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Bosco G, Vezzoli A, Brizzolari A, Paganini M, Giacon TA, Savini F, Gussoni M, Montorsi M, Dellanoce C, Mrakic-Sposta S. Consumption of Sylimarin, Pyrroloquinoline Quinone Sodium Salt and Myricetin: Effects on Alcohol Levels and Markers of Oxidative Stress-A Pilot Study. Nutrients 2024; 16:2965. [PMID: 39275279 PMCID: PMC11397684 DOI: 10.3390/nu16172965] [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: 07/30/2024] [Revised: 08/24/2024] [Accepted: 08/29/2024] [Indexed: 09/16/2024] Open
Abstract
BACKGROUND Alcohol abuse is one of the most common causes of mortality worldwide. This study aimed to investigate the efficacy of a treatment in reducing circulating ethanol and oxidative stress biomarkers. METHODS Twenty wine-drinking subjects were investigated in a randomized controlled, single-blind trial (ClinicalTrials.gov. Identifier: NCT06548503; Ethical Committee of the University of Padova (HEC-DSB/12-2023) to evaluate the effect of the intake of a product containing silymarin, pyrroloquinoline quinone sodium salt, and myricetin (referred to as Si.Pi.Mi. for this project) on blood alcohol, ethyl glucuronide (EtG: marker for alcohol consumption) and markers of oxidative stress levels (Reactive Oxygen Species-ROS, Total Antioxidant Capacity-TAC, CoQ10, thiols redox status, 8-isoprostane, NO metabolites, neopterin, and uric acid). The effects of the treatment versus placebo were evaluated acutely and after 1 week of supplementation in blood and/or saliva and urine samples. RESULTS Si.Pi.Mi intake reduced circulating ethanol after 120 min (-33%). Changes in oxidative stress biomarkers, particularly a TAC (range +9-12%) increase and an 8-isoprostane (marker of lipidic peroxidation) decrease (range -22-27%), were observed too. CONCLUSION After the administration of Si.Pi.Mi, the data seemed to suggest a better alcohol metabolism and oxidative balance in response to wine intake. Further verification is requested.
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Affiliation(s)
- Gerardo Bosco
- Department of Biomedical Sciences, University of Padua, 35122 Padua, Italy
| | - Alessandra Vezzoli
- Department of Biomedical Sciences, University of Padua, 35122 Padua, Italy
- Institute of Clinical Physiology, National Research Council (CNR), 20159 Milan, Italy
| | - Andrea Brizzolari
- Department of Biomedical Sciences, University of Padua, 35122 Padua, Italy
| | - Matteo Paganini
- Department of Biomedical Sciences, University of Padua, 35122 Padua, Italy
| | | | - Fabio Savini
- Pharmatoxicology Laboratory-Hospital "Santo Spirito", 65100 Pescara, Italy
| | - Maristella Gussoni
- Institute of Clinical Physiology, National Research Council (CNR), 20159 Milan, Italy
| | - Michela Montorsi
- Institute of Clinical Physiology, National Research Council (CNR), 20159 Milan, Italy
| | - Cinzia Dellanoce
- Institute of Clinical Physiology, National Research Council (CNR), 20159 Milan, Italy
| | - Simona Mrakic-Sposta
- Institute of Clinical Physiology, National Research Council (CNR), 20159 Milan, Italy
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Jiang Y, Li Y, Zhang Y, Hu D, Zhang S, Wang C, Huang S, Zhang A, Jia Z, You R. NSC228155 alleviates septic cardiomyopathy via protecting mitochondria and inhibiting inflammation. Int Immunopharmacol 2023; 116:109847. [PMID: 36774857 DOI: 10.1016/j.intimp.2023.109847] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/30/2023] [Accepted: 02/01/2023] [Indexed: 02/12/2023]
Abstract
Septic cardiomyopathy is a lethal symptom of sepsis. Discovery of effective therapy that prevents cardiac injury in sepsis is critical in the clinical management of sepsis. NSC228155 is a novel compound with therapeutic potential on acute kidney injury by preventing apoptosis and protecting mitochondria. Whether NSC228155 protects against septic cardiomyopathy is unclear. In the present study, adult C57BL/6J mice were i.p injected with 5 mg/kg/day NSC228155 for 2 days before 10 mg/kg lipopolysaccharide (LPS) injection. Cardiac functional testing and sampling for serum and tissue were performed 12 and 24 h post LPS injection, respectively. NSC228155 significantly improved cardiac function examined by echocardiography, decreased the serum lactate dehydrogenase (LDH) and creatine kinase-MB, and pathologically alleviated cardiac injury in LPS mice. Accordingly, NSC228155 attenuated cardiomyocytes' mitochondrial damage as shown by decreased damaged mitochondrial ratio and activated signals for mitochondrial biogenesis, dynamics and mitophagy in LPS mice model. Metabolomics analysis demonstrated that NSC228155 corrected the metabolic disturbance involved in oxidative stress and energy metabolism, and decreased tissue injury metabolites in LPS-stimulated cardiac tissue. In the LPS-stimulated cardiac cell culture derived from human induced pluripotent stem cells, NSC228155 effectively restored the beating frequency, decreased LDH release, and protected mitochondria. NSC228155 also inhibited inflammation shown by decreased pro-inflammatory mediators in both serum and cardiac tissue in LPS model. Taken together, NSC228155 significantly improved cardiac function by directly preventing against cardiac cell injury and inhibiting inflammation in LPS model, hence may be a potential novel therapy against septic cardiomyopathy.
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Affiliation(s)
- Yuteng Jiang
- School of Medicine, Southeast University, Nanjing, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
| | - Yanwei Li
- School of Medicine, Southeast University, Nanjing, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
| | - Yiyuan Zhang
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; Department of Nephrology, Huai'an Hospital Affiliated to Xuzhou Medical University, Huai'an, Jiangsu, China
| | - Dandan Hu
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
| | - Shengnan Zhang
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
| | - Chunli Wang
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
| | - Songming Huang
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
| | - Aihua Zhang
- School of Medicine, Southeast University, Nanjing, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China.
| | - Zhanjun Jia
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China.
| | - Ran You
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China.
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Guru A, Manjunathan T, Sudhakaran G, Juliet A, Gopinath P, Arockiaraj J. 6-Gingerdione Reduces Apoptotic Conditions in HepG2 Cells and Inhibits Inflammatory Cytokine Gene Expression in Alcoholic Liver Injured Zebrafish Larvae. Chem Biodivers 2023; 20:e202200959. [PMID: 36574474 DOI: 10.1002/cbdv.202200959] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 12/08/2022] [Indexed: 12/28/2022]
Abstract
Antioxidant natural products and their analogs especially phenolic compounds, exhibit diverse biological properties, including anti-inflammatory, antioxidant, and anticancer activities. Ginger which is widely used worldwide for various beneficial effects also contains several phenolic antioxidants, and 6-gingerol is one of the natural products studied extensively. However, the molecular mechanism of synthetically synthesized 6-gingerdione (compound 1) from 6-gingerol was not known. In this study, compound 1 and methylated 6-gingerdione (compound 2) were obtained semi synthetically from 6-gingerol. Compound 1 and 2 are subjected to SwissADME prediction. Then the protective effect of compound 1 was analyzed in 2 % EtOH induced HepG2 cells and zebrafish larvae. Hydroxyl and nitric oxide scavenging assays reveal that compound 1 showed more antioxidant activity than compound 2 at 50 μM. Moreover, compound 1 exhibited good anti-inflammatory activity via lipoxygenase inhibition and proteinase inhibition. Apoptosis and oxidative stress in HepG2 cells were induced by 2 % EtOH and treated with compound 1. Compound 1 significantly inhibited the EtOH induced nitric oxide production, apoptosis, and ROS generation in HepG2 cells. Encouraged by the in-vitro antioxidant and anti-inflammatory activities, compound 1 was then investigated for its protective effect in 2 % EtOH induced ALD zebrafish larva. Compound 1 protected the zebrafish larvae from liver injury by suppressing inflammatory (COX-2, TNF-α, and IL-1β) and lipogenic genes (C/EBP-α, SREBP1, and IL-1β) while upregulating the antioxidant gene. Our findings indicate that compound 1 synthesized from 6-gingerol ameliorated liver injury that likely, contributes to its potential antioxidant and anti-inflammatory properties.
