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Abdel-Wahhab KG, Ashry M, Hassan LK, El-Azma MH, Elqattan GM, Gadelmawla MHA, Mannaa FA. Hepatic and immune modulatory effectiveness of lactoferrin loaded Selenium nanoparticles on bleomycin induced hepatic injury. Sci Rep 2024; 14:21066. [PMID: 39256408 PMCID: PMC11387485 DOI: 10.1038/s41598-024-70894-6] [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: 03/26/2024] [Accepted: 08/22/2024] [Indexed: 09/12/2024] Open
Abstract
This study aimed to estimate the hepatic and immune ameliorating potential of extracted bovine lactoferrin (LF), Selenium nanoparticles (SeNPs) or their combination (LF/SeNPs) against bleomycin (BLM) induced hepatic injury. Fifty adult male rats (160-200 g) were equally divided into five groups: (1) the saline control group, (2) BLM-injected (15 mg/kg twice a week, ip), and (3-5) groups treated orally with LF (200 mg/kg/day), SeNPs (0.0486 mg/kg/day) or LF/SeNPs combination (200.0486 mg/kg/day) for 6 weeks post BLM-intoxication. Blood and liver samples were subjected to biochemical, histopathological, and immunohistochemical analyses. The results revealed that BLM caused a significant increase in hepatic lipid peroxidation and nitric oxide, as well as serum markers of liver functions (AST, ALT and GGT activities), and levels of GM-CSF, CD4, TNF-α, IL-1β, TGF-β1, fibronectin, triglycerides, cholesterol and LDL-C. Additionally, hepatic glutathione, Na+/K+-ATPase, and glutathione peroxidase, as well as serum HDL-C, total protein and albumin levels were significantly reduced. Moreover, BLM injection resulted in marked histopathological alterations and severe expression of caspase 3. Post-treatment of BLM-intoxicated rats with LF, SeNPs or LF/SeNPs combination obviously improved the BLM-induced hepatic damages; this was achieved from the marked modulations in the mentioned parameters, besides improving the histopathological hepatic architecture. It is worth mentioning that LF/SeNPs exerted the greatest potency. In conclusion, the obtained results demonstrated that LF, SeNPs and LF/SeNPs succeeded in attenuating the BLM-induced hepatic dysfunction. Therefore, these supplements might be used to protect against drug-associated side effects.
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Affiliation(s)
| | - Mahmoud Ashry
- Zoology Department, Faculty of Science, Al-Azhar University, Assuit, Egypt
| | - Laila K Hassan
- Dairy Department, National Research Centre, Giza, 12622, Egypt.
| | - Marwa H El-Azma
- Medical Physiology Department, National Research Centre, Giza, 12622, Egypt
| | - Ghada M Elqattan
- Medical Physiology Department, National Research Centre, Giza, 12622, Egypt
| | | | - Fathia A Mannaa
- Medical Physiology Department, National Research Centre, Giza, 12622, Egypt
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Caetano-da-Silva JE, Gonçalves-Santos E, Domingues ELBC, Caldas IS, Lima GDA, Diniz LF, Gonçalves RV, Novaes RD. The mitochondrial uncoupler 2,4-dinitrophenol modulates inflammatory and oxidative responses in Trypanosoma cruzi-induced acute myocarditis in mice. Cardiovasc Pathol 2024; 72:107653. [PMID: 38740356 DOI: 10.1016/j.carpath.2024.107653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 05/08/2024] [Accepted: 05/09/2024] [Indexed: 05/16/2024] Open
Abstract
By uncoupling oxidative phosphorylation, 2,4-dinitrophenol (DNP) attenuates reactive oxygen species (ROS) biosynthesis, which are known to aggravate infectious myocarditis in Chagas disease. Thus, the impact of DNP-based chemotherapy on Trypanosoma cruzi-induced acute myocarditis was investigated. C56BL/6 mice uninfected and infected untreated and treated daily with 100 mg/kg benznidazole (Bz, reference drug), 5 and 10 mg/kg DNP by gavage for 11 days after confirmation of T. cruzi infection were investigated. Twenty-four hours after the last treatment, the animals were euthanized and the heart was collected for microstructural, immunological and biochemical analyses. T. cruzi inoculation induced systemic inflammation (e.g., cytokines and anti-T. cruzi IgG upregulation), cardiac infection (T. cruzi DNA), oxidative stress, inflammatory infiltrate and microstructural myocardial damage in untreated mice. DNP treatment aggravated heart infection and microstructural damage, which were markedly attenuated by Bz. DNP (10 mg/kg) was also effective in attenuating ROS (total ROS, H2O2, and O2-), nitric oxide (NO), lipid (malondialdehyde - MDA) and protein (protein carbonyl - PCn) oxidation, TNF, IFN-γ, IL-10, and MCP-1/CCL2, anti-T. cruzi IgG, cardiac troponin I levels, as well as inflammatory infiltrate and cardiac damage in T. cruzi-infected mice. Our findings indicate that DNP aggravated heart infection and microstructural cardiomyocytes damage in infected mice. These responses were related to the antioxidant and anti-inflammatory properties of DNP, which favors infection by weakening the pro-oxidant and pro-inflammatory protective mechanisms of the infected host. Conversely, Bz-induced cardioprotective effects combined effective anti-inflammatory and antiparasitic responses, which protect against heart infection, oxidative stress, and microstructural damage in Chagas disease.
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Affiliation(s)
- José Edson Caetano-da-Silva
- Programa de Pós-Graduação em Ciências Biológicas, Universidade Federal de Alfenas, Alfenas, 37130-001, Minas Gerais, Brazil
| | - Elda Gonçalves-Santos
- Programa de Pós-Graduação em Biociências Aplicadas à Saúde, Universidade Federal de Alfenas, Alfenas, 37130-001, Minas Gerais, Brazil
| | - Elisa L B C Domingues
- Programa de Pós-Graduação em Biociências Aplicadas à Saúde, Universidade Federal de Alfenas, Alfenas, 37130-001, Minas Gerais, Brazil
| | - Ivo S Caldas
- Programa de Pós-Graduação em Ciências Biológicas, Universidade Federal de Alfenas, Alfenas, 37130-001, Minas Gerais, Brazil; Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, Alfenas, 37130-001, Minas Gerais, Brazil
| | - Graziela D A Lima
- Programa de Pós-Graduação em Biociências Aplicadas à Saúde, Universidade Federal de Alfenas, Alfenas, 37130-001, Minas Gerais, Brazil; Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, Alfenas, 37130-001, Minas Gerais, Brazil
| | - Lívia F Diniz
- Programa de Pós-Graduação em Ciências Biológicas, Universidade Federal de Alfenas, Alfenas, 37130-001, Minas Gerais, Brazil; Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, Alfenas, 37130-001, Minas Gerais, Brazil
| | - Reggiani V Gonçalves
- Departamento de Biologia Animal, Programa de Pós-Graduação em Biologia Animal, Universidade Federal de Viçosa, Viçosa, 36570-900, Minas Gerais, Brazil
| | - Rômulo D Novaes
- Programa de Pós-Graduação em Ciências Biológicas, Universidade Federal de Alfenas, Alfenas, 37130-001, Minas Gerais, Brazil; Programa de Pós-Graduação em Biociências Aplicadas à Saúde, Universidade Federal de Alfenas, Alfenas, 37130-001, Minas Gerais, Brazil; Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, Alfenas, 37130-001, Minas Gerais, Brazil; Departamento de Biologia Animal, Programa de Pós-Graduação em Biologia Animal, Universidade Federal de Viçosa, Viçosa, 36570-900, Minas Gerais, Brazil.
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Kadsanit N, Worsawat P, Sakonsinsiri C, McElroy CR, Macquarrie D, Noppawan P, Hunt AJ. Sustainable methods for the carboxymethylation and methylation of ursolic acid with dimethyl carbonate under mild and acidic conditions. RSC Adv 2024; 14:16921-16934. [PMID: 38799212 PMCID: PMC11124730 DOI: 10.1039/d4ra02122c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 05/07/2024] [Indexed: 05/29/2024] Open
Abstract
Ursolic acid is a triterpene plant extract that exhibits significant potential as an anti-cancer, anti-tumour, and anti-inflammatory agent. Its direct use in the pharmaceutical industry is hampered by poor uptake of ursolic acid in the human body coupled with rapid metabolism causing a decrease in bioactivity. Modification of ursolic acid can overcome such issues, however, use of toxic reagents, unsustainable synthetic routes and poor reaction metrics have limited its potential. Herein, we demonstrate the first reported carboxymethylation and/or methylation of ursolic acid with dimethyl carbonate (DMC) as a green solvent and sustainable reagent under acidic conditions. The reaction of DMC with ursolic acid, in the presence of PTSA, ZnCl2, or H2SO4-SiO2 yielded the carboxymethylation product 3β-[[methoxy]carbonyl]oxyurs-12-en-28-oic acid, the methylation product 3β-methoxyurs-12-en-28-oic acid and the dehydration product urs-2,12-dien-28-oic acid. PTSA demonstrated high conversion and selectivity towards the previously unreported carboxymethylation of ursolic acid, while the application of formic acid in the system led to formylation of ursolic acid (3β-formylurs-12-en-28-oic acid) in quantitative yields via esterification, with DMC acting solely as a solvent. Meanwhile, the methylation product of ursolic acid, 3β-methoxyurs-12-en-28-oic acid, was successfully synthesised with FeCl3, demonstrating exceptional conversion and selectivity, >99% and 99%, respectively. Confirmed with the use of qualitative and quantitative green metrics, this result represents a significant improvement in conversion, selectivity, safety, and sustainability over previously reported methods of ursolic acid modification. It was demonstrated that these methods could be applied to other triterpenoids, including corosolic acid. The study also explored the potential pharmaceutical applications of ursolic acid, corosolic acid, and their derivatives, particularly in anti-inflammatory, anti-cancer, and anti-tumour treatments, using molecular ADMET and docking methods. The methods developed in this work have led to the synthesis of novel molecules, thus creating opportunities for the future investigation of biological activity and the modification of a wide range of triterpenoids applying acidic DMC systems to deliver novel active pharmaceutical intermediates.
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Affiliation(s)
- Nuttapong Kadsanit
- Materials Chemistry Research Center (MCRC), Department of Chemistry and Centre of Excellence for Innovation in Chemistry, Faculty of Science, Khon Kaen University Khon Kaen 40002 Thailand
| | - Pattamabhorn Worsawat
- Materials Chemistry Research Center (MCRC), Department of Chemistry and Centre of Excellence for Innovation in Chemistry, Faculty of Science, Khon Kaen University Khon Kaen 40002 Thailand
| | - Chadamas Sakonsinsiri
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University Khon Kaen 40002 Thailand
| | - Con R McElroy
- School of Chemistry, University of Lincoln Brayford Pool Campus Lincoln LN6 7TS UK
- Green Chemistry Centre of Excellence, Department of Chemistry, University of York Heslington York YO10 5DD UK
| | - Duncan Macquarrie
- Green Chemistry Centre of Excellence, Department of Chemistry, University of York Heslington York YO10 5DD UK
| | - Pakin Noppawan
- Department of Chemistry, Faculty of Science, Mahasarakham University Maha Sarakham 44150 Thailand
| | - Andrew J Hunt
- Materials Chemistry Research Center (MCRC), Department of Chemistry and Centre of Excellence for Innovation in Chemistry, Faculty of Science, Khon Kaen University Khon Kaen 40002 Thailand
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Sarmah D, Sengupta R. A Review on the Role of Phytoconstituents Chrysin on the Protective Effect on Liver and Kidney. Curr Drug Discov Technol 2024; 21:e251023222716. [PMID: 37921185 DOI: 10.2174/0115701638242317231018144944] [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: 01/30/2023] [Revised: 07/07/2023] [Accepted: 07/18/2023] [Indexed: 11/04/2023]
Abstract
BACKGROUND The chance of contracting significant diseases increases due to an unhealthy and contemporary lifestyle. Chrysin is a flavonoid of the flavone class in numerous plants, including Passiflora and Pelargonium. Chrysin has long been used to treat a variety of illnesses. Chrysin, an essential flavonoid, has many pharmacological actions, including anticancer, antiviral, anti-inflammatory, anti-arthritic, depressive, hypolipidemic, hepatoprotective, and nephroprotective activity. PURPOSE This explorative review was commenced to provide a holistic review of flavonoids confirming that Chrysin has a therapeutic potential on the liver and kidney and reduces the hepatotoxicity and nephrotoxicity induced by diverse toxicants, which can be helpful for the toxicologists, pharmacologists, and chemists to develop new safer pharmaceutical products with chrysin and other toxicants. STUDY DESIGN The most relevant studies that were well-explained and fit the chosen topic best were picked. The achieved information was analyzed to determine the outcome by screening sources by title, abstract, and whole work. Between themselves, the writers decided on the studies to be considered. The necessary details were systematically organized into titles and subtitles and compressively discussed. METHOD The information presented in this review is obtained using targeted searches on several online platforms, including Google Scholar, Scifinder, PubMed, Science Direct, ACS publications, and Wiley Online Library. The works were chosen based on the inclusion criteria agreed upon by all authors. RESULTS Chrysin is a promising bioactive flavonoid with significant health benefits, and its synthetic replacements are being utilized as pharmaceuticals to treat various diseases. Findings revealed that Chrysin exhibits hepatoprotective actions against several hepatotoxicants like 2,3,7,8 tetrachlorodibenzo- p-dioxin, carbon tetrachloride (CCl4), cisplatin, and others by lowering the levels of liver toxicity biomarkers and enhancing antioxidant levels. Additionally, chrysin has potential nephroprotective properties against various nephrotoxicants, like Cisplatin, Doxorubicin, Paracetamol, Gentamicin, Streptazosin, and others by dropping kidney toxicity marker levels, reducing oxidative stress, and improving the antioxidant level. CONCLUSION According to this revised study, chrysin is a promising phytoconstituent that can be utilized as an alternate treatment for various medications that cause hepatotoxicity and nephrotoxicity. With active chrysin, several dosage forms targeting the liver and kidneys can be formulated.
