ABSTRACT
This study aims to investigate the mitigating effect and mechanism of Cichorium glandulosum n-butanol extraction site(CGE) on the disease in carbon tetrachloride(CCl_4)-induced chronic liver injury model in rats. A chronic liver injury model was constructed by subcutaneous injection of CCl_4 olive oil solution, and after four weeks of CGE treatment, serum levels of aspartate aminotransferase(AST), alanine aminotransferase(ALT), alkaline phosphatase(AKP), hydroxyproline(HYP), interleukin-4(IL-4), interleukin-6(IL-6), malondialdehyde(MDA), superoxide dismutase(SOD), and tumor necrosis factor-α(TNF-α) were detected. Liver tissue was processed by hematoxylin-eosin(HE) staining and Masson staining to observe the structure of the rat liver. qPCR and Western blot were used to examine the expression of transforming growth factor-ß1(TGF-ß1)/small mothers against decapentaplegic(Smad), Toll-like receptor 4(TLR4), α-smooth muscle actin(α-SMA), and fibronectin(Fn) in rat liver tissue and hepatic stellate-T6(HSC-T6) and evaluate the inhibitory effect of CGE on HSC activation. The results showed that CGE could significantly reduce the serum levels of AST, ALT, AKP, HYP, and affect the levels of related inflammatory indexes including IL-4, IL-6, and TNF-α, and MDA in CCl_4-induced chronic liver injury in rats and had no effect on SOD activity, which could delay the process of liver injury, alleviate the hepatic collagen deposition and inflammatory infiltration, and had significant efficacy in mitigating chronic liver injury in rats. CGE could inhibit α-SMA and TLR4 protein expression in the liver tissue and reverse the increased TGF-ß1/Smad, Fn, and TLR4-related expression in HSC-T6 in vitro. The above results indicated that CGE exerted hepatoprotective effects in rats by inhibiting HSC activation and alleviated CCl_4-induced chronic liver injury in rats and could ameliorate inflammatory response and slight liver fibrosis in rat liver tissue. Its pharmacodynamic mechanism might be related to TGF-ß1/Smad and TLR4-related expression.
Subject(s)
Carbon Tetrachloride , Liver , Rats, Sprague-Dawley , Animals , Rats , Carbon Tetrachloride/adverse effects , Male , Liver/metabolism , Liver/drug effects , Liver/injuries , 1-Butanol/chemistry , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/administration & dosage , Humans , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Superoxide Dismutase/metabolism , Superoxide Dismutase/genetics , Alanine Transaminase/blood , Aspartate Aminotransferases/blood , Transforming Growth Factor beta1/metabolism , Transforming Growth Factor beta1/genetics , Interleukin-6/genetics , Interleukin-6/metabolism , Malondialdehyde/metabolism , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Interleukin-4/genetics , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Chemical and Drug Induced Liver Injury, Chronic/metabolism , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/drug therapy , Chemical and Drug Induced Liver Injury/geneticsABSTRACT
Sepsis is a systemic inflammatory response syndrome caused by infection, with high morbidity and mortality. Sepsis-induced liver injury(SILI) is one of the manifestations of sepsis-induced multiple organ syndrome. At present, there is no recommended pharmacological intervention for the treatment of SILI. traditional Chinese medicine(TCM), based on the holism and dialectical treatment concept, shows the therapeutic characteristics of multi-target and multi-pathway and can comprehensively prevent and treat SILI by interfering with inflammatory factors, inflammatory signaling pathways, and anti-oxidative stress and inhibiting apoptosis. This article reviewed the experimental studies on the treatment of SILI with TCM to clarify its pathogenic mechanism and therapeutic characteristics, so as to provide more ideas and directions for the development or preparation of new drugs.
Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Drugs, Chinese Herbal , Sepsis , Humans , Medicine, Chinese Traditional , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Sepsis/complications , Sepsis/drug therapy , Apoptosis , Signal Transduction , Drugs, Chinese Herbal/therapeutic use , Drugs, Chinese Herbal/pharmacologyABSTRACT
OBJECTIVE: Azvudine is an effective treatment for patients infected with common COVID-19. However, physicians have reported a series of adverse reactions, including multiple cases of liver injury, caused by azvudine in clinical practice. This study assessed the incidence, clinical features, and associated risk factors of liver injury induced by azvudine in real-world settings, offering guidance for safe clinical use. MATERIALS AND METHODS: This study utilized the Chinese Hospital Pharmacovigilance System (CHPS) to retrospectively analyze the treatment of COVID-19 patients with azvudine at Changsha Central Hospital from December 19, 2022, to June 6, 2023. A case-control study was conducted to analyze the occurrence of azvudine-induced liver injury in COVID-19 patients who triggered a CHPS alert compared to normal COVID-19 patients. RESULTS: Among the total of 2,141 COVID-19 patients, 31 (1.45%) developed azvudine-induced liver injury, which is classified as an occasional adverse reaction. Liver injury was observed in 93.55% of patients between days 4 and 12 of the azvudine treatment, with elevated transaminases as the primary clinical manifestation. Univariate and binary logistic regression analyses indicated that low albumin levels and co-administration of low-molecular-weight heparin were statistically significant risk factors (p < 0.05). CONCLUSION: This study represents the first investigation of azvudine-induced liver injury and high-risk patients using the CHPS. The findings provide valuable insights to promote the safety of anti-COVID-19 drugs, serving as an important reference for future drug safety measures.
