Induced Liver Injury Research Articles

Isolicoflavonol ameliorates acute liver injury via inhibiting NLRP3 inflammasome activation through boosting Nrf2 signaling in vitro and in vivo

BackgroundNOD like receptor pyrin domain containing 3 (NLRP3) inflammasome is involved in innate immunity, and related to liver injury. However, no inflammasome inhibitors are clinically available until now. Our previous research suggests that isolicoflavonol (ILF), isolated from Macaranga indica, is a potent NLRP3 inflammasome inhibitor, but its mechanism is unclear. MethodsFluorescent imaging and Western blot assay were used to ascertain the effects of ILF on pyroptosis and NLRP3 inflammasome activation in macrophages. Next, Nrf2 signal pathway, its downstream gene transcription and expression were further investigated. ML385, a Nrf2 inhibitor, was used to verify whether ILF targets Nrf2 signaling. A carbon tetrachloride induced liver injury model was introduced to evaluate the liver protection activity of ILF in mice. ResultsThis work revealed that ILF inhibited macrophage LDH release and IL-1β secretion in a dose-dependent manner. ILF had no significant cytotoxic effect on macrophage, it reduced pyroptosis and Gasdermin D N-terminal fragment formation. Moreover, ILF inhibited IL-1β maturation and Caspase-1 cleavage, but did not affect NLRP3, pro-Caspase-1, pro-IL-1β and ASC expression. ILF decreased ASC speck rate and reduced ASC oligomer formation. ILF decreased aggregated JC-1 formation restoring mitochondria membrane potential. In addition, ILF increased Nrf2 expression, extended Nrf2 lifespan and upregulated Nrf2 signaling pathway in macrophages whether the NLRP3 inflammasome was activated or not. Besides, ILF increased Nrf2 nuclear translocation, maintained a high proportion of Nrf2 in the nucleus, and upregulated ARE-related gene transcription and expression. Furthermore, Nrf2 signal inhibition attenuated compound ILF-mediated inhibition of pyroptosis, inflammasome activation and upregulation of Nrf2 signaling. ILF in a liver injury mouse model inhibited NLRP3 inflammasome activation and enhanced Nrf2 signaling. ConclusionOur study verified that ILF ameliorates liver injury via inhibiting NLRP3 inflammasome activation through boosting Nrf2 signaling, and highlighted that ILF is a potent anti-inflammatory drug for inflammasome-related liver diseases.

A traditional medicinal food <i>Arum rupicola</i> (Kardeh) ameliorates thioacetamide-induced hepatotoxicity in animal model: Role of PCNA/Bax, oxidative stress, and inflammatory cytokines

Nutraceuticals are major contributors to human health because of their modulatory effects on various physiological and pathological processes. Arum rupicola (Kardeh) is a traditional medicinal food used for many gastrointestinal and enzymatic disorders. The present study evaluates the acute toxicity and hepatoprotective effects of methanolic extracts of Arum rupicola (MEAR) in rat with thioacetamide (TAA)-induced liver injury in rat. Thirty Sprague-Dawley rats were divided into five groups: Group A, normal control, and group B, TAA control groups were treated orally with 10% tween 20; group C reference rat received daily of 50 mg/kg silymarin drug; Groups D and E rat received daily doses of 250 mg/kg and 500 mg/kg MEAR, respectively. In addition, group B–E received three injections of 200 mg/kg TAA weekly for 60 days. The safety evaluation of MEAR revealed nontoxic effects at 2,000 and 5,000 mg/kg dosage in rat. TAA inoculation provoked significant hepatotoxic alterations indicated by increased hepatocyte proliferation, endothelial tissue injury, ambiguous nucleus, and elevated cytoplasmic vacuoles. TAA treatment initiated increased inflammatory response and necrosis process in different areas of hepatic tissues. Meanwhile, MEAR treatment showed significant prophylaxis against TAA-induced hepatotoxicity, supported by its suppressing actions on oxidative stress, and apoptotic and inflammatory mediators. MEAR treatment significantly down-regulated proliferating cell nuclear antigen (PCNA) in both liver and spleen parenchymal tissues, lowered pro-apoptotic Bcl-2-associated X (Bax) proteins, reduced inflammatory and redox mediators, lowered transforming growth factor-beta tissue expression and malondialdehyde content, while, increased antioxidants (superoxide dismutase, catalase, and glutathione peroxidase). The outcomes provided significant hepatoprotective potential of MEAR mediated by its modulatory effects on several cellular pathways, making it a viable source of a potent pharmaceutical discovery.

