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Kakavand G, Arabzadeh S, Mohebbi S, Saeedfar K, Abedini A, Mardani M. Impact of remdesivir treatment on factor VIII gene expression and hematological parameters in COVID-19 patients. Microb Pathog 2025; 204:107536. [PMID: 40187577 DOI: 10.1016/j.micpath.2025.107536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 03/27/2025] [Accepted: 04/02/2025] [Indexed: 04/07/2025]
Abstract
The novel coronavirus, COVID-19, which was first identified in December 2019 rapidly spread worldwide and was declared a global pandemic. Beyond respiratory symptoms, COVID-19 often results in coagulation and vascular endothelium disorders, causing increased clotting and bleeding, which are closely linked to the acute phase of the infection. Factor VIII is a crucial protein in the blood coagulation cascade, and elevated FVIII levels have been linked to thrombotic events in COVID-19, highlighting the need to understand its behavior during treatment. Remdesivir is an antiviral drug that has shown promise in reducing recovery time and mortality rates in COVID-19 patients. This study aims to examine the changes in blood factors and the expression of the factor VIII gene in patients treated with Remdesivir. Blood samples were collected from 30 COVID-19 patients before and after Remdesivir treatment and from 20 healthy individuals. Patients with underlying diseases were excluded from the study. RNA was extracted from these samples, followed by cDNA synthesis. The expression of the factor VIII gene was analyzed using Real-Time PCR. The results indicated that blood factors such as Urea, ALK, AST, WBC, and CRP were elevated in the patient group compared to the control group. At the same time, FBS, Urea, ALK, AST, WBC, RDW, INR, and K levels increased in the Remdesivir treatment group (P < 0.001). Conversely, MCHC, RBC, and Ca levels decreased in both patient and treatment groups compared to the control group (P < 0.001). The expression of the FVIII gene was upregulated approaching 2 times in COVID-19 patients and 1.5-fold in the treatment group compared to the control group (P < 0.001). However, no significant changes were observed in FVIII expression before and after Remdesivir treatment. However, a positive correlation between RBC, FBS, and Urea in the patient group and a negative correlation between RDW and FVIII expression levels was observed. In the treatment group, FVIII expression level correlated negatively with Urea, P, and RDW. These findings suggest that elevated FVIII levels are associated with disease severity and excessive coagulation in COVID-19 patients. Additionally, Remdesivir does not appear to exacerbate the coagulation process.
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Affiliation(s)
- Ghazal Kakavand
- Department of Biology, Faculty of Basic Science, Ale Taha Institute of Higher Education, Tehran, Iran
| | - Somayeh Arabzadeh
- Department of Biology, Faculty of Basic Science, Ale Taha Institute of Higher Education, Tehran, Iran
| | - Sohameh Mohebbi
- Department of Biology, Faculty of Basic Science, Ale Taha Institute of Higher Education, Tehran, Iran.
| | - Kayvan Saeedfar
- Tracheal Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Atefeh Abedini
- Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoud Mardani
- Shahid Beheshti University of Medical Sciences, Infectious Disease Department, Loghman Hakim Hospital, Tehran, Iran
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Guermazi F, Jbir R, Bouaziz I, Atheymen R, Mnif D, Ben Ali N, Ksouda K, Zghal K, Baati I, Masmoudi J. [Acute cytolytic hepatitis followed by edema associated with the use of antipsychotics neuroleptics: A case report and review of the literature]. Therapie 2025; 80:348-351. [PMID: 39665911 DOI: 10.1016/j.therap.2024.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 10/30/2024] [Accepted: 11/12/2024] [Indexed: 12/13/2024]
Affiliation(s)
- Fatma Guermazi
- Service de psychiatrie 'A', CHU Hedi Chaker, 3029 Sfax, Tunisie
| | - Rabeb Jbir
- Service de psychiatrie 'A', CHU Hedi Chaker, 3029 Sfax, Tunisie.
| | - Imen Bouaziz
- Centre régional de pharmacovigilance, faculté de médecine de Sfax, université de Sfax, 3029 Sfax, Tunisie
| | - Rim Atheymen
- Centre régional de pharmacovigilance, faculté de médecine de Sfax, université de Sfax, 3029 Sfax, Tunisie
| | - Dorra Mnif
- Service de psychiatrie 'A', CHU Hedi Chaker, 3029 Sfax, Tunisie
| | - Nourelhouda Ben Ali
- Centre régional de pharmacovigilance, faculté de médecine de Sfax, université de Sfax, 3029 Sfax, Tunisie
| | - Kamilia Ksouda
- Centre régional de pharmacovigilance, faculté de médecine de Sfax, université de Sfax, 3029 Sfax, Tunisie
| | - Khaled Zghal
- Centre régional de pharmacovigilance, faculté de médecine de Sfax, université de Sfax, 3029 Sfax, Tunisie
| | - Imen Baati
- Service de psychiatrie 'A', CHU Hedi Chaker, 3029 Sfax, Tunisie
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Jamali F, Jafary F, Aarabi MH, Goudarzi F, Koohshekan B, Mohammadalipour A. Exploring the oxidative mechanism of methotrexate on catalase enzyme: an in vitro study. Free Radic Res 2025; 59:289-296. [PMID: 40094853 DOI: 10.1080/10715762.2025.2481517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 02/23/2025] [Accepted: 03/13/2025] [Indexed: 03/19/2025]
Abstract
Methotrexate (MTX) is a well-known anti-metabolite agent recognized for its oxidative effects, particularly in the liver where the enzyme catalase is abundant. This research aimed to clarify the impact of MTX on the behavior of liver catalase. The cytotoxicity of HepG2 cells was assessed across various concentrations of MTX. Following that, the examination focused on the generation of reactive oxygen species (ROS) and the activity of catalase. Furthermore, the kinetic activity of bovine liver catalase (BLC) was examined in the presence of MTX. Finally, the interaction between MTX and the enzyme's protein structure was investigated using docking and dynamic light scattering (DLS) methods. The results indicated a significant decrease in catalase activity and a significant increase in ROS production in HepG2 cells treated with MTX. Although the activity of BLC remained unaffected by MTX directly, molecular docking and DLS techniques revealed MTX binding to BLC, inhibiting its tetramerization. The oxidative effects of MTX were associated with elevated ROS levels in cellular processes, leading to excessive catalase activity and subsequent suicide inactivation. Furthermore, MTX influenced the protein structure of catalase.
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Affiliation(s)
- Fatemeh Jamali
- Department of Clinical Biochemistry and Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
| | - Farzaneh Jafary
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
- Clinical Research Development Center, Najafabad Branch, Islamic Azad University, Najafabad, Iran
| | - Mohammad Hossein Aarabi
- Department of Clinical Biochemistry and Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
| | - Farjam Goudarzi
- Regenerative Medicine Research Center, Kermanshah University of Medical Sciences, Kermanshah, I.R. Iran
| | - Bahareh Koohshekan
- Department of Clinical Biochemistry and Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
| | - Adel Mohammadalipour
- Department of Clinical Biochemistry and Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
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Qian Y, Zhao J, Wu H, Kong X. Innate immune regulation in inflammation resolution and liver regeneration in drug-induced liver injury. Arch Toxicol 2025; 99:115-126. [PMID: 39395921 DOI: 10.1007/s00204-024-03886-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Accepted: 10/02/2024] [Indexed: 10/14/2024]
Abstract
Drug-induced liver injury (DILI) is an acute liver injury that poses a significant threat to human health. In severe cases, it can progress into chronic DILI or even lead to liver failure. DILI is typically caused by either intrinsic hepatotoxicity or idiosyncratic metabolic or immune responses. In addition to the direct damage drugs inflict on hepatocytes, the immune responses and liver inflammation triggered by hepatocyte death can further exacerbate DILI. Initially, we briefly discussed the differences in immune cell activation based on the type of liver cell death (hepatocytes, cholangiocytes, and LSECs). We then focused on the role of various immune cells (including macrophages, monocytes, neutrophils, dendritic cells, liver sinusoidal endothelial cells, eosinophils, natural killer cells, and natural killer T cells) in both the liver injury and liver regeneration stages of DILI. This article primarily reviews the role of innate immune regulation mediated by these immune cells in resolving inflammation and promoting liver regeneration during DILI, as well as therapeutic approaches targeting these immune cells for the treatment of DILI. Finally, we discussed the activation and function of liver progenitor cells (LPCs) during APAP-induced massive hepatic necrosis and the involvement of chronic inflammation in DILI.
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Affiliation(s)
- Yihan Qian
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, China
| | - Jie Zhao
- Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Hailong Wu
- Shanghai Key Laboratory of Molecular Imaging, Collaborative Innovation Center for Biomedicines, Shanghai University of Medicine and Health Sciences, Shanghai, China.
| | - Xiaoni Kong
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, China.
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Hamed M, Abou Khalil NS, Alghriany AA, El-Din H. Sayed A. The protective effects of dietary microalgae against hematological, biochemical, and histopathological alterations in pyrogallol-intoxicated Clarias gariepinus. Heliyon 2024; 10:e40930. [PMID: 39759355 PMCID: PMC11699231 DOI: 10.1016/j.heliyon.2024.e40930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 11/05/2024] [Accepted: 12/03/2024] [Indexed: 01/07/2025] Open
Abstract
Microalgae have well-established health benefits for farmed fish. Thus, this study aims to explore the potential protective effects of Spirulina platensis, Chlorella vulgaris, and Moringa oleifera against pyrogallol-induced hematological, hepatic, and renal biomarkers in African catfish (Clarias gariepinus), as well as the histopathological changes in the liver and kidney. Fish weighing 200 ± 25 g were divided into several groups: group 1 served as the control, group 2 was exposed to 10 mg/L of pyrogallol, and groups 3, 4, and 5 were exposed to the same concentration of pyrogallol, supplemented with S. platensis at 20 g/kg diet, C. vulgaris at 50 g/kg diet, and M. oleifera at 5 g/kg diet, respectively, for 15 days. Exposure to pyrogallol led to decreased packed cell volume (PCV) and lymphocyte count, but these effects were alleviated by microalgae interventions. C. vulgaris and M. oleifera equally restored PCV and increased lymphocyte counts. Supplementation with C. vulgaris and M. oleifera successfully normalized both neutrophil and eosinophil counts. Pyrogallol intoxication engenders an increase in glycemic status, but C. vulgaris and M. oleifera effectively mitigated this rise. Pyrogallol-exposed fish exhibited signs of renal dysfunction, with increased serum creatinine and total cholesterol levels. A significant decrease in both erythrocytic cellular and nuclear abnormalities was observed following supplementation with microalgae. C. vulgaris and M. oleifera showed promise in decreasing serum glucose and creatinine levels, and improving hematological parameters, while S. platensis exhibited limited efficacy in this regard. Exposure to pyrogallol led to a notable decrease in serum superoxide dismutase activity and total antioxidant capacity (TAC), accompanied by an increase in serum malondialdehyde (MDA) levels. Diets enriched with C. vulgaris and M. oleifera effectively restored these parameters to normal levels, whereas S. platensis did not induce significant changes. None of the microalgae improved TAC except for M. oleifera, which significantly enhanced it. MDA levels returned to control levels equally and significantly across all groups. Interleukin-6 levels did not exhibit significant differences between any of the groups. Collectively, the histopathological changes induced by pyrogallol were most prominently alleviated in the pyrogallol + C. vulgaris and pyrogallol + M. oleifera groups, and to a limited degree in the pyrogallol + S. platensis group. While the tested microalgae did not cause hepatic or renal dysfunction, they did lead to metabolic abnormalities. The incorporation of microalgae into the diet holds significant importance in mitigating the metabolic and histological toxicity of pyrogallol and should be considered in the formulation of fish feed.
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Affiliation(s)
- Mohamed Hamed
- Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Skip Bertman Drive, Baton Rouge, LA, 70803, USA
- Department of Zoology, Faculty of Science, Al-Azhar University (Assiut branch), Assiut, 71524, Egypt
| | - Nasser S. Abou Khalil
- Department of Medical Physiology, Faculty of Medicine, Assiut University, Assiut, Egypt
- Department of Animal Physiology and Biochemistry, Faculty of veterinary Medicine, Badr University, Assuit, Egypt
| | | | - Alaa El-Din H. Sayed
- Department of Zoology, Faculty of Science, Assiut University, Assiut, 71516, Egypt
- Molecular Biology Research & Studies Institute, Assiut University, 71516, Assiut, Egypt
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Rentschler S, Doss S, Kaiser L, Weinschrott H, Kohl M, Deigner HP, Sauer M. Metabolic Biomarkers of Liver Failure in Cell Models and Patient Sera: Toward Liver Damage Evaluation In Vitro. Int J Mol Sci 2024; 25:13739. [PMID: 39769500 PMCID: PMC11677895 DOI: 10.3390/ijms252413739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 11/29/2024] [Accepted: 12/20/2024] [Indexed: 01/11/2025] Open
Abstract
Recent research has concentrated on the development of suitable in vitro cell models for the early identification of hepatotoxicity during drug development in order to reduce the number of animal models and to obtain a better predictability for hepatotoxic reactions in humans. The aim of the presented study was to identify translational biomarkers for acute liver injury in human patients that can serve as biomarkers for hepatocellular injury in vivo and in vitro in simple cell models. Therefore, 188 different metabolites from patients with acute-on-chronic liver failure before and after liver transplantation were analyzed with mass spectrometry. The identified potential metabolic biomarker set, including acylcarnitines, phosphatidylcholines and sphingomyelins, was used to screen primary and permanent hepatocyte culture models for their ability to model hepatotoxic responses caused by different drugs with known and unknown hepatotoxic potential. The results obtained suggest that simple in vitro cell models have the capability to display metabolic responses in biomarkers for liver cell damage in course of the treatment with different drugs and therefore can serve as a basis for in vitro models for metabolic analysis in drug toxicity testing. The identified metabolites should further be evaluated for their potential to serve as a metabolic biomarker set indicating hepatocellular injury in vitro as well as in vivo.