Subject(s)
Azides , COVID-19 , Chemical and Drug Induced Liver Injury, Chronic , Deoxycytidine/analogs & derivatives , Humans , Heparin, Low-Molecular-Weight/adverse effects , Pharmacovigilance , Retrospective Studies , Case-Control Studies , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Prospective Studies , Risk Factors , AlbuminsABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: The use of antineoplastic drugs, such as cisplatin, in clinical practice can cause adverse effects in patients, such as liver injury, which limits their long-term use. Therefore, there is an urgent need to develop alternative therapeutic strategies or drugs to minimize cisplatin-induced liver injury. Huangqi, the root of Astragalus membranaceus, is extensively used in traditional Chinese medicine (TCM) and has been employed in treating diverse liver injuries. Astragalus membranaceus contains several bioactive constituents, including triterpenoid saponins, one of which, astragaloside IV (ASIV), has been reported to have anti-inflammatory and antioxidant stress properties. However, its potential in ameliorating cisplatin-induced liver injury has not been explored. AIM OF THE STUDY: The objective of this study was to examine the mechanism by which ASIV protects against cisplatin-induced liver injury. MATERIALS AND METHODS: This study established a model of cisplatin-induced liver injury in mice, followed by treatment with various doses of astragaloside IV (40 mg/kg, 80 mg/kg). In addition, a model of hepatocyte ferroptosis in AML-12 cells was established using RSL3. The mechanism of action of astragaloside IV was investigated using a range of methods, including Western blot assay, qPCR, immunofluorescence, histochemistry, molecular docking, and high-content imaging system. RESULTS: The findings suggested a significant improvement in hepatic injury, inflammation and oxidative stress phenotypes with the administration of ASIV. Furthermore, network pharmacological analyses provided evidence that a major pathway for ASIV to attenuate cisplatin-induced hepatic injury entailed the cell death cascade pathway. It was observed that ASIV effectively inhibited ferroptosis both in vivo and in vitro. Subsequent experimental outcomes provided further validation of ASIV's ability to hinder ferroptosis through the inhibition of PPARα/FSP1 signaling pathway. The current findings suggest that ASIV could function as a promising phytotherapy composition to alleviate cisplatin-induced liver injury. CONCLUSIONS: The current findings suggest that astragaloside IV could function as a promising phytotherapy composition to alleviate cisplatin-induced liver injury.
Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Ferroptosis , Saponins , Triterpenes , Humans , Mice , Animals , Cisplatin/toxicity , Molecular Docking Simulation , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Saponins/pharmacology , Saponins/therapeutic use , Saponins/chemistry , Triterpenes/pharmacology , Triterpenes/therapeutic use , Triterpenes/chemistryABSTRACT
BACKGROUND AND AIMS: The use of corticosteroids in chronic drug-induced liver injury (DILI) is an important issue. Our previous randomized controlled trial showed that patients with chronic DILI benefited from a 48-week steroid stepwise reduction (SSR) regimen. However, it remains unclear whether a shorter course of therapy can achieve similar efficacy. In this study, we aimed to assess whether a 36-week SSR can achieve efficacy similar to that of 48-week SSR. METHODS: A randomized open-label trial was performed. Eligible patients were randomly assigned to the 36- or 48-week (1:1) SSR group. Liver biopsies were performed at baseline and at the end of treatment. The primary outcome was the proportion of patients with relapse rate (RR). The secondary outcomes were improvement in liver histology and safety. RESULTS: Of the 90 participants enrolled, 84 (87.5%) completed the trial, and 62 patients (68.9%) were women. Hepatocellular damage was observed in 53.4% of the cohort. The RR was 7.1% in the 36-week SSR group but 4.8% in the 48-week SSR group, as determined by per-protocol set analysis (p = 1.000). Significant histological improvements in histological activity (93.1% vs. 92.9%, p = 1.000) and fibrosis (41.4% vs. 46.4%, p = .701) were observed in both the groups. Biochemical normalization time did not differ between the two groups. No severe adverse events were observed. CONCLUSIONS: Both the 36- and 48-week SSR regimens demonstrated similar biochemical response and histological improvements with good safety, supporting 36-week SSR as a preferable therapeutic choice (ClinicalTrials.gov, NCT03266146).
Subject(s)
Liver , Humans , Female , Male , Middle Aged , Prospective Studies , Adult , Liver/pathology , Liver/drug effects , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Chemical and Drug Induced Liver Injury, Chronic/etiology , Treatment Outcome , Glucocorticoids/administration & dosage , Glucocorticoids/adverse effects , Recurrence , Aged , Chemical and Drug Induced Liver Injury/etiology , Drug Administration ScheduleABSTRACT
BACKGROUND: Chronic liver injury (CLI) is a complex condition that requires effective therapeutic interventions. The Yi-Shan-Hong (YSH) formula is an empirically derived remedy that has shown effectiveness and safety in the management of chronic liver damage. However, the bioactive components and multifaceted mechanisms of YSH remain inadequately understood. PURPOSE: To examine the bioactive compounds and functional processes that contribute to the therapeutic benefits of YSH against CLI. METHODS: Serum pharmacochemistry and network pharmacology were employed to identify active compounds and possible targets of YSH in CLI. In addition, YSH was also given in three doses to d-(+)-galactosamine hydrochloride (D-GalN) -induced CLI rats to test its therapeutic efficacy. RESULTS: The analysis of serum samples successfully detected 25 compounds from YSH. Searches on the databases resulted in 277 genes as being correlated with chemicals in YSH, and 397 genes associated with CLI. In vivo experiments revealed that YSH displayed a notable therapeutic impact on liver injury caused by d-GalN. This was evidenced by enhanced liver function and histopathological improvements, reduced oxidative stress response, proinflammatory factors, and fibrosis levels. Importantly, no discernible adverse effects were observed. Furthermore, the administration of YSH treatment reversed the activation of AKT phosphorylation caused by d-GalN, aligning with the findings of the network pharmacology study. CONCLUSION: These findings provide preclinical evidence of YSH's therapeutic value in CLI and highlight its hepatoprotective action via the PI3K/AKT signaling pathway.