S1939 The Evolving Landscape of Drug Induced Liver Injury (DILI): Tracking New Drug Culprits

S1939 The Evolving Landscape of Drug Induced Liver Injury (DILI): Tracking New Drug Culprits

S4339 Herb Hazard: Ashwagandha Induced Liver Injury

S4339 Herb Hazard: Ashwagandha Induced Liver Injury

S4617 A Rare Drug Induced Liver Injury leading to Liver Transplantation

S4617 A Rare Drug Induced Liver Injury leading to Liver Transplantation

S3977 A Rare Case of Drug Induced Liver Injury Secondary to Ustekinumab and Risankizumab in a Crohn’s Disease Patient

S3977 A Rare Case of Drug Induced Liver Injury Secondary to Ustekinumab and Risankizumab in a Crohn’s Disease Patient

S4469 Watch Out for Off-Label Weight Loss Medication Use: Zonisamide-Induced Drug Reaction with Eosinophilia and Systemic Symptoms and Severe Drug Induced Liver Injury

S4469 Watch Out for Off-Label Weight Loss Medication Use: Zonisamide-Induced Drug Reaction with Eosinophilia and Systemic Symptoms and Severe Drug Induced Liver Injury

Geraniol alleviates liver injury induced by bisphenol A via modulating NLRP3/caspase-1 pathway and gut microbiota in mice model.

Bisphenol A has become a global public health problem. As an antioxidant, geraniol has potential preventive effects against toxicity. This study analyzes the preventive effect of geraniol against BPA induced liver injury in CD-1 mice. Geraniol administration significantly ameliorated BPA induced liver damage by the increase in superoxide dismutase/catalase enzymatic activities, and decrease in malonaldehyde level; prompted a significant reduction in the expression levels of inflammatory cytokines (TNF-α, IL-1β, and IL-6), and pyroptosis biomarkers (NLRP3, ASC, and caspase-1); up-regulated the expression of claudin-1, ZO-1, and occludin markedly, which exhibited intestinal barrier function. Also, geraniol treatment optimized the composition and diversity of gut microbiota. It may be summarized that geraniol showed protective effects on liver injury induced by BPA and further revealed that the mechanism might be located on improving intestinal physical barrier function, down-regulating pyroptosis biomarkers, and normalizing intestinal microbiota, consequently reducing inflammatory response in the liver.

S4442 A Novel Case of Pyridostigmine Induced Liver Injury

S4442 A Novel Case of Pyridostigmine Induced Liver Injury

Long-term liver deportalisation in stable and time prolonged prehepatic portal hypertension model affects expression of hypoxia, angiogenesis, apoptosis, and autophagy markers in the young rats’ liver

prehepatic portal hypertension in children cause severe and life-threatening complications, that highlights the need in in-depth investigations of pathogenetic mechanisms, which contribute to prehepatic portal hypertension-associated liver pathology. In developed stable experimental prehepatic portal hypertension model in adolescent rat males we aimed to assess the expression levels of the key molecular markers of hypoxia, angiogenesis, autophagy, and apoptosis in the liver tissue after 6-month deportalization. Partial portal vein ligation was performed in 4-week old male rats. After 6-months tissue samples from PHP-model, sham operated and control animals were studied by western blot to identify protein levels of markers related to prehepatic portal hypertension -induced liver injury. Partial portal vein occlusion upregulated hypoxia inducible factor -1α (by 4.67 folds vs. control, p<0.001) and vascular endothelial growth factor protein expression levels (by 2.33 folds vs. control, p<0.001) suggesting chronic hypoxia development. Abnormally high levels of angiostatin isoforms were found (by 9.88 folds vs. control, p<0.001) to signify angiogenesis dysregulation. Significant caspase-3 (23.4-fold increase vs. control, p<0.001) overexpression is executive phase of apoptotic cell death evidence. Dramatic LC3 level expression indicates existence of crosstalk between autophagy and apoptosis that contribute to fibrotic changes. Hypoxia-induced events, impaired angiogenesis regulation, enhanced autophagy and apoptosis are contributing factors of prehepatic portal hypertension -induced liver injury. A better understanding of subtle molecular mechanisms of this pathology may pave the way for innovative treatment options.