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Affiliation(s)
- Simone Rentschler
- Institute of Precision Medicine, Furtwangen University, Jakob-Kienzle-Straße 17, 78054 VS-Schwenningen, Germany
| | - Sandra Doss
- Fraunhofer Institute IZI (Leipzig), Department Rostock, Schillingallee 68, 18057 Rostock, Germany
| | - Lars Kaiser
- Institute of Precision Medicine, Furtwangen University, Jakob-Kienzle-Straße 17, 78054 VS-Schwenningen, Germany
| | - Helga Weinschrott
- Institute of Precision Medicine, Furtwangen University, Jakob-Kienzle-Straße 17, 78054 VS-Schwenningen, Germany
| | - Matthias Kohl
- Institute of Precision Medicine, Furtwangen University, Jakob-Kienzle-Straße 17, 78054 VS-Schwenningen, Germany
| | - Hans-Peter Deigner
- Institute of Precision Medicine, Furtwangen University, Jakob-Kienzle-Straße 17, 78054 VS-Schwenningen, Germany
- Faculty of Science, Tuebingen University, Auf der Morgenstelle 8, 72076 Tübingen, Germany
- Department of Anesthesiology and Intensive Care Medicine, University Hospital of Rostock, Schillingallee 35, 18057 Rostock, Germany
| | - Martin Sauer
- Fraunhofer Institute IZI (Leipzig), Department Rostock, Schillingallee 68, 18057 Rostock, Germany
- Department of Anesthesiology and Intensive Care Medicine, University Hospital of Rostock, Schillingallee 35, 18057 Rostock, Germany
- Center for Anesthesiology and Intensive Care Medicine, Hospital of Magdeburg, Birkenallee 34, 39130 Magdeburg, Germany
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Jiajing C, Shuqi Y, Haoyan M, Pingwei W, Dongge L, Yanping L, Qianqian C, Saleh F, Shuping R. Perfluorooctane sulfonate causes damage to L-02 cells via Wnt/β-catenin signal path and endoplasmic reticulum stress pathway. Toxicol Ind Health 2024; 40:653-666. [PMID: 39217409 DOI: 10.1177/07482337241277259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Perfluorooctane sulfonate (PFOS) is one of the most widely used perfluorinated compounds, and as an environmental endocrine disruptor and environmental persistent pollutant, the threat of PFOS to human health is of increasing concern. Exposure to PFOS has been shown to be closely associated with liver disease, but the intrinsic molecular targets and mechanisms of PFOS-induced liver damage are not well understood. This study was conducted to explore whether the Wnt/β-Catenin signaling pathway and the endoplasmic reticulum stress signaling pathway are involved in damage of PFOS to the liver. In this study, we used the CCK-8 method to detect cell viability, a microscope and DAPI staining to observe cell morphology, flow cytometry to detect cell ROS and apoptosis levels; and Western blot to detect the expressions of proteins in the WNT/β-Catenin, endoplasmic reticulum stress and apoptosis-related pathways. We found that PFOS activated WNT/β-Catenin and endoplasmic reticulum stress-related pathways in L-02 cells and could lead to the development of oxidative stress and apoptosis. Our findings showed that PFOS could cause damage to L-02 cells, and the WNT/β-Catenin signaling and endoplasmic reticulum stress pathways were involved in the changes caused by PFOS to L-02 cells, which provided a new theoretical basis for studying the hepatotoxicity and mechanism of PFOS. PFOS can lead to increased intracellular ROS levels, causing oxidative stress, endoplasmic reticulum stress and activation of the WNT/β-catenin signaling pathway. Our experimental results showed that PFOS can cause damage to L-02 cells, and the WNT/β-Catenin signaling pathway and endoplasmic reticulum stress pathway are involved in the process of damage caused by PFOS to L-02 cells.
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Affiliation(s)
- Cui Jiajing
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun, China
- Department of Occupational and Environmental Health, School of Public Health, Capital Medical University, Beijing, China
| | - Yan Shuqi
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun, China
| | - Ma Haoyan
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun, China
| | - Wang Pingwei
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun, China
| | - Liu Dongge
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun, China
| | - Liu Yanping
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun, China
| | - Chen Qianqian
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun, China
| | - Fajrin Saleh
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun, China
| | - Ren Shuping
- Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun, China
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Rosario SA, Mikhail E, Encalada Soto D. Norethindrone-Associated Transaminitis in Endometriosis Patients: A Case Series and Literature Review. Cureus 2024; 16:e67023. [PMID: 39280397 PMCID: PMC11402480 DOI: 10.7759/cureus.67023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 08/16/2024] [Indexed: 09/18/2024] Open
Abstract
In this case series, we discuss 10 cases of norethindrone-induced transaminitis and conduct a literature review of this rare adverse event. A retrospective chart review was conducted on 10 patients (median age: 33 years) with diverse endometriosis phenotypes who received norethindrone and subsequently developed transaminitis, which is defined as elevated alanine transaminase (ALT) and aspartate transaminase (AST) levels. This condition was diagnosed in both asymptomatic and symptomatic patients, either during the work-up of acute symptoms or incidentally through routine lab tests. Our objective was to assess and characterize a case series of transaminitis associated with norethindrone use in endometriosis patients, detailing clinical presentations, management strategies, and outcomes. All cases exhibited normalization of liver function tests after discontinuation, occurring within one to 12 months with varying intervals of liver function testing. Patients receiving higher dosages (10 mg daily) demonstrated quicker resolution (average: four months). The reported adverse effects included nausea, vomiting, headache, rash, polyarthralgia, and abnormal uterine bleeding. Vigilant management, including prompt discontinuation, consistently resulted in the resolution of transaminitis. This study underscores the importance of continuous monitoring of liver function, even in asymptomatic patients on norethindrone therapy. Further investigations are imperative to identify specific groups susceptible to this adverse event.
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Affiliation(s)
- Shawn Alexa Rosario
- Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, USA
| | - Emad Mikhail
- Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, USA
| | - Diana Encalada Soto
- Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, USA
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Shan C, Miao F, Guo G. Ameliorative Effect of Macadamia Nut Protein Peptides on Acetaminophen-Induced Acute Liver Injury in Mice. J Med Food 2024; 27:257-266. [PMID: 38386536 DOI: 10.1089/jmf.2023.k.0192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2024] Open
Abstract
This study aims to examine the ameliorative effect of macadamia nut protein peptides (MPP) on acetaminophen (APAP)-induced liver injury (AILI) in mice, and develop a new strategy for identifying hepatoprotective functional foods. The molecular weight distribution and amino acid composition of MPP were first studied. Forty mice were then randomized into four groups: control group (CON), APAP model group, APAP+MPP low-dose group (APAP+L-MPP), and APAP+MPP high-dose group (APAP+H-MPP). The APAP+L-MPP (320 mg/kg per day) and APAP+H-MPP (640 mg/kg per day) groups received continuous MPP gavage for 2 weeks. A 12 h of APAP (200 mg/kg) gavage resulted in liver damage. Pathological alterations, antioxidant index levels, expression of toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB), and associated inflammatory factors were determined for each treatment group. The results revealed that the total amino acid content of MPP was 39.58 g/100 g, with Glu, Arg, Asp, Leu, Tyr, and Gly being the major amino acids. The molecular weight range of 0-1000 Da accounted for 73.54%, and 0-500 Da accounted for 62.84% of MPP. MPP ameliorated the pathological morphology and reduced the serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase of AILI in mice. MPP significantly increased the activities of superoxide dismutase and glutathione peroxidase in the liver compared with the APAP group. MPP inhibited the expression of TLR4, NF-κB, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) genes in AILI mice. MPP also inhibited the expression levels of inflammatory factors (TNF-α and IL-6). Our study concludes that MPP alleviates AILI in mice by enhancing antioxidant capacity and inhibiting TLR4/NF-κB pathway-related gene activation.
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Affiliation(s)
- Chunlan Shan
- Department of Animal Medicine, College of Animal Science, Guizhou University, Guiyang, China
| | - Fujun Miao
- Economic Forest Research Institute, Yunnan Academy of Forestry and Grassland, Kunming, China
| | - Gangjun Guo
- Tropical Agricultural Products Development and Utilization Research Center, Yunnan Institute of Tropical Crops, Jinghong, China
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10
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Badamasi IM, Muhammad M, Umar AA, Madugu UAM, Gadanya MA, Aliyu IA, Kabir IM, Umar IA, Johnson O, Stanslas J. Role of the IL8 rs4073 polymorphism in central nervous system toxicity in patients receiving multidrug-resistant tuberculosis treatment. J Bras Pneumol 2024; 50:e20230338. [PMID: 38359298 PMCID: PMC11095930 DOI: 10.36416/1806-3756/e20230338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 11/01/2023] [Indexed: 02/17/2024] Open
Abstract
OBJECTIVE To determine the role of the IL8 rs4073 polymorphism in predicting the risk of central nervous system (CNS) toxicity in patients receiving standard pharmacological treatment for multidrug-resistant tuberculosis (MDR-TB). METHODS A cohort of 85 consenting MDR-TB patients receiving treatment with second-line antituberculosis drugs had their blood samples amplified for the IL8 (rs4073) gene and genotyped. All patients were clinically screened for evidence of treatment toxicity and categorized accordingly. Crude and adjusted associations were assessed. RESULTS The chief complaints fell into the following categories: CNS toxicity; gastrointestinal toxicity; skin toxicity; and eye and ear toxicities. Symptoms of gastrointestinal toxicity were reported by 59% of the patients, and symptoms of CNS toxicity were reported by 42.7%. With regard to the genotypes of IL8 (rs4073), the following were identified: AA, in 64 of the study participants; AT, in 7; and TT, in 11. A significant association was found between the dominant model of inheritance and CNS toxicity for the crude model (p = 0.024; OR = 3.57; 95% CI, 1.18-10.76) and the adjusted model (p = 0.031; OR = 3.92; 95% CI, 1.13-13.58). The AT+TT genotype of IL8 (rs4073) showed a 3.92 times increased risk of CNS toxicity when compared with the AA genotype. CONCLUSIONS The AT+TT genotype has a tendency to be associated with an increased risk of adverse clinical features during MDR-TB treatment.
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Affiliation(s)
- Ibrahim Mohammed Badamasi
- . Pharmacogenomic Unit, Department of Human Anatomy, Faculty of Basic Medical Sciences - FBMS - College of Medicine, Bayero University, Kano, Kano, Nigeria
| | - Muktar Muhammad
- . Pharmacogenomic Unit, Department of Human Anatomy, Faculty of Basic Medical Sciences - FBMS - College of Medicine, Bayero University, Kano, Kano, Nigeria
| | - Aishat Ahmad Umar
- . Pharmacogenomic Unit, Department of Human Anatomy, Faculty of Basic Medical Sciences - FBMS - College of Medicine, Bayero University, Kano, Kano, Nigeria
| | - Umm-ayman Misbahu Madugu
- . Pharmacogenomic Unit, Department of Human Anatomy, Faculty of Basic Medical Sciences - FBMS - College of Medicine, Bayero University, Kano, Kano, Nigeria
| | - Muktar Ahmed Gadanya
- . Department of Community Medicine, Faculty of Clinical Sciences, Bayero University, Kano, Kano, Nigeria
| | - Isa Abubakar Aliyu
- . Department of Medical Laboratory Science, Faculty of Allied Health Sciences - FAHS - Bayero University, Kano, Kano, Nigeria
| | - Imam Malik Kabir
- . Department of Medical Laboratory Science, Faculty of Allied Health Sciences - FAHS - Bayero University, Kano, Kano, Nigeria
| | - Ibrahim Aliyu Umar
- . Kano State TB and Leprosy Control Program, Kano State Ministry of Health, Kano, Nigeria
| | - Ochigbo Johnson
- . Kano State Infectious Disease Hospital, Kano State Ministry of Health, Kano, Nigeria
| | - Johnson Stanslas
- . Pharmacotherapeutics Lab, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
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Wu Y, Sun LL, Han HH, He XP, Cao W, James TD. Selective FRET nano probe based on carbon dots and naphthalimide-isatin for the ratiometric detection of peroxynitrite in drug-induced liver injury. Chem Sci 2024; 15:757-764. [PMID: 38179535 PMCID: PMC10762965 DOI: 10.1039/d3sc05010f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Accepted: 11/22/2023] [Indexed: 01/06/2024] Open
Abstract
Drug-induced liver injury (DILI) is the most common cause for acute liver failure in the USA and Europe. However, most of DILI cases can recover or be prevented if treatment by the offending drug is discontinued. Recent research indicates that peroxynitrite (ONOO-) can be a potential indicator to diagnose DILI at an early stage. Therefore, the establishment of an assay to detect and track ONOO- in DILI cases is urgently needed. Here, a FRET-based ratiometric nano fluorescent probe CD-N-I was developed to detect ONOO- with high selectivity and excellent sensitivity. This probe consists of carbon dots and a naphthalimide-isatin peroxynitrite sensing system assembled based on electrostatic interactions. Using CD-N-I we were able to detect exogenous ONOO- in live cells and endogenous ONOO- in APAP-induced liver injury of HepG2 cells.
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Affiliation(s)
- Yueci Wu
- Department of Chemistry, University of Bath Bath BA2 7AY UK
| | - Lu-Lu Sun
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery Yantai Shandong 264117 P. R. China
- Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences Shanghai 201203 P. R. China
| | - Hai-Hao Han
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery Yantai Shandong 264117 P. R. China
- Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences Shanghai 201203 P. R. China
| | - Xiao-Peng He
- Key Laboratory for Advanced Materials, Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Center for Materiobiology and Dynamic Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology 130 Meilong Rd Shanghai 200237 P. R. China
- The International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Eastern Hepatobiliary Surgery Hospital Shanghai 200438 P. R. China
| | - Weiguo Cao
- Department of Chemistry, Shanghai University Shanghai 200444 P. R. China
| | - Tony D James
- Department of Chemistry, University of Bath Bath BA2 7AY UK
- School of Chemistry and Chemical Engineering, Henan Normal University Xinxiang 453007 P. R. China
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12
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Abdalla ZA, Abtar AN, Kareem AA, Ahmed ZA, Aziz TA. Study of the effect of bezafibrate with ginkgo biloba extracts in an animal model of hepatotoxicity induced by doxorubicin. Biochem Biophys Rep 2023; 36:101582. [PMID: 38059266 PMCID: PMC10696391 DOI: 10.1016/j.bbrep.2023.101582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 11/08/2023] [Accepted: 11/12/2023] [Indexed: 12/08/2023] Open
Abstract
This study aimed to evaluate the hepatoprotective effect of combining bezafibrate with ginkgo biloba in doxorubicin-induced hepatotoxicity in rats. Thirty Wister albino rats were allocated into five groups: The negative control group, the positive control group, both received 1 ml of D.W, bezafibrate group received (100 mg/kg), ginkgo biloba group received (60 mg/kg) and the fifth group received bezafibrate + ginkgo biloba. All the treatments were for 14 days along with doxorubicin on days 11-14 except for the negative control. Blood samples were used for the measurement of ALT, AST, ALP, total protein, total bilirubin, albumin, globulin, GSH, catalase, and IL-6. Liver tissue was sent for histopathological examination. The combination of ginkgo biloba and bezafibrate significantly decreased AST, ALP, AST/ALT ratio, albumin/globulin ratio, and IL-6 with significant elevations of catalase, and GSH. The combination group produced more hepatoprotection. This could be attributed to the additive anti-inflammatory and antioxidant effects of the combination.
