Crocus sativus L. Extract Containing Polyphenols Modulates Oxidative Stress and Inflammatory Response against Anti-Tuberculosis Drugs-Induced Liver Injury

The purpose of this study is to analyze the polyphenolic rich extract of Crocus sativus L. petals (CSP) in modulating liver oxidative stress and inflammatory response status against rifampicin isoniazid (INH-RIF) drug-induced liver injury. The INH-RIF was administered for 14 days with varying doses in Wistar rats, while silymarin was administered as standard dose. We report the defensive impacts of CSP against INH-RIF induced liver oxidative stress and proinflammatory cytokine. The CSP treatment at both doses significantly controlled all modulating biochemical hepatic injury indicators and resulted in the attenuation of arbitral INH-RIF damage. The components present in CSP identified by LC–ESI-Q-TOF–MS were found to be flavonoids and fatty acids. It can be inferred that CSP possesses a hepatoprotective capacity against INH-RIF-mediated hepatic injury, which may prove to be a medically beneficial natural product for the management of drug-induced liver injury.

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Drug-Induced Liver Injury: Clinical Evidence of N-Acetyl Cysteine Protective Effects

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/3320325 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Yonela Ntamo ◽

Khanyisani Ziqubu ◽

Nireshni Chellan ◽

Bongani B. Nkambule ◽

Tawanda M. Nyambuya ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Injury ◽

Hepatic Injury ◽

Clinical Evidence ◽

Antioxidant Properties ◽

Pathological Feature ◽

Protective Effects ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Acetyl Cysteine

Oxidative stress is a key pathological feature implicated in both acute and chronic liver diseases, including drug-induced liver injury (DILI). The latter describes hepatic injury arising as a direct toxic effect of administered drugs or their metabolites. Although still underreported, DILI remains a significant cause of liver failure, especially in developed nations. Currently, it is understood that mitochondrial-generated oxidative stress and abnormalities in phase I/II metabolism, leading to glutathione (GSH) suppression, drive the onset of DILI. N-Acetyl cysteine (NAC) has attracted a lot of interest as a therapeutic agent against DILI because of its strong antioxidant properties, especially in relation to enhancing endogenous GSH content to counteract oxidative stress. Thus, in addition to updating information on the pathophysiological mechanisms implicated in oxidative-induced hepatic injury, the current review critically discusses clinical evidence on the protective effects of NAC against DILI, including the reduction of patient mortality. Besides injury caused by paracetamol, NAC can also improve liver function in relation to other forms of liver injury such as those induced by excessive alcohol intake. The implicated therapeutic mechanisms of NAC extend from enhancing hepatic GSH levels to reducing biomarkers of paracetamol toxicity such as keratin-18 and circulating caspase-cleaved cytokeratin-18. However, there is still lack of evidence confirming the benefits of using NAC in combination with other therapies in patients with DILI.

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Isoniazid and Rifampicin Produce Hepatic Fibrosis through an Oxidative Stress-Dependent Mechanism

International Journal of Hepatology ◽

10.1155/2020/6987295 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Ayan Biswas ◽

Suman Santra ◽

Debasree Bishnu ◽

Gopal Krishna Dhali ◽

Abhijit Chowdhury ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Injury ◽

Hepatic Fibrosis ◽

Stellate Cell ◽

Progressive Increase ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Stress Dependent ◽

Liver Collagen

Background & Aims. Chronic hepatitis (CH) has emerged as a distinct outcome of drug-induced liver injury (DILI). Combination therapy of Isoniazid (INH) and Rifampicin (RMP) which is widely used for prolonged periods can cause acute hepatotoxicity and has been also incriminated in chronic DILI. We sought evidence of the production of hepatic fibrosis on long-term INH-RMP treatment through experiments in BALB/c mice exposed to INH-RMP. Methods. A combined dose of INH (50 mg) and RMP (100 mg) per kg body weight per day was administered to mice by oral gavage, 6 days a week, for 4 to 24 weeks for the assessment of liver injury, oxidative stress, and development of hepatic fibrosis, including demonstration of changes in key fibrogenesis linked pathways and mediators. Results. Progressive increase in markers of hepatic stellate cell (HSC) activation associated with changes in matrix turnover was observed between 12 and 24 weeks of INH-RMP treatment along with the elevation of liver collagen content and significant periportal fibrosis. These were associated with concurrent apoptosis of the hepatocytes, increase in hepatic cytochrome P450 2E1 (CYP2E1), NADPH oxidase (NOX) activity, and development of hepatic oxidative stress. Conclusions. INH-RMP can activate HSC through generation of NOX-mediated oxidative stress, leading to the development of liver fibrosis.