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Affiliation(s)
- Debika Sarmah
- Department of Pharmacology, Girijananda Chowdhury Institute of Pharmaceutical Science, Hatkhowapara Azara, Guwahati, 17, India
| | - Rupa Sengupta
- Department of Pharmacognosy, Girijananda Chowdhury Institute of Pharmaceutical Science, Hatkhowapara Azara, Guwahati, 17, India
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Alshehri FS, Alorfi NM. Protective role of resveratrol against VCM-induced hepatotoxicity in male wistar rats. Front Pharmacol 2023; 14:1130670. [PMID: 36825158 PMCID: PMC9941161 DOI: 10.3389/fphar.2023.1130670] [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: 12/23/2022] [Accepted: 01/30/2023] [Indexed: 02/10/2023] Open
Abstract
Background: Vancomycin is a glycopeptide antibiotic with a high risk of acute liver injury. Resveratrol is believed to protect the liver against toxicity. Aim: To investigate the ability of resveratrol to attenuate vancomycin-induced liver toxicity in rats injected with vancomycin. Method: Twenty-four adult male Wistar rats were distributed into three groups. The control group received only a vehicle, while the treated group received either vancomycin 200 (mg/kg, i. p.) only or vancomycin (200 mg/kg, i. p.) with resveratrol (20 mg/kg, oral gavage). All groups received their dose once daily for 7 days. Hepatic damage was assessed by measuring biochemical parameter levels in serum, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH). Also, antioxidants and inflammation biomarkers such as Interleukin-6 (IL-6), malondialdehyde (MDA), nitric oxide (NO), and glutathione (GSH) were measured. Furthermore, the vancomycin-induced pathological changes in the liver were evaluated by histopathological studies. Results: In the vancomycin-treated group, hepatic serum biomarkers such as AST, ALT, ALP, IL-6, and MDA were elevated, while NO and GSH were depleted. However, resveratrol co-treatment with vancomycin prevented the elevation of AST, ALT, ALP, IL-6, and MDA and it protected the liver from NO and GSH depletion. Also, regarding vancomycin-induced degeneration of hepatocytes, resveratrol co-treatment with vancomycin prevented such degeneration and improved mononuclear cells in the liver. Conclusion: The results showed that oral administration of resveratrol has a significant hepatoprotective effect against vancomycin-induced hepatotoxicity.
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Affiliation(s)
| | - Nasser M. Alorfi
- Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
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Sun L, He D, Liu Y, Wei Y, Wang L. Corynoline protects against zearalenone-induced liver injury by activating the SIRT1/Nrf2 signaling pathway. J Biochem Mol Toxicol 2023; 37:e23224. [PMID: 36161741 DOI: 10.1002/jbt.23224] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 08/22/2022] [Accepted: 09/16/2022] [Indexed: 01/18/2023]
Abstract
Corynoline has been reported to have anti-inflammatory and antioxidative effects. In the present study, the potential protective effects of corynoline against zearalenone (ZEA)-induced liver injury were investigated. ZEA was administered daily for 5 days. Then, liver tissues were used for subsequent experiments. Corynoline attenuated liver histopathological changes induced by ZEA. The production of tumor necrosis factor-α and interleukin-1β in liver tissues, as well as aspartate aminotransferase and alanine aminotransferase in serum, was also inhibited by corynoline. Meanwhile, ZEA-induced MPO activity and MDA content were both attenuated by corynoline. ZEA-induced NF-κB p65 and IκBα phosphorylation were inhibited by corynoline. Furthermore, SIRT1, Nrf2, and HO-1 expression were increased by corynoline. In addition, the protective effects of corynoline against liver injury were reversed by the SIRT1 inhibitor EX-527. Taken together, corynoline protected against ZEA-induced liver injury by activating the SIRT1/Nrf2 signaling pathway.
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Affiliation(s)
- Liqun Sun
- Department of Pathogenobiology, Jilin University Mycology Research Center, College of Basic Medical Sciences, Jilin University, Changchun, Jilin Province, China
| | - Dan He
- Department of Pathogenobiology, Jilin University Mycology Research Center, College of Basic Medical Sciences, Jilin University, Changchun, Jilin Province, China
| | - Yuhuan Liu
- Department of Pathogenobiology, Jilin University Mycology Research Center, College of Basic Medical Sciences, Jilin University, Changchun, Jilin Province, China
| | - Yunyun Wei
- Department of Pathogenobiology, Jilin University Mycology Research Center, College of Basic Medical Sciences, Jilin University, Changchun, Jilin Province, China
| | - Li Wang
- Department of Pathogenobiology, Jilin University Mycology Research Center, College of Basic Medical Sciences, Jilin University, Changchun, Jilin Province, China
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Shen C, Liang D, Wang X, Shao W, Geng K, Wang X, Sun H, Xie H. Predictive performance and verification of physiologically based pharmacokinetic model of propylthiouracil. Front Pharmacol 2022; 13:1013432. [PMID: 36278167 PMCID: PMC9579312 DOI: 10.3389/fphar.2022.1013432] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 09/20/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Propylthiouracil (PTU) treats hyperthyroidism and thyroid crisis in all age groups. A variety of serious adverse effects can occur during clinical use and require attention to its pharmacokinetic and pharmacodynamic characteristics in various populations.Objective: To provide information for individualized dosing and clinical evaluation of PTU in the clinical setting by developing a physiologically based pharmacokinetic (PBPK) model, predicting ADME characteristics, and extrapolating to elderly and pediatric populations.Methods: Relevant databases and literature were retrieved to collect PTU’s pharmacochemical properties and ADME parameters, etc. A PBPK model for adults was developed using PK-Sim® software to predict tissue distribution and extrapolated to elderly and pediatric populations. The mean fold error (MFE) method was used to compare the differences between predicted and observed values to assess the accuracy of the PBPK model. The model was validated using PTU pharmacokinetic data in healthy adult populations.Result: The MFE ratios of predicted to observed values of AUC0-t, Cmax, and Tmax were mainly within 0.5 and 2. PTU concentrations in various tissues are lower than venous plasma concentrations. Compared to healthy adults, the pediatric population requires quantitative adjustment to the appropriate dose to achieve the same plasma exposure levels, while the elderly do not require dose adjustments.Conclusion: The PBPK model of PTU was successfully developed, externally validated, and applied to tissue distribution prediction and special population extrapolation, which provides a reference for clinical individualized drug administration and evaluation.
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Affiliation(s)
- Chaozhuang Shen
- Graduate School, Wannan Medical College, Wuhu, Anhui, China
- *Correspondence: Chaozhuang Shen, ; Hua Sun, ; Haitang Xie,
| | - Dahu Liang
- Anhui Provincial Center for Drug Clinical Evaluation, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
| | - Xiaohu Wang
- Graduate School, Wannan Medical College, Wuhu, Anhui, China
| | - Wenxin Shao
- Graduate School, Wannan Medical College, Wuhu, Anhui, China
| | - Kuo Geng
- Graduate School, Wannan Medical College, Wuhu, Anhui, China
| | - Xingwen Wang
- Graduate School, Wannan Medical College, Wuhu, Anhui, China
| | - Hua Sun
- Anhui Provincial Center for Drug Clinical Evaluation, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- *Correspondence: Chaozhuang Shen, ; Hua Sun, ; Haitang Xie,
| | - Haitang Xie
- Anhui Provincial Center for Drug Clinical Evaluation, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- *Correspondence: Chaozhuang Shen, ; Hua Sun, ; Haitang Xie,
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Bai F, Du W, Liu X, Su L, Li Z, Chen T, Ge X, Li Q, Yang H, Song J. A NO-Responsive Ratiometric Fluorescent Nanoprobe for Monitoring Drug-Induced Liver Injury in the Second Near-Infrared Window. Anal Chem 2021; 93:15279-15287. [PMID: 34748309 DOI: 10.1021/acs.analchem.1c02238] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Currently, drug-induced liver injury (DILI) has become a huge concern for the majority of modern medicine, whereas the diagnosis of DILI is still in its infancy due to the lack of appropriate methods. Herein, based on the fact that nitric oxide (NO) has been recognized as an early unifying, direct, and vital biomarker for DILI, we rationally designed and developed a NO-responsive ratiometric fluorescent nanoprobe DCNP@MPS@IR NO to quantitatively detect NO and monitor DILI in the second near-infrared (NIR-II) window. In the presence of NO, due to the conversion of IR NO into IR RA and excellent stability of the downconversion nanoparticle (DCNP), DCNP@MPS@IR NO could present a "Turn-On" fluorescence signal at 1050 nm under 808 nm excitation (F1050 Em, 808 Ex) and an "Always-On" fluorescence signal at 1550 nm under 980 nm excitation (F1550 Em, 980 Ex), which led to a "Turn-On" ratiometric fluorescence signal F1050 Em, 808 Ex/F1550 Em, 980 Ex. DCNP@MPS@IR NO was then successfully applied in vitro to selectively detect NO, at a linear concentration range of 0-100 μM with a limit of detection of 0.61 μM. In vivo results revealed that DCNP@MPS@IR was available to quantify NO in acetaminophen (APAP)-induced liver injury, monitor DILI, and screen an antidote for APAP through NIR-II ratiometric fluorescence imaging. We envision that our nanoprobe DCNP@MPS@IR NO might become a really useful biotechnology tool for visualizing and early diagnosis of drug-induced liver injury and revealing the mechanism of drug hepatotoxicity in the clinic in the near future.
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Affiliation(s)
- Feicheng Bai
- MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, Fuzhou University, Fuzhou 350108, People's Republic of China
| | - Wei Du
- MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, Fuzhou University, Fuzhou 350108, People's Republic of China
| | - Xia Liu
- MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, Fuzhou University, Fuzhou 350108, People's Republic of China
| | - Lichao Su
- MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, Fuzhou University, Fuzhou 350108, People's Republic of China
| | - Zhi Li
- MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, Fuzhou University, Fuzhou 350108, People's Republic of China
| | - Tao Chen
- MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, Fuzhou University, Fuzhou 350108, People's Republic of China
| | - Xiaoguang Ge
- MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, Fuzhou University, Fuzhou 350108, People's Republic of China
| | - Qingqing Li
- MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, Fuzhou University, Fuzhou 350108, People's Republic of China
| | - Huanghao Yang
- MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, Fuzhou University, Fuzhou 350108, People's Republic of China
| | - Jibin Song
- MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, Fuzhou University, Fuzhou 350108, People's Republic of China
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Choi YJ, Park JW, Lim Y, Seo S, Hwang DY. In vivo impact assessment of orally administered polystyrene nanoplastics: biodistribution, toxicity, and inflammatory response in mice. Nanotoxicology 2021; 15:1180-1198. [PMID: 34731582 DOI: 10.1080/17435390.2021.1996650] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
To assess the in vivo impact of nanoplastics (NP) and coagulation-based purified NP (PurNP), this study analyzed for alterations in the biodistribution, toxicity and inflammatory response in ICR mice exposed to three different doses of NP (5, 25, and 50 mg/kg) and PurNP for 2 weeks. Except water consumption, which was dose-dependently and significantly increased in all NP-treated groups, most factors assessed for feeding behaviors and excretions remained constant, without any significant change. Orally administered NP was detected in the intestine, kidneys, and liver at all concentrations, although the accumulation was higher in the intestine than in the kidneys and liver. No significant alterations were detected in the levels of serum biochemical markers and histopathological structures. However, compared to the vehicle group, expressions of the inflammatory response proteins (iNOS and COX-2) and mRNA levels of the inflammatory cytokines were remarkably increased in the liver, kidneys, and intestine of NP-treated mice. A similar increase was detected in the oxidative stress responses, including ROS concentration, SOD activity, and Nrf2 expression. Furthermore, similar inflammatory responses were observed in the PurNP-treated group, as compared to the vehicle-treated group. The results presented in this study provide the first strong evidence that oral administration of NP for 2 weeks results in high accumulation in the liver, kidneys, and intestine of ICR mice, and induces severe inflammatory and oxidative stress responses. These results additionally confirm the efficacy of water purification using the tannic acid-mediated coagulation removal technique.
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Affiliation(s)
- Yun Ju Choi
- Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Republic of Korea
| | - Jun Woo Park
- Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Republic of Korea
| | - Yong Lim
- Department of Clinical Laboratory Science, College of Nursing and Healthcare Science, Dong-Eui University, Busan, Republic of Korea
| | - Sungbaek Seo
- Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Republic of Korea
| | - Dae Youn Hwang
- Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Republic of Korea
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Jazaeri F, Sheibani M, Nezamoleslami S, Moezi L, Dehpour AR. Current Models for Predicting Drug-induced Cholestasis: The Role of Hepatobiliary Transport System. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2021; 20:1-21. [PMID: 34567142 PMCID: PMC8457732 DOI: 10.22037/ijpr.2020.113362.14254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Drug-induced cholestasis is the main type of liver disorder accompanied by high morbidity and mortality. Evidence for the role of hepatobiliary pumps in the cholestasis patho-mechanism is constantly increasing. Recognition of the interactions of chemical agents with these transporters at the initial phases of drug discovery can help develop new drug candidates with low cholestasis potential. This review delivers an outline of the role of these transport proteins in bile creation. It addresses the pathophysiological mechanism for drug-induced cholestasis. In-vitro models, including cell-based and membrane-based approaches and In-vivo models such as genetic knockout animals, are considered. The benefits and restrictions of each model are discussed in this review. Current understandings into the cellular and molecular process that control the activity of hepatobiliary pumps have directed to a better understanding of the pathophysiology of drug-induced cholestasis. A combination of in-vitro monitoring for transport interaction, in-silico predicting systems, and consideration of and metabolic and physicochemical properties must cause more effective monitoring of possible liver problems.