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Affiliation(s)
- Ajay Guru
- Department of Conservative Dentistry and Endodontics, Saveetha Dental College and Hospitals, SIMATS, Chennai 600 077, Tamil Nadu, India
| | - Tamilvelan Manjunathan
- Department of Chemistry, College of Engineering and Technology, SRM Institute of Science and Technology, Kattankulathur 603 203, Chennai, Tamil Nadu, India
| | - Gokul Sudhakaran
- Department of Biotechnology, College of Science and Humanities, SRM Institute of Science and Technology, Kattankulathur 603 203, Chennai, Tamil Nadu, India
| | - Annie Juliet
- Foundation for Aquaculture Innovations and Technology Transfer (FAITT), Thoraipakkam, Chennai 600 097, Tamil Nadu, India
| | - Pushparathinam Gopinath
- Department of Chemistry, College of Engineering and Technology, SRM Institute of Science and Technology, Kattankulathur 603 203, Chennai, Tamil Nadu, India
| | - Jesu Arockiaraj
- Department of Conservative Dentistry and Endodontics, Saveetha Dental College and Hospitals, SIMATS, Chennai 600 077, Tamil Nadu, India
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Cysteine Donor-Based Brain-Targeting Prodrug: Opportunities and Challenges. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4834117. [PMID: 35251474 PMCID: PMC8894025 DOI: 10.1155/2022/4834117] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 02/11/2022] [Indexed: 12/20/2022]
Abstract
Overcoming blood-brain barrier (BBB) to improve brain bioavailability of therapeutic drug remains an ongoing concern. Prodrug is one of the most reliable approaches for delivering agents with low-level BBB permeability into the brain. The well-known antioxidant capacities of cysteine (Cys) and its vital role in glutathione (GSH) synthesis indicate that Cys-based prodrug could potentiate therapeutic drugs against oxidative stress-related neurodegenerative disorders. Moreover, prodrug with Cys moiety could be recognized by the excitatory amino acid transporter 3 (EAAT3) that is highly expressed at the BBB and transports drug into the brain. In this review, we summarized the strategies of crossing BBB, properties of EAAT3 and its natural substrates, Cys and its donors, and Cys donor-based brain-targeting prodrugs by referring to recent investigations. Moreover, the challenges that we are faced with and future research orientations were also addressed and proposed. It is hoped that present review will provide evidence for the pursuit of novel Cys donor-based brain-targeting prodrug.
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Liu J, Guo C, Hao P, Wang P, Li L, Wang Y, Li X. Protection effect of thymosin β4 on ethanol injury in corneal stromal keratocyte. BMC Ophthalmol 2022; 22:33. [PMID: 35062902 PMCID: PMC8783420 DOI: 10.1186/s12886-022-02255-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 01/04/2022] [Indexed: 12/02/2022] Open
Abstract
Purpose To investigate the protective effects of thymosin β4 (Tβ4) on ethanol injured human corneal keratocytes (HCKs). Methods HCKs and BALB/c mice were chosen as the study subject. Ethanol was used to treat the cells and corneal stroma of mice to build the ethanol injured model in vitro and vivo respectively. CCK-8 was used to evaluate the cell metabolic activity. DCFH-DA was used to detect the intracellular reactive oxygen species level. TUNEL was chose to detect the cell apoptosis rate. The cell proliferation and migration were investigated by using wound healing insert. Wound healing of corneal surface and stroma was observed by using fluorescein sodium eyedrop and HE stain. RT-qPCR, ELISA, and immunostaining were performed to detect gene and protein expression in keratocytes or corneal stroma tissue of mice. Results Ethanol induced oxidative stress injury and cell apoptosis on HCKs, and Tβ4 can alleviate it by up-regulating the expression of Bcl-2, catalase, and CuZnSOD, and inhibiting the expression of Caspase-3. Tβ4 promotes the proliferation of HCKs and the process of corneal wound healing. It may relevant to the up-regulated expression of Ki67. Conclusions Our study established an ethanol-injured corneal stroma model in both vitro and vivo. The present study confirmed that Tβ4 play a protective effect on the reconstruction process of ethanol-injured corneal stroma.
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Yeşiltepe O, Güler Çelik E, Geyik C, Gümüş ZP, Odaci Demirkol D, Coşkunol H, Timur S. Preparation of glutathione loaded nanoemulsions and testing of hepatoprotective activity on THLE-2 cells. Turk J Chem 2021; 45:436-451. [PMID: 34104055 PMCID: PMC8164205 DOI: 10.3906/kim-2007-54] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 01/06/2021] [Indexed: 12/29/2022] Open
Abstract
To improve bioavailability and stability of hydrophobic and hydrophilic compounds, nanoemulsions are good alternatives as delivery systems because of their nontoxic and nonirritant nature. Glutathione (GSH) suffers from low stability in water, where its encapsulation in nanoemulsions is a powerful strategy to its stability in aqueous systems. The aim of this study was to obtain nanoemulsions from the hydrophobic/hydrophilic contents of N. sativa seed oil so as to improve GSH stability along with bioavailability of N. sativa seed oil. Then, the prepared nanoemulsions were tested for in vitro hepatoprotective activity against ethanol toxicity. To the best of our knowledge, there is no study on the test of nanoemulsions by the combination of Nigella sativa seed oils and GSH in hepatoprotective activity. Here, nanoemulsions with different contents were prepared using Nigella sativa seed oils. Content analyses and characterisation studies of prepared nanoemulsions were carried out. In order to investigate the protective effects against to ethanol exposure, THLE-2 cells were pretreated with nanoemulsions for 2 h with the maximum benign dose (0.5 mg/mL of nanoemulsions). Ethanol (400 mM) was introduced to pretreated cells and nontreated cells for 48- or 72-h periods, followed by cell viability assay was carried out. Fluorescence microscopy tests revealed the introduction of the nanoemulsions into THLE-2 cells. The findings show that nanoformulations have promising in vitro hepatoprotective effects on the THLE-2 cell line against ethanol exposure.
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Affiliation(s)
- Ozan Yeşiltepe
- Institute on Drug Abuse Toxicology and Pharmaceutical Science, Ege University, İzmir Turkey
| | - Emine Güler Çelik
- Department of Biochemistry, Faculty of Science, Ege University, İzmir Turkey
| | - Caner Geyik
- Institute on Drug Abuse Toxicology and Pharmaceutical Science, Ege University, İzmir Turkey.,Department of Medical Biochemistry, Faculty of Medicine, İstinye University, İstanbul Turkey
| | - Zinar Pınar Gümüş
- Institute on Drug Abuse Toxicology and Pharmaceutical Science, Ege University, İzmir Turkey.,Central Research Testing and Analysis Laboratory Research and Application Center, Ege University, İzmir Turkey
| | | | - Hakan Coşkunol
- Department of Psychiatry, Faculty of Medicine, Ege University, İzmir Turkey
| | - Suna Timur
- Department of Biochemistry, Faculty of Science, Ege University, İzmir Turkey.,Central Research Testing and Analysis Laboratory Research and Application Center, Ege University, İzmir Turkey
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Proteoglycan isolated from Corbicula fluminea exerts hepato-protective effects against alcohol-induced liver injury in mice. Int J Biol Macromol 2020; 142:1-10. [DOI: 10.1016/j.ijbiomac.2019.12.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 11/18/2019] [Accepted: 12/01/2019] [Indexed: 12/27/2022]
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Mocelin R, Marcon M, da Rosa Araujo AS, Herrmann AP, Piato A. Withdrawal effects following repeated ethanol exposure are prevented by N-acetylcysteine in zebrafish. Prog Neuropsychopharmacol Biol Psychiatry 2019; 93:161-170. [PMID: 30946939 DOI: 10.1016/j.pnpbp.2019.03.014] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 03/12/2019] [Accepted: 03/29/2019] [Indexed: 12/18/2022]
Abstract
Alcohol abuse is a highly prevalent condition that substantially contributes to global morbidity and mortality. Most available pharmacological treatments offer little efficacy as relapse rates are high, due in part to the symptoms experienced during abstinence. The roles of oxidative stress and glutamatergic transmission in alcohol withdrawal have been demonstrated in several studies, suggesting that restoration of oxidative status and glutamatergic function may represent a new pharmacological target to prevent the behavioral and biochemical alterations observed during withdrawal. A well-known antioxidant and glutamatergic modulator, N-acetylcysteine (NAC), has shown promise in treating a variety of psychiatric conditions, including substance use disorders, and is a promising molecule in the management of alcohol withdrawal syndrome. Thus, the aim of this study was to investigate whether NAC is able to prevent the expression of behavioral and biochemical alterations induced by ethanol withdrawal in chronically exposed zebrafish. Animals were exposed to ethanol (1% v/v, 20 min) or control water, followed by treatment with NAC (1 mg/L, 10 min) or control water daily for 8 days; 24 h later, experimental animals were submitted to the novel tank test (NTT). Ethanol withdrawal decreased the distance traveled and increased the number of immobile episodes, indicating locomotor deficits; moreover, withdrawal decreased the number of entries and time spent in the top area, while increasing time spent in the bottom area, indicating anxiety-like behavior. Alcohol withdrawal also increased lipid peroxidation (TBARS) and decreased non-protein reduced sulfhydryl (NPSH) and superoxide dismutase (SOD) and catalase (CAT) activities. NAC attenuated these locomotor deficits and prevented the manifestation of anxiety-like behavior as well as the oxidative damage observed following ethanol withdrawal. Given its favorable safety profile, additional clinical and preclinical studies are warranted to unravel the long-term effects of NAC in the context of alcohol abuse and the exact mechanisms involved. Nevertheless, our study adds to the existing body of evidence supporting the clinical evaluation of NAC in substance abuse disorders.