Subject(s)
Drugs, Chinese Herbal , Liver , Network Pharmacology , Oxidative Stress , Rats, Sprague-Dawley , Animals , Drugs, Chinese Herbal/pharmacology , Male , Oxidative Stress/drug effects , Rats , Liver/drug effects , Galactosamine , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Signal Transduction/drug effectsABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucopyranoside (TSG) as the primary constituent of Polygonum multiflorum Thumb. (PM) possesses anti-oxidative, antihypercholesterolemic, anti-tumor and many more biological activities. The root of PM has been used as a tonic medicine for thousands of years. However, cases of PM-induced liver injury are occasionally reported, and considered to be related to the host immune status. AIM OF THE STUDY: The primary toxic elements and specific mechanisms PM causing liver damage are still not thoroughly clear. Our study aimed to investigate the influences of TSG on the immune response in idiosyncratic hepatotoxicity of PM. MATERIALS AND METHODS: The male C57BL/6 mice were treated with different doses of TSG and the alterations in liver histology, serum liver enzyme levels, proportions of T cells and cytokines secretion were evaluated by hematoxylin and eosin (HE), RNA sequencing, quantitative real time polymerase chain reaction (qRT-PCR), Flow cytometry (FCM), and enzyme-linked immunosorbent assay (ELISA), respectively. Then, primary spleen cells from drug-naive mice were isolated and cultured with TSG in vitro. T cell subsets proliferation and cytokines secretion after treated with TSG were assessed by CCK8, FCM and ELISA. In addition, mice were pre-treated with anti-CD25 for depleting regulatory T cells (Tregs), and then administered with TSG. Liver functions and immunological alterations were analyzed to evaluate liver injury. RESULTS: Data showed that TSG induced liver damage, and immune cells infiltration in the liver tissues. FCM results showed that TSG could activate CD4+T and CD8+T in the liver. Results further confirmed that TSG notably up-regulated the levels of inflammatory cytokines including TNF-α, IFN-γ, IL-18, perforin and granzyme B in the liver tissues. Furthermore, based on transcriptomics profiles, some immune system-related pathways including leukocyte activation involved in inflammatory response, leukocyte cell-cell adhesion, regulation of interleukin-1 beta production, mononuclear cell migration, antigen processing and presentation were altered in TSG treated mice. CD8+T/CD4+T cells were also stimulated by TSG in vitro. Interestingly, increased proportion of Tregs was observed after TSG treatment in vitro and in vivo. Foxp3 and TGF-ß1 mRNA expressions were up-regulated in the liver tissues. Depletion of Tregs moderately enhanced TSG induced the secretion of inflammatory cytokines in serum. CONCLUSIONS: Our findings showed that TSG could trigger CD4+T and CD8+T cells proliferation, promote cytokines secretion, which revealed that adaptive immune response associated with the mild liver injury cause by TSG administration. Regulatory T cells (Tregs) mainly sustain immunological tolerance, and in this study, the progression of TSG induced liver injury was limited by Tregs. The results of our investigations allow us to preliminarily understand the mechanisms of PM related idiosyncratic hepatotoxicity.
Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Fallopia multiflora , Polygonum , Stilbenes , Mice , Male , Animals , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Mice, Inbred C57BL , Cytokines/genetics , Immunity , Stilbenes/toxicity , Stilbenes/therapeutic useABSTRACT
Tyrosine kinase inhibitors (TKIs) are highly efficient small-molecule anticancer drugs. Despite the specificity and efficacy of TKIs, they can produce off-target effects, leading to severe liver toxicity, and even some of them are labeled as black box hepatotoxicity. Thus, we focused on representative TKIs associated with severe hepatic adverse events, namely lapatinib, pazopanib, regorafenib, and sunitinib as objections of study, then integrated drug side-effect data from United State Food and Drug Administration (U.S. FDA) and network pharmacology to elucidate mechanism underlying TKI-induced liver injury. Based on network pharmacology, we constructed a specific comorbidity module of high risk of serious adverse effects and created drug-disease networks. Enrichment analysis of the networks revealed the depletion of all-trans-retinoic acid and the involvement of down-regulation of the HSP70 family-mediated endoplasmic reticulum (ER) stress as key factors in TKI-induced liver injury. These results were further verified by transcription data. Based on the target prediction results of drugs and reactive metabolites, we also shed light on the association between toxic metabolites and severe hepatic adverse reactions, and thinking HSPA8, HSPA1A, CYP1A1, CYP1A2 and CYP3A4 were potential therapeutic or preventive targets against TKI-induced liver injury. In conclusion, our research provides comprehensive insights into the mechanism underlying severe liver injury caused by TKIs, offering a better understanding of how to enhance patient safety and treatment efficacy.
Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Chemical and Drug Induced Liver Injury , United States , Humans , Protein Kinase Inhibitors/adverse effects , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Network Pharmacology , Chemical and Drug Induced Liver Injury/drug therapyABSTRACT
Stachydrine, a prominent bioactive alkaloid derived from Leonurus heterophyllus, is a significant herb in traditional medicine. It has been noted for its anti-inflammatory and antioxidant characteristics. Consequently, we conducted a study of its hepatoprotective effect and the fundamental mechanisms involved in acetaminophen (APAP)-induced liver injury, utilizing a mouse model. Mice were intraperitoneally administered a hepatotoxic dose of APAP (300 mg/kg). Thirty minutes after APAP administration, mice were treated with different concentrations of stachydrine (0, 2.5, 5, and 10 mg/kg). Animals were sacrificed 16 h after APAP injection for serum and liver tissue assays. APAP overdose significantly elevated the serum alanine transferase levels, hepatic pro-inflammatory cytokines, malondialdehyde activity, phospho-extracellular signal-regulated kinase (ERK), phospho-protein kinase B (AKT), and macrophage-stimulating protein expression. Stachydrine treatment significantly decreased these parameters in mice with APAP-induced liver damage. Our results suggest that stachydrine may be a promising beneficial target in the prevention of APAP-induced liver damage through attenuation of the inflammatory response, inhibition of the ERK and AKT pathways, and expression of macrophage-stimulating proteins.
Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Chemical and Drug Induced Liver Injury , Proline , Animals , Mice , Acetaminophen/toxicity , Chemical and Drug Induced Liver Injury/drug therapy , Chemical and Drug Induced Liver Injury/prevention & control , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Chemical and Drug Induced Liver Injury, Chronic/metabolism , Extracellular Signal-Regulated MAP Kinases/drug effects , Extracellular Signal-Regulated MAP Kinases/metabolism , Liver/metabolism , Macrophages/metabolism , Oxidative Stress , Proline/analogs & derivatives , Proto-Oncogene Proteins c-akt/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Macrophage Colony-Stimulating Factor/drug effects , Macrophage Colony-Stimulating Factor/metabolismABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Gentiana kurroo Royle is a medicinal plant mentioned as Traymana in Ayurveda. In the folklore, it is used to cure fever, stomach ache, skin diseases and liver disorders. However, limited reports are available on the therapeutic potential of Gentiana kurroo Royle against alcohol-induced liver damage. AIM OF THE STUDY: To assess the effectiveness of the hydroethanolic extract of Gentiana kurroo Royle rhizome (GKRE) against alcohol-induced liver injury and explore the mechanism of action. MATERIALS AND METHODS: GKRE was characterized using UHPLC-QTOF-MS/MS. The binding affinity of the identified compound was studied in silico. In vitro studies were performed in the Huh-7 cell line. An acute oral toxicity study (2 g/kg BW) of GKRE was done in rats following OECD 420 guidelines. In the efficacy study, rats were treated with 50% ethanol (5 mL/kg BW, orally) for 4 weeks, followed by a single intraperitoneal dose of CCl4 (30%; 1 mL/kg BW) to induce liver injury. After 4th week, the rats were treated with GKRE at 100, 200 and 400 mg/kg BW doses for the next fifteen days. The biochemical and antioxidant parameters were analyzed using commercial kits and a biochemistry analyzer. Histopathology, gene and protein expressions were studied using qRT PCR and western blotting. RESULTS: Thirteen compounds were detected in GKRE. Few compounds showed a strong interaction with the fibrotic and inflammatory proteins in silico. GKRE reduced (p < 0.05) the ethanol-induced ROS production and inflammation in Huh-7 cells. The acute oral toxicity study revealed no adverse effect of GKRE in rats at 2 g/kg BW. GKRE improved (p < 0.05) the body and liver weights in ethanol-treated rats. GKRE improved (p < 0.05) the mRNA levels of ADH, SREBP1c and mitochondrial biogenesis genes in the liver tissues. GKRE also improved (p < 0.05) the liver damage markers, lipid peroxidation and levels of antioxidant enzymes in the liver. A reduced severity (p < 0.05) of pathological changes, fibrotic tissue deposition and caspase 3/7 activity were observed in the liver tissues of GKRE-treated rats. Further, GKRE downregulated (p < 0.05) the expression of fibrotic (TGFß, αSMA and SMADs) and inflammatory markers (TNFα, IL6, IL1ß and NFκB) in the liver. CONCLUSION: GKRE showed efficacy against alcohol-induced liver damage by inhibiting oxidative stress, apoptosis, inflammation and fibrogenesis in the liver.
Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Chemical and Drug Induced Liver Injury , Gentiana , Liver Diseases, Alcoholic , Rats , Animals , Antioxidants/pharmacology , Antioxidants/metabolism , Ethanol/toxicity , Gentiana/chemistry , Rhizome/metabolism , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Plant Extracts/chemistry , Tandem Mass Spectrometry , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Oxidative Stress , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/metabolism , Liver , Liver Diseases, Alcoholic/drug therapy , Chemical and Drug Induced Liver Injury/drug therapy , Chemical and Drug Induced Liver Injury/prevention & control , Chemical and Drug Induced Liver Injury/metabolismABSTRACT
INTRODUCTION: There is a high morbidity and mortality rate in mechanical trauma (MT)-induced hepatic injury. Currently, the molecular mechanisms underlying liver MT are largely unclear. Exploring the underlying mechanisms and developing safe and effective medicines to alleviate MT-induced hepatic injury is an urgent requirement. The aim of this study was to reveal the role of mitochondria-associated ER membranes (MAMs) in post-traumatic liver injury, and ascertain whether melatonin protects against MT-induced hepatic injury by regulating MAMs. METHODS: Hepatic mechanical injury was established in Sprague-Dawley rats and primary hepatocytes. A variety of experimental methods were employed to assess the effects of melatonin on hepatic injury, apoptosis, MAMs formation, mitochondrial function and signaling pathways. RESULTS: Significant increase of IP3R1 expression and MAMs formation were observed in MT-induced hepatic injury. Melatonin treatment at the dose of 30 mg/kg inhibited IP3R1-mediated MAMs and attenuated MT-induced liver injury in vivo. In vitro, primary hepatocytes cultured in 20% trauma serum (TS) for 12 h showed upregulated IP3R1 expression, increased MAMs formation and cell injury, which were suppressed by melatonin (100 µmol/L) treatment. Consequently, melatonin suppressed mitochondrial calcium overload, increased mitochondrial membrane potential and improved mitochondrial function under traumatic condition. Melatonin's inhibitory effects on MAMs formation and mitochondrial calcium overload were blunted when IP3R1 was overexpressed. Mechanistically, melatonin bound to its receptor (MR) and increased the expression of phosphorylated ERK1/2, which interacted with FoxO1 and inhibited the activation of FoxO1 that bound to the IP3R1 promoter to inhibit MAMs formation. CONCLUSION: Melatonin prevents the formation of MAMs via the MR-ERK1/2-FoxO1-IP3R1 pathway, thereby alleviating the development of MT-induced liver injury. Melatonin-modulated MAMs may be a promising therapeutic therapy for traumatic hepatic injury.
Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Melatonin , Animals , Rats , Calcium/metabolism , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Melatonin/pharmacology , Melatonin/therapeutic use , Rats, Sprague-DawleyABSTRACT
BACKGROUND: Liver injury associated with oxaliplatin (L-OHP)-based chemotherapy can significantly impact the treatment outcomes of patients with colorectal cancer liver metastases, especially when combined with surgery. To date, no definitive biomarker that can predict the risk of liver injury has been identified. This study aimed to investigate whether organoids can be used as tools to predict the risk of liver injury. METHODS: We examined the relationship between the clinical signs of L-OHP-induced liver injury and the responses of patient-derived liver organoids in vitro. Organoids were established from noncancerous liver tissues obtained from 10 patients who underwent L-OHP-based chemotherapy and hepatectomy for colorectal cancer. RESULTS: Organoids cultured in a galactose differentiation medium, which can activate the mitochondria of organoids, showed sensitivity to L-OHP cytotoxicity, which was significantly related to clinical liver toxicity induced by L-OHP treatment. Organoids from patients who presented with a high-grade liver injury to the L-OHP regimen showed an obvious increase in mitochondrial superoxide levels and a significant decrease in mitochondrial membrane potential with L-OHP exposure. L-OHP-induced mitochondrial oxidative stress was not observed in the organoids from patients with low-grade liver injury. CONCLUSIONS: These results suggested that L-OHP-induced liver injury may be caused by mitochondrial oxidative damage. Furthermore, patient-derived liver organoids may be used to assess susceptibility to L-OHP-induced liver injury in individual patients.
Subject(s)
Antineoplastic Agents , Chemical and Drug Induced Liver Injury, Chronic , Colorectal Neoplasms , Humans , Oxaliplatin/adverse effects , Colorectal Neoplasms/pathology , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Organoids/pathology , Antineoplastic Agents/adverse effectsABSTRACT
BACKGROUND: Intravenous vancomycin therapy can cause liver injury as well as "drug reaction with eosinophilia and systemic symptoms" (DRESS) syndrome. This study aimed to better define the clinical features and HLA associations of vancomycin-induced liver injury. OBJECTIVE: To describe clinical, biochemical, and temporal characteristics of vancomycin-induced liver injury. METHODS: Cases of liver injury with recent exposure to vancomycin who were enrolled in the US Drug-induced Liver Injury Network between 2004 and 2020 were assessed. Sequencing of HLA alleles was performed on stored blood samples. RESULTS: Among 1697 cases of drug-induced liver injury identified between 2004 and 2021, 9 (0.5%) were attributed to intravenous vancomycin. The 9 cases included 6 men, median age 60 years (range, 23-85 days), and treatment for 26 days (range, 1-34 days). The clinical presentation was DRESS syndrome in 8 patients, of whom 6 received corticosteroids. Liver injury varied from hepatocellular to cholestatic and from mild (n = 5) to fatal (n = 1). In survivors, liver injury and DRESS syndrome ultimately resolved. HLA typing demonstrated the HLA-A∗32:01 allele in 7 vancomycin cases (78%, all with DRESS syndrome), versus 1 of 81 cases (1.2%) exposed but not attributed to vancomycin, and 113 of 1708 cases (6.6%) without vancomycin exposure. The allele frequency in vancomycin cases was 0.44 compared with less than 0.04 in US populations. CONCLUSIONS: Vancomycin-induced liver injury is commonly associated with DRESS syndrome and linked to HLA-A∗32:01. HLA-A∗32:01 testing could be considered early to risk-stratify patients using long-term intravenous vancomycin therapy.
Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Chemical and Drug Induced Liver Injury , Drug Hypersensitivity Syndrome , Eosinophilia , Humans , Male , Middle Aged , Chemical and Drug Induced Liver Injury/genetics , Chemical and Drug Induced Liver Injury/drug therapy , Chemical and Drug Induced Liver Injury, Chronic/complications , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Drug Hypersensitivity Syndrome/drug therapy , Eosinophilia/drug therapy , HLA-A Antigens , Vancomycin/adverse effects , FemaleABSTRACT
OBJECTIVES: Preclinical evidence is needed to assess drug-metabolite behaviour in compromised liver function for developing the best antitubercular treatment (ATT) re-introduction regimen in drug-induced liver injury (DILI). The pharmacokinetic behavior of rifampicin (RMP) and its active metabolite des-acetyl-rifampicin (DARP) in DILI's presence is unknown. To study the pharmacokinetic behavior of RMP and DARP in the presence of carbon tetrachloride (CCl4) plus ATT-DILI in rats. METHODS: Thirty rats used in the experiment were divided equally into six groups. We administered a single 0.5â¯mL/kg CCl4 intraperitoneal injection in all rats. Groups II, III, IV, and V were started on daily oral RMP alone, RMP plus isoniazid (INH), RMP plus pyrazinamide (PZA), and the three drugs INH, RMP, and PZA together, respectively, for 21-days subsequently. Pharmacokinetic (PK) sampling was performed at 0, 0.5, 1, 3, 6, 12, and 24â¯h post-dosing on day 20. We monitored LFT at baseline on days-1, 7, and 21 and sacrificed the rats on the last day of the experiment. RESULTS: ATT treatment sustained the CCl4-induced liver injury changes. A significant rise in mean total bilirubin levels was observed in groups administered rifampicin. The triple drug combination group demonstrated 1.43- and 1.84-times higher area-under-the-curve values of RMP (234.56±30.66 vs. 163.55±36.14⯵gâ¯h/mL) and DARP (16.15±4.50 vs. 8.75±2.79⯵gâ¯h/mL) compared to RMP alone group. Histological and oxidative stress changes supported underlying liver injury and PK alterations. CONCLUSIONS: RMP metabolism inhibition by PZA, more than isoniazid, was well preserved in the presence of underlying liver injury.
Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Chemical and Drug Induced Liver Injury , Rats , Animals , Rifampin/pharmacokinetics , Rifampin/therapeutic use , Isoniazid/pharmacokinetics , Isoniazid/therapeutic use , Rats, Wistar , Carbon Tetrachloride , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Antitubercular Agents/pharmacokinetics , Antitubercular Agents/therapeutic use , Chemical and Drug Induced Liver Injury/drug therapyABSTRACT
Adriamycin (ADR) is an important chemotherapeutic drug, but it has serious side effects such as hepatotoxicity. This study aimed to evaluate whether N-acetylcysteine (NAC) has hepatoprotective effects against ADR-induced hepatotoxicity in rats. In addition, it was aimed to determine how Meteorin-Like (MtrnL), which has pleiotropic effects on immunology, inflammation, and metabolism, is affected by ADR and/or NAC applications in liver tissue. 28 rats were randomly assigned to one of four equal groups in the study: control (no treatment), NAC (150 mg/kg/day of NAC intraperitoneally (i.p), ADR (15 mg/kg only on the first day of the experiment), and ADR + NAC (ADR 15 mg/kg on the first day of the experiment + 150 mg/kg/day NAC i.p). After 15 days, liver enzyme levels in serum, oxidant/antioxidant parameters in liver tissue, histopathological changes, caspase 3 (Casp3) and heat shock protein 70 (HSP-70) immunoreactivities, and MtrnL levels were examined. Histopathological changes, liver enzyme levels, as well as HSP-70, and Casp3 immunoreactivities increased due to ADR application. Additionally, MtrnL levels in liver tissue were significantly increased as a result of ADR application. However, it was detected that the NAC application significantly regulated the ADR-induced changes. Furthermore, it was determined that NAC administration regulated the changes in ADR-induced oxidative stress parameters. We propose that NAC may exert a hepatoprotective effect by regulating ADR-induced altered oxidative stress parameters, MtrnL levels, Casp3, and HSP-70 immunoreactivities in the liver.