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Affiliation(s)
- Farahnaz Jazaeri
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,F. J. and M. Sh. contributed equally to this work
| | - Mohammad Sheibani
- Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,F. J. and M. Sh. contributed equally to this work
| | - Sadaf Nezamoleslami
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Leila Moezi
- Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ahmad-Reza Dehpour
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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11
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Geib T, Moghaddam G, Supinski A, Golizeh M, Sleno L. Protein Targets of Acetaminophen Covalent Binding in Rat and Mouse Liver Studied by LC-MS/MS. Front Chem 2021; 9:736788. [PMID: 34490218 PMCID: PMC8417805 DOI: 10.3389/fchem.2021.736788] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 08/04/2021] [Indexed: 01/11/2023] Open
Abstract
Acetaminophen (APAP) is a mild analgesic and antipyretic used commonly worldwide. Although considered a safe and effective over-the-counter medication, it is also the leading cause of drug-induced acute liver failure. Its hepatotoxicity has been linked to the covalent binding of its reactive metabolite, N-acetyl p-benzoquinone imine (NAPQI), to proteins. The aim of this study was to identify APAP-protein targets in both rat and mouse liver, and to compare the results from both species, using bottom-up proteomics with data-dependent high resolution mass spectrometry and targeted multiple reaction monitoring (MRM) experiments. Livers from rats and mice, treated with APAP, were homogenized and digested by trypsin. Digests were then fractionated by mixed-mode solid-phase extraction prior to liquid chromatography-tandem mass spectrometry (LC-MS/MS). Targeted LC-MRM assays were optimized based on high-resolution MS/MS data from information-dependent acquisition (IDA) using control liver homogenates treated with a custom alkylating reagent yielding an isomeric modification to APAP on cysteine residues, to build a modified peptide database. A list of putative in vivo targets of APAP were screened from data-dependent high-resolution MS/MS analyses of liver digests, previous in vitro studies, as well as selected proteins from the target protein database (TPDB), an online resource compiling previous reports of APAP targets. Multiple protein targets in each species were found, while confirming modification sites. Several proteins were modified in both species, including ATP-citrate synthase, betaine-homocysteine S-methyltransferase 1, cytochrome P450 2C6/29, mitochondrial glutamine amidotransferase-like protein/ES1 protein homolog, glutamine synthetase, microsomal glutathione S-transferase 1, mitochondrial-processing peptidase, methanethiol oxidase, protein/nucleic acid deglycase DJ-1, triosephosphate isomerase and thioredoxin. The targeted method afforded better reproducibility for analysing these low-abundant modified peptides in highly complex samples compared to traditional data-dependent experiments.
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Affiliation(s)
- Timon Geib
- Chemistry Department, Université du Québec à Montréal, Montréal, QC, Canada
| | - Ghazaleh Moghaddam
- Chemistry Department, Université du Québec à Montréal, Montréal, QC, Canada
| | - Aimee Supinski
- Chemistry Department, Université du Québec à Montréal, Montréal, QC, Canada
| | - Makan Golizeh
- Chemistry Department, Université du Québec à Montréal, Montréal, QC, Canada
| | - Lekha Sleno
- Chemistry Department, Université du Québec à Montréal, Montréal, QC, Canada
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12
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Long N, Le Gresley A, Wren SP. Thiazolidinediones: An In-Depth Study of Their Synthesis and Application to Medicinal Chemistry in the Treatment of Diabetes Mellitus. ChemMedChem 2021; 16:1716-1735. [PMID: 33844475 PMCID: PMC8251912 DOI: 10.1002/cmdc.202100177] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Indexed: 12/25/2022]
Abstract
2,4-Thiazolidinedione (TZD) is a privileged and highly utilised scaffold for the development of pharmaceutically active compounds. This sulfur-containing heterocycle is a versatile pharmacophore that confers a diverse range of pharmacological activities. TZD has been shown to exhibit biological action towards a vast range of targets interesting to medicinal chemists. In this review, we attempt to provide insight into both the historical conventional and the use of novel methodologies to synthesise the TZD core framework. Further to this, synthetic procedures utilised to substitute the TZD molecule at the activated methylene C5 and N3 position are reviewed. Finally, research into developing clinical agents, which act as modulators of peroxisome proliferator-activated receptors gamma (PPARγ), protein tyrosine phosphatase 1B (PTP1B) and aldose reductase 2 (ALR2), are discussed. These are the three most targeted receptors for the treatment of diabetes mellitus (DM).
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Affiliation(s)
- Nathan Long
- Department of Chemical & Pharmaceutical SciencesFaculty of ScienceEngineering & ComputingKingston University LondonPenrhyn RoadSurreyKT1 2EEUK
| | - Adam Le Gresley
- Department of Chemical & Pharmaceutical SciencesFaculty of ScienceEngineering & ComputingKingston University LondonPenrhyn RoadSurreyKT1 2EEUK
| | - Stephen P. Wren
- Department of Chemical & Pharmaceutical SciencesFaculty of ScienceEngineering & ComputingKingston University LondonPenrhyn RoadSurreyKT1 2EEUK
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13
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Bansod S, Saifi MA, Godugu C. Molecular updates on berberine in liver diseases: Bench to bedside. Phytother Res 2021; 35:5459-5476. [PMID: 34056769 DOI: 10.1002/ptr.7181] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 04/05/2021] [Accepted: 05/18/2021] [Indexed: 12/14/2022]
Abstract
Liver diseases are life-threatening illnesses and are the major cause of mortality and morbidity worldwide. These may include liver fibrosis, liver cirrhosis, and drug-induced liver toxicity. Liver diseases have a wide prevalence globally and the fifth most common cause of death among all gastrointestinal disorders. Several novel therapeutic approaches have emerged for the therapy of liver diseases that may provide better clinical outcomes with improved safety. The use of phytochemicals for the amelioration of liver diseases has gained considerable popularity. Berberine (BBR), an isoquinoline alkaloid of the protoberberine type, has emerged as a promising molecule for the treatment of gastrointestinal disorders. Accumulating studies have proved the hepatoprotective effects of BBR. BBR has been shown to modulate multiple signaling pathways implicated in the pathogenesis of liver diseases including Akt/FoxO2, PPAR-γ, Nrf2, insulin, AMPK, mTOR, and epigenetic pathways. In the present review, we have emphasized the important pharmacological activities and mechanisms of BBR in liver diseases. Further, we have reviewed various pharmacokinetic and toxicological barriers of this promising phytoconstituent. Finally, formulation-based novel approaches are also summarized to overcome the clinical hurdles for BBR.
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Affiliation(s)
- Sapana Bansod
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Mohd Aslam Saifi
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Chandraiah Godugu
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
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14
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The water-soluble non-starch polysaccharides from natural resources against excessive oxidative stress: A potential health-promoting effect and its mechanisms. Int J Biol Macromol 2021; 171:320-330. [PMID: 33421468 DOI: 10.1016/j.ijbiomac.2021.01.022] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 12/26/2020] [Accepted: 01/04/2021] [Indexed: 12/14/2022]
Abstract
The water-soluble non-starch polysaccharides isolated from natural resources have become research hotpots in the field of food science and human health due to widely distributed in nature and low toxicity. It has indicated that the health-promoting effect of water-soluble non-starch polysaccharides were partly attributable to against excessive oxidative stress. Indeed, excessive oxidative stress in the body has been reported in occurrence of disease. The water-soluble non-starch polysaccharides from natural resources exhibit antioxidant activity to against oxidative stress via scavenging free radicals promoting antioxidant enzymes activity and/or regulating antioxidant signaling pathways. In this review, the water-soluble non-starch polysaccharides as medicine agent and the factor affecting antioxidant as well as the relationship between oxidative stress and disease are summarized, and the mechanisms of water-soluble non-starch polysaccharides therapy in disease are also discussed. It will provide a theoretical basis for natural polysaccharides used for the treatment of diseases.
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15
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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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16
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Offor U, Naidu ECS, Ogedengbe OO, Aniekan PI, Azu OO. Momordica charantia mitigates hepatic injury following adjuvant treatment with antiretroviral drugs in diabetic animal models. Toxicol Res 2020; 36:37-44. [PMID: 32042712 PMCID: PMC6990367 DOI: 10.1007/s43188-019-00004-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 08/12/2018] [Accepted: 03/05/2019] [Indexed: 11/25/2022] Open
Abstract
Momordica charantia (M. charantia) is a medicinal plant, used in traditional practice for treating diseases like hypertension and diabetes mellitus. This study investigated the possible hepato-protective effect of M. charantia following treatment with highly active antiretroviral therapy (HAART) in diabetic rats. 48 adult male Sprague Dawley rats were divided into seven groups (A-G) of 7 animals per group and treated according to protocols. Diabetes was induced with streptozotocin (STZ) by intraperitoneal injection (45 mg/kg body weight). The animals were euthanized on the 10th week with liver removed for examination and blood obtained via cardiac puncture and centrifuged to collect the sera. Blood glucose levels (BGL) were consistently and significantly raised (p < 0.05) in all groups not receiving the adjuvant M. charantia. Treatment with M. charantia reverses the increase in BGL to near normal. Markers of liver injury assayed showed significant increase (p < 0.05) in AST, ALP and ALT levels in groups not receiving M. charantia. Adjuvant HAART and M. charantia caused significant declines in the liver enzymes (p < 0.05). Serum GGT was not markedly altered. Treatment with M. charantia significantly restored liver enzymes elevations to near normal comparable to control. Histopathological observations ranged from severe hepatocellular distortions, necrosis and massive fibrosis following treatment of HAART in diabetic groups not receiving M. charantia. Treatment with M. charantia did not show any sign of hepatotoxicity as judged from the histological and biochemical observations.
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Affiliation(s)
- Ugochukwu Offor
- Discipline of Clinical Anatomy, School of Laboratory Medicine and Medical Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
| | - Edwin C. S. Naidu
- Discipline of Clinical Anatomy, School of Laboratory Medicine and Medical Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
| | - Oluwatosin O. Ogedengbe
- Discipline of Clinical Anatomy, School of Laboratory Medicine and Medical Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
- Department of Anatomy, College of Medicine and Health Sciences, Afe Babalola University, Ado Ekiti, Nigeria
| | - Peter I. Aniekan
- Discipline of Clinical Anatomy, School of Laboratory Medicine and Medical Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
- Department of Anatomy, Faculty of Basic Medical Sciences, University of Uyo-Nigeria, Uyo, Nigeria
| | - Onyemaechi O. Azu
- Discipline of Clinical Anatomy, School of Laboratory Medicine and Medical Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
- Department of Anatomy, School of Medicine, University of Namibia, Windhoek, Namibia
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17
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Tavakoli M, Tsekouras K, Day R, Dunn KW, Pressé S. Quantitative Kinetic Models from Intravital Microscopy: A Case Study Using Hepatic Transport. J Phys Chem B 2019; 123:7302-7312. [PMID: 31298856 PMCID: PMC6857640 DOI: 10.1021/acs.jpcb.9b04729] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The liver performs critical physiological functions, including metabolizing and removing substances, such as toxins and drugs, from the bloodstream. Hepatotoxicity itself is intimately linked to abnormal hepatic transport, and hepatotoxicity remains the primary reason drugs in development fail and approved drugs are withdrawn from the market. For this reason, we propose to analyze, across liver compartments, the transport kinetics of fluorescein-a fluorescent marker used as a proxy for drug molecules-using intravital microscopy data. To resolve the transport kinetics quantitatively from fluorescence data, we account for the effect that different liver compartments (with different chemical properties) have on fluorescein's emission rate. To do so, we develop ordinary differential equation transport models from the data where the kinetics is related to the observable fluorescence levels by "measurement parameters" that vary across different liver compartments. On account of the steep non-linearities in the kinetics and stochasticity inherent to the model, we infer kinetic and measurement parameters by generalizing the method of parameter cascades. For this application, the method of parameter cascades ensures fast and precise parameter estimates from noisy time traces.
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Affiliation(s)
- Meysam Tavakoli
- Department of Physics, Indiana University-Purdue University, Indianapolis, Indiana 46202, United States
| | | | - Richard Day
- Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - Kenneth W. Dunn
- Department of Medicine and Biochemistry, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - Steve Pressé
- Center for Biological Physics, Arizona State University, Tempe, Arizona 85287, United States
- School of Molecular Sciences, Arizona State University, Tempe, Arizona 85287, United States
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18
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Vásquez-Garzón VR, Ramírez-Cosmes A, Reyes-Jiménez E, Carrasco-Torres G, Hernández-García S, Aguilar-Ruiz SR, Torres-Aguilar H, Alpuche J, Pérez-Campos Mayoral L, Pina-Canseco S, Arellanes-Robledo J, Villa-Treviño S, Baltiérrez-Hoyos R. Liver damage in bleomycin-induced pulmonary fibrosis in mice. Naunyn Schmiedebergs Arch Pharmacol 2019; 392:1503-1513. [PMID: 31312848 DOI: 10.1007/s00210-019-01690-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 07/03/2019] [Indexed: 12/12/2022]
Abstract
Pulmonary fibrosis is an emerging disease with a poor prognosis and high mortality rate that is even surpassing some types of cancer. This disease has been linked to the concomitant appearance of liver cirrhosis. Bleomycin-induced pulmonary fibrosis is a widely used mouse model that mimics the histopathological and biochemical features of human systemic sclerosis, an autoimmune disease that is associated with inflammation and expressed in several corporal systems as fibrosis or other alterations. To determine the effects on proliferation, redox and inflammation protein expression markers were analyzed by immunohistochemistry. Analyses showed a significant increase in protein oxidation levels by lipoperoxidation bio-products and in proliferation and inflammation processes. These phenomena were associated with the induction of the redox status in mice subjected to 100 U/kg bleomycin. These findings clearly show that the bleomycin model induces histopathological alterations in the liver and partially reproduces the complexity of systemic sclerosis. Our results using the bleomycin-induced pulmonary fibrosis model provide a protocol to investigate the mechanism underlying the molecular alteration found in the liver linked to systemic sclerosis.
