the treatment of DILI were investigated by network pharmacology. Subsequently, a comprehensive network of network pharmacology and metabolomics was established to find the key genes. Finally, molecular docking technology was used to further verify the key targets. As a result, four key genes including TYMS, IMPDH2, DHODH, and ASAH1 were identified. The proteins produced by these genes had high affinity with the corresponding diterpenoids. These results indicate that the components of I.excisoides play a liver-protective role by affecting the aforesaid key genes and key proteins. Our results offer a novel strategy for determining the pharmacological effects and potential targets of natural compounds.

A system that delivers an antioxidant to mitochondria for the treatment of drug-induced liver injury

Mitochondria, a major source of reactive oxygen species (ROS), are intimately involved in the response to oxidative stress in the body. The production of excessive ROS affects the balance between oxidative responses and antioxidant defense mechanisms thus perturbing mitochondrial function eventually leading to tissue injury. Therefore, antioxidant therapies that target mitochondria can be used to treat such diseases and improve general health. This study reports on an attempt to establish a system for delivering an antioxidant molecule coenzyme Q10 (CoQ10) to mitochondria and the validation of its therapeutic efficacy in a model of acetaminophen (APAP) liver injury caused by oxidative stress in mitochondria. A CoQ10-MITO-Porter, a mitochondrial targeting lipid nanoparticle (LNP) containing encapsulated CoQ10, was prepared using a microfluidic device. It was essential to include polyethylene glycol (PEG) in the lipid composition of this LNP to ensure stability of the CoQ10, since it is relatively insoluble in water. Based on transmission electron microscope (TEM) observations and small angle X-ray scattering (SAXS) measurements, the CoQ10-MITO-Porter was estimated to be a 50 nm spherical particle without a regular layer structure. The use of the CoQ10-MITO-Porter improved liver function and reduced tissue injury, suggesting that it exerted a therapeutic effect on APAP liver injury.

Zebrafish as a model for drug induced liver injury: state of the art and beyond

Zebrafish as a preclinical drug induced liver injury (DILI) model provides multiple advantages ranging from ease of breeding and maintenance, availability of different strains and transgenic fish amenable to study liver function, and highly conserved liver structure and function with the human liver. In this review, the authors have aimed to provide an account of the metabolic enzymes that take roles in drug detoxification in both human and zebrafish in a comparative manner and exemplify several recent models in studying liver functionality. Moreover, the authors emphasize the difficulties associated with studying idiosyncratic DILI in preclinical models and propose that zebrafish could be an important complement to mice in testing functions of genes that are associated with DILI with respect to different drugs in human genome-wide association studies (GWAS) Catalog. Finally, this review highlights the state-of-the-art in the development of novel transgenic reporter strains that can be used to study degree and molecular mechanisms of hepatotoxicity caused by drugs in zebrafish. All of these will help researchers to use effectively the available resources in the zebrafish DILI models, while advocating potential leads that can be taken to provide advancements in a better understanding and treatment of DILI.

Comparative analysis of clinical diagnosis and treatment guidelines for drug-induced liver injury at home and abroad

Drug-induced liver injury influencing factors are complex and have diverse clinical manifestations. Simple and reliable diagnostic methods are still deficient, and further classification of toxicological mechanisms is required. There are numerous pertinent discrepancies between domestic and international guidelines aimed at drug-induced liver injury diagnosis and treatment, with partial to no consensus on the content. The American Gastroenterological Association's 2021 Clinical Guidelines, the Asia-Pacific Association for the Study of the Liver's 2021 Consensus Guidelines, the Council for International Organizations of Medical Sciences' 2020 International Consensus, the European Society's Hepatology Committee's 2019 Clinical Practice Guidelines, and the 2015 Chinese Medical Association Guidelines are five influential clinical guidelines on drug-induced liver injury at home and abroad. The epidemiology, risk factors, diagnosis and evaluation, treatment management, and other contents, particularly traditional Chinese medicine, were compared and analyzed using other relevant consensus opinions or guidelines in order to improve understanding and provide a reference for clinical diagnosis and treatment of drug-induced liver injury.