Correlation between Kupffer Cell Infiltration and Liver Parenchymal Cell Damages in Immunosuppressed Drugs-Induced Rats

The liver is the largest organ in the body, composed of both parenchymal and non-parenchymal cells. Chemical substances and various drugs can induce liver injury and involve Kupffer cells which are non-parenchymal cells that release biologically active substances, promoting pathological processes. This study aimed to evaluate the correlation between the number of Kupffer cells and liver parenchymal cell damages in immunosuppressed, drug-induced rats. The study was conducted from July to December 2019 at the Oral Biology Laboratory of the Faculty of Dentistry and the Biochemical Laboratory of the Faculty of Medicine at Universitas Hang Tuah Surabaya. Twelve healthy male Wistar rats were divided into two groups: Healthy (H) and Immunosuppressed Drug-Induced (ID) groups. Immunosuppression was induced using dexamethasone (0.5 mg/day/rat), administered orally for 14 days, combined with tetracycline (1%/day/rat). Liver samples from all rats were examined for Kupffer cell count and parenchymal cell damages were assessed using a light microscope with 400x magnification. Results revealed a significant difference in the number of Kupffer cells and liver parenchymal cell damages between the H and ID groups (p<0.05). Pearson correlation analysis indicated a significant correlation between Kupffer cell number and parenchymal cell damages (p=0.000). Continuous administration of immunosuppressive drugs may activate Kupffer cells, leading to damage of liver parenchymal cells. In conclusion, the infiltration of Kupffer cells is associated with liver parenchymal cell damages, mediated by various factors in the immunosuppressed drug-induced rat model.

TIPE2 protein restrains invariant NKT activation and protects against immune-mediated hepatitis in mice.

Concanavalin A (ConA) administration induces a rapid and severe liver injury in mice, and invariant natural killer T (iNKT) cells are recognized to be the key effector cells in this process. However, the underlying regulatory mechanisms are not well defined. We found that iNKT cells constitutively expressed TIPE2 (Tumor necrosis factor-α-induced protein 8-like 2, or TNFAIPL2). Genetic TIPE2 ablation strongly sensitized mice to ConA-induced hepatitis, accompanied with hyperactivation of iNKT cells. Moreover, Tipe2-/- mice were also more susceptible to α-galactosylceramide (αGalCer)-induced liver injury, with elevated serum ALT level and enhanced proinflammatory cytokine production. CD1d signaling blockade or iNKT cell elimination through antibodies reduced the effect of TIPE2 deficiency on liver injury. Mechanistic studies revealed that TIPE2 in iNKT cells functioned as a negative regulator, limiting iNKT cell activity and cytokine production through PIP3- AKT/mTOR pathway. TIPE2-mediated protection from liver injury was further validated by the administration of adeno-associated viruses expressing TIPE2, which effectively ameliorated ConA-induced hepatic injury. However, TIPE2 was dispensable in two other liver injury models, including D-GalN/LPS and APAP-induced hepatitis. Our findings reveal a new role of TIPE2 in the attenuation of iNKT cell-mediated hepatic injury. We propose that TIPE2 serves as an important regulator of immune homeostasis in the liver, and might be exploited for the therapeutic treatment of autoimmune liver diseases.

Assessment of Antioxidant and Hepatoprotective Effects of Kappaphycus alvarezii (Doty) Doty ex Silva Against Carbon Tetrachloride-Induced Liver Injury in Rats

Kappaphycus alvarezii (Doty) Doty ex Silva, commonly known as red algae, holds economic significance as a primary source of κ-carrageenan, which exhibits promising medicinal and therapeutic properties. This study aims to assess the antioxidant potential as well as hepatoprotective activity of the ethanolic extract of K. alvarezii (EEKA). The assays utilised to determine the antioxidant properties of EEKA were total phenolic content (TPC) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging. In addition, the ability of EEKA to ameliorate experimentally induced liver injury in Sprague-Dawley rats caused by carbon tetrachloride (CCl4) was evaluated. The biochemical assays involved measuring liver marker enzymes (AST and ALT) in serum as well as determining the levels of reduced glutathione (GSH), lipid peroxidation (LPO) via malondialdehyde, catalase (CAT), and glutathione S-transferase (GST) in liver homogenates. The TPC and DPPH radical scavenging activity of EEKA demonstrated relatively low antioxidant properties compared to standard references. However, CCl4-induced groups exhibited significantly increased levels of AST and ALT, along with depletion of antioxidant status (GSH, CAT, and GST) indicated by LPO. Pretreatment with EEKA resulted in slightly decreased liver marker enzyme activity and LPO, coupled with an increase in antioxidant status. These findings suggest that EEKA contains active principles capable of counteracting the hepatotoxic effects induced by CCl4.