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Affiliation(s)
- Zhwan Azad Abdalla
- Department of Clinical Pharmacy, College of Pharmacy, University of Sulaimani, Sulaimani, Kurdistan Region, Iraq
| | - Asoo Nihad Abtar
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Sulaimani, Sulaimani, Kurdistan Region, Iraq
| | - Ahmed Azad Kareem
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Sulaimani, Sulaimani, Kurdistan Region, Iraq
| | - Zheen Aorahman Ahmed
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Sulaimani, Sulaimani, Kurdistan Region, Iraq
| | - Tavga Ahmed Aziz
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Sulaimani, Sulaimani, Kurdistan Region, Iraq
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Guo Y, Lv H, Lv J, Jiang Z. Metabolite profiling and identification of enzymes responsible for the metabolism of hirsutine, a major alkaloid from Uncaria rhynchophylla. Xenobiotica 2023; 53:474-483. [PMID: 37819730 DOI: 10.1080/00498254.2023.2269417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 10/07/2023] [Indexed: 10/13/2023]
Abstract
The in vitro metabolism of hirsutine was determined using liver microsomes and human recombinant cytochrome P450 enzymes. Under the current conditions, a total of 14 phase I metabolites were tentatively identified.Ketoconazole showed significant inhibitory effect on the metabolism of hirsutine. Human recombinant cytochrome P450 enzyme analysis revealed that metabolism of hirsutine was mainly catalysed by CYP3A4.Our data revealed that hirsutine was metabolised via mono-oxygenation, di-oxygenation, N-oxygenation, dehydrogenation, demethylation and hydrolysis.In glutathione (GSH)-supplemented liver microsomes, four GSH adducts were identified. Hirsutine underwent facile P450-mediated metabolic activation, forming reactive 3-methyleneindolenine and iminoquinone intermediates.This study provided valuable information on the metabolic fates of hirsutine in liver microsomes, which would aid in understanding the hepatotoxicity caused by hirsutine or hirsutine-containing herb preparation.
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Affiliation(s)
- Yiqing Guo
- Henan University of Chinese Medicine, Zhengzhou, China
| | - Huanhuan Lv
- The Third Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Jing Lv
- People's Hospital of Zhengzhou, Zhengzhou, China
| | - Zenghong Jiang
- School of Medicine, Hefei Technology College, Chaohu City, China
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14
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Tang P, Wu H, Wang M, Wang Y, Zhang R, Zhang X, Li X, Liang B, Xiao W. Layer-by-layer reinforced-mediated sustained-release nanoantioxidants for long-lasting prevention against drug-induced liver injury. Colloids Surf B Biointerfaces 2023; 230:113489. [PMID: 37574617 DOI: 10.1016/j.colsurfb.2023.113489] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 07/15/2023] [Accepted: 07/30/2023] [Indexed: 08/15/2023]
Abstract
Drug-induced liver injury (DILI) is a commonly encountered and diagnostically complex etiology of acute liver failure, characterized by early indications of hepatic oxidative stress. The most economical approach for DILI treatment is effective and durable oxidative stress prevention. Herein, we propose a long-lasting nanoantioxidant called PDA-Zn-BAI NPs characterized by sustained-release of baicalein (a natural antioxidant) for the long-lasting prevention of DILI. It is constructed using dopamine as an intermediate and layer-by-layer reinforcement strategy based on Zn2+-mediated coordination bonding, π-π stacking, and steric hindrance made of polydopamine network. Optimized PDA-Zn-BAI NPs performed a satisfactory sustained-release effect (36.67% ± 6.67 in normal condition and 60.32% ± 3.19 in acid condition of cumulative release within 5 days). Furthermore, it's been found that PDA-Zn-BAI NPs could continuously be accumulated in the liver with negligible hepatotoxicity and were activated to effectively scavenge reactive oxygen species to break off the damage of acetaminophen to the liver within 5 days (ALT as an indicator, > 70% prevention effect lasts for 5 days), which was vital for the long-lasting prevention of DILI. The long-lasting detoxification by PDA-Zn-BAI NPs in patients with DILI suggested a potential clinical application, especially for those patients who need prolonged administration of hepatotoxic drugs.
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Affiliation(s)
- Peng Tang
- Key Laboratory of Medicinal Chemistry for Natural Resource of Ministry of Education, Yunnan Characteristic Plant Extraction Laboratory, Yunnan Research & Development Center for Natural Products, School of Pharmacy and School of Chemical Science and Technology, State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming, 650091, P. R. China
| | - Huiyin Wu
- Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, 650091, P. R. China
| | - Mengru Wang
- Key Laboratory of Medicinal Chemistry for Natural Resource of Ministry of Education, Yunnan Characteristic Plant Extraction Laboratory, Yunnan Research & Development Center for Natural Products, School of Pharmacy and School of Chemical Science and Technology, State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming, 650091, P. R. China
| | - Yongpeng Wang
- Key Laboratory of Medicinal Chemistry for Natural Resource of Ministry of Education, Yunnan Characteristic Plant Extraction Laboratory, Yunnan Research & Development Center for Natural Products, School of Pharmacy and School of Chemical Science and Technology, State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming, 650091, P. R. China
| | - Ruihan Zhang
- Key Laboratory of Medicinal Chemistry for Natural Resource of Ministry of Education, Yunnan Characteristic Plant Extraction Laboratory, Yunnan Research & Development Center for Natural Products, School of Pharmacy and School of Chemical Science and Technology, State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming, 650091, P. R. China
| | - Xingjie Zhang
- Key Laboratory of Medicinal Chemistry for Natural Resource of Ministry of Education, Yunnan Characteristic Plant Extraction Laboratory, Yunnan Research & Development Center for Natural Products, School of Pharmacy and School of Chemical Science and Technology, State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming, 650091, P. R. China
| | - Xiaoli Li
- Key Laboratory of Medicinal Chemistry for Natural Resource of Ministry of Education, Yunnan Characteristic Plant Extraction Laboratory, Yunnan Research & Development Center for Natural Products, School of Pharmacy and School of Chemical Science and Technology, State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming, 650091, P. R. China.
| | - Bin Liang
- Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, 650091, P. R. China.
| | - Weilie Xiao
- Key Laboratory of Medicinal Chemistry for Natural Resource of Ministry of Education, Yunnan Characteristic Plant Extraction Laboratory, Yunnan Research & Development Center for Natural Products, School of Pharmacy and School of Chemical Science and Technology, State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming, 650091, P. R. China.
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15
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Maji S, Lee M, Lee J, Lee J, Lee H. Development of lumen-based perfusable 3D liver in vitro model using single-step bioprinting with composite bioinks. Mater Today Bio 2023; 21:100723. [PMID: 37502830 PMCID: PMC10368928 DOI: 10.1016/j.mtbio.2023.100723] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 06/07/2023] [Accepted: 07/06/2023] [Indexed: 07/29/2023] Open
Abstract
Hepatic sinusoids are uniquely organized structures that help maintain a spectrum of hepatic functions. Although several in vitro liver models have been developed to replicate liver sinusoids, most of these platforms require complex, multi-step fabrication methods making it difficult to achieve truly three-dimensional (3D) channel geometries. In this study, a single-step bioprinting technique was demonstrated to simultaneously print a chip platform and develop a perfusable vascularized liver sinusoid in vitro model. The integrated system uses a co-axial-based bioprinting approach to develop a liver sinusoid-like model that consists of a sacrificial core compartment containing a perfusable pre-vascular structure and an alginate-collagen-based shell compartment containing hepatocytes. The lumen-based perfusable 3D liver sinusoid-on-a-chip (LSOC-P) demonstrated significantly better hepatocyte viability, proliferation, and liver-specific gene and protein expression compared to a 3D hepatocyte-based core/shell model with static media and the standard hepatocyte-based 2D sandwich culture system. A drug toxicity evaluation of hepatotoxins highlighted the comparatively higher sensitivity of the LSOC system with a close estimation of the therapeutic range of safe drug concentrations for humans. In conclusion, the current findings indicate that the combinatorial single-step co-axial bioprinting technique is a promising fabrication approach for the development of a perfusable LSOC platform for drug screening applications.
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Affiliation(s)
- Somnath Maji
- Department of Mechanical and Biomedical Engineering, Kangwon National University, Chuncheon, Republic of Korea
| | - Minkyoung Lee
- Department of Animal Industry Convergence, Kangwon National University, Chuncheon, Republic of Korea
- Department of Smart Health Science and Technology, Kangwon National University, Chuncheon, Republic of Korea
| | - Jooyoung Lee
- Department of Smart Health Science and Technology, Kangwon National University, Chuncheon, Republic of Korea
| | - Jaehee Lee
- Department of Smart Health Science and Technology, Kangwon National University, Chuncheon, Republic of Korea
| | - Hyungseok Lee
- Department of Mechanical and Biomedical Engineering, Kangwon National University, Chuncheon, Republic of Korea
- Department of Smart Health Science and Technology, Kangwon National University, Chuncheon, Republic of Korea
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16
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Rao M, Nassiri V, Alhambra C, Snoeys J, Van Goethem F, Irrechukwu O, Aleo MD, Geys H, Mitra K, Will Y. AI/ML Models to Predict the Severity of Drug-Induced Liver Injury for Small Molecules. Chem Res Toxicol 2023. [PMID: 37294641 DOI: 10.1021/acs.chemrestox.3c00098] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Drug-induced liver injury (DILI), believed to be a multifactorial toxicity, has been a leading cause of attrition of small molecules during discovery, clinical development, and postmarketing. Identification of DILI risk early reduces the costs and cycle times associated with drug development. In recent years, several groups have reported predictive models that use physicochemical properties or in vitro and in vivo assay endpoints; however, these approaches have not accounted for liver-expressed proteins and drug molecules. To address this gap, we have developed an integrated artificial intelligence/machine learning (AI/ML) model to predict DILI severity for small molecules using a combination of physicochemical properties and off-target interactions predicted in silico. We compiled a data set of 603 diverse compounds from public databases. Among them, 164 were categorized as Most DILI (M-DILI), 245 as Less DILI (L-DILI), and 194 as No DILI (N-DILI) by the FDA. Six machine learning methods were used to create a consensus model for predicting the DILI potential. These methods include k-nearest neighbor (k-NN), support vector machine (SVM), random forest (RF), Naïve Bayes (NB), artificial neural network (ANN), logistic regression (LR), weighted average ensemble learning (WA) and penalized logistic regression (PLR). Among the analyzed ML methods, SVM, RF, LR, WA, and PLR identified M-DILI and N-DILI compounds, achieving a receiver operating characteristic area under the curve of 0.88, sensitivity of 0.73, and specificity of 0.9. Approximately 43 off-targets, along with physicochemical properties (fsp3, log S, basicity, reactive functional groups, and predicted metabolites), were identified as significant factors in distinguishing between M-DILI and N-DILI compounds. The key off-targets that we identified include: PTGS1, PTGS2, SLC22A12, PPARγ, RXRA, CYP2C9, AKR1C3, MGLL, RET, AR, and ABCC4. The present AI/ML computational approach therefore demonstrates that the integration of physicochemical properties and predicted on- and off-target biological interactions can significantly improve DILI predictivity compared to chemical properties alone.
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Affiliation(s)
- Mohan Rao
- Discovery, Product Development and Supply (DPDS), Preclinical Sciences and Translational Safety (PSTS), Predictive Investigative and Translational Toxicology (PITT), Janssen Pharmaceutical Companies of Johnson and Johnson, La Jolla, California 92121, United States
| | - Vahid Nassiri
- Open Analytics, Jupiterstraat 20, 2600 Antwerpen, Belgium
| | - Cristóbal Alhambra
- Discovery, Product Development and Supply (DPDS), Preclinical Sciences and Translational Safety (PSTS), Predictive Investigative and Translational Toxicology (PITT), Janssen Pharmaceutical Companies of Johnson and Johnson, La Jolla, California 92121, United States
| | - Jan Snoeys
- Discovery, Product Development and Supply (DPDS), Preclinical Sciences and Translational Safety (PSTS), Predictive Investigative and Translational Toxicology (PITT), Janssen Pharmaceutical Companies of Johnson and Johnson, La Jolla, California 92121, United States
| | - Freddy Van Goethem
- Discovery, Product Development and Supply (DPDS), Preclinical Sciences and Translational Safety (PSTS), Predictive Investigative and Translational Toxicology (PITT), Janssen Pharmaceutical Companies of Johnson and Johnson, La Jolla, California 92121, United States
| | - Onyi Irrechukwu
- Discovery, Product Development and Supply (DPDS), Preclinical Sciences and Translational Safety (PSTS), Predictive Investigative and Translational Toxicology (PITT), Janssen Pharmaceutical Companies of Johnson and Johnson, La Jolla, California 92121, United States
| | - Michael D Aleo
- TOXinsights LLC, Boiling Springs, Pennsylvania 17007, United States
| | - Helena Geys
- Discovery, Product Development and Supply (DPDS), Preclinical Sciences and Translational Safety (PSTS), Predictive Investigative and Translational Toxicology (PITT), Janssen Pharmaceutical Companies of Johnson and Johnson, La Jolla, California 92121, United States
| | - Kaushik Mitra
- Discovery, Product Development and Supply (DPDS), Preclinical Sciences and Translational Safety (PSTS), Predictive Investigative and Translational Toxicology (PITT), Janssen Pharmaceutical Companies of Johnson and Johnson, La Jolla, California 92121, United States
| | - Yvonne Will
- Discovery, Product Development and Supply (DPDS), Preclinical Sciences and Translational Safety (PSTS), Predictive Investigative and Translational Toxicology (PITT), Janssen Pharmaceutical Companies of Johnson and Johnson, La Jolla, California 92121, United States
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Kucukakcali Z, Colak C, Gozukara Bag HG, Balikci Cicek I, Ozhan O, Yildiz A, Danis N, Koc A, Parlakpinar H, Akbulut S. Modeling Based on Ensemble Learning Methods for Detection of Diagnostic Biomarkers from LncRNA Data in Rats Treated with Cis-Platinum-Induced Hepatotoxicity. Diagnostics (Basel) 2023; 13:1583. [PMID: 37174973 PMCID: PMC10177870 DOI: 10.3390/diagnostics13091583] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 04/20/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
BACKGROUND The first aim of this study is to perform bioinformatic analysis of lncRNAs obtained from liver tissue samples from rats treated with cisplatin hepatotoxicity and without pathology. Another aim is to identify possible biomarkers for the diagnosis/early diagnosis of hepatotoxicity by modeling the data obtained from bioinformatics analysis with ensemble learning methods. METHODS In the study, 20 female Sprague-Dawley rats were divided into a control group and a hepatotoxicity group. Liver samples were taken from rats, and transcriptomic and histopathological analyses were performed. The dataset achieved from the transcriptomic analysis was modeled with ensemble learning methods (stacking, bagging, and boosting). Modeling results were evaluated with accuracy (Acc), balanced accuracy (B-Acc), sensitivity (Se), specificity (Sp), positive predictive value (Ppv), negative predictive value (Npv), and F1 score performance metrics. As a result of the modeling, lncRNAs that could be biomarkers were evaluated with variable importance values. RESULTS According to histopathological and immunohistochemical analyses, a significant increase was observed in the sinusoidal dilatation and Hsp60 immunoreactivity values in the hepatotoxicity group compared to the control group (p < 0.0001). According to the results of the bioinformatics analysis, 589 lncRNAs showed different expressions in the groups. The stacking model had the best classification performance among the applied ensemble learning models. The Acc, B-Acc, Se, Sp, Ppv, Npv, and F1-score values obtained from this model were 90%, 90%, 80%, 100%, 100%, 83.3%, and 88.9%, respectively. lncRNAs with id rna-XR_005492522.1, rna-XR_005492536.1, and rna-XR_005505831.1 with the highest three values according to the variable importance obtained as a result of stacking modeling can be used as predictive biomarker candidates for hepatotoxicity. CONCLUSIONS Among the ensemble algorithms, the stacking technique yielded higher performance results as compared to the bagging and boosting methods on the transcriptomic data. More comprehensive studies can support the possible biomarkers determined due to the research and the decisive results for the diagnosis of drug-induced hepatotoxicity.