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Affiliation(s)
- Ricieri Mocelin
- Laboratory of Psychopharmacology and Behavior, Basic Sciences Institute of Health, Graduate Program in Biological Sciences: Neuroscience, Federal University of Rio Grande do Sul, Porto Alegre, RS 90050-170, Brazil
| | - Matheus Marcon
- Laboratory of Psychopharmacology and Behavior, Basic Sciences Institute of Health, Graduate Program in Biological Sciences: Neuroscience, Federal University of Rio Grande do Sul, Porto Alegre, RS 90050-170, Brazil
| | - Alex Sander da Rosa Araujo
- Laboratory of Cardiovascular Physiology and Reactive Oxygen Species, Basic Sciences Institute of Health, Federal University of Rio Grande do Sul, Porto Alegre, RS 90050-170, Brazil
| | - Ana Paula Herrmann
- Graduate Program in Biological Sciences: Pharmacology and Therapeutics, Basic Sciences Institute of Health, Federal University of Rio Grande do Sul, Porto Alegre, RS 90050-170, Brazil
| | - Angelo Piato
- Laboratory of Psychopharmacology and Behavior, Basic Sciences Institute of Health, Graduate Program in Biological Sciences: Neuroscience, Federal University of Rio Grande do Sul, Porto Alegre, RS 90050-170, Brazil; Graduate Program in Biological Sciences: Pharmacology and Therapeutics, Basic Sciences Institute of Health, Federal University of Rio Grande do Sul, Porto Alegre, RS 90050-170, Brazil; Zebrafish Neuroscience Research Consortium (ZNRC), Los Angeles, United States.
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Gould RL, Pazdro R. Impact of Supplementary Amino Acids, Micronutrients, and Overall Diet on Glutathione Homeostasis. Nutrients 2019; 11:E1056. [PMID: 31083508 PMCID: PMC6566166 DOI: 10.3390/nu11051056] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Revised: 05/06/2019] [Accepted: 05/08/2019] [Indexed: 12/22/2022] Open
Abstract
Glutathione (GSH) is a critical endogenous antioxidant found in all eukaryotic cells. Higher GSH concentrations protect against cellular damage, tissue degeneration, and disease progression in various models, so there is considerable interest in developing interventions that augment GSH biosynthesis. Oral GSH supplementation is not the most efficient option due to the enzymatic degradation of ingested GSH within the intestine by γ-glutamyltransferase, but supplementation of its component amino acids-cysteine, glycine, and glutamate-enhances tissue GSH synthesis. Furthermore, supplementation with some non-precursor amino acids and micronutrients appears to influence the redox status of GSH and related antioxidants, such as vitamins C and E, lowering systemic oxidative stress and slowing the rate of tissue deterioration. In this review, the effects of oral supplementation of amino acids and micronutrients on GSH metabolism are evaluated. And since specific dietary patterns and diets are being prescribed as first-line therapeutics for conditions such as hypertension and diabetes, the impact of overall diets on GSH homeostasis is also assessed.
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Affiliation(s)
- Rebecca L Gould
- Department of Foods and Nutrition, University of Georgia, Athens, GA 30602, USA.
| | - Robert Pazdro
- Department of Foods and Nutrition, University of Georgia, Athens, GA 30602, USA.
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Chen J, Ye C, Hu X, Huang C, Yang Z, Li P, Wu A, Xue X, Lin D, Yang H. Serum metabolomics model and its metabolic characteristics in patients with different syndromes of dyslipidemia based on nuclear magnetic resonance. J Pharm Biomed Anal 2019; 167:100-113. [PMID: 30763881 DOI: 10.1016/j.jpba.2018.12.042] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 12/22/2018] [Accepted: 12/28/2018] [Indexed: 12/27/2022]
Abstract
Dyslipidemia is known as a common clinical disease that affects the health of millions of people around the world. The treatment of dyslipidemia with traditional Chinese medicine (TCM) is generally based on the accurate identification of disease syndromes. TCM syndromes are judged by traditional four-diagnosis method, which is subjective and fuzzy. Additionally, the judgment of TCM syndromes highly depend on doctors' own clinical experience. In this present study, we used nuclear magnetic resonance (NMR)-based serum metabolomics patterns to figure out the metabolic characteristics of different syndromes in patients with dyslipidemia. In total, we enrolled 60 patients with dyslipidemia (30 cases with Spleen and Kidney Yang Deficiency syndrome (SKYD) and 30 cases with Phlegm-Dampness Retention syndrome (PDR)) and 20 healthy controls. Based on NMR technique, the serum metabolomics patterns of patients with different syndromes and healthy controls were analyzed, in the hope of screening the different metabolites among different syndromes and the differential metabolic pathway, as well as exploring the changes of metabolic network among different syndromes of dyslipidemia. The results suggested that the serum metabolomics patterns based on NMR was used to identify serum metabolites in patients with dyslipidemia of SKYD and PDR as well as healthy controls. Besides, it was found that the metabolic patterns of these three groups can be distinguished well and the different metabolites between different syndromes can be screened. From the point of view of metabolites, the metabolic characteristics of the patients with PDR were mainly the accumulation of noxious metabolites, while the metabolic characteristics of the patients with SKYD were mainly the lack of metabolites with protective function. From the point of view of metabolic mode, there were different metabolic patterns in patients with different syndromes of dyslipidemia in liver metabolism, oxidation, inflammatory reaction as well as energy metabolism, which reflects the difference of syndromes from different angles. The differences in metabolic outcomes among patients with different syndromes of dyslipidemia had a close association with to the effects of multiple signaling pathways. This study identified the characteristics of serum metabolic model of patients with different syndromes of dyslipidemia and the potential differential metabolites and characteristic metabolic characteristics of syndromes in order to understand the biological characteristics of patients with dyslipidemia of SKYD and PDR.
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Affiliation(s)
- Jing Chen
- Medical Department, The Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Chao Ye
- Orthopedics Department (2 ward), Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaomin Hu
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Caihua Huang
- Department of Physical Education, Xiamen University of Technology, Xiamen, China
| | - Zheng Yang
- SATCM Key Laboratory of Renowned Physician and Classical Formula, Beijing University of Chinese Medicine, Beijing, China
| | - Pengyang Li
- Orthopedics Department (2 ward), Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Aiming Wu
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaolin Xue
- Department of Diagnostics of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
| | - Donghai Lin
- College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China.
| | - Huimin Yang
- Neurology Department (3 ward), Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
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Decreased glucose-6-phosphate dehydrogenase activity along with oxidative stress affects visual contrast sensitivity in alcoholics. Alcohol 2018; 73:17-24. [PMID: 30172164 DOI: 10.1016/j.alcohol.2018.03.007] [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: 10/26/2017] [Revised: 02/15/2018] [Accepted: 03/16/2018] [Indexed: 11/21/2022]
Abstract
OBJECTIVE To evaluate oxidative stress and glucose-6-phosphate dehydrogenase (G6PD) status of alcoholics and discern their association, if any, with visual contrast sensitivity function. METHODS Forty male alcoholic subjects and 36 male non-alcoholic subjects with the same age and nutritional status were enrolled in this study. Serum malondialdehyde (MDA) level and glucose-6-phosphate dehydrogenase (G6PD) activity of erythrocytes were determined by spectrophotometric assay. Contrast sensitivity (CS) function of study subjects was measured using the Rabin Contrast Sensitivity Test (Precision Vision®, La Salle, Illinois, United States). RESULTS Serum MDA levels were significantly higher (p < 0.0001) and erythrocyte G6PD activity was significantly lower (p = 0.0026) in alcoholic subjects compared to the controls. CS scores of both eyes were also found to be decreased significantly in alcoholic subjects (both at p < 0.0001) compared to control subjects. On the other hand, CS scores of the alcoholic subjects were inversely correlated with the serum MDA level (r = -0.746, p < 0.0001) and directly correlated with erythrocyte G6PD activity (r = 0.78, p < 0.0001). A strong inverse correlation (r = -0.84, p < 0.0001) was also observed between serum MDA level and erythrocyte G6PD activity of alcoholic subjects. CONCLUSION Reduced G6PD activity and increased serum MDA level might be the key cause of the early visual abnormalities, such as reduced CS function of the alcoholic subjects.
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Ali H, Assiri MA, Shearn CT, Fritz KS. Lipid peroxidation derived reactive aldehydes in alcoholic liver disease. CURRENT OPINION IN TOXICOLOGY 2018; 13:110-117. [PMID: 31263795 DOI: 10.1016/j.cotox.2018.10.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Lipid peroxidation is a known consequence of oxidative stress and is thought to play a key role in numerous disease pathologies, including alcoholic liver disease (ALD). The overaccumulation of lipid peroxidation products during chronic alcohol consumption results in pathogenic lesions on protein, DNA, and lipids throughout the cell. Molecular adducts due to secondary end products of lipid peroxidation impact a host of biochemical processes, including inflammation, antioxidant defense, and metabolism. The aggregate burden of lipid peroxidation which occurs due to chronic alcohol metabolism, including downstream signaling events, contributes to the development and progression of ALD. In this current opinion we highlight recent studies and approaches relating cellular mechanisms of lipid peroxidation to the pathogenesis of alcoholic liver disease.