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Affiliation(s)
- V R Vásquez-Garzón
- CONACYT-Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca, Oax, Mexico
| | - A Ramírez-Cosmes
- Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca, Oax, Mexico
| | - E Reyes-Jiménez
- Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca, Oax, Mexico
| | - G Carrasco-Torres
- CINVESTAV, Programa de Nanociencias y Nanotecnología, Ciudad de México, Mexico
| | | | - S R Aguilar-Ruiz
- Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca, Oax, Mexico
| | - H Torres-Aguilar
- Facultad de Ciencias Químicas, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca, Oax, Mexico
| | - J Alpuche
- CONACYT-Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca, Oax, Mexico
| | | | - S Pina-Canseco
- Centro de Investigación Facultad de Medicina, UNAM-UABJO, Oaxaca, Oax, Mexico
| | | | - S Villa-Treviño
- CINVESTAV, Departamento de Biología Celular, Ciudad de México, Mexico
| | - R Baltiérrez-Hoyos
- CONACYT-Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca, Oax, Mexico.
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19
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Yang Q, Salim L, Yan C, Gong Z. Rapid Analysis of Effects of Environmental Toxicants on Tumorigenesis and Inflammation Using a Transgenic Zebrafish Model for Liver Cancer. MARINE BIOTECHNOLOGY (NEW YORK, N.Y.) 2019; 21:396-405. [PMID: 30852708 DOI: 10.1007/s10126-019-09889-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 02/21/2019] [Indexed: 06/09/2023]
Abstract
Liver cancer remains to be a major health concern in the world today. Several major risk factors such as hepatitis viral infection and non-alcoholic steatohepatitis have been well established for causing liver cancer, but the contribution of environmental pollutants to liver inflammation and carcinogenesis remains poorly studied. Here, we aimed at the development of a rapid assay to test selected environmental toxicants for their potential roles in induction of inflammation and stimulation of liver tumorigenesis. By using an established kras oncogene transgenic zebrafish model for liver cancer, we tested a total of eight selected chemicals. First, using LPS (lipopolysaccharides) as a positive control, we confirmed its effects on induction of inflammation and stimulation of liver tumorigenesis as indicated by increases of neutrophils and the size of oncogenic livers respectively. Next, we tested two heavy metals (arsenic and chromium) and five organic toxicants (bisphenol A, lindane, N-nitrosodiethylamine, and 3,3',4,4',5-pentachlorobiphenyl [PCB126], and 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]). We observed a good correlation on induction of inflammation and their ability for stimulation of liver tumorigenesis. Most toxicants, namely chromium, bisphenol A, lindane, N-nitrosodiethylamine, and PCB126, resulted in increased inflammation and liver tumorigenesis, while arsenic and TCDD had opposite effects. Thus, our study established a screening system to rapidly assess the effects of candidate chemicals on liver tumorigenesis and inflammation.
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Affiliation(s)
- Qiqi Yang
- Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore, Singapore
| | - Lyana Salim
- Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore, Singapore
| | - Chuan Yan
- Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore, Singapore
| | - Zhiyuan Gong
- Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore, Singapore.
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20
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Wang S, Tian Y, Lu S, Wang R, Shang H, Zhang X, Zhang C, Sun G, Xu X, Sun X. Design and synthesis of acetaminophen probe APAP-P1 for identification of the toxicity targets thioredoxin reductase-1 in HepaRG cells. RSC Adv 2019; 9:15224-15228. [PMID: 35514855 PMCID: PMC9064191 DOI: 10.1039/c9ra00483a] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Accepted: 04/21/2019] [Indexed: 12/12/2022] Open
Abstract
Drug-induced liver injury is one of the main causes of drug non-approval and drug withdrawal by the Food and Drug Administration (FDA). Acetaminophen (APAP) is a widely used non-steroidal anti-inflammatory drug for treating fever and headache. APAP is considered safe at therapeutic doses; however, there have been reports of acute liver injury following the administration of APAP. To explore APAP hepatotoxicity and its mechanisms, we designed and synthesized a new click chemistry probe, APAP-P1, in our current study. We introduced the PEG-azide probe linker into the acetyl group of acetaminophen. First, we evaluated the probe toxicity in HepaRG cells and found that it still retained hepatotoxicity. We also found that this probe APAP-P1 can be metabolized by HepaRG cells. This demonstrated that the APAP-P1 probe still kept its metabolism characteristics. Using this probe, we pulled down its potential targets in vivo and in vitro. APAP can directly target TrxR1; thus, we tested for this interaction by Western blotting of pull-down proteins. The results showed that APAP-P1 can pull down TrxR1 in vivo and in vitro.
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Affiliation(s)
- Shan Wang
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100193 P. R. China .,Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education Beijing 100193 P. R. China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine Beijing 100193 P. R. China.,Zhong guan cun Open Laboratory of the Research and Development of Natural Medicine and Health Products Beijing 100193 P. R. China.,Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine Prescription Beijing 100193 P. R. China
| | - Yu Tian
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100193 P. R. China .,Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education Beijing 100193 P. R. China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine Beijing 100193 P. R. China.,Zhong guan cun Open Laboratory of the Research and Development of Natural Medicine and Health Products Beijing 100193 P. R. China.,Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine Prescription Beijing 100193 P. R. China
| | - Shan Lu
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100193 P. R. China .,Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education Beijing 100193 P. R. China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine Beijing 100193 P. R. China.,Zhong guan cun Open Laboratory of the Research and Development of Natural Medicine and Health Products Beijing 100193 P. R. China.,Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine Prescription Beijing 100193 P. R. China
| | - Ruiying Wang
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100193 P. R. China .,Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education Beijing 100193 P. R. China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine Beijing 100193 P. R. China.,Zhong guan cun Open Laboratory of the Research and Development of Natural Medicine and Health Products Beijing 100193 P. R. China.,Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine Prescription Beijing 100193 P. R. China
| | - Hai Shang
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100193 P. R. China .,Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education Beijing 100193 P. R. China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine Beijing 100193 P. R. China.,Zhong guan cun Open Laboratory of the Research and Development of Natural Medicine and Health Products Beijing 100193 P. R. China.,Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine Prescription Beijing 100193 P. R. China
| | - Xuelian Zhang
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100193 P. R. China .,Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education Beijing 100193 P. R. China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine Beijing 100193 P. R. China.,Zhong guan cun Open Laboratory of the Research and Development of Natural Medicine and Health Products Beijing 100193 P. R. China.,Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine Prescription Beijing 100193 P. R. China
| | - Chenyang Zhang
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100193 P. R. China .,Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education Beijing 100193 P. R. China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine Beijing 100193 P. R. China.,Zhong guan cun Open Laboratory of the Research and Development of Natural Medicine and Health Products Beijing 100193 P. R. China.,Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine Prescription Beijing 100193 P. R. China
| | - Guibo Sun
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100193 P. R. China .,Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education Beijing 100193 P. R. China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine Beijing 100193 P. R. China.,Zhong guan cun Open Laboratory of the Research and Development of Natural Medicine and Health Products Beijing 100193 P. R. China.,Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine Prescription Beijing 100193 P. R. China
| | - Xudong Xu
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100193 P. R. China .,Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education Beijing 100193 P. R. China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine Beijing 100193 P. R. China.,Zhong guan cun Open Laboratory of the Research and Development of Natural Medicine and Health Products Beijing 100193 P. R. China.,Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine Prescription Beijing 100193 P. R. China
| | - Xiaobo Sun
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100193 P. R. China .,Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education Beijing 100193 P. R. China.,Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine Beijing 100193 P. R. China.,Zhong guan cun Open Laboratory of the Research and Development of Natural Medicine and Health Products Beijing 100193 P. R. China.,Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine Prescription Beijing 100193 P. R. China
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Zhang L, Wang T, Zhao BS, Zhang JX, Yang S, Fan CL, Li P. Effect of 2″- O-Rhamnosyl Icariside II, Baohuoside I and Baohuoside II in Herba Epimedii on Cytotoxicity Indices in HL-7702 and HepG2 Cells. Molecules 2019; 24:molecules24071263. [PMID: 30939785 PMCID: PMC6479309 DOI: 10.3390/molecules24071263] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Revised: 03/29/2019] [Accepted: 03/30/2019] [Indexed: 01/14/2023] Open
Abstract
Herba Epimedii, a commonly used Chinese medicine, has attracted much attention recently because of its potential hepatotoxic effects. 2″-O-Rhamnosyl icariside II, baohuoside I and baohuoside II are the main components of Herba Epimedii, and previous research indicates that these three compounds are related to the hepatotoxicity of Herba Epimedii. To test this idea, in this study, HL-7702 and HepG2 cells were chosen as the in vitro models and the influences of these three compounds on a series of cytotoxicity indices, including ALT, AST, LDH, SOD, GSH, MDA, ROS and MMP, were determined. The results showed that at certain concentrations, the three compounds had different effects on the indices. Among them, baohuoside I at high concentration (32 μg/mL) displayed more significant cytotoxicity than the other two compounds; therefore, it was inferred to be more closely correlated with the liver injury induced by Herba Epimedii combined with the previous study, and its toxic mechanisms may be involved in increasing oxidative stress and inducing apoptosis. The findings of this study may provide evidence of the toxic composition of Herba Epimedii to preliminarily discuss the toxic mechanisms and provide improved guidance for its clinical safety.
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Affiliation(s)
- Lin Zhang
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Chaoyang District, Beijing 10029, China.
| | - Ting Wang
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Chaoyang District, Beijing 10029, China.
| | - Bao-Sheng Zhao
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Chaoyang District, Beijing 10029, China.
| | - Jing-Xuan Zhang
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Chaoyang District, Beijing 10029, China.
| | - Song Yang
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Chaoyang District, Beijing 10029, China.
| | - Chun-Lan Fan
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Chaoyang District, Beijing 10029, China.
| | - Pin Li
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Chaoyang District, Beijing 10029, China.
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22
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Singh H, Lata S, Dhole TN, Gangakhedkar RR. Occurrence of CYP2B6 516G>T polymorphism in patients with ARV-associated hepatotoxicity. Mol Genet Genomic Med 2019; 7:e00598. [PMID: 30864294 PMCID: PMC6465650 DOI: 10.1002/mgg3.598] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 11/14/2018] [Accepted: 01/10/2019] [Indexed: 01/11/2023] Open
Abstract
Background Hepatic enzyme cytochrome P450 2B6 (CYP2B6) plays a role in the metabolism of efavirenz drugs. CYP2B6 516G>T variation showed an implication for HIV treatment. Methods CYP2B6 516G>T polymorphism was genotyped in a total 165 HIV patients that include 34 with and 131 without hepatotoxicity and 155 healthy individuals by the PCR‐RFLP. Results In patients with hepatotoxicity, the prevalence of CYP2B6 516TT genotype was higher as compared to healthy individuals (35.3% vs. 30.5%, OR = 1.74). Patients with hepatotoxicity using tobacco had a higher prevalence of genotypes CYP2B6 516GT, 516TT, 516GT+TT as compared to healthy individuals (28.57% vs. 25.93%; 57.14% vs. 29.63%; 85.71% vs. 55.56%). Likewise, hepatotoxicity in patients consuming alcohol showed higher distributions of CYP2B6 516GT, 516TT, 516GT+TT genotypes (57% vs. 25.93%; 42.86% vs. 33.33%; 71.43% vs. 59.26%). Nevirapine users with hepatotoxicity overrepresented genotypes CYP2B6 TT and 516GT+TT as compared to efavirenz users (47.83% vs. 45.45%, OR = 6.88, 65.22% vs. 54.55%, OR = 1.56). Similarly, in nevirapine +alcohol users with hepatotoxicity, the frequency of CYP2B6 516GT, 516GT+TT genotypes was higher than with nevirapine +alcohol nonusers (40.0% vs. 11.11%, OR = 8.00, 80.0% vs. 27.78%, OR = 4.00). In HIV patients, nevirapine users had higher frequency of CYP2B6 516GT, 516GT+TT genotypes as compared to efavirenz users (42.02% vs. 25.00%, OR = 2.53; 72.27% vs. 58.33%, OR = 1.86). Likewise, in HIV patients, genotypes CYP2B6 516GT, 516GT+TT were predominant with nevirapine +alcohol users as compared to nevirapine +alcohol nonusers (57.89% vs. 34.57%, OR = 2.46; 78.95% vs. 69.14%, OR = 1.67). In multivariate logistic regression, taking nevirapine had a protection for severity of ARV‐associated hepatotoxicity (OR = 0.23, p = 0.005). Conclusions No significant association was detected between CYP2B6 516G>T polymorphism and susceptibility to ARV‐associated hepatotoxicity.