4-Phenylbutyric acid suppresses psoralen-induced hepatotoxicity by inhibiting ERS and reestablishing mitochondrial fusion-fission balance in mice

Psoralen is a main active molecule of the traditional Chinese herb medicine Fructus Psoraleae. Our previous studies have shown that psoralen induced liver injury through the endoplasmic reticulum stress (ERS) signaling pathways. In this article, we studied whether the ERS inhibitor, 4-phenylbutyrate acid (4-PBA) could inhibit the liver toxicity caused by psoralen, and explored the underlying mechanisms. Mice were given the solvent, 20 mg/kg, 40 mg/kg, 80 mg/kg of psoralen, or 80 mg/kg of psoralen plus 4-PBA for 14 days. We found that 4-PBA significantly reduced the serum LDH and liver tissue MDA level, increased the activities of SOD and CAT, reduced liver weight and coefficient, repaired histopathological damage, and inhibited hepatocytes apoptosis induced by psoralen. RNA-seq transcriptomics found that except for the endoplasmic reticulum, the mitochondria was severely affected by psoralen. And genes involved in mitochondrial fusion, apoptosis, protein folding, and autophagy were found differently expressed in the psoralen group. Further studies found that 4-PBA inhibited the overexpression of GRP78 and CHOP, increased the Bcl-2/Bax ratio, and reduced the expression of Caspase-3. Moreover, 4-PBA reduced the overexpression of mitochondrial fission protein DRP1, increased the expression of fusion proteins Mfn-2 and OPA1, but has no inhibitory effects on autophagy proteins Atg5 or LC3A/B. In conclusion, 4-PBA inhibited ERS and reestablished mitochondrial fusion-fission balance, thereby blocking cell apoptosis, oxidative stress, and mitochondrial dysfunction, thus prevented against psoralen-induced hepatotoxicity.

Protective effect of Ficus capensis lyophilized extract against carboplatin-induced liver injury via inhibition of oxidative stress and inflammation in rats

Patients who are receiving carboplatin therapy for cancer often experience toxic side effects. This study examined the effects of lyophilized aqueous leaf extracts of F. capensis (LALEFC) on oxidative stress and inflammatory markers in albino rats with carboplatin-damaged livers. We randomly assigned 35 rats to five experimental groups. Groups 2–5 underwent liver injury induction using carboplatin, while groups 1 and 2 served as the normal and carboplatin control groups, respectively. Groups 3–5 were the treatment groups. Treatments were performed for 17 days. We analyzed the quantitative phytochemical constituents of LALEFC using standard procedures and analyzed the liver oxidative stress and inflammatory markers using liver homogenate. The phytochemical constituents of LALEFC (mg/100 g) occur in the following order: The most abundant compounds were phenols (1577.72 ± 0.008), flavonoids (1253.13 ± 0.007), tannins (878.97 ± 0.007), alkaloids (652.66 ± 0.007), glycosides (314.39 ± 0.011), and terpenoids (261.18 ± 0.154), while steroids (0.573 ± 0.062), saponins (0.370 ± 0.003), and HCN (0.254.00 ± 0.006) were found in trace amount. The study of oxidative stress and inflammatory markers showed that giving carboplatin to rats greatly increased the levels of interleukin-1 (IL-1), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), nuclear factor-kappa B (NF-α), malondialdehyde (MDA), reactive oxygen species (ROS), and caspase-3 activity. It also decreased the levels of reduced glutathione (GSH) and the activities of glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD). D). However, coadministration of LALEFC significantly restored the altered oxidative and inflammatory responses. This finding suggested that carboplatin induced liver injury through redox imbalance, which elevated the expression of inflammatory markers. LALEFC's restoration of altered markers could be relevant in the treatment of carboplatin-induced liver injury.

Interpretable multitemporal liver function indicator model for prediction and risk factor analysis of drug induced liver injury

The occurrence of liver injury during cancer treatment is extremely harmful. The risk factors for drug.induced liver injury (DILI) in the pancreatic cancer population have not been investigated. This study aims to develop and validate an interpretable decision tree (DT) model for the early prediction of DILI in pancreatic cancer patients using multitemporal clinical data and screening for related risk factors. A retrospective collection of data was conducted on 307 patients, the training set (n = 215) was used to develop the model, and the test set (n = 92) was used to evaluate the model. The classification and regression trees algorithm was employed to establish the DT model. The Shapley Additive explanations (SHAP) method was used to facilitate clinical interpretation. Model performance was assessed using AUC and the Hosmer‒Lemeshow test. The DT model exhibited superior diagnostic efficacy, the AUC values were 0.995 and 0.994 in the training and test sets, respectively. Four risk factors associated with DILI occurrence were identified: delta.albumin, delta.ALT, and post (AST: ALT), and post.GGT. The multiperiod liver function indicator.based interpretable DT model predicted DILI occurrence in the pancreatic cancer population and contributes to personalized clinical management of pancreatic cancer patients.