Subject(s)
Acetylcysteine , Chemical and Drug Induced Liver Injury, Chronic , Rats , Animals , Acetylcysteine/pharmacology , Acetylcysteine/metabolism , Acetylcysteine/therapeutic use , Doxorubicin/toxicity , Caspase 3/metabolism , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Chemical and Drug Induced Liver Injury, Chronic/metabolism , Chemical and Drug Induced Liver Injury, Chronic/pathology , Liver/metabolism , Antioxidants/metabolism , Oxidative StressABSTRACT
Lycopene is a carotenoid widely used for its dominant antioxidant properties and beneficial health effects. Silver nanoparticles (AgNP) have gained attention for use in many medicinal and consumer products, leading to animal, human, and environmental exposure. This study investigated the dose-dependent effects of lycopene on AgNP-induced hepatotoxicity in albino mice. The four experimental groups, comprising eight albino mice each, were as follows: Group I, vehicle control (C); Group II, AgNP-treated (5 mg/kg/day) (AgNP); Group III, AgNP/lycopene-treated (5 + 10 mg/kg/day) (AgNP + LP10); and Group IV, AgNP/lycopene-treated (5 + 100 mg/kg/day) (AgNP + LP100). All solutions were orally administered to the mice once in a day for consecutive 14 days. The levels of serum aspartate transaminase, alanine transaminase, alkaline phosphatase, and total bilirubin were significantly higher in the AgNP-treated group than in the control group but significantly lower in the AgNP + LP100 group than in the AgNP-treated group. A significant decrease in reduced glutathione level and superoxide dismutase activity and an increase in lipid peroxidation were observed in the AgNP-treated group; these were significantly suppressed in the AgNP+LP100 as compared to AgNP-treated group. Histopathological examination showed substantial morphological alterations in hepatic tissues in the AgNP, which were adequately improved in the low and high dose lycopene-treated groups. The dose of 100 mg/kg/day of lycopene was more effective than 10 mg/kg/day, as pretreatment with high dose lycopene significantly diminished the adverse changes occurred due to AgNP in liver weight, hepatic architecture, serum functional markers, and antioxidant markers. Thus, present study shows that pretreatment with lycopene offers protection against AgNP-induced hepatotoxicity and oxidative stress.
Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Chemical and Drug Induced Liver Injury , Metal Nanoparticles , Humans , Mice , Animals , Lycopene/pharmacology , Lycopene/metabolism , Antioxidants/metabolism , Metal Nanoparticles/toxicity , Silver/toxicity , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Chemical and Drug Induced Liver Injury, Chronic/metabolism , Chemical and Drug Induced Liver Injury, Chronic/pathology , Liver/metabolism , Oxidative Stress , Lipid Peroxidation , Chemical and Drug Induced Liver Injury/metabolismABSTRACT
OBJECTIVES: The hepatotoxicity of irinotecan has been widely implicated in the treatment of multiple solid tumours. However, there are few studies on the influencing factors of irinotecan-induced hepatotoxicity. Herein, we investigated the risk factors for irinotecan-induced liver injury among 421 patients receiving irinotecan-based regimens (IBRs). DESIGN: Retrospective multi-centre cross-sectional study. SETTING: This study surveyed four hospitals in China. PARTICIPANTS: After excluding participants with missing variables, we retrospectively collected the demographic, clinical and therapeutic data of 421 patients who received IBRs in four hospitals between January 2020 and December 2021 and divided the patients into two groups: those without liver injury and those with liver injury. RESULTS: The 421 enrolled patients were grouped (liver injury group: n=92; control group: n=329) according to their hepatic biochemical monitoring parameters. In our study, the multivariate logistic regression results showed that three to four cycles of chemotherapy (OR (95% CI): 2.179 (1.272 to 3.733); p=0.005) and liver metastasis (OR (95% CI): 1.748 (1.079 to 2.833); p=0.023) were independent risk factors for irinotecan-induced liver injury. The Cox proportional hazards model demonstrated that alcohol consumption history (OR (95% CI): 2.032 (1.183 to 3.491); p=0.010) and a cumulative dose of irinotecan ≥1000 mg (OR (95% CI): 0.362 (0.165 to 0.792); p=0.011) were significantly correlated with the onset time of irinotecan-induced liver injury. CONCLUSIONS: These findings suggest that patients with liver metastasis or who received three to four cycles of chemotherapy should undergo rigorous liver function monitoring to prevent or reduce the incidence of irinotecan-induced liver injury. Moreover, patients with a history of alcohol consumption should also be closely monitored.
Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Liver Neoplasms , Humans , Irinotecan/therapeutic use , Camptothecin/adverse effects , Cross-Sectional Studies , Retrospective Studies , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Chemical and Drug Induced Liver Injury, Chronic/etiology , Liver Neoplasms/secondary , Risk Factors , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
Cisplatin (CIS) is an effective chemotherapy against different solid cancers. However, the adverse effects, including hepatotoxicity, limit its clinical use. 7-hydroxycoumarin (7-HC) possesses antioxidant and hepatoprotective activities, but its protective effect against CIS hepatotoxicity has not been investigated. This study evaluated the effect of 7-HC on liver injury, oxidative stress (OS), and inflammation provoked by CIS. Rats received 7-HC (25, 50, and 100 mg/kg) orally for 2 weeks followed by intraperitoneal injection of CIS (7 mg/kg) at day 15. CIS increased serum transaminases, alkaline phosphatase (ALP), and bilirubin and provoked tissue injury accompanied by elevated reactive oxygen species (ROS), malondialdehyde (MDA), and nitric oxide (NO). Liver nuclear factor (NF)-κB p65, inducible NO synthase (iNOS), pro-inflammatory cytokines, Bax, and caspase-3 were upregulated, and antioxidant defenses and Bcl-2 were decreased in CIS-treated rats, while 7-HC prevented liver injury and ameliorated OS, inflammatory and apoptosis markers. In addition, 7-HC enhanced nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase (HO)-1 in CIS-administered rats and in silico studies revealed its binding affinity toward HO-1. In conclusion, 7-HC protected against CIS hepatotoxicity by mitigating OS and inflammatory response and modulating Nrf2/HO-1 pathway.