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Affiliation(s)
- Zeynep Kucukakcali
- Department of Biostatistics and Medical Informatics, Faculty of Medicine, Inonu University, 44280 Malatya, Turkey; (Z.K.); (H.G.G.B.); (I.B.C.); (S.A.)
| | - Cemil Colak
- Department of Biostatistics and Medical Informatics, Faculty of Medicine, Inonu University, 44280 Malatya, Turkey; (Z.K.); (H.G.G.B.); (I.B.C.); (S.A.)
| | - Harika Gozde Gozukara Bag
- Department of Biostatistics and Medical Informatics, Faculty of Medicine, Inonu University, 44280 Malatya, Turkey; (Z.K.); (H.G.G.B.); (I.B.C.); (S.A.)
| | - Ipek Balikci Cicek
- Department of Biostatistics and Medical Informatics, Faculty of Medicine, Inonu University, 44280 Malatya, Turkey; (Z.K.); (H.G.G.B.); (I.B.C.); (S.A.)
| | - Onural Ozhan
- Department of Pharmacology, Faculty of Medicine, Inonu University, 44280 Malatya, Turkey; (O.O.)
| | - Azibe Yildiz
- Department of Histology and Embryology, Faculty of Medicine, Inonu University, 44280 Malatya, Turkey;
| | - Nefsun Danis
- Department of Medical Biology and Genetics, Faculty of Medicine, Inonu University, 44280 Malatya, Turkey; (N.D.); (A.K.)
| | - Ahmet Koc
- Department of Medical Biology and Genetics, Faculty of Medicine, Inonu University, 44280 Malatya, Turkey; (N.D.); (A.K.)
| | - Hakan Parlakpinar
- Department of Pharmacology, Faculty of Medicine, Inonu University, 44280 Malatya, Turkey; (O.O.)
| | - Sami Akbulut
- Department of Biostatistics and Medical Informatics, Faculty of Medicine, Inonu University, 44280 Malatya, Turkey; (Z.K.); (H.G.G.B.); (I.B.C.); (S.A.)
- Department of Surgery, Faculty of Medicine, Inonu University, 44280 Malatya, Turkey
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18
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Rakhshan A, Rahmati Kamel B, Saffaei A, Tavakoli-Ardakani M. Hepatotoxicity Induced by Azole Antifungal Agents: A Review Study. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2023; 22:e130336. [PMID: 38116543 PMCID: PMC10728840 DOI: 10.5812/ijpr-130336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 01/31/2023] [Accepted: 02/21/2023] [Indexed: 12/21/2023]
Abstract
Context Fungal infections are very common, and several medications are used to treat them. Azoles are prescribed widely to treat fungal infections. In addition to therapeutic effects, any drug can be accompanied by side effects in patients. One of the most important complications in this regard is liver injury. Therefore, hepatotoxicity induced by azole antifungal drugs were reviewed in this study. Evidence Acquisition English scientific papers were evaluated to review the effects of hepatotoxicity by azole antifungal agents, and the related studies' results were summarized using a table. The systematic search was implemented on electronic databases, including PubMed, Google Scholar, and Science Direct. Original articles and review articles that were published before April 1, 2022, were included in the study. Those articles without available full text or non-English articles were excluded. Also, articles that reported pediatric data were excluded. Results Most studies have reported the effects of hepatotoxicity by azole antifungal agents, and their mechanisms have been described. Conclusions Clinical evaluations regarding the hepatotoxicity of antifungal agents provided in the literature were reviewed. Therefore, it is recommended to prescribe these drugs with caution in high-risk patients suffering from liver diseases, and patients should be monitored for hepatotoxicity. However, more research is needed to evaluate the hepatotoxicity of azole antifungal agents and select appropriate drugs according to cost-effectiveness and the side effects' profiles, relying on lower incidence of this liver complication.
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Affiliation(s)
- Amin Rakhshan
- Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bardia Rahmati Kamel
- Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Saffaei
- Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maria Tavakoli-Ardakani
- Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Pharmaceutical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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19
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Ursolic Acid and Solasodine as Potent Anti-Mycobacterial Agents for Combating Paratuberculosis: An Anti-Inflammatory and In Silico Analysis. MOLECULES (BASEL, SWITZERLAND) 2022; 28:molecules28010274. [PMID: 36615467 PMCID: PMC9822293 DOI: 10.3390/molecules28010274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 12/19/2022] [Accepted: 12/20/2022] [Indexed: 01/01/2023]
Abstract
Mycobacterium avium subspecies paratuberculosis (MAP) infection in domestic livestock causes persistent diarrhea, weight loss, and death and is also a potential cause of Crohn's disease (CD) in humans; notably, treatments against MAP are insufficient, costly, and can cause adverse reactions. Hence, plant-derived bioactive constituents have been taken into consideration in this regard. Herein, we present the results of two bioactive constituents (Solasodine and Ursolic acid) that were evaluated for their safety and efficacy against MAP protein (Dephospho-Coenzyme A kinase (DPCK) by utilizing in vitro assays and different tools of in silico biology. The ADME/t-test, the drug-likeness property test, pharmacophore modelling, and PASS prediction have proven that both the constituents have better binding capacities than the available antibiotic drugs used to target protein inhibition pathways. Through our observations, it can be inferred that these two phytochemicals can be adequately used to treat paratuberculosis, thereby combating inflammatory bowel disorders (IBD) of an autoimmune nature.
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Cione E, Abrego Guandique DM, Caroleo MC, Luciani F, Colosimo M, Cannataro R. Liver Damage and microRNAs: An Update. Curr Issues Mol Biol 2022; 45:78-91. [PMID: 36661492 PMCID: PMC9857663 DOI: 10.3390/cimb45010006] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 12/12/2022] [Accepted: 12/20/2022] [Indexed: 12/28/2022] Open
Abstract
One of the major organs in the body with multiple functions is the liver. It plays a central role in the transformation of macronutrients and clearance of chemicals and drugs. The serum biomarkers often used to indicate liver damage are not specifically for drug-induced liver injury (DILI) or liver injury caused by other xenobiotics, nor for viral infection. In this case, microRNAs (miRNAs) could play an exciting role as biomarkers of specific liver damage. In this review, we aimed to update the current literature on liver damage induced by drugs, as acute conditions and viral infections mediated by the hepatitis B virus (HBV) linked these two conditions to advanced research, with a focus on microRNAs as early biomarkers for liver damage. The undoubtable evidence that circulating miR-122 could be used as a human biomarker of DILI came from several studies in which a strong increase of it was linked with the status of liver function. In infancy, there is the possibility of an early miRNA detection for hepatitis B virus infection, but there are a lack of solid models for studying the HVB molecular mechanism of infection in detail, even if miRNAs do hold unrealized potential as biomarkers for early detection of hepatitis B virus infection mediated by HBV.
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Affiliation(s)
- Erika Cione
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
- Galascreen Laboratories, University of Calabria, 87036 Rende, Italy
| | - Diana Marisol Abrego Guandique
- Galascreen Laboratories, University of Calabria, 87036 Rende, Italy
- Department of Health Sciences, University of Magna Graecia Catanzaro, 88100 Catanzaro, Italy
| | - Maria Cristina Caroleo
- Galascreen Laboratories, University of Calabria, 87036 Rende, Italy
- Department of Health Sciences, University of Magna Graecia Catanzaro, 88100 Catanzaro, Italy
| | - Filippo Luciani
- Infectious Disease Unit Annunziata Hospital, 87100 Cosenza, Italy
| | - Manuela Colosimo
- Microbiology Unit Pugliese Ciaccio Hospital, 88100 Catanzaro, Italy
| | - Roberto Cannataro
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
- Galascreen Laboratories, University of Calabria, 87036 Rende, Italy
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Wang Q, Huang Y, Li Y, Zhang L, Tang H, Zhang J, Cheng G, Zhao M, Lu T, Zhang Q, Luo P, Zhu Y, Xia F, Zhang Y, Liu D, Wang C, Li H, Qiu C, Wang J, Guo Q. Glycyrrhizic Acid Mitigates Tripterygium-Glycoside-Tablet-Induced Acute Liver Injury via PKM2 Regulated Oxidative Stress. Metabolites 2022; 12:1128. [PMID: 36422270 PMCID: PMC9694034 DOI: 10.3390/metabo12111128] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/11/2022] [Accepted: 11/14/2022] [Indexed: 09/01/2023] Open
Abstract
Tripterygium glycoside tablet (TGT), as a common clinical drug, can easily cause liver damage due to the narrow therapeutic window. Glycyrrhizic acid (GA) has a hepatoprotective effect, but the characteristics and mechanism of GA's impact on TGT-induced acute liver injury by regulating oxidative stress remain unelucidated. In this study, TGT-induced acute liver injury models were established in vitro and in vivo. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AKP), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), catalase (CAT), lactate dehydrogenase (LDH), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) were quantified. The anti-apoptotic effect of GA was tested using flow cytometry. Potential target proteins of GA were profiled via activity-based protein profiling (ABPP) using a cysteine-specific (IAA-yne) probe. The results demonstrate that GA markedly decreased the concentrations of ALT, AST, AKP, MDA, LDH, TNF-α, IL-1β and IL-6, whereas those of SOD, GSH and CAT increased. GA could inhibit TGT-induced apoptosis in BRL-3A cells. GA bound directly to the cysteine residue of PKM2. The CETSA and enzyme activity results validate the specific targets identified. GA could mitigate TGT-induced acute liver injury by mediating PKM2, reducing oxidative stress and inflammation and reducing hepatocyte apoptosis.
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Affiliation(s)
- Qixin Wang
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Yuwen Huang
- College of Food Science and Engineering, Bohai University, Jinzhou 121013, China
| | - Yu Li
- Institute for History of Chinese Medicine and Medical Literature, China Academy of Chinese Medical Sciences, Beijing 100073, China
| | - Luyun Zhang
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Huan Tang
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Junzhe Zhang
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Guangqing Cheng
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Minghong Zhao
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Tianming Lu
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Qian Zhang
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Piao Luo
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Yinhua Zhu
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Fei Xia
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Ying Zhang
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Dandan Liu
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Chen Wang
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Haiyan Li
- School of Medicine, Foshan University, Foshan 528000, China
| | - Chong Qiu
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Jigang Wang
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
- School of Public Health, Guangxi Medical University, Nanning 530021, China
| | - Qiuyan Guo
- Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
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22
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Shojaeifard MB, Hojjati S, Vojdani S, Keshavarz S. Protective Effect of Hydroalcoholic Extract of Clove on Thioacetamide-Induced Hepatotoxicity Animal Model: Effects Hydroalcoholic Extract of Clove Against Hepatotoxicity. Galen Med J 2022; 11:e1603. [PMID: 36660448 PMCID: PMC9833295 DOI: 10.31661/gmj.v11i.1603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND The drug-induced liver injury (DILI) has a wide range of clinical presentations, from asymptomatic liver enzyme elevations to cirrhosis. Herbal dietary supplements may be beneficial to reduce the risk of hepatotoxicity. This study aimed to evaluate the effects of different doses of clove extracts on humoral factors in rats with hepatotoxicity induced by thioacetamide. MATERIALS AND METHODS In this experimental study, rats were divided into nine groups (10 rats per each). The Control group received no treatment. The Sham group was treated with oral administration of distilled water (0.5 ml) for 21 days. The positive control group received thioacetamide (50 mg/kg for three days) intraperitoneally. The clove group was divided into three subgroups and given daily oral administrations of 50, 150, and 300 mg/kg of clove hydroalcoholic extracts (for 21 days). Rats in the experimental group were divided into three subgroups and subjected to 50 mg/kg thioacetamide injection after receiving hydroalcoholic extracts of clove (50, 150, and 300 mg/kg, respectively) for 21 days in the last three days. All rats were sacrificed after 48 hours to measure liver function parameters (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total plasma protein, and albumin). RESULTS The rats that received thioacetamide showed liver damage by increased serum liver biomarkers and decreased levels of total plasma protein and albumin compared to the control group. The different doses of clove extract resulted in a significant improvement of liver damage by reduced serum liver enzymes levels and increased total plasma protein and albumin. CONCLUSION Oral administration of the different doses of the clove extract (50, 150, and 300 mg/kg) for 21 consecutive days could significantly improve the changes associated with serum biomarkers of hepatotoxicity. [GMJ.2022;11:e1603].