Standardize the diagnosis and treatment of drug-induced liver injury, and strengthen clinical and translational research

As a liver disease with the most complex clinical phenotype, drug-induced liver injury (DILI) poses great challenges in diagnosis and management in clinical practice. Although guidelines based on the latest research advances can provide clinicians with guidance on the identification, diagnosis, and management of DILI, the overall level of evidence in this field is relatively low and high-level evidence is limited. Therefore, we should interpret guidelines with caution and look forward to more clinical and translational research to address the huge unmet clinical needs in DILI.

Treatment of Drug-Induced Liver Injury.

Current pharmacotherapy options of drug-induced liver injury (DILI) remain under discussion and are now evaluated in this analysis. Needless to say, the use of the offending drug must be stopped as soon as DILI is suspected. Normal dosed drugs may cause idiosyncratic DILI, and drugs taken in overdose commonly lead to intrinsic DILI. Empirically used but not substantiated regarding efficiency by randomized controlled trials (RCTs) is the intravenous antidote treatment with N-acetylcysteine (NAC) in patients with intrinsic DILI by N-acetyl-p-aminophenol (APAP) overdose. Good data recommending pharmacotherapy in idiosyncratic DILI caused by hundreds of different drugs are lacking. Indeed, a recent analysis revealed that just eight RCTs have been published, and in only two out of eight trials were DILI cases evaluated for causality by the worldwide used Roussel Uclaf Causality Assessment Method (RUCAM), representing overall a significant methodology flaw, as results of DILI RCTs lacking RUCAM are misleading since many DILI cases are known to be attributable erroneously to nondrug alternative causes. In line with these major shortcomings and mostly based on anecdotal reports, glucocorticoids (GCs) and other immuno-suppressants may be given empirically in carefully selected patients with idiosyncratic DILI exhibiting autoimmune features or caused by immune checkpoint inhibitors (ICIs), while some patients with cholestatic DILI may benefit from ursodeoxycholic acid use; in other patients with drug-induced hepatic sinusoidal obstruction syndrome (HSOS) and coagulopathy risks, the indication for anticoagulants should be considered. In view of many other mechanistic factors such as the hepatic microsomal cytochrome P450 with a generation of reactive oxygen species (ROS), ferroptosis with toxicity of intracellular iron, and modification of the gut microbiome, additional therapy options may be available in the future. In summation, stopping the offending drug is still the first line of therapy for most instances of acute DILI, while various therapies are applied empirically and not based on good data from RCTs awaiting further trials using the updated RUCAM that asks for strict exclusion and inclusion details like liver injury criteria and provides valid causality rankings of probable and highly probable grades.

Investigation of the mechanism of traditional Mongolian medicine Gurigumu-13 pill for treating acetaminophen-induced liver injury using a network pharmacology and metabolomics approach

: Gurigumu-13 Pill (GRGM) is a traditional Mongolian medicine prescription that has a liver-protective effect. However, the underlying therapeutic mechanisms of GRGM for acetaminophen-induced liver injury (APAP) are still unknown. The preventive impact of GRGM on APAP-induced drug-induced liver injury (DILI) and its protective mechanism were examined in this work. : The core targets and signaling pathways of GRGM in the treatment of DILI were explored by network pharmacology strategy. Histopathological and biochemical indices were used to confirm the therapeutic effect of GRGM. Metabolomics strategy was used to explore the plasma metabolic spectrum of rats, and the potential biomarkers were annotated and clustering analyzed. : The results of network pharmacology analysis showed that AKT1, TNF, EGFR, ESR1, CCND1 and SRC may be important targets of GRGM for the treatment of DILI, and that GRGM may decrease the inflammatory response and oxidative stress by acting on many targets. Histopathological results showed that GRGM could create complete liver cells that showed an orderly formation and inhibited the inflammation. The results of the biochemical indices showed that GRGM could inhibit the expression of ALT, AST, TNF-α and TGF-β1. The DILI process was linked to 21 different metabolites, with a majority of which involved in the Glycosyl phosphidylinositol (GPI) anchor biosynthesis and the glycophyte metabolism pathway. : This study speculated that GRGM might have various protective effects on DILI through multi-components, multi-targets and multi-pathways. Metabolomics showed that GRGM could play a therapeutic role by interfering with the metabolic characteristics of DILI rats. The present work might provide a new insights into the relationships between GRGM and APAP-induced DILI.