Subject(s)
Antioxidants , Chemical and Drug Induced Liver Injury, Chronic , Rats , Animals , Antioxidants/metabolism , Cisplatin/toxicity , NF-E2-Related Factor 2/metabolism , Up-Regulation , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Oxidative Stress , Inflammation/metabolism , NF-kappa B/metabolism , Umbelliferones/pharmacology , ApoptosisABSTRACT
BACKGROUND: Drug-induced liver injury (DILI) is an adverse reaction caused by ampicillin/sulbactam (ABPC/SBT). The albumin-bilirubin (ALBI) score is an index of hepatic functional reserve. However, the relationship between ABPC/SBT-induced DILI and ALBI score remains unknown; therefore, we aimed to elucidate the risk of ABPC/SBT-induced DILI based on the ALBI score. METHODS: This was a single-center, retrospective, case-control study using electronic medical records. A total of 380 patients were enrolled in the present study, and the primary outcome was ABPC/SBT-induced DILI. The ALBI score was calculated using serum albumin and total bilirubin levels. In addition, we performed COX regression analysis using age ≥75 years, dose ≥9 g/day, alanine aminotransferase (ALT) ≥21 IU/L, and ALBI score ≥-2.00 as covariates. We also performed 1:1 propensity score matching between non-DILI and DILI groups. RESULTS: The incidence of DILI was 9.5% (36/380). According to COX regression analysis, the adjusted hazard ratio for ABPC/SBT-induced DILI with an ALBI score ≥-2.00 was 2.55 (95% confidence interval: 1.256-5.191, P = 0.010), suggesting that patients with baseline ALBI score ≥-2.00 may be at high risk for ABPC/SBT-induced DILI. However, significant differences were not observed in cumulative risk for DILI between non-DILI and DILI patients regarding an ALBI score ≥-2.00 after propensity score matching (P = 0.146). CONCLUSION: These findings suggest that ALBI score may be a simple and potentially useful index for predicting ABPC/SBT-induced DILI. In patients with an ALBI score ≥-2.00, frequent liver function monitoring should be considered to prevent ABPC/SBT-induced DILI.
Subject(s)
Ampicillin , Bacterial Infections , Chemical and Drug Induced Liver Injury, Chronic , Sulbactam , Aged , Humans , Age Factors , Ampicillin/adverse effects , Bacterial Infections/drug therapy , Bilirubin/therapeutic use , Case-Control Studies , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Drug Therapy, Combination , Retrospective Studies , Serum Albumin , Sulbactam/adverse effectsABSTRACT
INTRODUCTION: Curcumin is a naturally occurring compound that has antioxidant properties, acts as a hepatoprotective, and lowers lipid peroxidation. However, curcumin's low solubility and bioavailability are its primary drawbacks and prevent its use as a therapeutic agent. In this study, curcumin nanoparticles will be created using the ultrasonic-assisted extraction method, and their effectiveness against paracetamol-induced changes in ALT, AST, SOD, MDA, and TNF-α will be compared to that of pure curcumin. PURPOSE: This study aimed to determine the hepatoprotective effect of curcumin nanoparticles in paracetamol- induced rats as a model for liver injury. METHODS: Thirty-six male Wistar rats, aged 6 to 8 weeks, with a minimum weight of 120 grams, were used in an experimental laboratory investigation with a post-test-only group design. Rats in each group received 100 mg/kgBW pure curcumin, 100 mg/kgBW curcumin nanoparticles, and 50 mg/kgBW curcumin nanoparticles for 7 days before paracetamol induction. On day 8, 300 mg/kgBW of paracetamol was intraperitoneally injected to cause liver damage. One of the groups received NAC as an antidote 10 hours after paracetamol induction. Detection of ALT and AST using a Chemistry Analyzer. ELISA approach for the detection of SOD, MDA, and TNF-α. The Roenigk score was calculated by two examiners after the liver histopathology preparations were stained using the Hematoxylin-Eosin method. Post hoc analyses were performed after the One Way Annova and Kruskal Wallis tests to examine the data. RESULTS: According to PSA results, the smallest formula that formed curcumin nanoparticles (10.2 nm) was 8 g of curcumin formula mixed with a mixture of Tween 20 4.5 ml, Kolliphor EL 1.5 ml, Propylene Glycol 1.5 ml, and Capryol 90 1 ml for 21 minutes using an ultrasonic process. MDA and TNF-α levels, as well as the liver's histological Roenigk score, were significantly lower in the 100 mg/kgBB pure curcumin group (C100) when compared to the model group (model). The levels of AST, MDA, TNF-α, and the liver histopathology score were significantly lower in the 100 mg/kgBB (NC100) and 50 mg/kgBB (NC50) curcumin nanoparticle groups compared to the model group (model) and pure curcumin group (C100) (p< 0.05). CONCLUSION: Curcumin nanoparticles showed better hepatoprotective ability than pure curcumin.