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Affiliation(s)
- Hadi Ali
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Mohammed A Assiri
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Colin T Shearn
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Kristofer S Fritz
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO
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Fu X, Zhong Z, Hu F, Zhang Y, Li C, Yan P, Feng L, Shen J, Huang B. The protective effects of selenium-enriched Spirulina platensis on chronic alcohol-induced liver injury in mice. Food Funct 2018; 9:3155-3165. [PMID: 29862408 DOI: 10.1039/c8fo00477c] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The aim of this study was to investigate the protective effect and mechanism of selenium-enriched Spirulina platensis (S. platensis) on chronic alcohol-induced liver injury. Selenium incubation raises the nutrition quality of S. platensis by absorption enhancement of functional elements. Our results demonstrated that the effective dose of selenium-enriched S. platensis on HL7702 cells treated with alcohol was 200 μg ml-1, containing 20% selenium. Selenium-enriched S. platensis could raise the cell survival rate by decreasing the expression of p53, Caspase3, LC3, and Caspase1 and by increasing the expression of p70s6k. In vivo experiments, where mice were pretreated with selenium-enriched S. platensis, exhibited obvious inhibition of the liver function index and this pretreatment enhanced the activity of GSH-Px and SOD in alcohol induced mice. In summary, our results indicate that the protective mechanism of selenium-enriched S. platensis on chronic alcoholic liver injury is associated with the activity enhancement of antioxidant enzymes and immunity, the inhibition of DNA damage and apoptosis, accompanied with autophagy and pyroptosis.
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Affiliation(s)
- Xiang Fu
- School of life Science, Anhui University, Hefei, 230601 China.
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You Y, Li WZ, Zhang S, Hu B, Li YX, Li HD, Tang HH, Li QW, Guan YY, Liu LX, Bao WL, Shen X. SNX10 mediates alcohol-induced liver injury and steatosis by regulating the activation of chaperone-mediated autophagy. J Hepatol 2018; 69:129-141. [PMID: 29452206 DOI: 10.1016/j.jhep.2018.01.038] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 01/03/2018] [Accepted: 01/30/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. However, the cellular defense mechanisms underlying ALD are not well understood. Recent studies highlighted the involvement of chaperone-mediated autophagy (CMA) in regulating hepatic lipid metabolism. Sorting nexin (SNX)-10 has a regulatory function in endolysosomal trafficking and stabilisation. Here, we investigated the roles of SNX10 in CMA activation and in the pathogenesis of alcohol-induced liver injury and steatosis. METHODS Snx10 knockout (Snx10 KO) mice and their wild-type (WT) littermates fed either the Lieber-DeCarli liquid alcohol diet or a control liquid diet, and primary cultured WT and Snx10 KO hepatocytes stimulated with ethanol, were used as in vivo and in vitro ALD models, respectively. Activation of CMA, liver injury parameters, inflammatory cytokines, oxidative stress and lipid metabolism were measured. RESULTS Compared with WT littermates, Snx10 KO mice exhibited a significant amelioration in ethanol-induced liver injury and hepatic steatosis. Both in vivo and in vitro studies showed that SNX10 deficiency upregulated lysosome-associated membrane protein type 2A (LAMP-2A) expression and CMA activation, which could be reversed by SNX10 overexpression in vitro. LAMP-2A interference confirmed that the upregulation of Nrf2 and AMPK signalling pathways induced by SNX10 deficiency relied on CMA activation. Pull-down assays revealed an interaction between SNX10 and cathepsin A (CTSA), a key enzyme involved in LAMP-2A degradation. Deficiency in SNX10 inhibited CTSA maturation and increased the stability of LAMP-2A, resulting in an increase in CMA activity. CONCLUSIONS SNX10 controls CMA activity by mediating CTSA maturation, and, thus, has an essential role in alcohol-induced liver injury and steatosis. Our results provide evidence for SNX10 as a potential promising therapeutic target for preventing or ameliorating liver injury in ALD. LAY SUMMARY Alcoholic liver disease is a major cause of morbidity and mortality worldwide. Recent studies highlight the involvement of chaperone-mediated autophagy (CMA) in regulating hepatic lipid metabolism. Our study reveals that deficiency of sorting nexin (SNX) 10 increases the stability of LAMP-2A by inhibiting cathepsin A maturation, resulting in the increase of CMA activity and, thus, alleviates alcohol-induced liver injury and steatosis.
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Affiliation(s)
- Yan You
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Wan-Zhen Li
- Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Sulin Zhang
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Bin Hu
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Yue-Xuan Li
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Hai-Dong Li
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Huan-Huan Tang
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Qian-Wen Li
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Yun-Yun Guan
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Li-Xin Liu
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Wei-Lian Bao
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Xiaoyan Shen
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
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Ezhilarasan D. Oxidative stress is bane in chronic liver diseases: Clinical and experimental perspective. Arab J Gastroenterol 2018; 19:56-64. [PMID: 29853428 DOI: 10.1016/j.ajg.2018.03.002] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Revised: 12/09/2016] [Accepted: 03/08/2018] [Indexed: 02/06/2023]
Abstract
Oxidative stress plays an important role in the pathogenesis of various chronic liver diseases (CLD) and increasing evidence have confirmed the contributory role of oxidative stress in the pathogenesis of drugs and chemical-induced CLD. Chronic liver injury is manifested as necrosis, cholestasis, fibrosis, and cirrhosis. Chronic administration of anti-tubercular, anti-retroviral, immunosuppressive drugs is reported to induce free radical generation during their biotransformation in the liver. Further, these reactive intermediates are said to induce profibrogenic cytokines, several inflammatory markers, collagen synthesis during the progression of hepatic fibrosis. Oxidative stress and free radicals are reported to induce activation and proliferation of hepatic stellate cells in the injured liver leading to the progression of CLD. Hence, to counteract or to scavenge these reactive intermediates, several plant-derived antioxidant principles have been effectively employed against oxidative stress and came out with promising results in human and experimental models of CLD. This review summarizes the relationships between oxidative stress and different liver pathogenesis induced by drugs and xenobiotics, focusing upon different chronic liver injury induced by alcohol, antitubercular drugs and hyperactivity of antiretroviral drugs in HIV patients, viral hepatitis infection induced oxidative stress.
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Affiliation(s)
- Devaraj Ezhilarasan
- Department of Pharmacology, Saveetha Dental College, Saveetha Institue of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu-600 077, India.
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Park JH, Lee DH, Park MS, Jung YS, Hong JT. C-C chemokine receptor type 5 deficiency exacerbates alcoholic fatty liver disease through pro-inflammatory cytokines and chemokines-induced hepatic inflammation. J Gastroenterol Hepatol 2017; 32:1258-1264. [PMID: 27859576 DOI: 10.1111/jgh.13657] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 11/15/2016] [Accepted: 11/15/2016] [Indexed: 01/29/2023]
Abstract
BACKGROUND AND AIM Chemokines and chemokine receptors implicated with alcoholic liver disease. Studies have shown that inflammation and oxidative stress induce fat molecules aggregation in liver. We evaluated the relationship between alcoholic fatty liver disease and C-C chemokine receptor 5 (CCR5) and impact of inflammation and oxidative stress in fat molecule deposition. METHODS Lieber-DeCarli diet containing ethanol or isocaloric control diets were fed to wild-type and CCR5 knockout mice for 10 days and gavaged with a single dose of ethanol or isocaloric maltose dextrin at 11th day. Cytokine, chemokine, and reactive oxygen species levels were measured in liver tissues to study the role of CCR5 in alcoholic fatty liver disease. RESULTS C-C chemokine receptor type 5 knockout mice exacerbated ethanol-induced liver injury. Serum levels of aspartate aminotransferase and alanine aminotransferase were higher in CCR5 knockout mice than wild-type mice, and CCR5 knockout mice showed more severe lipid accumulation in liver tissue than wild-type mice after ethanol feeding. Increased expressions of pro-inflammatory cytokines TNF-α and IL-6 and chemokines CCL2, CCL3, CCL4, and CCL5 result in exacerbation of hepatitis in CCR5 knockout mice after ethanol feeding. Oxidative stress induced by reactive oxygen species was more severe in CCR5 knockout mice, and increasing level of fatty acid import and decreasing level of lipid degradation resulted in lipid accumulation in ethanol-fed CCR5 knockout mice. CONCLUSION Deficiency of CCR5 exacerbates alcoholic fatty liver disease by hepatic inflammation induced by pro-inflammatory cytokines and chemokines and oxidative stress.