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Severe Drug-Induced Liver Injury from Combination Encorafenib/Binimetinib

Case Reports in Oncological Medicine ◽

10.1155/2019/3051945 ◽

2019 ◽

Vol 2019 ◽

pp. 1-4 ◽

Cited By ~ 1

Author(s):

Nicholas Gravbrot ◽

Srinath Sundararajan

Keyword(s):

Liver Injury ◽

Liver Function ◽

Combination Therapy ◽

Hepatic Injury ◽

Mek Inhibitor ◽

New Combination ◽

Normal Range ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

First Case

Encorafenib/binimetinib is a new combination BRAF/MEK inhibitor used in the treatment of advanced or metastatic BRAFV600-mutant melanoma. Though generally tolerated well, mild to moderate aminotransferase elevations are common. However, significant liver injury has not been demonstrated in the literature. Here, we report the first case of severe hepatic injury associated with encorafenib/binimetinib in a 58-year-old gentleman requiring admission and extensive workup. He was successfully treated by withdrawing the combination therapy, and liver function returned to normal range.

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ZnT8 Deficiency Protects From APAP-Induced Acute Liver Injury by Reducing Oxidative Stress Through Upregulating Hepatic Zinc and Metallothioneins

Frontiers in Pharmacology ◽

10.3389/fphar.2021.721471 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wen Su ◽

Mingji Feng ◽

Yuan Liu ◽

Rong Cao ◽

Yiao Liu ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Injury ◽

Serum Levels ◽

Zinc Transporter ◽

Hepatocyte Proliferation ◽

Glycogen Depletion ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Cytochrome P450 Family ◽

Jnk Activation

Zinc transporter 8 (ZnT8) is an important zinc transporter highly expressed in pancreatic islets. Deficiency of ZnT8 leads to a marked decrease in islet zinc, which is thought to prevent liver diseases associated with oxidative stress. Herein, we aimed to investigate whether loss of islet zinc affects the antioxidant capacity of the liver and acute drug-induced liver injury. To address this question, we treated ZnT8 knockout (KO) or wild-type control mice with 300 mg/ kg acetaminophen (APAP) or phosphate-buffered saline (PBS). Unexpectedly, we found that loss of ZnT8 in mice ameliorated APAP-induced injury and was accompanied by inhibition of c-Jun N-terminal kinase (JNK) activation, reduced hepatocyte death, and decreased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). An increase in hepatic glutathione (GSH) was observed, corresponding to a decrease in malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) levels. APAP-induced inflammation and glycogen depletion were alleviated. In contrast, no significant changes were observed in cytochrome P450 family 2 subfamily E member 1 (CYP2E1), the main enzyme responsible for drug metabolism. Elevated levels of hepatic zinc and metallothionein (MT) were also observed, which may contribute to the hepatoprotective effect in ZnT8 KO mice. Taken together, these results suggest that ZnT8 deficiency protects the liver from APAP toxicity by attenuating oxidative stress and promoting hepatocyte proliferation. This study provides new insights into the functions of ZnT8 and zinc as key mediators linking pancreatic and hepatic functions.

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EZH2 Alleviates Antituberculosis Drug-Induced Liver Injury in Mice by Reducing H3K27 Trimethylation at the Nrf2 Promoter

10.21203/rs.3.rs-701850/v1 ◽

2021 ◽

Author(s):

pei shengfei ◽

luming yang ◽

lin wang ◽

xuelei gao ◽

yu guo ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Injury ◽

Transcriptional Activation ◽

Target Genes ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Preventative Measures ◽

Oxidative Stress Pathway ◽

Stress Pathway

Abstract BackgroundAnti-tuberculosis drug-induced liver injury (ADLI) limits the treatment of tuberculosis. The mechanisms underlying ADLI are unclear and there are no effective preventative measures to avoid this complication. MethodsIn this stuy, the protein contents of EZH2, Nrf2, NQO1 and HO-1 were detected by ELISA kit, while those of EZH2 and Nrf2 were determined by Western blot. The Chip experiment was used to detect the level of H3K27me3 in the Nrf2 promoter region.The liver were analyzed histopathologically in vivo using hematoxylin and eosin staining.ResultsHere we developed a murine model of ADLI that recapitulates liver injury in the human disease. Using this model, we investigated the potential involvement of the enhancer of zeste homolog 2 methyltransferase (EZH2), a histone methyltransferase which inhibits the transcriptional activation of the Nrf2-ARE oxidative stress pathway. Compared to controls, mice livers with ADLI showed decreased expression of EZH2 together with reduced H3K27me3 marks in the Nrf2 promoter. This was accompanied by increased expression of Nrf2 and its target genes NQO1 and HO-1. Liver injury in the mice with ADLI could be alleviated to an extent by in vivo delivery of siRNAs targeting EZH2, which further downregulated EZH2 expression and H3K27me3 levels in the Nrf2 promoter along with accompanying increases in Nrf2, NQO1 and HO-1 expression. ConclusionsTherefore, inhibiting EZH2 likely reduced liver damage in ADLI by enhancing this key anti-oxidative stress pathway. Our results establish a role for EZH2 in a mouse model of ADLI and furthermore provides valuable mechanistic insights into the development of ADLI pathology.