Histologic Features of Liver Injury Associated With SARS-CoV-2 Messenger RNA Vaccines.

Many drugs can induce liver injury; however, vaccine-induced liver injury is a rare phenomenon. SARS-CoV-2 messenger RNA (mRNA) vaccines are now widely administered, and clinical evidence of liver injury has been reported. To characterize the histologic features of SARS-CoV-2 mRNA vaccine-associated liver injury. Thirteen liver biopsies from 12 patients with elevated liver enzymes clinically favored to be secondary to SARS-CoV-2 mRNA vaccine were identified between 2021 and 2022. Demographics, clinical information, and histologic features of liver biopsies were reviewed. All patients (median age, 58 years; M:F = 4:8) received at least 1 dose of SARS-CoV-2 mRNA vaccines (7 Pfizer and 5 Moderna). Four patients had a history of liver disease. Nine patients developed symptoms between 1 day and 2 months after receiving the vaccine dose. Viral serologies were negative. Drug-induced liver injury was thought to be less likely clinically in the 3 patients who had started new medications. Autoimmune antibodies were detected in 9 patients. Moderate to severe active hepatitis was the dominant histologic pattern of injury (9 of 13 biopsies; 69%). Resolving hepatitis, cholestatic hepatitic injury, and bile duct injury were identified in 1 biopsy each. All patients recovered spontaneously or with steroid therapy except one patient who developed autoimmune hepatitis. Moderate to severe active hepatitis is commonly observed in SARS-CoV-2 mRNA vaccine-associated liver injury, and female patients may be more susceptible to injury. Liver injury resolves spontaneously or with steroid treatment. In rare cases, these vaccines may trigger an underlying immune condition.

Exploring the Mechanism of Modified Zexie Decoction Against Metabolic Associated Fatty Liver Disease Based on Network Pharmacology and Experimental Validation.

The incidence of metabolic-associated fatty liver disease (MAFLD) increases annually. Modified Zexie Decoction (MZXD) can treat this disease; however, their mechanisms of action are uncertain. This study evaluated the mechanisms of MZXD against MAFLD based on network pharmacology, molecular docking, and in vivo experiments. The main active compounds, targets and signaling pathways of MZXD against MAFLD were obtained using network pharmacological analysis. Underlying mechanisms were validated by molecular docking and in vivo assays. Forty-one active ingredients and 197 intersection targets were identified. The main active ingredients include quercetin, luteolin, isorhamnetin, 3-methylhexane, and 3β- acetoxyatractylone. The main targets were TP53, JUN, HSP90AA1, MAPK1, MAPK3, AKT1, NF-κB p65, TNF, ESR1, FOS, and IL-6. The pathway enrichment analysis indicated that MZXD was related to the IL-17, TNF, and PI3K-AKT signaling pathways. Molecular docking suggested that these active ingredients bound strongly to TNF, IL-6, and NF-κB p65, which are integral components of the TNF pathway. In the rat MAFLD model, MZXD attenuated high-fat diet( HFD)-induced liver injury and lipid accumulation, decreased the serum levels of the inflammatory mediators TNF-α, IL6, and IL-1β, and inhibited the protein expression of TNF-α, IL6, p- IKB-α and p-NF-κB p65. Furthermore, immunohistochemistry results showed that MZXD attenuated the F4/80 staining intensity of the liver compared with the model group. Collectively, our results suggested that MZXD could improve MAFLD by downregulating TNF/NF-κB signaling mediated macrophage activation.

P15-14 Characterisation of liver-derived T-cells during and upon resolution of CFTR modulator induced liver injury

P15-14 Characterisation of liver-derived T-cells during and upon resolution of CFTR modulator induced liver injury

P01-54 New fluorescent probes for quick assessment of drug induced liver injury effects on bile canaliculi dynamism and albumin expression

P01-54 New fluorescent probes for quick assessment of drug induced liver injury effects on bile canaliculi dynamism and albumin expression