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Affiliation(s)
- HariOm Singh
- Department of Molecular Biology, National AIDS Research Institute, Pune, India
| | - Sonam Lata
- Department of Molecular Biology, National AIDS Research Institute, Pune, India
| | - T N Dhole
- Department of Microbiology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
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23
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Yan X, Zhuo Y, Bian X, Li J, Zhang Y, Ma L, Lu G, Guo MQ, Wu JL, Li N. Integrated Proteomics, Biological Functional Assessments, and Metabolomics Reveal Toosendanin-Induced Hepatic Energy Metabolic Disorders. Chem Res Toxicol 2019; 32:668-680. [DOI: 10.1021/acs.chemrestox.8b00350] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Xiaojing Yan
- State Key Laboratory for Quality Research of Chinese Medicines, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao
- Changzhou Affiliated Hospital of Nanjing University of Chinese Medicine, 25 Heping North Road, Changzhou 213003, China
| | - Yue Zhuo
- State Key Laboratory for Quality Research of Chinese Medicines, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao
| | - Xiqing Bian
- State Key Laboratory for Quality Research of Chinese Medicines, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao
| | - Jianmin Li
- State Key Laboratory for Quality Research of Chinese Medicines, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao
| | - Yida Zhang
- State Key Laboratory for Quality Research of Chinese Medicines, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao
| | - Lidong Ma
- State Key Laboratory for Quality Research of Chinese Medicines, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao
| | - Guanghua Lu
- School of Ethnic Medicine, Chengdu University of Traditional Medicine, Chengdu 611137, China
| | - Ming-Quan Guo
- Key Laboratory of Plant Germplasm Enhancement and Specialty Agriculture, Wuhan Botanical Garden, Sino-Africa Joint Research Center, Chinese Academy of Sciences, Wuhan 430074, China
| | - Jian-Lin Wu
- State Key Laboratory for Quality Research of Chinese Medicines, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao
| | - Na Li
- State Key Laboratory for Quality Research of Chinese Medicines, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao
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24
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Transgenic expression of tgfb1a induces hepatic inflammation, fibrosis and metastasis in zebrafish. Biochem Biophys Res Commun 2018; 509:175-181. [PMID: 30581008 DOI: 10.1016/j.bbrc.2018.12.098] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 12/13/2018] [Indexed: 12/14/2022]
Abstract
TGFB signaling pathway plays a key role on liver disease progression. In our previous study, we have demonstrated the oncogenic ability of Tgfb signaling pathway as a chronic induction of tgfb1a specifically in hepatocytes led to both hepatocellular carcinoma (HCC) and cholangiocarcinoma in zebrafish. Here we would like to examine the potential mechanisms of Tgfb1a induced tumorigenesis. As majority of HCC developed from the background of liver inflammation and fibrosis, by immune-fluorescent staining on markers of liver inflammation, we indeed observed a progressively increased liver inflammation during tumorigenesis. Examination of liver fibrosis also revealed marked increase of liver fibrosis during early liver tumorigenesis and it was dramatically dropped in late liver tumorigenesis. Hence, induction of tgfb1a drives HCC through association of liver inflammation and fibrosis. Furthermore, we found high expression of EMT markers in late liver tumorigenesis, indicating a tumor metastasis potential. These observations are generally consistent with the molecular mechanisms of hepatocarcinogenesis in human.
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25
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Xie Y, Zhou X, Pei H, Chen MC, Sun ZL, Xue YR, Tian XT, Huang CG. Metabolism, pharmacokinetics, and hepatic disposition of xanthones and saponins on Zhimu treatments for exploratively interpreting the discrepancy between the herbal safety and timosaponin A3-induced hepatotoxicity. Acta Pharmacol Sin 2018; 39:1923-1934. [PMID: 29795136 DOI: 10.1038/s41401-018-0012-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 01/11/2018] [Accepted: 01/31/2018] [Indexed: 11/09/2022]
Abstract
Timosaponin A3, a saponin in Zhimu, elicited hepatotoxicity via oxidative stress. However, the clinical medication of Zhimu has been historically regarded as safe, probably associated with the antioxidants it contains. However, the related information on the in vivo levels of timosaponin A3 and antioxidants remained unclear on Zhimu treatments. Therefore, a combination of the in vitro metabolism, including microbiota-mediated and liver-mediated metabolism, and in vivo pharmacokinetics and hepatic disposition, was conducted for three xanthones (neomangiferin, mangiferin, and norathyriol) and three saponins (timosaponin B2, timosaponin B3, and timosaponin A3) on Zhimu treatments. Consequently, following oral administration of Zhimu decoction to rats, those saponins and xanthones were all observed in the plasma with severe liver first-pass effect, where mangiferin was of the maximum exposure. Despite the ignorable content in the herb, timosaponin A3 elicited sizable hepatic exposure as the microbiota-mediated metabolite of saponins in Zhimu. The similar phenomenon also occurred to norathyriol, the microbiota-mediated metabolite of xanthones. However, the major prototypes in Zhimu were of limited hepatic exposure. We deduced the hepatic collection of norathyriol, maximum circulating levels of mangiferin, and timosaponin B2 and mangiferin interaction may directly or indirectly contribute to the whole anti-oxidation of Zhimu, and then resisted the timosaponin A3-induced hepatotoxicity. Thus, our study exploratively interpreted the discrepancy between herbal safety and timosaponin A3-induced hepatotoxicity. However, given the considerable levels and slow eliminated rate of timosaponin A3 in the liver, more attention should be paid to the safety on the continuous clinical medication of Zhimu in the future.
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26
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Fernández-Murga ML, Petrov PD, Conde I, Castell JV, Goméz-Lechón MJ, Jover R. Advances in drug-induced cholestasis: Clinical perspectives, potential mechanisms and in vitro systems. Food Chem Toxicol 2018; 120:196-212. [PMID: 29990576 DOI: 10.1016/j.fct.2018.07.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 07/05/2018] [Accepted: 07/06/2018] [Indexed: 12/12/2022]
Abstract
Despite growing research, drug-induced liver injury (DILI) remains a serious issue of increasing importance to the medical community that challenges health systems, pharmaceutical industries and drug regulatory agencies. Drug-induced cholestasis (DIC) represents a frequent manifestation of DILI in humans, which is characterised by an impaired canalicular bile flow resulting in a detrimental accumulation of bile constituents in blood and tissues. From a clinical point of view, cholestatic DILI generates a wide spectrum of presentations and can be a diagnostic challenge. The drug classes mostly associated with DIC are anti-infectious, anti-diabetic, anti-inflammatory, psychotropic and cardiovascular agents, steroids, and other miscellaneous drugs. The molecular mechanisms of DIC have been investigated since the 1980s but they remain debatable. It is recognised that altered expression and/or function of hepatobiliary membrane transporters underlies some forms of cholestasis, and this and other concomitant mechanisms are very likely in DIC. Deciphering these processes may pave the ways for diagnosis, prognosis and prevention, for which currently major gaps and caveats exist. In this review, we summarise recent advances in the field of DIC, including clinical aspects, the potential mechanisms postulated so far and the in vitro systems that can be useful to investigate and identify new cholestatic drugs.
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Affiliation(s)
- M Leonor Fernández-Murga
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
| | - Petar D Petrov
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Isabel Conde
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
| | - Jose V Castell
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Spain
| | - M José Goméz-Lechón
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain.
| | - Ramiro Jover
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Spain.
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27
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Ramirez-Vargas MA, Flores-Alfaro E, Uriostegui-Acosta M, Alvarez-Fitz P, Parra-Rojas I, Moreno-Godinez ME. Effects of exposure to malathion on blood glucose concentration: a meta-analysis. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2018; 25:3233-3242. [PMID: 29235025 DOI: 10.1007/s11356-017-0890-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 11/29/2017] [Indexed: 06/07/2023]
Abstract
Exposure to malathion (an organophosphate pesticide widely used around the world) has been associated with alterations in blood glucose concentration in animal models. However, the results are inconsistent. The aim of this meta-analysis was to evaluate whether malathion exposure can disturb the concentrations of blood glucose in exposed rats. We performed a literature search of online databases including PubMed, EBSCO, and Google Scholar and reviewed original articles that analyzed the relation between malathion exposure and glucose levels in animal models. The selection of articles was based on inclusion and exclusion criteria. The database search identified thirty-five possible articles, but only eight fulfilled our inclusion criteria, and these studies were included in the meta-analysis. The effect of malathion on blood glucose concentration showed a non-monotonic dose-response curve. In addition, pooled analysis showed that blood glucose concentrations were 3.3-fold higher in exposed rats than in the control group (95% CI, 2-5; Z = 3.9; p < 0.0001) in a random-effect model. This result suggested that alteration of glucose homeostasis is a possible mechanism of toxicity associated with exposure to malathion.
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Affiliation(s)
- Marco Antonio Ramirez-Vargas
- Laboratorio De Toxicología y Salud Ambiental, Facultad De Ciencias Químico Biológicas, Universidad Autónoma De Guerrero, Av. Lázaro Cárdenas s/n, Ciudad Universitaria, 39070, Chilpancingo, Guerrero, Mexico
| | - Eugenia Flores-Alfaro
- Laboratorio De Investigación En Epidemiologia Clínica y Molecular, Facultad De Ciencias Químico Biológicas, Universidad Autónoma De Guerrero, Chilpancingo, Mexico
| | - Mayrut Uriostegui-Acosta
- Laboratorio de Inmunotoxicogenómica, Escuela Superior de Ciencias Naturales, Universidad Autónoma De Guerrero, Chilpancingo, Mexico
| | - Patricia Alvarez-Fitz
- Laboratorio De Toxicología y Salud Ambiental, Facultad De Ciencias Químico Biológicas, Universidad Autónoma De Guerrero, Av. Lázaro Cárdenas s/n, Ciudad Universitaria, 39070, Chilpancingo, Guerrero, Mexico
| | - Isela Parra-Rojas
- Laboratorio De Investigación En Obesidad y Diabetes, Facultad De Ciencias Químico Biológicas, Universidad Autónoma De Guerrero, Chilpancingo, Mexico
| | - Ma Elena Moreno-Godinez
- Laboratorio De Toxicología y Salud Ambiental, Facultad De Ciencias Químico Biológicas, Universidad Autónoma De Guerrero, Av. Lázaro Cárdenas s/n, Ciudad Universitaria, 39070, Chilpancingo, Guerrero, Mexico.
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28
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Wang A, Li D, Wang S, Zhou F, Li P, Wang Y, Lin L. γ-Mangostin, a xanthone from mangosteen, attenuates oxidative injury in liver via NRF2 and SIRT1 induction. J Funct Foods 2018. [DOI: 10.1016/j.jff.2017.11.047] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
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29
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Buckner SL, Pruitt AN, Thomas CN, Amin MY, Miller LL, Wiley FE, Sabbatini ME. Di-N-octylphthalate acts as a proliferative agent in murine cell hepatocytes by regulating the levels of TGF-β and pro-apoptotic proteins. Food Chem Toxicol 2017; 111:166-175. [PMID: 29128616 DOI: 10.1016/j.fct.2017.11.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2017] [Revised: 10/09/2017] [Accepted: 11/05/2017] [Indexed: 11/17/2022]
Abstract
Di-n-octylphthalate (DNOP) is a phthalate used in the manufacturing of a wide variety of polyvinyl chloride-containing medical and consumer products. A study on chronic exposure to DNOP in rodents showed the development of pre-neoplastic hepatic lesions following exposure to a tumor initiator. The objective of this study was to identify the mechanisms by which DNOP leads to pre-neoplastic hepatic lesions. Mouse hepatocyte AML-12 and FL83B cells were treated with DNOP. The rate of cell proliferation was increased in treated cells in a concentration-dependent manner. DNOP increased the expression of transforming growth factor-β (tgf-β) in both cell lines, and primary culture mouse hepatocytes. The TGF-β receptor inhibitor LY2109761 impaired the effect of DNOP. The presence of pro-apoptotic proteins decreased in the presence of DNOP. Our observation indicates that DNOP, through an increase in the expression of tgf-β and a decrease in the levels of pro-apoptotic proteins, acts as a proliferative agent in normal mouse hepatocytes. We also studied the morphological and functional changes of the mouse liver upon a short-term treatment of DNOP. Mice exposed to DNOP displayed an epithelial-to-mesenchymal transition and cholestasis, which was reflected in an increase in hepatic bile acids and glutathione levels.
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Affiliation(s)
- Shelby L Buckner
- Department of Biological Sciences, Summerville Campus, Augusta University, 2500 Walton Way, Augusta, GA 30904, United States
| | - Allison N Pruitt
- Department of Biological Sciences, Summerville Campus, Augusta University, 2500 Walton Way, Augusta, GA 30904, United States
| | - Cecilia N Thomas
- Department of Biological Sciences, Summerville Campus, Augusta University, 2500 Walton Way, Augusta, GA 30904, United States
| | - Monisha Y Amin
- Department of Biological Sciences, Summerville Campus, Augusta University, 2500 Walton Way, Augusta, GA 30904, United States
| | - Laurence L Miller
- Department of Psychological Sciences, Summerville Campus, Augusta University, 2500 Walton Way, Augusta, GA 30904, United States
| | - Faith E Wiley
- Department of Biological Sciences, Summerville Campus, Augusta University, 2500 Walton Way, Augusta, GA 30904, United States
| | - Maria Eugenia Sabbatini
- Department of Biological Sciences, Summerville Campus, Augusta University, 2500 Walton Way, Augusta, GA 30904, United States.
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30
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Hamid M, Liu D, Abdulrahim Y, Liu Y, Qian G, Khan A, Gan F, Huang K. Amelioration of CCl4-induced liver injury in rats by selenizing Astragalus polysaccharides: Role of proinflammatory cytokines, oxidative stress and hepatic stellate cells. Res Vet Sci 2017; 114:202-211. [DOI: 10.1016/j.rvsc.2017.05.002] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 04/05/2017] [Accepted: 05/01/2017] [Indexed: 12/13/2022]
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Hamid M, Liu D, Abdulrahim Y, Khan A, Qian G, Huang K. Inactivation of Kupffer Cells by Selenizing Astragalus Polysaccharides Prevents CCl 4-Induced Hepatocellular Necrosis in the Male Wistar Rat. Biol Trace Elem Res 2017; 179:226-236. [PMID: 28243851 DOI: 10.1007/s12011-017-0970-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 02/14/2017] [Indexed: 01/29/2023]
Abstract
Selenizing astragalus polysaccharides-3 (sAPS3) was prepared by nitric acid-sodium selenite method. The effects of sAPS3 on carbon tetrachloride (CCl4) induced hepatocellular necrosis, and its underlying mechanisms were studied in male Wistar rats. Hepatic damage was induced by intraperitoneal injection of CCl4 twice a week, for 3 weeks. Meanwhile, the rats in addition to CCl4 were also exposed to sodium selenite (SS), astragalus polysaccharides (APS), SS + APS or sAPS3, in parallel by oral gavage once a day for 3 weeks. At the end of 3 weeks, blood and liver tissue were taken. Serum was collected to test the levels of alanine aminotransferase, aspartate aminotransferase and antioxidant status parameters. Liver tissue was collected for histopathological examination and determination of messenger RNA (mRNA) expression levels of CD68, TNF-α, IL-1β and ATG7 followed by the measurements of CD68, IL-1β and LC3II by immunohistochemistry assay (IHC), or TNF-α by immunofluorescence assay (IFA). The results showed that sAPS3 effectively ameliorated CCl4 induced hepatocellular necrosis and inflammation and significantly decreased the levels of aspartate aminotransferase, alanine aminotransferase, malondialdehyde and the expression levels of Kupffer cells (KCs)-specific biomarker CD68 and proinflammatory cytokines produced by activated KCs such as IL-1β and TNF-α (P < 0.01). While increasing the levels of total antioxidant capacity, glutathione, glutathione peroxidase and superoxide dismutase (P < 0.05) and reduced the expression levels of a key regulator of autophagy in KCs ATG7 or LC3II (P < 0.05). These findings indicate that sAPS3 could ameliorate CCl4-induced hepatocellular necrosis by inactivation of Kupffer cells and its activity may be superior to the application of selenium, APS or combination of selenium with APS.