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Phenylpropionc acid produced by gut microbiota alleviates acetaminophen-induced hepatotoxicity

10.1101/811984 ◽

2019 ◽

Author(s):

Sungjoon Cho ◽

Xiaotong Yang ◽

Kyoung-Jae Won ◽

Vanessa Leone ◽

Nathaniel Hubert ◽

...

Keyword(s):

Liver Injury ◽

Gut Microbiota ◽

Hepatic Injury ◽

Gut Bacteria ◽

Toxic Metabolite ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Protein Levels ◽

Cyp 2E1 ◽

Gut Microbe

ABSTRACTAcetaminophen (APAP) overdose causes hepatic injury and is major contributor to acute liver injury cases. To investigate potential roles of gut microbiota in APAP-induced liver injury, C57BL/6 mice from Jackson (JAX) or Taconic (TAC) were challenged with APAP. TAC mice were more susceptible to APAP toxicity, and this disappeared upon co-housing of JAX and TAC mice. When the cecum contents from JAX and TAC mice were transplanted to germ-free mice, the mice that received TAC gut microbiota exhibited more significant hepatotoxicity after APAP administration. Non-targeted metabolomic analysis using portal vein serum and liver tissue of the mice led to identification of 19 metabolites the levels of which are associated with JAX or TAC gut microbiota. A gut bacteria-derived metabolite phenylpropionic acid (PPA) levels in cecum contents and blood were higher in mice harboring JAX gut microbiota. PPA supplementation in drinking water alleviated APAP-induced hepatotoxicity in TAC mice. This was accompanied by reduced hepatic protein levels of cytochrome P450 (CYP) 2E1, the enzyme responsible for APAP bioactivation to a toxic metabolite. This illustrates a gut microbe-liver interaction mediated by a gut bacteria-derived metabolite in modulating drug-induced liver injury.

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Metformin and Probiotics Interplay in Amelioration of Ethanol-Induced Oxidative Stress and Inflammatory Response in an In Vitro and In Vivo Model of Hepatic Injury

Mediators of Inflammation ◽

10.1155/2021/6636152 ◽

2021 ◽

Vol 2021 ◽

pp. 1-31

Author(s):

Farhin Patel ◽

Kirti Parwani ◽

Dhara Patel ◽

Palash Mandal

Keyword(s):

Oxidative Stress ◽

Lipid Metabolism ◽

Liver Injury ◽

Inflammatory Response ◽

Er Stress ◽

Hepg2 Cells ◽

Hepatic Injury ◽

And Oxidative Stress

Alcohol-induced liver injury implicates inflammation and oxidative stress as important mediators. Despite rigorous research, there is still no Food and Drug Administration (FDA) approved therapies for any stage of alcoholic liver disease (ALD). Interestingly, metformin (Met) and several probiotic strains possess the potential of inhibiting alcoholic liver injury. Therefore, we investigated the effectiveness of combination therapy using a mixture of eight strains of lactic acid-producing bacteria, commercialized as Visbiome® (V) and Met in preventing the ethanol-induced hepatic injury using in vitro and in vivo models. Human HepG2 cells and male Wistar rats were exposed to ethanol and simultaneously treated with probiotic V or Met alone as well as in combination. Endoplasmic reticulum (ER) stress markers, inflammatory markers, lipid metabolism, reactive oxygen species (ROS) production, and oxidative stress were evaluated, using qRT-PCR, Oil red O staining, fluorimetry, and HPLC. In vitro, probiotic V and Met in combination prevented ethanol-induced cellular injury, ER stress, oxidative stress, and regulated lipid metabolism as well as inflammatory response in HepG2 cells. Probiotic V and Met also promoted macrophage polarization towards the M2 phenotype in ethanol-exposed RAW 264.7 macrophage cells. In vivo, combined administration of probiotic V and Met ameliorated the histopathological changes, inflammatory response, hepatic markers (liver enzymes), and lipid metabolism induced by ethanol. It also improved the antioxidant markers (HO-1 and Nrf-2), as seen by their protein levels in both HepG2 cells as well as liver tissue using ELISA. Hence, probiotic V may act, in addition to the Met, as an effective preventive treatment against ethanol-induced hepatic injury.