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Affiliation(s)
| | - Sarah Hojjati
- Department of Exercise Physiology, Shiraz Branch, Islamic Azad University, Shiraz, Iran
| | - Salman Vojdani
- Non-Communicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Simin Keshavarz
- Department of Physiology, Marvdasht Branch, Islamic Azad University, Marvdasht, Iran
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Wang T, Miao L, Shao H, Wei X, Yan M, Zuo X, Zhang J, Hai X, Fan G, Wang W, Hu L, Zhou J, Zhao Y, Xie Y, Wang J, Guo S, Jin L, Li H, Liu H, Wang Q, Chen J, Li S, Dong Y. Voriconazole therapeutic drug monitoring and hepatotoxicity in critically ill patients: A nationwide multi-centre retrospective study. Int J Antimicrob Agents 2022; 60:106692. [PMID: 36372345 DOI: 10.1016/j.ijantimicag.2022.106692] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 10/01/2022] [Accepted: 11/06/2022] [Indexed: 11/13/2022]
Abstract
OBJECTIVES To characterize trough concentrations (Cmin) of voriconazole and associated hepatotoxicity, and to determine predictors of hepatotoxicity and identify high-risk groups in critically ill patients. METHODS This was a nationwide, multi-centre, retrospective study. Cmin and hepatotoxicity were studied from 2015 to 2020 in 363 critically ill patients who received voriconazole treatment. Logistic regression and classification and regression tree (CART) models were used to identify high-risk patients. RESULTS Large interindividual variability was observed in initial voriconazole Cmin and concentrations ranged from 0.1 mg/L to 18.72 mg/L. Voriconazole-related grade ≥2 hepatotoxicity developed in 101 patients, including 48 patients with grade ≥3 hepatotoxicity. The median time to hepatotoxicity was 3 days (range 1-24 days), and 83.2% of cases of hepatotoxicity occurred within 7 days of voriconazole initiation. Voriconazole Cmin was significantly associated with hepatotoxicity. The CART model showed that significant predictors of grade ≥2 hepatotoxicity were Cmin >3.42 mg/L, concomitant use of trimethoprim-sulfamethoxazole or tigecycline, and septic shock. The model predicted that the incidence of grade ≥2 hepatotoxicity among these high-risk patients was 48.3-63.4%. Significant predictors of grade ≥3 hepatotoxicity were Cmin >6.87 mg/L, concomitant use of at least three hepatotoxic drugs, and septic shock; the predictive incidence among these high-risk patients was 22.7-36.8%. CONCLUSION Higher voriconazole Cmin, septic shock and concomitant use of hepatotoxic drugs were the strongest predictors of hepatotoxicity. Plasma concentrations of voriconazole should be monitored early (as soon as steady state is achieved) to avoid hepatotoxicity.
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Affiliation(s)
- Taotao Wang
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Liyan Miao
- Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Hua Shao
- Department of Pharmacy, Zhongda Hospital, Southeast University, Nanjing, China
| | - Xiaohua Wei
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Miao Yan
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xiaocong Zuo
- Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Jun Zhang
- Department of Clinical Pharmacy, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Xin Hai
- Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Guangjun Fan
- Department of Pharmacy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Wei Wang
- Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Linlin Hu
- Department of Pharmacy, Zhongda Hospital, Southeast University, Nanjing, China
| | - Jian Zhou
- Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yichang Zhao
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yueliang Xie
- Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Jingjing Wang
- Department of Clinical Pharmacy, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Sixun Guo
- Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Liu Jin
- Department of Pharmacy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China; Department of Pharmacy, Liyang Hospital of Chinese Medicine, Changzhou, China
| | - Hao Li
- Department of Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Hui Liu
- Department of Biobank, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Quanfang Wang
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jiaojiao Chen
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Sihan Li
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yalin Dong
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
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Nutrition, Bioactive Components, and Hepatoprotective Activity of Fruit Vinegar Produced from Ningxia Wolfberry. Molecules 2022; 27:molecules27144422. [PMID: 35889295 PMCID: PMC9319210 DOI: 10.3390/molecules27144422] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/02/2022] [Accepted: 07/04/2022] [Indexed: 02/05/2023] Open
Abstract
Wolfberry (Lycium barbarum L.) is a nutritious and medicinal fruit, and deeply processed products of wolfberry needs to be improved. In this study, nutrition, bioactive compounds, and hepaprotective activity were explored in wolfberry vinegar (WFV). The contents of nutrients including total sugar and protein in WFV samples were 2.46 and 0.27 g/100 mL, respectively. Total phenolic and flavonoid contents in WFV were 2.42 mg GAE/mL and 1.67 mg RE/mL, respectively. p-Hydroxybenzoic acid and m-hydroxycinnamic acid were the main polyphenols in WFV. The antioxidant activity of WFV were 20.176 mM Trolox/L (ABTS), 8.614 mM Trolox/L (FRAP), and 26.736 mM Trolox/L (DPPH), respectively. In addition, WFV treatment effectively alleviated liver injury by improving histopathological changes and reducing liver biochemical indexes in CCl4-treated mice. WFV alleviated oxidative damage by inhibiting oxidative levels and increasing antioxidant levels. These results suggest that WFV can be utilized as a functional food to prevent oxidative liver injury.
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Yousuf S, Shabir S, Singh MP. Protection Against Drug-Induced Liver Injuries Through Nutraceuticals via Amelioration of Nrf-2 Signaling. JOURNAL OF THE AMERICAN NUTRITION ASSOCIATION 2022; 42:495-515. [PMID: 35771985 DOI: 10.1080/27697061.2022.2089403] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hepatotoxicity caused by the overdose of various medications is a leading cause of drug-induced liver injury. Overdose of drugs causes hepatocellular necrosis. Nutraceuticals are reported to prevent drug-induced liver failure. The present article aims to review the protection provided by various medicinal plants against hepatotoxic drugs. Ayurveda is considered a conventional restorative arrangement in India. It is consistently used for ages and is still used today to cure drug-induced hepatotoxicity by focusing on antioxidant stress response pathways such as the nuclear factor erythroid-2 (Nrf-2) antioxidant response element signaling pathway. Nrf-2 is a key transcription factor that entangles Kelch-like ECH-associating protein 1, a protein found in the cell cytoplasm. Some antioxidant enzymes, such as gamma glycine cysteine ligase (γ-GCL) and heme oxygenase-1 (HO-1), are expressed in Nrf-2 targeted genes. Their expression, in turn, decreases the stimulation of hepatic macrophages and induces the messenger RNA (mRNA) articulation of proinflammatory factors including tumor necrosis factor α. This review will cover various medicinal plants from a mechanistic view and how they stimulate and interact with Nrf-2, the master regulator of the antioxidant response to counterbalance oxidative stress. Interestingly, therapeutic plants have become popular in the medical sector due to safer yet effective supplementation for the prevention and treatment of new human diseases. The contemporary study is expected to collect information on a variety of therapeutic traditional herbs that have been studied in the context of drug-induced liver toxicity, as nutraceuticals are the most effective treatments for oxidative stress-induced hepatotoxicity. They are less genotoxic, have a lower cost, and are readily available. Together, nutraceuticals exert protective effects against drug-induced hepatotoxicity through the inhibition of oxidative stress, inflammation, and apoptosis. Its mechanism(s) are considered to be associated with the γ-GCL/HO-1 and Nrf-2 signaling pathways. KEY TEACHING POINTSThe liver is the most significant vital organ that carries out metabolic activities of the body such as the synthesis of glycogen, the formation of triglycerides and cholesterol, as well as the formation of bile.Acute liver failure is caused by the consumption of certain drugs; drug-induced liver injury is the major condition.The chemopreventive activity of nutraceuticals may be related to oxidative stress reduction and attenuation of biosynthetic processes involved in hepatic injury via amelioration of the nuclear factor erythroid-2 (Nrf-2) signaling pathway.Nrf-2 is a key transcription factor that is found in the cell cytoplasm resulting in the expression of various genes such as gamma glycine cysteine ligase and heme oxygenase-1.Nutraceutical-rich phytochemicals possess high antioxidant activity, which helps in the prevention of hepatic injury.
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Affiliation(s)
- Sumaira Yousuf
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, India
| | - Shabnam Shabir
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, India
| | - Mahendra P Singh
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, India
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Xu Y, Xu B, Wang J, Jin H, Xu S, Wang G, Zhen L. Peroxynitrite‐Promoted Persulfide Prodrugs with Protective Potential against Paracetamol Poisoning. Chemistry 2022; 28:e202200540. [DOI: 10.1002/chem.202200540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Indexed: 11/06/2022]
Affiliation(s)
- Ya‐Wen Xu
- Key Laboratory of Drug Metabolism and Pharmacokinetics China Pharmaceutical University 24 Tongjia Xiang Nanjing 210009 Jiangsu P. R. China
| | - Bi‐Xin Xu
- Key Laboratory of Drug Metabolism and Pharmacokinetics China Pharmaceutical University 24 Tongjia Xiang Nanjing 210009 Jiangsu P. R. China
| | - Jiankun Wang
- Key Laboratory of Drug Metabolism and Pharmacokinetics China Pharmaceutical University 24 Tongjia Xiang Nanjing 210009 Jiangsu P. R. China
| | - Hao‐Wen Jin
- Key Laboratory of Drug Metabolism and Pharmacokinetics China Pharmaceutical University 24 Tongjia Xiang Nanjing 210009 Jiangsu P. R. China
| | - Si‐Tao Xu
- Key Laboratory of Drug Metabolism and Pharmacokinetics China Pharmaceutical University 24 Tongjia Xiang Nanjing 210009 Jiangsu P. R. China
| | - Guangji Wang
- Key Laboratory of Drug Metabolism and Pharmacokinetics China Pharmaceutical University 24 Tongjia Xiang Nanjing 210009 Jiangsu P. R. China
| | - Le Zhen
- Key Laboratory of Drug Metabolism and Pharmacokinetics China Pharmaceutical University 24 Tongjia Xiang Nanjing 210009 Jiangsu P. R. China
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Peri V, Yu C, Vaz K, Asadi K, Grace J. Herb-Induced Liver Injury: A Report on Two Australian Cases. Cureus 2022; 14:e24686. [PMID: 35663668 PMCID: PMC9162901 DOI: 10.7759/cureus.24686] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/29/2022] [Indexed: 11/12/2022] Open
Abstract
Two 40-year-old males were admitted to our tertiary hepatology unit with acute hepatitis after presentation with generalized abdominal pain, nausea, and jaundice. There was no history of paracetamol overdose, and common viral and autoimmune causes were excluded through serology. Imaging and liver biopsy were performed with both investigations demonstrating non-specific features of hepatic inflammation. A history of herbal supplement use was elucidated in each patient, which was deemed to be the cause of liver injury in both men. Each patient recovered within two months of presentation following the withdrawal of the offending agent and supportive care.
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Guan S, Chen X, Chen Y, Wan G, Su Q, Liang H, Yang Y, Fang W, Huang Y, Zhao H, Zhuang W, Liu S, Wang F, Feng W, Zhang X, Huang M, Wang X, Zhang L. FOXO3 mutation predicting gefitinib-induced hepatotoxicity in NSCLC patients through regulation of autophagy. Acta Pharm Sin B 2022; 12:3639-3649. [PMID: 36176901 PMCID: PMC9513443 DOI: 10.1016/j.apsb.2022.02.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 01/13/2022] [Accepted: 01/14/2022] [Indexed: 11/25/2022] Open
Abstract
Hepatotoxicity is a common side effect for patients treated with gefitinib, but the related pathogenesis is unclear and lacks effective predictor and management strategies. A multi-omics approach integrating pharmacometabolomics, pharmacokinetics and pharmacogenomics was employed in non-small cell lung cancer patients to identify the effective predictor for gefitinib-induced hepatotoxicity and explore optional therapy substitution. Here, we found that patients with rs4946935 AA, located in Forkhead Box O3 (FOXO3) which is a well-known autophagic regulator, had a higher risk of hepatotoxicity than those with the GA or GG variant (OR = 18.020, 95%CI = 2.473 to 459.1784, P = 0.018) in a gefitinib-concentration dependent pattern. Furthermore, functional experiments identified that rs4946935_A impaired the expression of FOXO3 by inhibiting the promotor activity, increasing the threshold of autophagy initiation and inhibiting the autophagic activity which contributed to gefitinib-induced liver injury. In contrast, erlotinib-induced liver injury was independent on the variant and expression levels of FOXO3. This study reveals that FOXO3 mutation, leading to autophagic imbalance, plays important role in gefitinib-induced hepatotoxicity, especially for patients with high concentration of gefitinib. In conclusion, FOXO3 mutation is an effective predictor and erlotinib might be an appropriately and well-tolerated treatment option for patients carrying rs4946935 AA.