Rational choice of hepatoprotectors for drug-induced liver injury

The article deals with a review of the current literature on the clinical use of hepatoprotectors in drug-induced liver injury. The literature was searched in Scopus, Web of Science, PubMed and other databases. Risk factors, pathogenetic mechanisms of liver damage, international diagnostic criteria and treatment for drug-induced liver injuries are considered. Clinical and pharmacological approaches to the choice of hepatoprotectors for the management of drug-induced liver injury are substantiated. The positive effects of ademetionine, a hepatoprotector, are highlighted— choleretic, cholekinetic, regenerating, antioxidant and antitoxic. In accordance with the principles of evidence-based medicine, it has been found that the indisputable advantage of ademetionine in the comprehensive treatment of drug-induced liver injury is its high clinical effectiveness as a mean of pathogenetic treatment of cholestasis, hepatocellular lesions and their combinations.

Epigallocatechin-3-gallate Mo nanoparticles (EGM NPs) efficiently treat liver injury by strongly reducing oxidative stress, inflammation and endoplasmic reticulum stress.

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.

S3014 Hepatotoxic Effects of Whey Protein Supplementation

Introduction: Currently, more than 50% of Americans take dietary supplements. Whey is a commonly used protein supplement that is often viewed as safe, with only rare reports of drug-induced liver injury (DILI). Here, we report an unusual case of severe liver injury following whey protein consumption. Case Description/Methods: A 40-year-old female with obesity and well-controlled hypothyroidism presented with 3 days of nausea and painless jaundice. Her only home medication was levothyroxine. Two months prior, she began drinking whey protein shakes (each containing 20 grams of protein) twice daily to aid with weight loss. She denied use of alcohol, recreational drugs, herbal supplements, and recent medication changes. On physical exam, she was alert and oriented x4, with jaundice and scleral icterus present. Lab work was significant for ALT 2,502, AST 1,434, total bilirubin 11.0, INR 1.42, and platelets 217,000. Acetaminophen and salicylate levels were unremarkable. Her whey protein supplementation was immediately stopped and a workup for transaminitis was initiated. RUQ ultrasound was unremarkable. Evaluation for other causes of acute liver injury, including viral hepatitis (A, B, C, E), EBV, CMV, HIV, hemochromatosis, Wilson’s disease, and autoimmune hepatitis was unremarkable. A liver biopsy was performed, with pathology showing diffuse ballooning degeneration of hepatic parenchyma, numerous acidophil bodies, and dominant pericentral hepatocyte drop-out. A diagnosis of DILI (with predominant hepatocellular injury) was made. Following discontinuation of whey protein supplementation, the patient’s labs and clinical symptoms improved, and she was discharged home on hospital day 8. Discussion: This case highlights a rare occurrence of DILI secondary to whey protein consumption and emphasizes the importance of taking a thorough history when working up liver injury. Furthermore, in the treatment of DILI, we recommend cessation of all possible offending agents that were recently started, including supplements that are reputably marketed to be safe for consumption.

Tandem mass tag-based proteomics analysis reveals the effects of Guri Gumu-13 pill on drug-induced liver injury

The incidence of drug-induced liver injury (DILI) is second only to viral hepatitis and steatohepatitis in China, and DILI has become a serious public health problem that cannot be ignored. Guri Gumu-13 pill (GRGM) is a traditional Chinese medicine (TCM), which has a protective effect on liver diseases. However, the underlying therapeutic mechanisms of GRGM for DILI are still vague. In this study, the protective effect of GRGM on acetaminophen (APAP)-induced DILI was investigated based on the proteomics clues. The effects of GRGM on APAP-induced DILI in rats were studied using tandem mass tag (TMT)-based quantitative proteomics technology. Besides, western blotting was exerted to verify related proteins. Using the TMT-based quantitative proteomics approach, 237 proteins were identified as regulated in APAP-induced DILI and 58 proteins were regulated by GRGM. The 17 overlapping differentially expressed proteins (DEPs) were identified, and 7 proteins were inversely regulated. Enrichment analysis of KEGG indicated that metabolic pathways, linoleic acid metabolism, and retinol metabolism might be affected in DILI. Next, Cyp2c11, Aldh1a1, and Fads2 were verified with molecular biotechnology. GRGM exerts therapeutic effects through multi-pathways regulation in the treatment of DILI. This work may provide proteomics clues for the continuation of research on DILI treatment with GRGM.