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Causality Evaluation of Drug-Induced Liver Injury in Newborns and Children in the Intensive Care Unit Using the Updated Roussel Uclaf Causality Assessment Method

Frontiers in Pharmacology ◽

10.3389/fphar.2021.790108 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ling Ye ◽

Zeying Feng ◽

Longjian Huang ◽

Chengjun Guo ◽

Xiong Wu ◽

...

Keyword(s):

Liver Injury ◽

Hepatic Injury ◽

Causality Assessment ◽

Sodium Succinate ◽

Assessment Method ◽

Drug Combinations ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Methylprednisolone Sodium Succinate ◽

Enzyme Metabolism

Purpose: Drug-induced liver injury (DILI) is a common adverse reaction in the clinic; however, there are relatively few reports of DILI in critically ill newborns and children. Making use of the Pediatric Intensive Care database (PIC), this study identifies which drugs are related to DILI in neonates and children in China.Methods: Using the PIC, we screened for patients whose liver was suspected of being injured by drugs during hospitalization. The medicine they used was then assessed by the Roussel Uclaf Causality Assessment Method (RUCAM). At the same time, we also collated drug combinations that may affect CYP (Cytochrome P) enzyme metabolism, which may cause DILI.Results: A total of 13,449 patients were assessed, of whom 77 newborns and 261 children were finally included. The main type of liver injury in neonates was mixed (83.1%), while the hepatic injury types of children were mostly distributed between hepatocellular (59.4%) and cholestatic (28.4%). In terms of the RUCAM assessment, the drugs that were most considered to cause or be associated with hepatic injury in newborns were medium and long chain fat emulsions (17%), sodium glycerophosphate (12%), and meropenem (9%); while omeprazole (11%), methylprednisolone sodium succinate (10%), and meropenem (8%) were the primary culprits of DILI in children. Drug combinations frequently seen in neonates that may affect CYP enzyme metabolism are omeprazole + budesonide (16.9%), dexamethasone + midazolam (10.4%), and midazolam + sildenafil (10.4%). In children, the commonly used drug combinations are fentanyl + midazolam (20.7%), ibuprofen + furosemide (18.4%), and diazepam + omeprazole (15.3%).Conclusions: In this study, medium and long chain fat emulsions and sodium glycerophosphate have been strongly associated with DILI in newborns, while omeprazole and methylprednisolone sodium succinate play an important role in the DILI of children. Also, attention should be paid to the effect on CYP enzymes when using multiple drugs at the same time. In future DILI cases, it is advisable to use the latest RUCAM for prospective study design so that complete case data and high RUCAM scores can be collected.

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A Severe Case of Drug-Induced Liver Injury after Gemcitabine Administration: A Highly Probable Causality Grading as Assessed by the Updated RUCAM Diagnostic Scoring System

Case Reports in Hepatology ◽

10.1155/2020/8812983 ◽

2020 ◽

Vol 2020 ◽

pp. 1-5

Author(s):

Ilenia Mascherona ◽

Caterina Maggioli ◽

Maira Biggiogero ◽

Oreste Mora ◽

Lucia Marelli

Keyword(s):

Liver Injury ◽

Hepatic Injury ◽

Clinical Presentation ◽

Acute Liver Injury ◽

Severe Case ◽

Suspected Drug ◽

Serum Enzyme ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Clinically Significant

Gemcitabine is an antineoplastic drug used in several forms of advanced pancreatic, lung, breast, ovarian, and bladder cancer. Common side effects include bone marrow suppression, fatigue, diarrhea, nausea, gastrointestinal upset, rash, alopecia, and stomatitis. Transient serum enzyme elevations could be observed during therapy, but clinically significant acute liver injury has been rarely associated with its use. Few cases of acute liver injury have been reported in the literature. We reported the clinical case of a 73--year-old man who developed clinically significant acute hepatic injury after using gemcitabine. Possible causes, clinical presentation, and treatments are discussed. According to the updated RUCAM score, the case was rated 10 points and became a suspected drug-induced liver injury. Moreover, on the liver biopsy, there were histological findings of mild-to-moderate portal hepatitis, eosinophilia, bile duct injury, and mild perisinusoidal fibrosis, suggesting drug damage.

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