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Abdel-Ghaffar WH, Abdelghffar EA. Pathophysiological effects of Tamiflu on liver and kidneys of male rats. BENI-SUEF UNIVERSITY JOURNAL OF BASIC AND APPLIED SCIENCES 2022; 11:15. [PMID: 35097134 PMCID: PMC8787452 DOI: 10.1186/s43088-021-00189-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Accepted: 12/21/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Tamiflu/oseltamivir phosphate (OP), an anti-influenza drug, has a highly doubted safety especially after many cases of abnormal behaviour and deaths reported after being used. Such controversy was also locally and globally generated, especially after being heavily used in COVID-19 treatment protocol. This study was designed to evaluate the effect of three different doses of OP on the liver and kidneys of male adult albino rats through histological approaches, measuring their DNA integrity and biochemical analyses. Different doses of Tamiflu applied to humans were converted to rats, then observed their effects on the liver and kidneys. Rats were divided into four groups. G1: considered as control group. The rest of the three treated groups were received the same calculated dose of Tamiflu (6.75 mg/kg b.w.) in three different durations. G2, G3 and G4 represented the animals orally received OP, in which the rats received OP twice for 5 consecutive days, once for 10 and 45 days, respectively. RESULTS Our data showed numerous deleterious necrotic and fibrotic histopathological changes in the liver, and kidneys; as well as necrotic DNA smears, by using electrophoresis, in OP-treated rats of G2 and G4. In addition, OP significantly increased the serum cellular hepatic/renal toxicity markers (ALT, AST, ALP, GGT, indirect bilirubin, urea, creatinine, uric acid, & Na+). Also, it showed a reduction in the levels of serum total protein, albumin and K+ ions in rats of G2 and G4 compared with G1. In G3, OP treatment did not significantly alter hepatic/renal histological, DNA integrity and biochemical analyses in rats. CONCLUSIONS The therapeutic and long-term prophylactic doses of OP most likely cause structural and functional hepato- and nephrotoxicity in experimentally subjected rats. So, caution must be taken during Tamiflu treatment, and not used for long durations and/or with repetitive doses (time- and/or accumulative-dose-dependent); especially with patients suffer from liver and/or kidney dysfunction, while the short-term prophylactic dose of OP appears to be relatively safe and could be explored for oral medications. GRAPHICAL ABSTRACT
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Affiliation(s)
| | - Eman A. Abdelghffar
- Department of Zoology, Faculty of Science, Ain Shams University, Cairo, Egypt
- Biology Department, Faculty of Science, Taibah University, Yanbu Branch, Saudi Arabia
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Fan W, Fan L, Wang Z, Yang L. Limonoids From the Genus Melia (Meliaceae): Phytochemistry, Synthesis, Bioactivities, Pharmacokinetics, and Toxicology. Front Pharmacol 2022; 12:795565. [PMID: 35140606 PMCID: PMC8819599 DOI: 10.3389/fphar.2021.795565] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 12/06/2021] [Indexed: 12/17/2022] Open
Abstract
Limonoids, as the vital bioactive chemical compounds in genus Melia plants, have attracted significant attention owing to their exclusive structural characteristics and remarkable biological activity. These compounds can be usually classified into two categories, including the ring-intact group and the ring-C-seco group. Benefiting from the development of separation and analysis technology, more than 200 limonoids have been isolated and identified from this genus. There is growing evidence that limonoids from genus Melia possess diverse pharmacological activities, especially anti-cancer effects, insecticidal activities, and anti-botulism effects. Toosendanin, one of the paramount limonoids, was considered as the pivotal bioactive marker in two medicinal herbs, including Melia toosendan Sieb. et Zucc and Melia azedarach L. In particular, limonoids are found to exhibit non-negligible toxic effects, a finding which needs further research. Besides this, the lack of clinical research data seriously hinders its further development and utilization, and necessary clinical trials should be taken into consideration. In this review, we systematically summarized the phytochemical compounds and their synthesis methods, pharmacological activities, and the structure–activity relationship, pharmacokinetics, and toxicology of genus Melia-derived limonoids. We believe that this up-to-date review could provide scientific evidence for the application of limonoids as agents beneficial to health in future clinical practice.
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Affiliation(s)
- Wenxiang Fan
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Linhong Fan
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhengtao Wang
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Zhengtao Wang, ; Li Yang,
| | - Li Yang
- The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Zhengtao Wang, ; Li Yang,
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31
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Ellison C, Hewitt M, Przybylak K. In Silico Models for Hepatotoxicity. Methods Mol Biol 2022; 2425:355-392. [PMID: 35188639 DOI: 10.1007/978-1-0716-1960-5_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
In this chapter, we review the state of the art of predicting human hepatotoxicity using in silico techniques. There has been significant progress in this area over the past 20 years but there are still some challenges ahead. Principally, these challenges are our partial understanding of a very complex biochemical system and our ability to emulate that in a predictive capacity. Here, we provide an overview of the published modeling approaches in this area to date and discuss their design, strengths and weaknesses. It is interesting to note the diversity in modeling approaches, whether they be statistical algorithms or evidenced-based approaches including structural alerts and pharmacophore models. Irrespective of modeling approach, it appears a common theme of access to appropriate, relevant, and high-quality data is a limitation to all and is likely to continue to be the focus of future research.
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Affiliation(s)
- Claire Ellison
- Human and Natural Sciences Directorate, School of Science, Engineering and Environment, University of Salford, Manchester, UK
| | - Mark Hewitt
- School of Pharmacy, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, UK.
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Zhou Y, Wang J, Zhang D, Liu J, Wu Q, Chen J, Tan P, Xing B, Han Y, Zhang P, Xiao X, Pei J. Mechanism of drug-induced liver injury and hepatoprotective effects of natural drugs. Chin Med 2021; 16:135. [PMID: 34895294 PMCID: PMC8665608 DOI: 10.1186/s13020-021-00543-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 11/21/2021] [Indexed: 02/06/2023] Open
Abstract
Drug-induced liver injury (DILI) is a common adverse drug reaction (ADR) and a serious threat to health that affects disease treatments. At present, no targeted clinical drugs are available for DILI. Traditional natural medicines have been widely used as health products. Some natural medicines exert specific hepatoprotective effects, with few side effects and significant clinical efficacy. Thus, natural medicines may be a promising direction for DILI treatment. In this review, we summarize the current knowledge, common drugs and mechanisms of DILI, as well as the clinical trials of natural drugs and their bioactive components in anticipation of the future development of potential hepatoprotective drugs.
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Affiliation(s)
- Yongfeng Zhou
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137 Sichuan China
- Department of Pharmacy, Medical Supplies Center of PLA General Hospital, 100#, West 4th Ring Middle Rd., Fengtai, Beijing, 10039 China
| | - Junnan Wang
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488 China
- Department of Pharmacy, Medical Supplies Center of PLA General Hospital, 100#, West 4th Ring Middle Rd., Fengtai, Beijing, 10039 China
| | - Dingkun Zhang
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137 Sichuan China
| | - Jiaxin Liu
- Department of Pharmacy, Medical Supplies Center of PLA General Hospital, 100#, West 4th Ring Middle Rd., Fengtai, Beijing, 10039 China
| | - Qinghua Wu
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137 Sichuan China
| | - Jiang Chen
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137 Sichuan China
| | - Peng Tan
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137 Sichuan China
| | - Boyu Xing
- Department of Pharmacy, Medical Supplies Center of PLA General Hospital, 100#, West 4th Ring Middle Rd., Fengtai, Beijing, 10039 China
| | - Yanzhong Han
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137 Sichuan China
- Department of Pharmacy, Medical Supplies Center of PLA General Hospital, 100#, West 4th Ring Middle Rd., Fengtai, Beijing, 10039 China
| | - Ping Zhang
- Department of Pharmacy, Medical Supplies Center of PLA General Hospital, 100#, West 4th Ring Middle Rd., Fengtai, Beijing, 10039 China
| | - Xiaohe Xiao
- Department of Liver Disease, Fifth Medical Center of PLA General Hospital, 100#, West 4th Ring Middle Rd., Fengtai, Beijing, 10039 China
| | - Jin Pei
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137 Sichuan China
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Korver S, Bowen J, Pearson K, Gonzalez RJ, French N, Park K, Jenkins R, Goldring C. The application of cytokeratin-18 as a biomarker for drug-induced liver injury. Arch Toxicol 2021; 95:3435-3448. [PMID: 34322741 PMCID: PMC8492595 DOI: 10.1007/s00204-021-03121-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 07/15/2021] [Indexed: 01/13/2023]
Abstract
Drug-induced liver injury (DILI) is a frequent and dangerous adverse effect faced during preclinical and clinical drug therapy. DILI is a leading cause of candidate drug attrition, withdrawal and in clinic, is the primary cause of acute liver failure. Traditional diagnostic markers for DILI include alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). Yet, these routinely used diagnostic markers have several noteworthy limitations, restricting their sensitivity, specificity and accuracy in diagnosing DILI. Consequently, new biomarkers for DILI need to be identified.A potential biomarker for DILI is cytokeratin-18 (CK18), an intermediate filament protein highly abundant in hepatocytes and cholangiocytes. Extensively researched in a variety of clinical settings, both full length and cleaved forms of CK18 can diagnose early-stage DILI and provide insight into the mechanism of hepatocellular injury compared to traditionally used diagnostic markers. However, relatively little research has been conducted on CK18 in preclinical models of DILI. In particular, CK18 and its relationship with DILI is yet to be characterised in an in vivo rat model. Such characterization of CK18 and ccCK18 responses may enable their use as translational biomarkers for hepatotoxicity and facilitate management of clinical DILI risk in drug development. The aim of this review is to discuss the application of CK18 as a biomarker for DILI. Specifically, this review will highlight the properties of CK18, summarise clinical research that utilised CK18 to diagnose DILI and examine the current challenges preventing the characterisation of CK18 in an in vivo rat model of DILI.
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Affiliation(s)
- Samantha Korver
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK.
- Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia.
| | - Joanne Bowen
- Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia
| | | | | | - Neil French
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK
| | - Kevin Park
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK
| | - Rosalind Jenkins
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK
| | - Christopher Goldring
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK
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Xing Y, Xing H, Ma Y, Liu Q, Xu S. In Vitro and In Vivo Studies of Metabolic Activation of Marrubiin, a Bioactive Constituent from Marrubium Vulgare. Chem Res Toxicol 2021; 34:2157-2165. [PMID: 34431289 DOI: 10.1021/acs.chemrestox.1c00250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Marrubiin, a furanoid compound, is a well-known diterpenoid lactone isolated from Marrubium vulgare, which displays a wide spectrum of pharmacological effects and potential hepatotoxicity. Considering that marrubiin contains a structural alert, furan ring, metabolic activation may be one of the major metabolic pathways, and the reactive metabolite may be involved in the hepatotoxicity. The present study was carried out to investigate the bioactivation mechanism of marrubiin in rats and humans. Marrubiin was initially metabolized into cis-butene-1,4-dial intermediate, which was readily trapped by glutathione (GSH) and N-acetyl-lysine (NAL) in the microsomal incubations supplemented with NADPH. A total of nine conjugates were detected and identified by high-resolution mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. M1-M3 and M6 and M7 were characterized as mono-GSH conjugates, and M4 and M5 were identified as bis-GSH conjugates. M8 and M9 were identified as NAL conjugates. In rat bile, five GSH conjugates (M1-M3; M6 and M7) were detected. M1, M8, and M9 were chemically synthesized, and their structures were characterized by 13C NMR. Sulfaphenazole, ticlopidine, and ketoconazole displayed significant inhibitory effect on the bioactivation of marrubiin. Further phenotyping revealed that CYP2C9, CYP2C19, and CYP3A4 were the primary enzymes catalyzing the bioactivation of marrubiin. The current study provides evidence for the CYP-dominated bioactivation of marrubiin to the corresponding cis-butene-1,4-dial intermediate, which enables us to better understand the potential side effects caused by marrubiin.
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Affiliation(s)
- Yongtian Xing
- Department of Pharmacy, Henan Provincial People's Hospital, Department of Pharmacy of Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, Henan 450003, China
| | - Han Xing
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, China
| | - Yongcheng Ma
- Department of Pharmacy, Henan Provincial People's Hospital, Department of Pharmacy of Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, Henan 450003, China
| | - Qingwang Liu
- Institute of Health & Medical Technology, Hefei Institute of Physical Science, Chinese Academy of Sciences, Hefei, Anhui Province 230031, China
| | - Suyan Xu
- Department of Pharmacy, Henan Provincial People's Hospital, Department of Pharmacy of Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, Henan 450003, China
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Ommati MM, Mobasheri A, Heidari R. Drug-induced organ injury in coronavirus disease 2019 pharmacotherapy: Mechanisms and challenges in differential diagnosis and potential protective strategies. J Biochem Mol Toxicol 2021; 35:e22795. [PMID: 33973313 PMCID: PMC8237057 DOI: 10.1002/jbt.22795] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 04/13/2021] [Accepted: 04/22/2021] [Indexed: 12/20/2022]
Abstract
The world is currently facing an unprecedented pandemic caused by a newly recognized and highly pathogenic coronavirus disease 2019 (COVID-19; induced by SARS-CoV-2 virus), which is a severe and ongoing threat to global public health. Since COVID-19 was officially declared a pandemic by the World Health Organization in March 2020, several drug regimens have rapidly undergone clinical trials for the management of COVID-19. However, one of the major issues is drug-induced organ injury, which is a prominent clinical challenge. Unfortunately, most drugs used against COVID-19 are associated with adverse effects in different organs, such as the kidney, heart, and liver. These side effects are dangerous and, in some cases, they can be lethal. More importantly, organ injury is also a clinical manifestation of COVID-19 infection. These adverse reactions are increasingly recognized as outcomes of COVID-19 infection. Therefore, the differential diagnosis of drug-induced adverse effects from COVID-19-induced organ injury is a clinical complication. This review highlights the importance of drug-induced organ injury, its known mechanisms, and the potential therapeutic strategies in COVID-19 pharmacotherapy. We review the potential strategies for the differential diagnosis of drug-induced organ injury. This information can facilitate the development of therapeutic strategies, not only against COVID-19 but also for future outbreaks of other emerging infectious diseases.
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Affiliation(s)
- Mohammad Mehdi Ommati
- College of Life SciencesShanxi Agricultural UniversityTaiguChina
- Pharmaceutical Sciences Research CenterShiraz University of Medical SciencesShirazIran
| | - Ali Mobasheri
- Research Unit of Medical Imaging, Physics and Technology, Faculty of MedicineUniversity of OuluOuluFinland
- Department of Regenerative MedicineState Research Institute Centre for Innovative MedicineVilniusLithuania
- Departments of Orthopedics, Rheumatology and Clinical ImmunologyUniversity Medical Center UtrechtUtrechtThe Netherlands
- Department of Joint SurgerySun Yat‐sen UniversityGuangzhouChina
| | - Reza Heidari
- Pharmaceutical Sciences Research CenterShiraz University of Medical SciencesShirazIran
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36
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Rasheed DM, Emad AM, Ali SF, Ali SS, Farag MA, Meselhy MR, Sattar EA. UPLC-PDA-ESI/MS metabolic profiling of dill shoots bioactive fraction; evidence of its antioxidant and hepatoprotective effects in vitro and in vivo. J Food Biochem 2021; 45:e13741. [PMID: 33904177 DOI: 10.1111/jfbc.13741] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 04/05/2021] [Accepted: 04/06/2021] [Indexed: 01/16/2023]
Abstract
Hydroxyl radical (• OH) scavenging capacity of aqueous dill (Anethum graveolens L.) shoot (ADSh) extract was assessed using electron paramagnetic resonance (EPR) spectroscopy. ADSh extract (at concentrations of 0.5 and 10 mg/ml) exerted high (OH) radical scavenging power. ADSh extract was further fractionated on Diaion HP-20 column to yield five fractions. EPR spin-trapping assay revealed fraction 4 (eluted with 75% aq. MeOH) to possess (• OH) radical scavenging capacity over a concentration range (0.01-10 mg/ml), whereas fraction 2 (eluted with 25% aq. MeOH) appeared to be pro-oxidant at concentration 0.01 mg/ml. UPLC-PDA-ESI-MS metabolite profiling of ADSh extract revealed 87 metabolites, of which 64 compounds were identified in fraction 4, the most active fraction. Furthermore, ADSh extract demonstrated a hepatoprotective effect against acetaminophen (APAP)-induced hepatotoxicity in rats. Pretreatment of rats with ADSh extract (200 mg/kg b.wt) markedly attenuated the increased in the serum hepatic enzyme levels. It also increased free glutathione level and total antioxidant capacity in the serum of treated rats. [Correction added on May 3, 2021, after first online publication: "rates" has been changed to "rats" in the previous sentence.] Additionally, levels of (TNF-α and IL-1β) were back to almost normal levels compared to the control group. The above findings suggest that ADSh extract has a protective effect against APAP-induced liver damage.