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Affiliation(s)
- Ju Ho Park
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Korea
| | - Dong Hun Lee
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Korea
| | - Mork Soon Park
- Raw Material Synthetic Factory, Dongkook Pharmaceutical company, Jincheon-gun, Korea
| | - Young Suk Jung
- College of Pharmacy, Pusan National University, Busan, Korea
| | - Jin Tae Hong
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Korea
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Sugimoto K, Takei Y. Pathogenesis of alcoholic liver disease. Hepatol Res 2017; 47:70-79. [PMID: 27138729 DOI: 10.1111/hepr.12736] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Revised: 04/26/2016] [Accepted: 04/29/2016] [Indexed: 02/06/2023]
Abstract
Alcoholic liver disease (ALD) has become one of the most critical health problems in many countries, including Japan. Liver injury in ALD ranges from steatosis and steatohepatitis to fibrosis, cirrhosis, and hepatocellular carcinoma. Many factors are thought to contribute to the development and progression of ALD, particularly insulin resistance, generation of reactive oxygen species during alcohol metabolism, adipokines from visceral adipose tissue, and endotoxin derived from the gut. Although the pathogenesis of ALD has been widely investigated, the precise mechanisms are yet to be elucidated and many questions remain. This article reviews the possible mechanisms for the development of ALD identified to date.
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Affiliation(s)
- Kazushi Sugimoto
- Department of Gastroenterology and Hepatology, Mie University School of Medicine, Tsu, Mie, Japan
| | - Yoshiyuki Takei
- Department of Gastroenterology and Hepatology, Mie University School of Medicine, Tsu, Mie, Japan
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Shui S, Cai X, Huang R, Xiao B, Yang J. The investigation of anti-inflammatory activity of Yi Guanjian decoction by serum metabonomics approach. J Pharm Biomed Anal 2017; 133:41-48. [DOI: 10.1016/j.jpba.2016.11.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Revised: 10/20/2016] [Accepted: 11/09/2016] [Indexed: 12/21/2022]
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Kalgutkar AS. Liabilities Associated with the Formation of “Hard” Electrophiles in Reactive Metabolite Trapping Screens. Chem Res Toxicol 2016; 30:220-238. [DOI: 10.1021/acs.chemrestox.6b00332] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Amit S. Kalgutkar
- Pharmacokinetics, Dynamics, and Metabolism − New Chemical
Entities, Pfizer Worldwide Research and Development, 610 Main
Street, Cambridge, Massachusetts 02139, United States
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Yimam M, Jiao P, Hong M, Jia Q. A Standardized Composition from Extracts ofMyristica Fragrans,Astragalus Membranaceus, andPoria CocosProtects Liver from Acute Ethanol Insult. J Med Food 2016; 19:780-8. [DOI: 10.1089/jmf.2016.0023] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Affiliation(s)
| | - Ping Jiao
- Unigen, Inc., Seattle, Washington, USA
| | - Mei Hong
- Unigen, Inc., Seattle, Washington, USA
| | - Qi Jia
- Unigen, Inc., Seattle, Washington, USA
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Chronic Glutathione Depletion Confers Protection against Alcohol-induced Steatosis: Implication for Redox Activation of AMP-activated Protein Kinase Pathway. Sci Rep 2016; 6:29743. [PMID: 27403993 PMCID: PMC4940737 DOI: 10.1038/srep29743] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 06/22/2016] [Indexed: 12/19/2022] Open
Abstract
The pathogenesis of alcoholic liver disease (ALD) is not well established. However, oxidative stress and associated decreases in levels of glutathione (GSH) are known to play a central role in ALD. The present study examines the effect of GSH deficiency on alcohol-induced liver steatosis in Gclm knockout (KO) mice that constitutively have ≈15% normal hepatic levels of GSH. Following chronic (6 week) feeding with an ethanol-containing liquid diet, the Gclm KO mice were unexpectedly found to be protected against steatosis despite showing increased oxidative stress (as reflected in elevated levels of CYP2E1 and protein carbonyls). Gclm KO mice also exhibit constitutive activation of liver AMP-activated protein kinase (AMPK) pathway and nuclear factor-erythroid 2–related factor 2 target genes, and show enhanced ethanol clearance, altered hepatic lipid profiles in favor of increased levels of polyunsaturated fatty acids and concordant changes in expression of genes associated with lipogenesis and fatty acid oxidation. In summary, our data implicate a novel mechanism protecting against liver steatosis via an oxidative stress adaptive response that activates the AMPK pathway. We propose redox activation of the AMPK may represent a new therapeutic strategy for preventing ALD.
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de Araújo Júnior RF, Garcia VB, Leitão RFDC, Brito GADC, Miguel EDC, Guedes PMM, de Araújo AA. Carvedilol Improves Inflammatory Response, Oxidative Stress and Fibrosis in the Alcohol-Induced Liver Injury in Rats by Regulating Kuppfer Cells and Hepatic Stellate Cells. PLoS One 2016; 11:e0148868. [PMID: 26891124 PMCID: PMC4758650 DOI: 10.1371/journal.pone.0148868] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Accepted: 01/25/2016] [Indexed: 12/14/2022] Open
Abstract
Aim To evaluate the anti-inflammatory, anti-oxidant and antifibrotic effects of carvedilol (CARV) in rats with ethanol-induced liver injury. Methods Liver injury was induced by gavage administration of alcohol (7 g/kg) for 28 consecutive days. Eighty Wistar rats were pretreated with oral CARV at 1, 3, or 5 mg/kg or with saline 1 h before exposure to alcohol. Liver homogenates were assayed for interleukin (IL)-1β, IL-10, and tumor necrosis factor (TNF)-α level as well as for myeloperoxidase (MPO) activity and malonyldialdehyde (MDA) and glutathione (GSH) levels. Serum aspartate aminotransferase (AST) activity and liver triglyceride (TG) levels were also assayed. Immunohistochemical analyses of cyclooxygenase 2 (COX-2), receptor activator of nuclear factor kappa-B/ligand (RANK/RANKL), suppressor of cytokine signalling (SOCS1), the Kupffer cell marker IBA-1 (ionized calcium-binding adaptor molecule 1), intercellular adhesion molecule 1 (ICAM-1), superoxide dismutase (SOD-1), and glutathione peroxidase (GPx-1) expression were performed. Confocal microscopy analysis of IL-1β and NF-κB expression and real-time quantitative PCR analysis for TNFα, PCI, PCIII, and NF-κB were performed. Results CARV treatment (5 mg/kg) during the alcohol exposure protocol was associated with reduced steatosis, hepatic cord degeneration, fibrosis and necrosis, as well as reduced levels of AST (p < 0.01), ALT (p < 0.01), TG (p < 0.001), MPO (p < 0.001), MDA (p < 0.05), and proinflammatory cytokines (IL-1β and TNF-α, both p < 0.05), and increased levels of the anti-inflammatory cytokine IL-10 (p < 0.001) and GSH (p < 0.05), compared to the alcohol-only group. Treatment with CARV 5 mg/kg also reduced expression levels of COX-2, RANK, RANKL, IBA-1, and ICAM-1 (all p < 0.05), while increasing expression of SOCS1, SOD-1, and GPx-1 (all p < 0.05) and decreasing expression of IL-1β and NF-κB (both, p < 0.05). Real-time quantitative PCR analysis showed that mRNA production of TNF-α, procollagen type I (PCI), procollagen type III (PCIII), and NF-κB were decreased in the alcohol-CARV 5 mg/kg group relative to the alcohol-only group. Conclusions CARV can reduce the stress oxidative, inflammatory response and fibrosis in ethanol-induced liver injury in a rat model by downregulating signalling of Kuppfer cells and hepatic stellate cells (HSCs) through suppression of inflammatory cytokines.