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Affiliation(s)
- Mohammed Hamid
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China
- Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowl, Nanjing Agricultural University, Nanjing, 210095, China
- College of Veterinary Sciences, University of Nyala, Nyala, Sudan
| | - Dandan Liu
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China
- Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowl, Nanjing Agricultural University, Nanjing, 210095, China
| | - Yassin Abdulrahim
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China
- Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowl, Nanjing Agricultural University, Nanjing, 210095, China
- College of Veterinary Sciences, University of Nyala, Nyala, Sudan
| | - Alamzeb Khan
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China
- Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowl, Nanjing Agricultural University, Nanjing, 210095, China
| | - Gang Qian
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China
- Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowl, Nanjing Agricultural University, Nanjing, 210095, China
| | - Kehe Huang
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China.
- Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowl, Nanjing Agricultural University, Nanjing, 210095, China.
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Hepatotoxicity and nephrotoxicity of saponin-enriched extract of Asparagus cochinchinensis in ICR mice. Lab Anim Res 2017; 33:57-67. [PMID: 28747969 PMCID: PMC5527148 DOI: 10.5625/lar.2017.33.2.57] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 02/07/2017] [Accepted: 03/16/2017] [Indexed: 11/21/2022] Open
Abstract
The inhibitory effects of Asparagus cochinchinensis against inflammatory response induced by lipopolysaccharide (LPS), substance P and phthalic anhydride (PA) treatment were recently reported for some cell lines and animal models. To evaluate the hepatotoxicity and nephrotoxicity of A. cochinchinensis toward the livers and kidneys of ICR mice, alterations in related markers including body weight, organ weight, urine composition, liver pathology and kidney pathology were analyzed in male and female ICR mice after oral administration of 150, 300 and 600 mg/kg body weight/day saponin-enriched extract of A. cochinchinensis (SEAC) for 14 days. The saponin, total flavonoid and total phenol levels were found to be 57.2, 88.5 and 102.1 mg/g in SEAC, respectively, and the scavenging activity of SEAC gradually increased in a dose-dependent manner. Moreover, body and organ weight, clinical phenotypes, urine parameters and mice mortality did not differ between the vehicle and SEAC treated group. Furthermore, no significant alterations were measured in alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), blood urea nitrogen (BUN) and the serum creatinine (Cr) in the SEAC treated group relative to the vehicle treated group. Moreover, the specific pathological features induced by most toxic compounds were not observed upon liver and kidney histological analysis. Overall, the results of the present study suggest that SEAC does not induce any specific toxicity in the livers and kidneys of male and female ICR mice at doses of 600 mg/kg body weight/day.
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Jang JK, Jang HJ, Kim JS, Kim TK. Focal fat deposition in the liver: diagnostic challenges on imaging. Abdom Radiol (NY) 2017; 42:1667-1678. [PMID: 28144721 DOI: 10.1007/s00261-017-1049-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
While focal fat deposition in the liver mostly occurs in typical locations related to non-portal venous supply, unusual patterns of focal fat deposition, including multi-nodular, mass-like, and perivascular patterns, mimic malignancies and cause diagnostic challenges. Patients with unusual focal fat deposition often have potential underlying etiologies such as diabetes, alcohol abuse, metabolic disease, or various medications/chemotherapy. Some cases can be explained by non-portal venous supply or ischemia. Chemical-shift MRI or contrast-enhanced ultrasound (CEUS) is useful for non-invasive diagnosis of focal fat deposition. We illustrate a series of US, CT, and MR imaging features of focal fatty deposition in the liver mimicking other conditions and seek possible causes. Understanding of imaging patterns of focal fat deposition and its potential causes can help a non-invasive diagnosis by performing confirmatory imaging tests and prevent unnecessary invasive procedures.
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Affiliation(s)
- Jong Keon Jang
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Hyun-Jung Jang
- Department of Medical Imaging, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Jin Sil Kim
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Tae Kyoung Kim
- Department of Medical Imaging, University Health Network, University of Toronto, Toronto, ON, Canada.
- Department of Medical Imaging, Toronto General Hospital, 585 University Avenue, Toronto, ON, M5G 2N2, Canada.
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Li Y, Xie X, Yang X, Li M, Jiao X, Sun Y, Wang X, Tang B. Two-photon fluorescent probe for revealing drug-induced hepatotoxicity via mapping fluctuation of peroxynitrite. Chem Sci 2017; 8:4006-4011. [PMID: 28580117 PMCID: PMC5434753 DOI: 10.1039/c7sc00303j] [Citation(s) in RCA: 136] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2017] [Accepted: 03/13/2017] [Indexed: 12/28/2022] Open
Abstract
Drug-induced injury has attracted increasing attention in public health issues. Among them, hepatotoxicity has been regarded as the leading clinical problem caused by drug toxicity. However, owing to the complexity of the involved pathophysiological mechanisms and the lack of noninvasive, straightforward, and real-time tools, drug-induced hepatotoxicity has rarely been predicted satisfactorily. In this paper, by utilizing the reactive species peroxynitrite (ONOO-) as a biomarker, we present a two-photon fluorescent probe, TP-KA, holding rapid response, high specificity and sensitivity towards ONOO-, to investigate drug (acetaminophen and tolcapone)-related liver injury and the remediate effect of N-acetyl cysteine (NAC). With the support of TP-KA, we obtained direct and visual evidence of the upregulation of ONOO- during drug challenge both in live cells and mice, which was accompanied by liver tissue injury and tyrosine nitration. These findings demonstrate that ONOO- is a good and appropriate biomarker of hepatotoxicity, and nitrosative stress may be necessary for acetaminophen and tolcapone to exert their toxicity. Moreover, TP-KA can be employed as a powerful tool to pre-detect drug-induced organism injury and study the effect of antidotes.
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Affiliation(s)
- Yong Li
- College of Chemistry , Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Molecular and Nano Science , Shandong Normal University , Jinan 250014 , P. R. China . ;
| | - Xilei Xie
- College of Chemistry , Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Molecular and Nano Science , Shandong Normal University , Jinan 250014 , P. R. China . ;
| | - Xiu'e Yang
- College of Chemistry , Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Molecular and Nano Science , Shandong Normal University , Jinan 250014 , P. R. China . ;
| | - Mengmeng Li
- College of Chemistry , Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Molecular and Nano Science , Shandong Normal University , Jinan 250014 , P. R. China . ;
| | - Xiaoyun Jiao
- College of Chemistry , Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Molecular and Nano Science , Shandong Normal University , Jinan 250014 , P. R. China . ;
| | - Yuhui Sun
- College of Chemistry , Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Molecular and Nano Science , Shandong Normal University , Jinan 250014 , P. R. China . ;
| | - Xu Wang
- College of Chemistry , Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Molecular and Nano Science , Shandong Normal University , Jinan 250014 , P. R. China . ;
| | - Bo Tang
- College of Chemistry , Chemical Engineering and Materials Science , Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong , Key Laboratory of Molecular and Nano Probes , Ministry of Education , Institute of Molecular and Nano Science , Shandong Normal University , Jinan 250014 , P. R. China . ;
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Singh H, Lata S, Nema V, Samani D, Ghate M, Gangakhedkar RR. CYP1A1m1 and CYP2C9*2 and *3 polymorphism and risk to develop ARV-associated hepatotoxicity and its severity. APMIS 2017; 125:523-535. [PMID: 28370504 DOI: 10.1111/apm.12683] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Accepted: 01/22/2017] [Indexed: 11/30/2022]
Abstract
Non-nucleoside reverse transcriptase inhibitors are metabolized in the liver by cytochrome P450 (CYP) isoenzymes. Variations in the genes encoding these enzymes may influence the activity of corresponding metabolizing enzymes. This study aimed at assessing association of CYP2C9*2 430C/T, CYP2C9*31075A/C, and CYP1A1m1 3801T/C polymorphism with risk to develop ARV Antiretroviral-associated hepatotoxicity and its severity. In this case-control study, genotyping of CYP2C9*2, CYP2C9*3, and CYP1A1m1 genes was done in 34 HIV-infected individuals with hepatotoxicity and 131 without hepatotoxicity, and 153 unrelated healthy individuals using PCR-RFLP. CYP1A1m13801CC genotype was likely to be associated with severe ARV-associated hepatotoxicity (OR = 1.78, p = 0.70). CYP1A1m13801CC genotype and combined genotype TC + CC were likely to be associated with development of ARV-associated hepatotoxicity (OR = 2.57, p = 0.08; OR = 1.42, p = 0.17). CYP1A1m1 3801CC genotype among advanced and intermediate HIV disease stage was likely to be associated with advancement of disease (OR = 2.56, p = 0.77; OR = 2.37, p = 0.45). CYP2C9*31075AC genotype among alcohol users was likely to be associated with development of ARV-associated hepatotoxicity (OR = 1.67, p = 0.38). CYP1A1m1 3801TC genotype and combined genotype TC + CC among nevirapine users were likely to be associated with severe ARV-associated hepatotoxicity (OR = 3.68, p = 0.27; OR = 4.91, p = 0.13). Among those who received nevirapine, presence of CYP1A1m1 3801TC genotype was likely to be associated with increased risk of development of ARV-associated hepatotoxicity (OR = 1.50, p = 0.78). CYP1A1m1 3801TC, 3801CC, and CYP2C9*3 1075AC genotypes among combined alcohol + nevirapine users increased the risk of development of ARV-associated hepatotoxicity (OR = 1.41, p = 0.53; OR = 1.49, p = 0.83; OR = 1.78, p = 0.35). In conclusion, individuals with CYP1A1m13801CC and 3801TC genotypes independently and in the presence of alcohol and nevirapine usage is likely to be associated with increased risk of development of ARV-associated hepatotoxicity, its severity, and advancement of disease. CYP2C9*31075AC genotype with combined alcohol and nevirapine usage indicated a risk for development of ARV-associated hepatotoxicity.
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Affiliation(s)
- HariOm Singh
- Department of Molecular Biology, National AIDS Research Institute, Pune, India
| | - Sonam Lata
- Department of Molecular Biology, National AIDS Research Institute, Pune, India
| | - Vijay Nema
- Department of Molecular Biology, National AIDS Research Institute, Pune, India
| | - Dharmesh Samani
- Department of Molecular Biology, National AIDS Research Institute, Pune, India
| | - Manisha Ghate
- Department of Clinical Sciences, National AIDS Research Institute, Pune, India
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Vasquez KO, Peterson JD. Early Detection of Acute Drug-Induced Liver Injury in Mice by Noninvasive Near-Infrared Fluorescence Imaging. J Pharmacol Exp Ther 2017; 361:87-98. [PMID: 28115551 PMCID: PMC5363778 DOI: 10.1124/jpet.116.238378] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Accepted: 01/18/2017] [Indexed: 01/05/2023] Open
Abstract
Hepatocellular and cholestatic forms of drug-induced liver injury (DILI) are major reasons for late-stage termination of small-molecule drug discovery research projects. Biochemical serum markers are limited in their ability to sensitively and specifically detect both of these common DILI forms in preclinical models, and tissue-specific approaches to assessing this are labor intensive, requiring extensive animal dosing, tissue preparation, and pathology assessment. In vivo fluorescent imaging offers noninvasive detection of biologic changes detected directly in the livers of living animals. Three different near-infrared fluorescent imaging probes, specific for cell death (Annexin-Vivo 750), matrix metalloproteases (MMPSense 750 FAST), and transferrin receptor (Transferrin-Vivo 750) were used to measure the effects of single bolus intraperitoneal doses of four different chemical agents known to induce liver injury. Hepatocellular injury-inducing agents, thioacetamide and acetaminophen, showed optimal injury detection with probe injection at 18-24 hours, the liver cholestasis-inducing drug rifampicin required early probe injection (2 hours), and chlorpromazine, which induces mixed hepatocellular/cholestatic injury, showed injury with both early and late injection. Different patterns of liver responses were seen among these different imaging probes, and no one probe detected injury by all four compounds. By using a cocktail of these three near-infrared fluorescent imaging probes, all labeled with 750-nm fluorophores, each of the four different DILI agents induced comparable tissue injury within the liver region, as assessed by epifluorescence imaging. A strategy of probe cocktail injection in separate cohorts at 2 hours and at 20-24 hours allowed the effective detection of drugs with either early- or late-onset injury.