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Affiliation(s)
- Dalia M Rasheed
- Pharmacognosy Department, Faculty of Pharmacy, October 6 University, Sixth of October, Egypt
| | - Ayat M Emad
- Pharmacognosy Department, Faculty of Pharmacy, October 6 University, Sixth of October, Egypt
| | - Sherifa F Ali
- Pharmacognosy Department, Faculty of Pharmacy, October 6 University, Sixth of October, Egypt.,Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Sameh S Ali
- Children's Cancer Hospital Egypt 57357, Cairo, Egypt.,Center for Aging and Associated Disease, Zewail City of Science and Technology, Sixth of October, Egypt
| | - Mohamed A Farag
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.,Department of Chemistry, School of Sciences & Engineering, The American University in Cairo, New Cairo, Egypt
| | - Meselhy R Meselhy
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Essam A Sattar
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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37
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Chen SS, Huang Y, Guo YM, Li SS, Shi Z, Niu M, Zou ZS, Xiao XH, Wang JB. Serum Metabolomic Analysis of Chronic Drug-Induced Liver Injury With or Without Cirrhosis. Front Med (Lausanne) 2021; 8:640799. [PMID: 33855035 PMCID: PMC8039323 DOI: 10.3389/fmed.2021.640799] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 03/08/2021] [Indexed: 12/25/2022] Open
Abstract
Background: Chronic drug-induced liver injury (DILI) occurs in up to 20% of all DILI patients. It presents a chronic pattern with persistent or relapsed episodes and may even progress to cirrhosis. However, its underlying development mechanism is poorly understood. Aims: To find serum metabolite signatures of chronic DILI with or without cirrhosis, and to elucidate the underlying mechanism. Methods: Untargeted metabolomics coupled with pattern recognition approaches were used to profile and extract metabolite signatures from 83 chronic DILI patients, including 58 non-cirrhosis (NC) cases, 14 compensated cirrhosis (CC) cases, and 11 decompensated cirrhosis (DC) cases. Results: Of the 269 annotated metabolites associated with chronic DILI, metabolic fingerprints associated with cirrhosis (including 30 metabolites) and decompensation (including 25 metabolites), were identified. There was a significantly positive correlation between cirrhosis-associated fingerprint (eigenmetabolite) and the aspartate aminotransferase-to-platelet ratio index (APRI) (r = 0.315, P = 0.003). The efficacy of cirrhosis-associated eigenmetabolite coupled with APRI to identify cirrhosis from non-cirrhosis patients was significantly better than APRI alone [area under the curve (AUC) value 0.914 vs. 0.573]. The decompensation-associated fingerprint (eigenmetabolite) can effectively identify the compensation and decompensation periods (AUC value 0.954). The results of the metabolic fingerprint pathway analysis suggest that the blocked tricarboxylic acid cycle (TCA cycle) and intermediary metabolism, excessive accumulation of bile acids, and perturbed amino acid metabolism are potential mechanisms in the occurrence and development of chronic DILI-associated cirrhosis. Conclusions: The metabolomic fingerprints characterize different stages of chronic DILI progression and deepen the understanding of the metabolic reprogramming mechanism of chronic DILI progression to cirrhosis.
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Affiliation(s)
- Shuai-shuai Chen
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Department of Liver Diseases, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China
| | - Ying Huang
- Department of Liver Diseases, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China
| | - Yu-ming Guo
- Department of Liver Diseases, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China
| | - Shan-shan Li
- Department of Liver Diseases, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China
| | - Zhuo Shi
- Department of Liver Diseases, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China
| | - Ming Niu
- Department of Poisoning Treatment, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China
| | - Zheng-sheng Zou
- Department of Liver Diseases, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China
| | - Xiao-he Xiao
- Department of Liver Diseases, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China
| | - Jia-bo Wang
- Department of Liver Diseases, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
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Sarkar B, Alam S, Rajib TK, Islam SS, Araf Y, Ullah MA. Identification of the most potent acetylcholinesterase inhibitors from plants for possible treatment of Alzheimer’s disease: a computational approach. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2021. [DOI: 10.1186/s43042-020-00127-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Being one of the rapidly growing dementia type diseases in the world, Alzheimer’s disease (AD) has gained much attention from researchers in the recent decades. Many hypotheses have been developed that describe different reasons for the development of AD. Among them, the cholinergic hypothesis depicts that the degradation of an important neurotransmitter, acetylcholine by the enzyme acetylcholinesterase (AChE), is responsible for the development of AD. Although, many anti-AChE drugs are already available in the market, their performance sometimes yields unexpected results. For this reason, research works are going on to find out potential anti-AChE agents both from natural and synthetic sources. In this study, 50 potential anti-AChE phytochemicals were analyzed using numerous tools of bioinformatics and in silico biology to find out the best possible anti-AChE agents among the selected 50 ligands through molecular docking, determination of the druglikeness properties, conducting the ADMET test, PASS and P450 site of metabolism prediction, and DFT calculations.
Result
The predictions of this study suggested that among the selected 50 ligands, bellidifolin, naringenin, apigenin, and coptisine were the 4 best compounds with quite similar and sound performance in most of the experiments.
Conclusion
In this study, bellidifolin, naringenin, apigenin, and coptisine were found to be the most effective agents for treating the AD targeting AChE. However, more in vivo and in vitro analyses are required to finally confirm the outcomes of this research.
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McLoughlin KS, Jeong CG, Sweitzer TD, Minnich AJ, Tse MJ, Bennion BJ, Allen JE, Calad-Thomson S, Rush TS, Brase JM. Machine Learning Models to Predict Inhibition of the Bile Salt Export Pump. J Chem Inf Model 2021; 61:587-602. [PMID: 33502191 DOI: 10.1021/acs.jcim.0c00950] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Cholestatic liver injury is frequently associated with drug inhibition of bile salt transporters, such as the bile salt export pump (BSEP). Reliable in silico models to predict BSEP inhibition directly from chemical structures would significantly reduce costs during drug discovery and could help avoid injury to patients. We report our development of classification and regression models for BSEP inhibition with substantially improved performance over previously published models. We assessed the performance effects of different methods of chemical featurization, data set partitioning, and class labeling and identified the methods producing models that generalized best to novel chemical entities.
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Affiliation(s)
- Kevin S McLoughlin
- Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, California 94501, United States
| | - Claire G Jeong
- GlaxoSmithKline, LLC 1250 S Collegeville Rd, Collegeville, Pennsylvania 19426, United States
| | - Thomas D Sweitzer
- GlaxoSmithKline, LLC 1250 S Collegeville Rd, Collegeville, Pennsylvania 19426, United States
| | - Amanda J Minnich
- Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, California 94501, United States
| | - Margaret J Tse
- GlaxoSmithKline, LLC 1250 S Collegeville Rd, Collegeville, Pennsylvania 19426, United States
| | - Brian J Bennion
- Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, California 94501, United States
| | - Jonathan E Allen
- Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, California 94501, United States
| | - Stacie Calad-Thomson
- GlaxoSmithKline, LLC 1250 S Collegeville Rd, Collegeville, Pennsylvania 19426, United States
| | - Thomas S Rush
- GlaxoSmithKline, LLC 1250 S Collegeville Rd, Collegeville, Pennsylvania 19426, United States
| | - James M Brase
- Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, California 94501, United States
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40
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Liu Y, Liu C, Liu Y, Ge Q, Sun C. Cytochrome P450 Mediated Bioactivation of Rutaevin, a Bioactive and Potentially Hepatotoxic Component of Evodia Rutaecarpa. Chem Res Toxicol 2020; 33:3054-3064. [PMID: 33305580 DOI: 10.1021/acs.chemrestox.0c00475] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Yutao Liu
- Department of Drug Clinical Trial Institution, Yantaishan Hospital, No. 91 Jiefang Road, Yantai 26400, Shandong Province, China
| | - Chang Liu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250000, Shandong Province, China
| | - Yamei Liu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250000, Shandong Province, China
| | - Quanli Ge
- Department of Pharmacy, Yantaishan Hospital, No. 91 Jiefang Road, Yantai 26400, Shandong Province, China
| | - Chen Sun
- Department of Internal Medicine, Yantai Municipal Government Hospital, No. 16 Yuhuangding West Road, Yantai 264000, Shandong Province, China
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41
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HepG2 (C3A) spheroids show higher sensitivity compared to HepaRG spheroids for drug-induced liver injury (DILI). Toxicol Appl Pharmacol 2020; 408:115279. [DOI: 10.1016/j.taap.2020.115279] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/25/2020] [Accepted: 10/11/2020] [Indexed: 12/20/2022]
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42
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Wan Z, Li H, Wu X, Zhao H, Wang R, Li M, Liu J, Liu Q, Wang R, Li X. Hepatoprotective effect of gentiopicroside in combination with leflunomide and/or methotrexate in arthritic rats. Life Sci 2020; 265:118689. [PMID: 33130083 DOI: 10.1016/j.lfs.2020.118689] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 10/27/2020] [Accepted: 10/27/2020] [Indexed: 02/07/2023]
Abstract
AIMS This study aimed to examine whether gentiopicroside (GPS) could exert hepatoprotective effects on leflunomide (LEF)- and/or methotrexate (MTX)-treated arthritic rats through anti-inflammatory and antioxidant pathways. MAIN METHODS We observed the external symptoms of joints, analysed serum indicators, measured haematological parameters and mRNA levels, and performed HE staining. KEY FINDINGS LEF and/or MTX combined with GPS ameliorated oxidative stress by increasing the mRNA levels of the antioxidant gene Nrf2, GCLC, HO-1, and NQO1, increasing the antioxidant enzymes superoxide dismutase (SOD), glutathione (GSH) and catalase (CAT), reducing the oxidant substance malondialdehyde (MDA), reducing the inflammatory response by decreasing the mRNA levels of NF-κB, tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), and inhibiting the secretion of the pro-inflammatory cytokines TNFα, IL-6, IL-1β and reducing C-reactive protein (CRP), as well as alleviating the external symptoms of arthritis. SIGNIFICANCE These results show that GPS plays an antioxidant and anti-inflammatory role in LEF- and/or MTX-treated arthritic rats by affecting the Nrf2 and NF-κB signalling pathways, thus exerting hepatoprotective effects.
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Affiliation(s)
- Zhijie Wan
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue, Zhengzhou 450001, China.
| | - He Li
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450001, China
| | - Xiaohan Wu
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue, Zhengzhou 450001, China
| | - Haiyun Zhao
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue, Zhengzhou 450001, China
| | - Ran Wang
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue, Zhengzhou 450001, China
| | - Mengmeng Li
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue, Zhengzhou 450001, China
| | - Jing Liu
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue, Zhengzhou 450001, China
| | - Qingfeng Liu
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue, Zhengzhou 450001, China
| | - Rui Wang
- Luohe Central Hospital Affiliated to Luohe Medical College, Luohe 462000, China.
| | - Xiaotian Li
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue, Zhengzhou 450001, China.
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Kucukler S, Darendelioğlu E, Caglayan C, Ayna A, Yıldırım S, Kandemir FM. Zingerone attenuates vancomycin-induced hepatotoxicity in rats through regulation of oxidative stress, inflammation and apoptosis. Life Sci 2020; 259:118382. [PMID: 32898532 DOI: 10.1016/j.lfs.2020.118382] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 08/17/2020] [Accepted: 08/29/2020] [Indexed: 12/20/2022]
Abstract
AIM Vancomycin (VCM) is a glycopeptide antibiotic widely used to treat serious infections caused by methicillin-resistant Staphylococcus aureus and has been associated with some severe side effects such as hepatotoxicity and nephrotoxicity. However, the underlying mechanism of VCM-induced hepatotoxicity is not yet fully understood. Therefore, the current study was designed to evaluate the protective effects of zingerone (Zin) against VCM-induced hepatotoxicity in rats. MATERIALS AND METHODS VCM was intraperitoneally administered at a dose of 200 mg/kg body weight (b.w.) for 7 days alone and in combination with the orally administered Zin (25 and 50 mg/kg b.w). KEY FINDINGS Zin treatment significantly improved VCM-induced hepatic lipid peroxidation, glutathione depletion, reduced antioxidant enzyme (superoxide dismutase, catalase and glutathione peroxidase) activities and liver function markers (aspartate aminotransferase, alkaline phosphatase and alanine aminotransferase). Histopathological integrity and immunohistochemical expression of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the VCM-induced liver tissue were ameliorated after Zin administration. In addition, Zin reversed the changes in levels and/or activities of inflammatory and apoptotic parameters such as nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), p53, cysteine aspartate specific protease-3 (caspase-3), cysteine aspartate specific protease-8 (caspase-8), cytochrome c, Bcl-2 associated X protein (Bax) and B-cell lymphoma-2 (Bcl-2) in the VCM-induced hepatotoxicity. SIGNIFICANCE Collectively, these results reveal probable ameliorative role of Zin against VCM-induced hepatotoxicity.