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Affiliation(s)
- Raimundo Fernandes de Araújo Júnior
- Postgraduate Program in Health Science, UFRN, Natal, RN, Brazil
- Postgraduate Program in Functional and Structural Biology/Department of Morphology/UFRN, Natal, RN, Brazil
- * E-mail:
| | | | | | | | | | | | - Aurigena Antunes de Araújo
- Department of Biophysics and Pharmacology, UFRN, Postgraduate Programs in Public Health and Pharmaceutical Science, Natal, RN, Brazil
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Lactobacillus rhamnosus CCFM1107 treatment ameliorates alcohol-induced liver injury in a mouse model of chronic alcohol feeding. J Microbiol 2015; 53:856-63. [DOI: 10.1007/s12275-015-5239-5] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Revised: 10/20/2015] [Accepted: 10/29/2015] [Indexed: 02/07/2023]
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The investigation of anti-inflammatory activity of volatile oil of Angelica sinensis by plasma metabolomics approach. Int Immunopharmacol 2015; 29:269-277. [PMID: 26578286 DOI: 10.1016/j.intimp.2015.11.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Revised: 10/29/2015] [Accepted: 11/05/2015] [Indexed: 11/17/2022]
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In Vivo Acute on Chronic Ethanol Effects in Liver: A Mouse Model Exhibiting Exacerbated Injury, Altered Metabolic and Epigenetic Responses. Biomolecules 2015; 5:3280-94. [PMID: 26610587 PMCID: PMC4693278 DOI: 10.3390/biom5043280] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Accepted: 11/17/2015] [Indexed: 01/06/2023] Open
Abstract
Chronic alcoholics who also binge drink (i.e., acute on chronic) are prone to an exacerbated liver injury but its mechanism is not understood. We therefore investigated the in vivo effects of chronic and binge ethanol ingestion and compared to chronic ethanol followed by three repeat binge ethanol on the liver of male C57/BL6 mice fed ethanol in liquid diet (4%) for four weeks followed by binge ethanol (intragastric administration, 3.5 g/kg body weight, three doses, 12h apart). Chronic followed by binge ethanol exacerbated fat accumulation, necrosis, decrease in hepatic SAM and SAM:SAH ratio, increase in adenosine levels, and elevated CYP2E1 levels. Histone H3 lysine acetylation (H3AcK9), dually modified phosphoacetylated histone H3 (H3AcK9/PS10), and phosphorylated H2AX increased after binge whereas phosphorylation of histone H3 ser 10 (H3S10) and H3 ser 28 (H3S28) increased after chronic ethanol-binge. Histone H3 lysine 4 and 9 dimethylation increased with a marked dimethylation in H3K9 in chronic ethanol binge group. Trimethylated histone H3 levels did not change. Nuclear levels of histone acetyl transferase GCN5 and histone deacetylase HDAC3 were elevated whereas phospho-CREB decreased in a distinctive manner. Taken together, acute on chronic ethanol ingestion caused amplification of liver injury and elicited characteristic profiles of histone modifications, metabolic alterations, and changes in nuclear protein levels. These findings demonstrate that chronic ethanol exposure renders liver more susceptible to repeat acute/binge ethanol induced acceleration of alcoholic liver disease.
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Qu BG, Wang H, Jia YG, Su JL, Wang ZD, Wang YF, Han XH, Liu YX, Pan JD, Ren GY. Changes in tumor necrosis factor-α, heat shock protein 70, malondialdehyde, and superoxide dismutase in patients with different severities of alcoholic fatty liver disease: a prospective observational study. Medicine (Baltimore) 2015; 94:e643. [PMID: 25789959 PMCID: PMC4602479 DOI: 10.1097/md.0000000000000643] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2014] [Revised: 02/18/2015] [Accepted: 02/20/2015] [Indexed: 01/26/2023] Open
Abstract
The relationships among inflammation, oxidative balance, and the severity of alcoholic fatty liver disease (AFLD) remain unknown. The aim of this study is to explore the relationships among tumor necrosis factor alpha (TNF-α), heat shock protein 70 (HSP70), malondialdehyde (MDA), superoxide dismutase (SOD), and the severity of AFLD.From January 2012 to December 2013, 162 participants were enrolled in this study and divided into 4 groups: 44 cases of mild AFLD (group A), 55 cases of moderate-to-severe AFLD (group B), 44 cases of alcohol consumption without AFLD (group C), and 20 cases of no alcohol consumption without AFLD (group D). A cross-sectional study was conducted by detecting the serum levels of TNF-α, HSP70, MDA, and SOD by enzyme-linked immunosorbent assay.The median serum levels of TNF-α and HSP70 among the 4 groups were statistically significant (P = 0.000 and 0.001, respectively). The median serum levels of TNF-α in groups A and B were significantly lower than in group C (P = 0.002 and 0.000, respectively), and the median serum level of TNF-α in group B was significantly lower than in group D (P = 0.023). In addition, the median serum level of HSP70 in group B was significantly lower than in groups A and C (P = 0.002 and 0.000, respectively), and the median serum level of HSP70 in group C was significantly higher than in group D (P = 0.044). However, the median serum level of MDA in group B was significantly lower than only group C (P = 0.008).Chronic alcohol ingestion without AFLD may result in a significant increase in the circulation of certain inflammatory markers; the severity of AFLD is associated with circulating inflammatory markers, and moderate-to-severe AFLD may result in a more significant reduction of these markers. However, moderate-to-severe AFLD may also result in a significant downregulation of oxidative stress products.
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Affiliation(s)
- Bao-Ge Qu
- From the Department of Gastroenterology (BQ, HW, YJ, JS, ZW, YW, XH, YL, JP, GR), Taishan Hospital, Taian, Shandong, and Taishan Medical College, Taian, Shandong, P.R. China
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Abstract
The transcription factor Nrf2 regulates the expression of important cytoprotective enzymes. Induction of cytochrome P450 2E1(CYP2E1) is one of the central pathways by which ethanol generates oxidative stress. CYP2E1 can be induced by ethanol and several low molecular weight chemicals such as pyrazole. The chapter discusses biochemical and toxicological effects of CYP2E1 and the effects of Nrf2 in modulating these actions of CYP2E1.Besides ethanol, CYP2E1 metabolizes and activates many other important toxicological compounds. One approach to try to understand basic effects and actions of CYP2E1 was to establish HepG2 cell lines that constitutively express human CYP2E1. Ethanol, polyunsaturated fatty acids and iron were toxic to the HepG2 cells which express CYP2E1 (E47 cells) but not control C34HepG2 cells which do not express CYP2E1.Toxicity was associated with enhanced oxidant stress and could be prevented by antioxidants and potentiated if glutathione (GSH) was removed. The E47 cells had higher GSH levels and a Twofold increase in catalase, cytosolic and microsomal glutathione transferase, and heme oxygenase-1 (HO-1) than control HepG2 cells due to activation of their respective genes. These activations were prevented by antioxidants, suggesting that reactive oxygen species (ROS) generated by CYP2E1 were responsible for the up-regulation of these antioxidant genes. This upregulation of antioxidant genes may reflect an adaptive mechanism to remove CYP2E1-derived oxidants. Increases in Nrf2 protein and mRNA were observed in livers of chronic alcohol-fed mice or rats and of pyrazole-treated rats or mice, conditions known to elevate CYP2E1. E47 cells showed increased Nrf2 mRNA and protein expression compared with control HepG2 C34 cells. Upregulation of antioxidant genes in E47 cells is dependent on Nrf2 and is prevented by siRNA-Nrf2. Blocking Nrf2 by siRNA-Nrf2 decreases GSH and increases ROS and lipid peroxidation, resulting in decreased mitochondrial membrane potential and loss of cell viability of E47 cells but not C34 cells. Nrf2 is activated and levels of Nrf2 protein and mRNA are increased when CYP2E1 is elevated. These results suggest that Nrf2 plays a key role in the adaptive response against increased oxidative stress caused by CYP2E1 in the HepG2 cells.
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Affiliation(s)
- Arthur I Cederbaum
- Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, One Gustave L Levy Place, 1603, New York, 10029, NY, USA,
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Deevska G, Sunkara M, Karakashian C, Peppers B, Morris AJ, Nikolova-Karakashian MN. Effect of procysteine on aging-associated changes in hepatic GSH and SMase: evidence for transcriptional regulation of smpd3. J Lipid Res 2014; 55:2041-52. [PMID: 25047167 DOI: 10.1194/jlr.m048223] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
In hepatocytes, aging-associated decline in GSH has been linked to activation of neutral SMase (nSMase), accumulation of bioactive ceramide, and inflammation. In this study, we seek to test whether dietary supplementation with the cysteine precursor, L-2-oxothiazolidine-4-carboxylic acid (OTC), would correct the aging-associated differences in hepatic GSH, nSMase, and ceramide. Young and aged mice were placed on a diet that either lacked sulfur-containing amino acids (SAAs) or had 0.5% OTC for 4 weeks. Mice fed standard chow were used as an additional control. SAA-deficient mice exhibited significant aging-associated differences in hepatic GSH, GSH/GSSG, ceramide, and nSMase. C24:1 ceramide, the major ceramide species in liver, was affected the most by aging, followed by the less abundant C16:0 ceramide. OTC supplementation eliminated the aging-associated differences in hepatic GSH and GSH/GSSG ratio. Surprisingly, however, instead of decreasing, the nSMase activity and ceramide increased in the OTC-fed mice irrespective of their age. These effects were due to elevated nSMase-2 mRNA and protein and appeared to be direct. Similar increases were seen in HepG2 cells following treatment with OTC. The OTC-fed aged mice also exhibited hepatic steatosis and triacylglyceride accumulation. These results suggest that OTC is a potent stimulant of nSMase-2 expression and that there may be unanticipated complications of OTC supplementation.