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Teratogenic Effect of Usnic Acid from Cladonia substellata Vainio during Organogenesis. BIOMED RESEARCH INTERNATIONAL 2017; 2017:5948936. [PMID: 28337452 PMCID: PMC5350305 DOI: 10.1155/2017/5948936] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 01/06/2017] [Accepted: 01/18/2017] [Indexed: 11/30/2022]
Abstract
Studies about toxicological potential of usnic acid are limited. This way, the vast majority of data available in the literature are related only to biological activities. This is the first study that aimed to evaluate the oral toxicity of usnic acid during the period of organogenesis. Females rats were distributed in the control groups, treated I and II, at doses of 15 and 25 mg/kg, administered by gavage during the 6° to 15° days of pregnancy. After 20 days the fetuses were removed and analyzed. A reduction in weight gain during pregnancy, increased resorption, reduction in the number of viable fetuses, and their body weight were observed. Morphological changes in the litter were visualized as exposure of the eye and atrophy of the limbs at the dose of 25 mg/kg. Histological analysis of the liver of the fetus showed reduction in the number of megakaryocytes between experimental groups and increase in the number of hepatocytes in a dose of 25 mg/kg. The experimental model used in this study reveals teratogenic effect of usnic acid in the period of organogenesis. Since this achievement, the importance of evaluating the toxic effects of natural substances is imperative, in order to elucidate the care in their indication as drug.
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Zhang Y, Han L, He Q, Chen W, Sun C, Wang X, Chen X, Wang R, Hsiao CD, Liu K. A rapid assessment for predicting drug-induced hepatotoxicity using zebrafish. J Pharmacol Toxicol Methods 2017; 84:102-110. [DOI: 10.1016/j.vascn.2016.12.002] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 11/09/2016] [Accepted: 12/06/2016] [Indexed: 12/12/2022]
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Dizdar OS, Ersoy A, Aksoy S, Ozel Coskun BD, Yildiz A. Analysis of liver function test abnormalities in kidney transplant recipients: 7 year experience. Pak J Med Sci 2016; 32:1330-1335. [PMID: 28083020 PMCID: PMC5216276 DOI: 10.12669/pjms.326.10725] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Objective: Immunosuppressive drugs, antimicrobial agents and infectious complications may cause liver function test abnormalities (LFTA) in kidney transplant recipients (KTR). The objectives of this study were to identify the outcome of (LFTA). To identify the risk factors affecting development and severity of hepatotoxicity in KTR. Methods: We retrospectively evaluated the medical records of KTR. Hepatotoxicity attacks were defined as impairment in liver function tests that was responsive to drug dose reduction or discontinuation, or treatment of specific causes such as infectious complications. Results: One hundred-fifty-six episodes of hepatotoxicity occurred in 107 patients in 281 KTR, with an incidence of 38%. Patients with hepatotoxicity episodes had a high total mortality rate, higher incidence of positive pre-transplant cytomegalovirus (CMV) IgM test, higher creatinine values during the first month post-transplant, underwent additional acute rejection episodes, and received fewer cyclosporin A based ID. Only positive CMV IgM testing was identified as a significant independent risk factor for hepatotoxicity in our multiple analysis. Mycophenolatemofetil (MMF) related hepatotoxicity was the most common cause of drug related LFTA. Conclusions: Patients with LFTA can have significant complications. Pre-transplant positive CMV IgM tests predispose transplant recipients to the development of LFTA during the post-transplant period. MMF can be a serious hepatotoxic drug.
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Affiliation(s)
- Oguzhan Sitki Dizdar
- Oguzhan Sitki Dizdar, Department of Internal Medicine and Clinical Nutrition, Kayseri Training and Research Hospital, Turkey
| | - Alparslan Ersoy
- Alparslan Ersoy, Professor, Department of Internal Medicine, Division of Nephrology, Uludag University Medical School, Turkey
| | - Savas Aksoy
- Savas Aksoy, Department of Internal Medicine, Division of Nephrology, Uludag University Medical School, Turkey
| | - Banu Demet Ozel Coskun
- Banu Demet Ozel Coskun, Department of Internal Medicine, Division of Gastroenterology, Kayseri Training and Research Hospital, Turkey
| | - Abdulmecit Yildiz
- Abdulmecit Yildiz, Department of Internal Medicine, Division of Nephrology, Uludag University Medical School, Turkey
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Ali H, Kabir N, Shah MR, Muhammad A, Ali S, Mehmood S, Ali A, Ali A, Jahan A. Hepatoprotective activity of viscosine is mediated by attenuation of hepatic macrophages and iNOS expression in CCl 4-intoxicated rats. Toxicol Res (Camb) 2016; 5:1688-1698. [PMID: 30090468 DOI: 10.1039/c6tx00165c] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 08/25/2016] [Indexed: 12/20/2022] Open
Abstract
This study investigated the molecular mechanism(s) of the protective effects of a C-alkylated flavonoid, viscosine on an animal model of CCl4-induced hepatotoxicity. Viscosine at 20, 50 and 100 mg kg-1 was orally administered in a dose dependent manner per day for 3 days before the CCl4 (1 : 1 v/v in olive oil, 1 ml kg-1) treatment and 2 days after the treatment. Hepatoprotection was assessed in terms of reduction in serum enzyme activities (ALT, AST, and ALP) that occur after CCl4 injury, and by histopathology and immunohistochemistry. The rise in serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) in CCl4-intoxicated rats was markedly suppressed by viscosine in a concentration dependent manner. The decrease in the activity of hepatic antioxidant enzyme, SOD, was significantly prevented by viscosine, likewise gradually the levels of MDA and GSH were also normalized compared to silymarin. Viscosine also reduced the CCl4-induced damaged area from 2% to 0% as assessed by histopathology and prevented the mixed inflammatory infiltrate. Viscosine attenuated the inflammation in the liver around the injured central vein region by downregulating the CCl4 induced activation of hepatic CD68+ macrophages, thereby reducing their number as well. The expression of inducible nitric oxide synthase (iNOS) was more potentially suppressed by viscosine compared to the FDA approved positive control silymarin. The results of this study indicate that viscosine could be effective in protecting the liver from acute CCl4-induced injury. The hepatoprotective mechanisms of viscosine may be related to the free radical scavenging and attenuation of oxidative stress, as well as to the inhibition of inflammatory response in the liver. Here, we are proposing a novel mechanism of action of viscosine and suggesting that it may be a safe and better in vivo antioxidant.
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Affiliation(s)
- Hamid Ali
- Department of Biosciences , COMSATS Institute of Information Technology , Park road , Chack Shehzad , Islamabad-44000 , Pakistan . ; ; ; Tel: +3329408516 ; Tel: +(03) 7967-4213.,Dr. Panjwani Center for Molecular Medicine and Drug Research , International Center for Chemical Sciences (ICCBS) , University of Karachi , Karachi-75270 , Pakistan
| | - Nurul Kabir
- Institute of Biological Sciences , Faculty of Science , University of Malaya , 50603 Kuala Lumpur , Malaysia
| | - Muhammad Raza Shah
- HEJ , Research Institute of Chemistry , International Center for Chemical Sciences (ICCBS) , University of Karachi , Karachi-75270 , Pakistan
| | - Akhtar Muhammad
- Department of Chemistry , Faculty of Sciences , Mugla Sitki Kocman University , Kotekli-48121 , Mugla , Turkey.,HEJ , Research Institute of Chemistry , International Center for Chemical Sciences (ICCBS) , University of Karachi , Karachi-75270 , Pakistan
| | - Safdar Ali
- Pakistan Institute of Engineering and Applied Sciences , Nilore , 45650 , Islamabad , Pakistan
| | - Shahab Mehmood
- Department of Biosciences , Shaheed Zulfikar Ali Bhutto Institute of Science and Technology , Karachi-75600 , Pakistan
| | - Amjad Ali
- Department of Biochemistry , Quaid-e-azam University , Islamabad , Pakistan
| | - Abid Ali
- Laboratory of Germplasm and Molecular Genetics , Department of Vegetable Sciences , College of Agriculture and Biotechnology , Zhejiang University , Hangzhou 310029 , PR-China
| | - Azra Jahan
- Department of Zoology , Hazara University , Mansehra , Khyber Pakhtunkhwa , Pakistan
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Fernando Bernal Q. FARMACOLOGÍA DE LOS ANTIRRETROVIRALES. REVISTA MÉDICA CLÍNICA LAS CONDES 2016. [DOI: 10.1016/j.rmclc.2016.09.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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Tan H, He Q, Li R, Lei F, Lei X. Trillin Reduces Liver Chronic Inflammation and Fibrosis in Carbon Tetrachloride (CCl4) Induced Liver Injury in Mice. Immunol Invest 2016; 45:371-82. [PMID: 27219527 DOI: 10.3109/08820139.2015.1137935] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
UNLABELLED Trillin is an active ingredient isolated from Dioscorea nipponica Makino. This study investigated the anti-inflammatory and anti-fibrosis effects of trillin on CCl4-induced hepatotoxicity in C57BL/6 mice. Chronic inflammation and fibrosis were induced by intraperitoneal administration of CCl4 0.5 μL/g of body weight twice a week for 6 weeks. Trillin (50 mg/kg, 100 mg/kg) was administered by gavage for 12 days before finishing the CCl4 induction. Aspartate amino-transferase (AST) and glutamic-pyruvic transaminase (ALT) in serum were determined by AST and ALT kits. Superoxidase dismutase (SOD) activity and malondialdehyde (MDA) levels in serum were assayed by SOD and MDA kits. Meanwhile, the levels of inflammatory mediators including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) in serum were detected by enzyme-linked immunosorbent assay (ELISA) method. Pathological changes were observed by hematoxylin-eosin (HE) staining. The proteins of the NF-κB pathway and the TGF-β/Smad pathway were measured by western blot. The trillin-treated group exhibited reduced AST, ALT, MDA, IL-6, TNF-α, and IL-1β, and increased SOD. Histological analyses of the trillin-treated group exhibited reduced inflammatory process and prevented liver fibrosis. Western blot analyses of the trillin-treated group showed reduced NF-κB pathway and TGF-β/Smad pathway. SIGNIFICANCE Based on the results of the present study, trillin can be used as a potential anti-inflammatory drug for chronic hepatic inflammation.
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Affiliation(s)
- Huabing Tan
- a Department of Infectious Diseases and Lab of Liver Disease, Renmin Hospital , Hubei University of Medicine , Shiyan , Hubei Province , China
| | - Qin He
- a Department of Infectious Diseases and Lab of Liver Disease, Renmin Hospital , Hubei University of Medicine , Shiyan , Hubei Province , China
| | - Rugui Li
- a Department of Infectious Diseases and Lab of Liver Disease, Renmin Hospital , Hubei University of Medicine , Shiyan , Hubei Province , China
| | - Feifei Lei
- a Department of Infectious Diseases and Lab of Liver Disease, Renmin Hospital , Hubei University of Medicine , Shiyan , Hubei Province , China
| | - Xu Lei
- a Department of Infectious Diseases and Lab of Liver Disease, Renmin Hospital , Hubei University of Medicine , Shiyan , Hubei Province , China
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Model-based contextualization of in vitro toxicity data quantitatively predicts in vivo drug response in patients. Arch Toxicol 2016; 91:865-883. [PMID: 27161439 PMCID: PMC5306109 DOI: 10.1007/s00204-016-1723-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 04/20/2016] [Indexed: 12/13/2022]
Abstract
Understanding central mechanisms underlying drug-induced toxicity plays a crucial role in drug development and drug safety. However, a translation of cellular in vitro findings to an actual in vivo context remains challenging. Here, physiologically based pharmacokinetic (PBPK) modeling was used for in vivo contextualization of in vitro toxicity data (PICD) to quantitatively predict in vivo drug response over time by integrating multiple levels of biological organization. Explicitly, in vitro toxicity data at the cellular level were integrated into whole-body PBPK models at the organism level by coupling in vitro drug exposure with in vivo drug concentration–time profiles simulated in the extracellular environment within the organ. PICD was exemplarily applied on the hepatotoxicant azathioprine to quantitatively predict in vivo drug response of perturbed biological pathways and cellular processes in rats and humans. The predictive accuracy of PICD was assessed by comparing in vivo drug response predicted for rats with observed in vivo measurements. To demonstrate clinical applicability of PICD, in vivo drug responses of a critical toxicity-related pathway were predicted for eight patients following acute azathioprine overdoses. Moreover, acute liver failure after multiple dosing of azathioprine was investigated in a patient case study by use of own clinical data. Simulated pharmacokinetic profiles were therefore related to in vivo drug response predicted for genes associated with observed clinical symptoms and to clinical biomarkers measured in vivo. PICD provides a generic platform to investigate drug-induced toxicity at a patient level and thus may facilitate individualized risk assessment during drug development.
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Hepatoprotective effect of grape seed oil against carbon tetrachloride induced oxidative stress in liver of γ-irradiated rat. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2016; 160:1-10. [PMID: 27085796 DOI: 10.1016/j.jphotobiol.2016.03.027] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Accepted: 03/21/2016] [Indexed: 12/15/2022]
Abstract
Carbon tetrachloride (CCl4) and ionizing radiation are well known environmental pollutants that generate free radicals and induce oxidative stress. The liver is the primary and major target organ responsible for the metabolism of drugs, toxic chemicals and affected by irradiation. This study investigated the effect of grape seed oil (GSO) on acute liver injury induced by carbon tetrachloride (CCl4) in γ-irradiated rats (7Gy). CCl4-intoxicated rats exhibited an elevation of ALT, AST activities, IL-6 and TNF-α level in the serum. Further, the levels of MDA, NO, NF-κB and the gene expression of CYP2E1, iNOS and Caspase-3 were increased, and SOD, CAT, GSH-Px, GST activities and GSH content were decreased. Furthermore, silent information regulator protein 1 (SIRT1) gene expression was markedly down-regulated. Additionally, alterations of the trace elements; copper, manganese, zinc and DNA fragmentation was observed in the hepatic tissues of the intoxicated group. These effects were augmented in CCl4-intoxicated-γ-irradiated rats. However, the administration of GSO ameliorated these parameters. GSO exhibit protective effects on CCl4 induced acute liver injury in γ-irradiated rats that could be attributed to its potent antioxidant, anti-inflammatory and anti-apoptotic activities. The induction of the antioxidant enzymes activities, down-regulation of the CYP2E1, iNOS, Caspase-3 and NF-κB expression, up-regulation of the trace elements concentration levels and activation of SIRT1 gene expression are responsible for the improvement of the antioxidant and anti-inflammatory status in the hepatic tissues and could be claimed to be the hepatoprotective mechanism of GSO.