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Affiliation(s)
- Sefa Kucukler
- Department of Biochemistry, Faculty of Veterinary Medicine, Ataturk University, 25240 Erzurum, Turkey.
| | - Ekrem Darendelioğlu
- Department of Molecular Biology and Genetics, Faculty of Science and Literature, Bingol University, 12000 Bingol, Turkey
| | - Cuneyt Caglayan
- Department of Biochemistry, Faculty of Veterinary Medicine, Bingol University, 12000 Bingol, Turkey.
| | - Adnan Ayna
- Department of Biochemistry, Faculty of Science and Literature, Bingol University, 12000 Bingol, Turkey
| | - Serkan Yıldırım
- Department of Pathology, Faculty of Veterinary Medicine, Ataturk University, 25240 Erzurum, Turkey
| | - Fatih Mehmet Kandemir
- Department of Biochemistry, Faculty of Veterinary Medicine, Ataturk University, 25240 Erzurum, Turkey
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44
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Mitochondrial dysfunction and apoptosis underlie the hepatotoxicity of perhexiline. Toxicol In Vitro 2020; 69:104987. [PMID: 32861758 DOI: 10.1016/j.tiv.2020.104987] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 07/29/2020] [Accepted: 08/25/2020] [Indexed: 12/12/2022]
Abstract
Perhexiline is an anti-anginal drug developed in the late 1960s. Despite its therapeutic success, it caused severe hepatoxicity in selective patients, which resulted in its withdrawal from the market. In the current study we explored the molecular mechanisms underlying the cytotoxicity of perhexiline. In primary human hepatocytes, HepaRG cells, and HepG2 cells, perhexiline induced cell death in a concentration- and time-dependent manner. Perhexiline treatment also caused a significant increase in caspase 3/7 activity at 2 h and 4 h. Pretreatment with specific caspase inhibitors suggested that both intrinsic and extrinsic apoptotic pathways contributed to perhexiline-induced cytotoxicity, which was confirmed by increased expression of TNF-α, cleavage of caspase 3 and 9 upon perhexiline treatment. Moreover, perhexiline caused mitochondrial dysfunction, demonstrated by the classic glucose-galactose assay at 4 h and 24 h. Results from JC-1 staining suggested perhexiline caused loss of mitochondrial potential. Blocking mitochondrial permeability transition pore using inhibitor bongkrekic acid attenuated the cytotoxicity of perhexiline. Western blotting analysis also showed decreased expression level of pro-survival proteins Bcl-2 and Mcl-1, and increased expression of pro-apoptotic protein Bad. Direct measurement of the activity of individual components of the mitochondrial respiratory complex demonstrated that perhexiline strongly inhibited Complex IV and Complex V and moderately inhibited Complex II and Complex II + III. Overall, our data demonstrated that both mitochondrial dysfunction and apoptosis underlies perhexiline-induced hepatotoxicity.
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45
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Oda S, Uchida Y, Aleo MD, Koza-Taylor PH, Matsui Y, Hizue M, Marroquin LD, Whritenour J, Uchida E, Yokoi T. An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol 2020; 95:149-168. [PMID: 32816093 DOI: 10.1007/s00204-020-02882-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 08/13/2020] [Indexed: 12/19/2022]
Abstract
Preventing clinical drug-induced liver injury (DILI) remains a major challenge, because DILI develops via multifactorial mechanisms. Immune and inflammatory reactions are considered important mechanisms of DILI; however, biomarkers from in vitro systems using immune cells have not been comprehensively studied. The aims of this study were (1) to identify promising biomarker genes for predicting DILI in an in vitro coculture model of peripheral blood mononuclear cells (PBMCs) with a human liver cell line, and (2) to evaluate these genes as predictors of DILI using a panel of drugs with different clinical DILI risk. Transcriptome-wide analysis of PBMCs cocultured with HepG2 or differentiated HepaRG cells that were treated with several drugs revealed an appropriate separation of DILI-positive and DILI-negative drugs, from which 12 putative biomarker genes were selected. To evaluate the predictive performance of these genes, PBMCs cocultured with HepG2 cells were exposed to 77 different drugs, and gene expression levels in PBMCs were determined. The MET proto-oncogene receptor tyrosine kinase (MET) showed the highest area under the receiver-operating characteristic curve (AUC) value of 0.81 among the 12 genes with a high sensitivity/specificity (85/66%). However, a stepwise logistic regression model using the 12 identified genes showed the highest AUC value of 0.94 with a high sensitivity/specificity (93/86%). Taken together, we established a coculture system using PBMCs and HepG2 cells and selected biomarkers that can predict DILI risk. The established model would be useful in detecting the DILI potential of compounds, in particular those that involve an immune mechanism.
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Affiliation(s)
- Shingo Oda
- Division of Clinical Pharmacology, Department of Drug Safety Sciences, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Yuka Uchida
- Division of Clinical Pharmacology, Department of Drug Safety Sciences, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Michael D Aleo
- Drug Safety Research and Development, Pfizer Inc, Groton, CT, USA
- TOXinsights LLC, East Lyme, CT, USA
| | | | - Yusuke Matsui
- Laboratory of Intelligence Healthcare, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masanori Hizue
- Drug Safety Research and Development, Pfizer Inc, Tokyo, Japan
| | - Lisa D Marroquin
- Drug Safety Research and Development, Pfizer Inc, Groton, CT, USA
| | | | - Eri Uchida
- Drug Safety Research and Development, Pfizer Inc, Tokyo, Japan
| | - Tsuyoshi Yokoi
- Division of Clinical Pharmacology, Department of Drug Safety Sciences, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
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Sarkar B, Ullah MA, Islam SS, Rahman MH, Araf Y. Analysis of plant-derived phytochemicals as anti-cancer agents targeting cyclin dependent kinase-2, human topoisomerase IIa and vascular endothelial growth factor receptor-2. J Recept Signal Transduct Res 2020; 41:217-233. [PMID: 32787531 DOI: 10.1080/10799893.2020.1805628] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cancer is caused by a variety of pathways, involving numerous types of enzymes. Among them three enzymes i.e. Cyclin-dependent kinase-2 (CDK-2), Human topoisomerase IIα, and Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) are three of the most common enzymes that are involved in the cancer development. Although many chemical drugs are already available in the market for cancer treatment, plant sources are known to contain a wide variety of agents that are proved to possess potential anticancer activity. In this experiment, total thirty phytochemicals were analyzed against the mentioned three enzymes using different tools of bioinformatics and in silico biology like molecular docking study, drug likeness property experiment, ADME/T test, PASS prediction, and P450 site of metabolism prediction as well as DFT calculation to determine the three best ligands among them that have the capability to inhibit the mentioned enzymes. From the experiment, Epigallocatechin gallate was found to be the best ligand to inhibit CDK-2, Daidzein showed the best inhibitory activities towards the Human topoisomerase IIα, and Quercetin was predicted to be the best agent against VEGFR-2. They were also predicted to be quite safe and effective agents to treat cancer. However, more in vivo and in vitro analyses are required to finally confirm their safety and efficacy in this regard.
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Affiliation(s)
- Bishajit Sarkar
- Department of Biotechnology and Genetic Engineering, Faculty of Biological Sciences, Jahangirnagar University, Savar, Dhaka, Bangladesh
| | - Md Asad Ullah
- Department of Biotechnology and Genetic Engineering, Faculty of Biological Sciences, Jahangirnagar University, Savar, Dhaka, Bangladesh
| | - Syed Sajidul Islam
- Department of Biotechnology and Genetic Engineering, Faculty of Biological Sciences, Jahangirnagar University, Savar, Dhaka, Bangladesh
| | - Md Hasanur Rahman
- Department of Biotechnology and Genetic Engineering, Faculty of Life Sciences, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh
| | - Yusha Araf
- Department of Genetic Engineering and Biotechnology, School of Life Sciences, Shahjalal University of Science and Technology, Sylhet, Bangladesh
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Machine-Learning Prediction of Oral Drug-Induced Liver Injury (DILI) via Multiple Features and Endpoints. BIOMED RESEARCH INTERNATIONAL 2020; 2020:4795140. [PMID: 32509859 PMCID: PMC7254069 DOI: 10.1155/2020/4795140] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 04/17/2020] [Indexed: 12/17/2022]
Abstract
Drug discovery is a costly process which usually takes more than 10 years and billions of dollars for one successful drug to enter the market. Despite all the safety tests, drugs may still cause adverse reactions and be restricted in use or even withdrawn from the market. Drug-induced liver injury (DILI) is one of the major adverse drug reactions, and computational models may be used to predict and reduce it. To assess the computational prediction performance of DILI, we curated DILI endpoints from three databases and prepared drug features including chemical descriptors, therapeutic classifications, gene expressions, and binding proteins. We trained machine-learning models to predict the various DILI endpoints using different drug features. Using the optimal feature sets, the top-performing models obtained areas under the receiver operating characteristic curve (AUC) around 0.8 for some DILI endpoints. We found that some features, including therapeutic classifications and proteins, have good prediction performance towards DILI. We also discovered that the severity of DILI endpoints as well as the selection of negative samples may significantly affect the prediction results. Overall, our study provided a comprehensive collection, curation, and prediction of DILI endpoints using various drug features, which may help the drug researchers to better understand and prevent DILI during the drug discovery process.
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Lotfy M, Al-Hammadi R, Palakkott AR, Yasin J, Al-Hammadi S, Ksiksi T. Hepatoprotective potentials of Acridocarpus orientalis in mice. CLINICAL PHYTOSCIENCE 2020. [DOI: 10.1186/s40816-020-00184-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Mourabit S, Fitzgerald JA, Ellis RP, Takesono A, Porteus CS, Trznadel M, Metz J, Winter MJ, Kudoh T, Tyler CR. New insights into organ-specific oxidative stress mechanisms using a novel biosensor zebrafish. ENVIRONMENT INTERNATIONAL 2019; 133:105138. [PMID: 31645010 DOI: 10.1016/j.envint.2019.105138] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 08/08/2019] [Accepted: 08/27/2019] [Indexed: 06/10/2023]
Abstract
BACKGROUND Reactive oxygen species (ROS) arise as a result from, and are essential in, numerous cellular processes. ROS, however, are highly reactive and if left unneutralised by endogenous antioxidant systems, can result in extensive cellular damage and/or pathogenesis. In addition, exposure to a wide range of environmental stressors can also result in surplus ROS production leading to oxidative stress (OS) and downstream tissue toxicity. OBJECTIVES Our aim was to produce a stable transgenic zebrafish line, unrestricted by tissue-specific gene regulation, which was capable of providing a whole organismal, real-time read-out of tissue-specific OS following exposure to a wide range of OS-inducing environmental contaminants and conditions. This model could, therefore, serve as a sensitive and specific mechanistic in vivo biomarker for all environmental conditions that result in OS. METHODS To achieve this aim, we exploited the pivotal role of the electrophile response element (EpRE) as a globally-acting master regulator of the cellular response to OS. To test tissue specificity and quantitative capacity, we selected a range of chemical contaminants known to induce OS in specific organs or tissues, and assessed dose-responsiveness in each using microscopic measures of mCherry fluorescence intensity. RESULTS We produced the first stable transgenic zebrafish line Tg (3EpRE:hsp70:mCherry) with high sensitivity for the detection of cellular RedOx imbalances, in vivo in near-real time. We applied this new model to quantify OS after exposure to a range of environmental conditions with high resolution and provided quantification both of compound- and tissue-specific ROS-induced toxicity. DISCUSSION Our model has an extremely diverse range of potential applications not only for biomonitoring of toxicants in aqueous environments, but also in biomedicine for identifying ROS-mediated mechanisms involved in the progression of a number of important human diseases, including cancer.
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Affiliation(s)
- Sulayman Mourabit
- Biosciences, College of Life and Environmental Sciences, University of Exeter, UK.
| | | | - Robert P Ellis
- Biosciences, College of Life and Environmental Sciences, University of Exeter, UK
| | - Aya Takesono
- Biosciences, College of Life and Environmental Sciences, University of Exeter, UK
| | - Cosima S Porteus
- Biosciences, College of Life and Environmental Sciences, University of Exeter, UK
| | - Maciej Trznadel
- Biosciences, College of Life and Environmental Sciences, University of Exeter, UK
| | - Jeremy Metz
- Biosciences, College of Life and Environmental Sciences, University of Exeter, UK
| | - Matthew J Winter
- Biosciences, College of Life and Environmental Sciences, University of Exeter, UK
| | - Tetsuhiro Kudoh
- Biosciences, College of Life and Environmental Sciences, University of Exeter, UK
| | - Charles R Tyler
- Biosciences, College of Life and Environmental Sciences, University of Exeter, UK.
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50
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Ma R, Fang W, Yang Z, Hu K. Liver proteome analysis of grass carp (Ctenopharyngodon idellus) following treatment with enrofloxacin. FISH PHYSIOLOGY AND BIOCHEMISTRY 2019; 45:1941-1952. [PMID: 31399919 DOI: 10.1007/s10695-019-00690-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 07/24/2019] [Indexed: 06/10/2023]
Abstract
Enrofloxacin is widely used for the prevention and control of bacterial diseases in aquaculture. The liver is crucial for enrofloxacin metabolism, but enrofloxacin can induce liver damage. Herein, we explored proteomic changes in the liver of grass carp (Ctenopharyngodon idellus) following treatment with enrofloxacin using isobaric tag for relative and absolute quantitation (iTRAQ) technology. All experiments included two biological replicates and blank controls. Among the 3082 proteins identified, 103 were differentially abundant, comprising 49 up- and 54 downregulated proteins. Gene Ontology (GO) annotation identified macromolecular complex (63.60%), intracellular non-membrane-bound organelle (51.50%), and non-membrane-bound organelle (51.50%) as the most enriched cellular component terms. Structural molecule activity (26.80%), structural constituent of ribosome (17.90%), and calcium ion binding (16.10%) were the top three molecular function terms. Organic substance biosynthetic process (37.80%), biosynthetic process (37.80%), and protein metabolic process (37.80%) were the top three biological process terms. The Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis found 17 enriched KEGG pathways, with protein digestion and absorption, extracellular matrix (ECM)-receptor interactions, and ribosome and focal adhesion the most significant (p < 0.001). Analysis of the most enriched pathways revealed that chymotrypsin-like precursor, pancreatic elastase precursor, Na+/K+ transporting ATPase, collagen, and dermatopontin were upregulated, while ribosomal proteins, alpha-actinin, and myosin light chain were downregulated. These findings suggest that enrofloxacin affects liver function and has a risk of inducing an inflammatory response in extrahepatic organs.
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Affiliation(s)
- Rongrong Ma
- School of Marine Sciences, Ningbo University, Ningbo, 315211, People's Republic of China
| | - Wenhong Fang
- Key Laboratory of East China Sea Fishery Resources Exploitation, Ministry of Agriculture, East China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shanghai, 200090, People's Republic of China
| | - Zhongying Yang
- Nanchang Academy of Agricultural Sciences, Nanchang, 330038, China
| | - Kun Hu
- College of Aquatic and Life, Shanghai Ocean University, Shanghai, 201306, People's Republic of China.
- College of Fisheries and Life Science, Shanghai Ocean University, 999 Hucheng Huan Road, Lingang New City, 201306, Shanghai, People's Republic of China.
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