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Affiliation(s)
- Gergana Deevska
- Department of Physiology, A. B. Chandler Medical Center, University of Kentucky, Lexington, KY 40536
| | - Manjula Sunkara
- Division of Cardiovascular Medicine, Gill Heart Institute, Lexington Veterans Affairs Medical Center, Lexington, KY 40536
| | - Claudia Karakashian
- Department of Physiology, A. B. Chandler Medical Center, University of Kentucky, Lexington, KY 40536
| | - Benjamin Peppers
- Department of Physiology, A. B. Chandler Medical Center, University of Kentucky, Lexington, KY 40536
| | - Andrew J Morris
- Division of Cardiovascular Medicine, Gill Heart Institute, Lexington Veterans Affairs Medical Center, Lexington, KY 40536
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Aroor AR, Restrepo RJ, Kharbanda KK, Shukla SD. Epigenetic histone modifications in a clinically relevant rat model of chronic ethanol-binge-mediated liver injury. Hepatol Int 2014. [PMID: 26201320 DOI: 10.1007/s12072-014-9546-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
PURPOSE Ethanol binge augments liver injury after chronic ethanol consumption in humans, but the mechanism behind the enhanced liver injury by ethanol binge is not known. In this study we used a clinically relevant rat model in which liver injury is amplified by binge after chronic ethanol treatment and investigated the importance of histone modifications. METHODS Eight-week-old Sprague-Dawley rats were fed ethanol in a liquid diet for 4 weeks. Control rats were fed an isocaloric liquid diet. This was followed by three binge administrations of ethanol (intragastric 5 g/kg body weight, 12 h apart). In the control, ethanol was replaced by water. Four hours after the last binge administration, liver samples were analyzed for histone modifications and parameters of liver injury. RESULTS Chronic ethanol administration alone caused an increase in histone H3 ser10 and ser28 (H3S10 or S28) phosphorylation, and binge ethanol reduced their levels. Levels of dually modified phosphoacetylated histone H3 (H3AcK9/PS10) increased after acute binge ethanol and remained same after chronic ethanol binge. In contrast, histone H3 lysine-9 acetylation (H3AcK9) was not increased after chronic ethanol but increased significantly after acute binge and chronic ethanol binge. Increase in histone acetylation was accompanied by increased phospho-ERK1/2 in the nuclear extracts. Increased acetylation after chronic ethanol binge was also accompanied by increased protein levels of GCN5 histone acetyl transferase and a modest increase in HDAC3 in the nucleus. Histone lysine-9 dimethylation was significantly increased after chronic ethanol binge. Chronic ethanol binge also resulted in a decrease in the SAM:SAH ratio with a relative decrease of SAM levels and a corresponding increase in SAH levels. CONCLUSIONS Ethanol binge after chronic ethanol altered the profile of site-specific histone modifications and may underlie the mechanism of augmented liver injury by chronic-ethanol-binge-treated rats.
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Affiliation(s)
- Annayya R Aroor
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Ricardo J Restrepo
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Kusum K Kharbanda
- Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
| | - Shivendra D Shukla
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, 65212, USA.
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Galicia-Moreno M, Gutiérrez-Reyes G. Papel del estrés oxidativo en el desarrollo de la enfermedad hepática alcohólica. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2014; 79:135-44. [DOI: 10.1016/j.rgmx.2014.03.001] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Revised: 03/19/2014] [Accepted: 03/26/2014] [Indexed: 12/23/2022]
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Galicia-Moreno M, Gutiérrez-Reyes G. The role of oxidative stress in the development of alcoholic liver disease. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2014. [DOI: 10.1016/j.rgmxen.2014.06.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Kawaratani H, Tsujimoto T, Douhara A, Takaya H, Moriya K, Namisaki T, Noguchi R, Yoshiji H, Fujimoto M, Fukui H. The effect of inflammatory cytokines in alcoholic liver disease. Mediators Inflamm 2013; 2013:495156. [PMID: 24385684 PMCID: PMC3872233 DOI: 10.1155/2013/495156] [Citation(s) in RCA: 167] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2013] [Accepted: 11/12/2013] [Indexed: 02/06/2023] Open
Abstract
Alcohol is the most common cause of liver disease in the world. Chronic alcohol consumption leads to hepatocellular injury and liver inflammation. Inflammatory cytokines, such as TNF-α and IFN-γ, induce liver injury in the rat model of alcoholic liver disease (ALD). Hepatoprotective cytokines, such as IL-6, and anti-inflammatory cytokines, such as IL-10, are also associated with ALD. IL-6 improves ALD via activation of the signal transducer and activator of transcription 3 (STAT3) and the subsequent induction of a variety of hepatoprotective genes in hepatocytes. IL-10 inhibits alcoholic liver inflammation via activation of STAT3 in Kupffer cells and the subsequent inhibition of liver inflammation. Alcohol consumption promotes liver inflammation by increasing translocation of gut-derived endotoxins to the portal circulation and activating Kupffer cells through the LPS/Toll-like receptor (TLR) 4 pathways. Oxidative stress and microflora products are also associated with ALD. Interactions between pro- and anti-inflammatory cytokines and other cytokines and chemokines are likely to play important roles in the development of ALD. The present study aims to conduct a systemic review of ALD from the aspect of inflammation.
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Affiliation(s)
- Hideto Kawaratani
- Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
| | - Tatsuhiro Tsujimoto
- Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
| | - Akitoshi Douhara
- Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
| | - Hiroaki Takaya
- Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
| | - Kei Moriya
- Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
| | - Tadashi Namisaki
- Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
| | - Ryuichi Noguchi
- Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
| | - Hitoshi Yoshiji
- Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
| | - Masao Fujimoto
- Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
| | - Hiroshi Fukui
- Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
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Sid B, Verrax J, Calderon PB. Role of oxidative stress in the pathogenesis of alcohol-induced liver disease. Free Radic Res 2013; 47:894-904. [PMID: 23800214 DOI: 10.3109/10715762.2013.819428] [Citation(s) in RCA: 77] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Chronic alcohol consumption is a well-known risk factor for liver disease, which represents a major cause of morbidity and mortality worldwide. The pathological process of alcohol-induced liver disease is characterized by a broad spectrum of morphological changes ranging from steatosis with minimal injury to more advanced liver damage, including steato-hepatitis and fibrosis/cirrhosis. Experimental and clinical studies increasingly show that the oxidative damage induced by ethanol contribute in many ways to the pathogenesis of alcohol hepatotoxicity. This article describes the contribution of oxidative mechanisms to liver damage by alcohol.
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Affiliation(s)
- B Sid
- Université Catholique de Louvain, Louvain Drug Research Institute, Toxicology and Cancer Biology Research Group (GTOX) , Brussels , Belgium
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Gallego-Durán R, Ampuero J, Funuyet J, Romero-Gómez M. [Alcoholic and non-alcoholic steatohepatitis: who is affected and what can we do for them?]. GASTROENTEROLOGIA Y HEPATOLOGIA 2013; 36:587-96. [PMID: 24011648 DOI: 10.1016/j.gastrohep.2013.06.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2013] [Accepted: 06/18/2013] [Indexed: 12/21/2022]
Abstract
The most common causes of steatohepatitis are alcohol intake and metabolic disorders. Several methods based on biochemical determinations (carbohydrate deficient transferrin) and questionnaires (AUDIT, CAGE, MALE) are useful for detecting surreptitious alcohol intake. Although new non-invasive methods are under development, based both on lipidomics (Owl-Liver(®)) and on biochemical determinations and anthropometric parameters (NAFLD Fibrosis score) or imaging methods (DeMILI NASH-MRi(®)), none has been proposed as definitive and the gold standard continues to be liver biopsy. The pathogenesis of alcoholic and non-alcoholic steatohepatitis shares some elements such as insulin resistance, cytochrome CYP2E1-mediated oxidative stress, adiponutrin and its PNPLA3 gene, and the microbiota. The first-line treatment consists of lifestyle changes, including giving up alcohol, diet and exercise.
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Affiliation(s)
- Rocío Gallego-Durán
- Unidad Médico-Quirúrgica de Enfermedades Digestivas y CIBERehd, Hospital Universitario de Valme, Universidad de Sevilla, Sevilla, España
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Saravanan N, Nalini N. Impact ofHemidesmus indicusR.Br. extract on ethanol-mediated oxidative damage in rat kidney. Redox Rep 2013; 12:229-35. [DOI: 10.1179/135100007x200290] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
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Leung TM, Nieto N. CYP2E1 and oxidant stress in alcoholic and non-alcoholic fatty liver disease. J Hepatol 2013; 58:395-8. [PMID: 22940046 DOI: 10.1016/j.jhep.2012.08.018] [Citation(s) in RCA: 383] [Impact Index Per Article: 31.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2012] [Revised: 07/30/2012] [Accepted: 08/05/2012] [Indexed: 12/20/2022]
Abstract
Alcoholic (ALD) and non-alcoholic fatty liver diseases (NAFLD) are clinical conditions leading to hepatocellular injury and inflammation resulting from alcohol consumption, high fat diet, obesity and diabetes, among others. Oxidant stress is a major contributing factor to the pathogenesis of ALD and NAFLD. Multiple studies have shown that generation of reactive oxygen species (ROS) is key for the progression of fatty liver to steatohepatitis. Cytochrome P450 2E1 (CYP2E1) plays a critical role in ROS generation and CYP2E1 is also induced by alcohol itself. This review summarizes the role of CYP2E1 in ALD and NAFLD.