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El-Hachem N, Grossmann P, Blanchet-Cohen A, Bateman AR, Bouchard N, Archambault J, Aerts HJ, Haibe-Kains B. Characterization of Conserved Toxicogenomic Responses in Chemically Exposed Hepatocytes across Species and Platforms. ENVIRONMENTAL HEALTH PERSPECTIVES 2016; 124:313-20. [PMID: 26173225 PMCID: PMC4786983 DOI: 10.1289/ehp.1409157] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Accepted: 07/09/2015] [Indexed: 05/03/2023]
Abstract
BACKGROUND Genome-wide expression profiling is increasingly being used to identify transcriptional changes induced by drugs and environmental stressors. In this context, the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation system (TG-GATEs) project generated transcriptional profiles from rat liver samples and human/rat cultured primary hepatocytes exposed to more than 100 different chemicals. OBJECTIVES To assess the capacity of the cell culture models to recapitulate pathways induced by chemicals in vivo, we leveraged the TG-GATEs data set to compare the early transcriptional responses observed in the liver of rats treated with a large set of chemicals with those of cultured rat and human primary hepatocytes challenged with the same compounds in vitro. METHODS We developed a new pathway-based computational pipeline that efficiently combines gene set enrichment analysis (GSEA) using pathways from the Reactome database with biclustering to identify common modules of pathways that are modulated by several chemicals in vivo and in vitro across species. RESULTS We found that some chemicals induced conserved patterns of early transcriptional responses in in vitro and in vivo settings, and across human and rat genomes. These responses involved pathways of cell survival, inflammation, xenobiotic metabolism, oxidative stress, and apoptosis. Moreover, our results support the transforming growth factor beta receptor (TGF-βR) signaling pathway as a candidate biomarker associated with exposure to environmental toxicants in primary human hepatocytes. CONCLUSIONS Our integrative analysis of toxicogenomics data provides a comprehensive overview of biochemical perturbations affected by a large panel of chemicals. Furthermore, we show that the early toxicological response occurring in animals is recapitulated in human and rat primary hepatocyte cultures at the molecular level, indicating that these models reproduce key pathways in response to chemical stress. These findings expand our understanding and interpretation of toxicogenomics data from human hepatocytes exposed to environmental toxicants.
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Affiliation(s)
- Nehme El-Hachem
- Integrative systems biology, Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada
- Department of Medicine, University of Montreal, Montréal, Quebec, Canada
| | - Patrick Grossmann
- Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | | | - Alain R. Bateman
- Department of Human Genetics, McGill University, Montreal, Quebec, Canada
| | - Nicolas Bouchard
- Department of Medicine, University of Montreal, Montréal, Quebec, Canada
- Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal, Montreal, Canada
| | - Jacques Archambault
- Laboratory of Molecular Virology, Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada
| | - Hugo J.W.L. Aerts
- Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Department of Radiology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Address correspondence to B. Haibe-Kains, Princess Margaret Cancer Centre, University Health Network, 101 College St., Toronto, ON, M5G 1L7, Canada. Telephone: 1 (416) 581-7628. E-mail: , or to H.J.W.L. Aerts, Department of Radiology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 USA. E-mail:
| | - Benjamin Haibe-Kains
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Medical Biophysics Department, University of Toronto, Toronto, Ontario, Canada
- Address correspondence to B. Haibe-Kains, Princess Margaret Cancer Centre, University Health Network, 101 College St., Toronto, ON, M5G 1L7, Canada. Telephone: 1 (416) 581-7628. E-mail: , or to H.J.W.L. Aerts, Department of Radiology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 USA. E-mail:
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Singh HO, Lata S, Angadi M, Bapat S, Pawar J, Nema V, Ghate MV, Sahay S, Gangakhedkar RR. Impact of GSTM1, GSTT1 and GSTP1 gene polymorphism and risk of ARV-associated hepatotoxicity in HIV-infected individuals and its modulation. THE PHARMACOGENOMICS JOURNAL 2015; 17:53-60. [PMID: 26667829 DOI: 10.1038/tpj.2015.88] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 09/15/2015] [Accepted: 11/02/2015] [Indexed: 12/29/2022]
Abstract
Glutathione S-transferase (GST) family is involved in a two-stage detoxification process of a wide range of environmental toxins, carcinogen and antiretroviral (ARV) therapy (ART) drugs. The aim of this study is to describe the impact of genetic polymorphisms of GSTM1, GSTT1 and GSTP1-313A/G in the risk of ARV-associated hepatotoxicity in HIV-infected individuals and its modulation in hepatotoxic patients. We enrolled a total of 34 patients with hepatotoxicity, 131 HIV-infected individuals without hepatotoxicity under non-nucleoside reverse transcriptase inhibitor containing ART and 153 unrelated healthy individuals. With a case-control design, polymorphisms of GSTM1, GSTT1 and GSTP1-313A/G gene were genotyped by PCR and restriction enzyme-length polymorphism. Genotypes of GSTT1 null were significantly higher in HIV-infected individuals as compared with healthy controls (P=0.01, odds ratio (OR)=1.54). HIV-infected individuals with GSTM1-null genotype showed higher risk (P=0.09, OR=1.37) for hepatotoxicity, but risk was not significant. On evaluating gene-gene interaction models, GSTM1 null and GSTT1 null showed significant association with the risk of hepatotoxicity in HIV-infected individuals (P=0.004, OR=2.67) owing to synergistic effect of these genes. Individuals with GSTT1-null and GSTM1-null genotypes showed higher risk of hepatotoxicity with advanced stage of (CD4<200) of HIV infection (P=0.18, OR=1.39; P=0.63, OR=1.13). In case-only analysis, GSTT1-null genotype among alcohol users showed elevated risk of hepatotoxicity in HIV-infected individuals (P=0.12, OR=1.36, 95% confidence interval (CI): 0.94-1.97) as compared with GSTT1 genotypes. The carriers GSTM1-null+GSTT1-null genotype among nevirapine user showed prominent risk of hepatotoxicity in HIV-infected individuals (P=0.12, OR=4.21, 95% CI: 0.60-29.54). Hence, we can conclude that GSTT1-null and GSTM1-null genotypes alone and in combination may predict the acquisition of hepatotoxicity.
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Affiliation(s)
- H O Singh
- Department of Molecular Biology, National AIDS Research Institute, Pune, India
| | - S Lata
- Department of Molecular Biology, National AIDS Research Institute, Pune, India
| | - M Angadi
- Department of Clinical Sciences, National AIDS Research Institute, Pune, India
| | - S Bapat
- Department of Clinical Sciences, National AIDS Research Institute, Pune, India
| | - J Pawar
- Department of Clinical Sciences, National AIDS Research Institute, Pune, India
| | - V Nema
- Department of Molecular Biology, National AIDS Research Institute, Pune, India
| | - M V Ghate
- Department of Clinical Sciences, National AIDS Research Institute, Pune, India
| | - S Sahay
- Department of Clinical Sciences, National AIDS Research Institute, Pune, India
| | - R R Gangakhedkar
- Department of Clinical Sciences, National AIDS Research Institute, Pune, India
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Toxicity of antioxidative extract collected from Styela clava tunics in ICR mice. Lab Anim Res 2015; 31:125-33. [PMID: 26472965 PMCID: PMC4602079 DOI: 10.5625/lar.2015.31.3.125] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 09/02/2015] [Accepted: 09/04/2015] [Indexed: 11/29/2022] Open
Abstract
Some polymers and bioactive compounds derived from Styela clava tunic (SCT) have been reported as traditional medicine for the treatment of inflammation, oxidative stress and surgical wounds although there is little scientific evidence of their liver and kidney toxicity. To investigate the toxicity of ethanol extracts of SCT (EtSCT) in the liver and kidney of ICR mice, alterations in related markers including body weight, organ weight, urine composition, liver pathology and kidney pathology were analyzed following oral administration of 50 and 100 mg/kg body weight/day of EtSCT for 14 days. EtSCT showed a high level of free radical scavenging activity for DPPH (93.1%) and NO (16.2%) as well as the presence of 14.8 mg/mL of flavonoids and 36.2 mg/mL of phenolics, while EtSCT treated groups did not show any significant alterations in the body and organ weight, clinical phenotypes, urine parameters or mice mortality when compared with the vehicle treated group. In addition, constant levels of serum biochemical markers including alanine phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN) and serum creatinine (CRE) were maintained. Moreover, no specific histopathological features induced by most toxic compounds were observed in liver and kidney sections stained with hematoxilin and eosin. Therefore, the present results indicate that EtSCT with strong antioxidant activity cannot induce any specific toxicity in liver and kidney organs of ICR at doses of 100 mg/kg body weight/day.
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Go J, Kim JE, Koh EK, Song SH, Seung JE, Park CK, Lee HA, Kim HS, Lee JH, An BS, Yang SY, Lim Y, Hwang DY. Hepatotoxicity and nephrotoxicity of gallotannin-enriched extract isolated from Galla Rhois in ICR mice. Lab Anim Res 2015; 31:101-10. [PMID: 26472962 PMCID: PMC4602076 DOI: 10.5625/lar.2015.31.3.101] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Revised: 06/23/2015] [Accepted: 07/16/2015] [Indexed: 12/14/2022] Open
Abstract
To evaluate the hepatotoxicity and nephrotoxicity of Galla Rhois (GR) toward the liver and kidney of ICR mice, alterations in related markers including body weight, organ weight, urine composition, liver pathology and kidney pathology were analyzed after oral administration of 250, 500 and 1,000 mg/kg body weight/day of gallotannin-enriched extract of GR (GEGR) for 14 days. GEGR contained 68.7±2.5% of gallotannin, 25.3±0.9% of gallic acid and 4.4±0.1% of methyl gallate. Also, the level of malondialdehyde (MDA), a marker of lipid peroxidation, was decreased with 19% in the serum of high dose GEGR (HGEGR)-treated mice. The body and organ weight, clinical phenotypes, urine parameters and mice mortality did not differ among GEGR-treated groups and the vehicle-treated group. Furthermore, no significant increase was observed in alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), blood urea nitrogen (BUN) and the serum creatinine (Cr) in the GEGR-treated group relative to the vehicle-treated group. Moreover, the specific pathological features induced by most toxic compounds such as CCl4 were not observed upon liver and kidney histological analysis. Overall, the results of the present study suggest that GEGR does not induce any specific toxicity in liver and kidney organs of ICR at doses of 1,000 mg/kg body weight/day, indicating that this is no observed adverse effect level (NOAEL).
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Affiliation(s)
- Jun Go
- Department of Biomaterials Science, College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Ji-Eun Kim
- Department of Biomaterials Science, College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Eun-Kyoung Koh
- Department of Biomaterials Science, College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Sung-Hwa Song
- Department of Biomaterials Science, College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Ji-Eun Seung
- Department of Biomaterials Science, College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Chan-Kyu Park
- Department of Biomaterials Science, College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Hyun-Ah Lee
- Department of Biomaterials Science, College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Hong-Sung Kim
- Department of Biomaterials Science, College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Jae-Ho Lee
- Department of Biomaterials Science, College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Beum-Soo An
- Department of Biomaterials Science, College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Seung-Yun Yang
- Department of Biomaterials Science, College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
| | - Yong Lim
- Department of Clinical Laboratory Science, College of Nursing and Healthcare Science, Dong-Eui University, Busan, Korea
| | - Dae-Youn Hwang
- Department of Biomaterials Science, College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Korea
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Trypanosoma cruzi infection and benznidazole therapy independently stimulate oxidative status and structural pathological remodeling of the liver tissue in mice. Parasitol Res 2015; 114:2873-81. [DOI: 10.1007/s00436-015-4488-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Accepted: 04/16/2015] [Indexed: 12/11/2022]
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Popov SS, Shulgin KK, Popova TN, Pashkov AN, Agarkov AA, de Carvalho MAAP. Effects of Melatonin-Aided Therapy on the Glutathione Antioxidant System Activity and Liver Protection. J Biochem Mol Toxicol 2015; 29:449-457. [PMID: 25903262 DOI: 10.1002/jbt.21705] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Revised: 03/06/2015] [Accepted: 03/10/2015] [Indexed: 11/08/2022]
Abstract
Acute hepatitis results from oxidative stress triggered by hepatotoxic drugs causing liver injury and the activation of caspases cascade. The glutathione antioxidant system protects against reactive oxygen species and mitigates development of these processes. The effectiveness of silymarin, a polyphenolic flavonoid, essenthiale, composed of phosphatidyl choline, and melaxen, a melatonin-correcting drug, as hepatoprotectors has been investigated. The variation of 6-sulfatoxymelatonin (aMT6s), resulting from the biotransformation of melatonin, and GSH has been measured. The activities of caspase-1 and caspase-3, glutathione antioxidant system, and NADPH-generating enzymes were determined. The aMT6s decreases in patients with drug hepatitis and recovers with administration of mexalen. GSH increased in the presence of the studied hepatoprotectors. Pathologically activated caspase-1 and caspase-3 decreased their activities in the presence of hepatoprotectors with melaxen showing the highest effect. The positive effect of melatonin appears to be related to the suppression of decompensation of the glutathione antioxidant system functions, recovery of liver redox status, and the attenuation of inhibition of the NADPH supply.
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Affiliation(s)
- Serguey S Popov
- Department of Endocrinology, Voronezh State Medical Academy, Voronezh, Russian Federation
| | - Konstantin K Shulgin
- Department of Medical Biochemistry and Microbiology, Voronezh State University, Voronezh, Russian Federation
| | - Tatyana N Popova
- Department of Medical Biochemistry and Microbiology, Voronezh State University, Voronezh, Russian Federation
| | - Aleksander N Pashkov
- Department of Biology and Ecology, Voronezh State Medical Academy, Voronezh, Russian Federation
| | - Aleksander A Agarkov
- Department of Medical Biochemistry and Microbiology, Voronezh State University, Voronezh, Russian Federation
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