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Affiliation(s)
- Tung-Ming Leung
- Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
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Selenium-Enriched Fatty Goose Liver Attenuates Alcohol-Induced Liver Injury in Mice by Enhancing Antioxidant Capability. J Poult Sci 2013. [DOI: 10.2141/jpsa.0120090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
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Rehman S, Chandel N, Salhan D, Rai P, Sharma B, Singh T, Husain M, Malhotra A, Singhal PC. Ethanol and vitamin D receptor in T cell apoptosis. J Neuroimmune Pharmacol 2012; 8:251-61. [PMID: 23054367 DOI: 10.1007/s11481-012-9393-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2012] [Accepted: 07/30/2012] [Indexed: 02/07/2023]
Abstract
Ethanol has been demonstrated to cause T cell apoptosis. In the present study, we evaluated the role of VDR and the renin angiotensin system (RAS) in oxidative stress-induced T cell apoptosis. Ethanol-treated human T cells displayed down regulation of vitamin D receptor (VDR) and the activation of the RAS in the form of enhanced T cell renin expression and angiotensin II (Ang II) production. The silencing of VDR with siRNA displayed the activation of the RAS, and activation of the VDR resulted in the down regulation of the RAS. It suggested that ethanol-induced T cell RAS activation was dependent on the VDR status. T cell ROS generation by ethanol was found to be dose dependent. Conversely, ethanol-induced ROS generation was inhibited if VDR was activated or Ang II was blocked by an angiotensin II type 1 (AT1) receptor blocker (Losartan). Furthermore, it was observed that ethanol not only induced double strand breaks in T cells but also attenuated DNA repair response, whereas, VDR activation inhibited ethanol-induced double strand breaks and also enhanced DNA repairs. Since free radical scavengers inhibited ethanol-induced DNA damage, it would indicate that ethanol-induced DNA damage was mediated through ROS generation. These findings indicated that ethanol-induced T cell apoptosis was mediated through ROS generation in response to ethanol-induced down regulation of VDR and associated activation of the RAS.
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Affiliation(s)
- Shabina Rehman
- Immunology Center, Feinstein Institute for Medical Research, Hofstra North Shore LIJ Medical School, 100 Community Drive, Great Neck, NY 11021, USA
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Kim IH, Kim DG, Hao P, Wang Y, Kim SH, Kim SW, Lee SO, Lee ST. Anti-fibrotic effects of L-2-oxothiazolidine-4-carboxylic acid via modulation of nuclear factor erythroid 2-related factor 2 in rats. BMB Rep 2012; 45:348-353. [PMID: 22732220 DOI: 10.5483/bmbrep.2012.45.6.276] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
L-2-Oxothiazolidine-4-carboxylic acid (OTC) is a cysteine prodrug that maintains glutathione in tissues. The present study was designed to investigate anti-fibrotic and anti-oxidative effects of OTC via modulation of nuclear factor erythroid 2-related factor 2 (Nrf2) in an in vivo thioacetamide (TAA)-induced hepatic fibrosis model. Treatment with OTC (80 or 160 mg/kg) improved serum liver function parameters and significantly ameliorated liver fibrosis. The OTC treatment groups exhibited significantly lower expression of α-smooth muscle actin, transforming growth factor-β 1, and collagen α 1 mRNA than that in the TAA model group. Furthermore, the OTC treatment groups showed a significant decrease in hepatic malondialdehyde level compared to that in the TAA model group. Nrf2 and heme oxygenase-1 expression increased significantly in the OTC treatment groups compared with that in the TAA model group. Taken together, these results suggest that OTC restores the anti- oxidative system by upregulating Nrf2; thus, ameliorating liver injury and a fibrotic reaction.
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Affiliation(s)
- In Hee Kim
- Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Jeonju 561-712, Korea
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Ostojić JN, Mladenović D, Ninković M, Vučević D, Bondžić K, Ješić-Vukićević R, Radosavljević T. The effects of cold-induced stress on liver oxidative injury during binge drinking. Hum Exp Toxicol 2012; 31:387-396. [PMID: 22297701 DOI: 10.1177/0960327111433899] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The aim of our study was to evaluate the effects of cold stress on hepatic oxidative damage during binge drinking in rats. Male Wistar rats were divided into the following groups: group 1: control; group 2: ethanol-treated; group 3: stress-exposed; group 4: stress-exposed and ethanol-treated group. Oxidative and nitrosative stress parameters in the liver were determined spectrophotometrically, 12 h after treatment. Liver malondialdehyde concentration was significantly higher in group 4 when compared with groups 2 and 3. The highest increase in nitric oxide concentration was demonstrated in group 4 in comparison with groups 2 and 3. Superoxide dismutase (SOD) activity was significantly lower in group 4 when compared with groups 2 and 3. Ethanol administration induced a larger decrease in the activity of copper-/zinc-SOD in group 4 in comparison with group 2. Activity of manganese-SOD (Mn-SOD) was significantly higher in groups 3 and 4, when compared with control values, but the greatest increase in the activity of Mn-SOD was demonstrated in group 2. We also evaluated statistically significant decrease in the level of reduced gluthatione in the liver of group 4 in comparison with group 3. Based on our study, it can be concluded that cold-exposed stress and binge ethanol drinking have additive effects in imbalance between pro-oxidant and antioxidant defense system in liver.
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Al Moutaery M, Al Rayes H, Al Swailam R, Elfaki I, Khan HA, Arshaduddin M, Tariq M. Protective effect of a cysteine prodrug and antioxidant, L-2-oxothiazolidine-4-carboxylate, against ethanol-induced gastric lesions in rats. EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY : OFFICIAL JOURNAL OF THE GESELLSCHAFT FUR TOXIKOLOGISCHE PATHOLOGIE 2012; 64:233-237. [PMID: 20829008 DOI: 10.1016/j.etp.2010.08.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2010] [Revised: 08/12/2010] [Accepted: 08/15/2010] [Indexed: 02/05/2023]
Abstract
Earlier studies have suggested an important role of glutathione (GSH) in cytoprotection against free radicals induced oxidative damage. This study reports gastroprotective effects of a cysteine precursor, L-2-oxothiazolidine-4-carboxylate (OTC), in experimental models of gastric secretion and ulceration. Acid secretion studies (volume and acidity) were undertaken in pylorus-ligated rats whereas the gastric lesions were induced by ethanol. Different groups of animals were treated with OTC (0, 100, 200 and 400 mg/kg). The levels of gastric wall mucus, nonprotein sulfhydryls (NP-SH) and myeloperoxidase (MPO) were measured in the glandular stomach of rats following ethanol-induced gastric lesions. Both medium and high doses of OTC significantly reduced the volume and acidity of gastric secretion in pylorus-ligated rats. Pretreatment with OTC significantly and dose-dependently attenuated the formation of ethanol-induced gastric lesion. OTC significantly protected the gastric mucosa against ethanol-induced depletion of gastric wall mucus, NP-SH and MPO. The gastroprotective effects of OTC may be attributed to its ability to inhibit neutrophils activity and replenish GSH demand.
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Affiliation(s)
- Meshal Al Moutaery
- Prince Sultan Cardiac Center, Armed Forces Hospital, Riyadh, Saudi Arabia
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44
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L-arginine and glycine supplementation in the repair of the irradiated colonic wall of rats. Int J Colorectal Dis 2011; 26:561-8. [PMID: 21350937 DOI: 10.1007/s00384-011-1154-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/01/2011] [Indexed: 02/04/2023]
Abstract
PURPOSE Radiotherapy is widely used for cancer treatment but has harmful effects. This study aimed to assess the effects of L-arginine and glycine supplementation on the colon wall of rats submitted to abdominal irradiation. METHODS Forty male Wistar rats were randomly divided into four groups: I-healthy, II-irradiated with no amino acid supplementation, III-irradiated and supplemented with L-arginine, and IV-irradiated and supplemented with glycine. The animals received supplementation for 14 days, with irradiation being applied on the eighth day of the experiment. All animals underwent laparotomy on the 15th day for resection of a colonic segment for stereologic analysis. Parametric and nonparametric tests were used for statistical analysis, with the level of significance set at p ≤0.05. RESULTS Stereologic analysis showed that irradiation induced a reduction of the total volume of the colon wall of group II and III animals compared to healthy controls, but not of group IV animals supplemented with glycine. The mucosal layer of the irradiated animals of all groups was reduced compared to healthy group I animals, but supplementation with L-arginine and glycine was effective in maintaining the epithelial surface of the mucosal layer. CONCLUSION The present results suggest that glycine supplementation had a superior effect on the irradiated colon wall compared to L-arginine supplementation since it was able to maintain the thickness of the wall and the epithelial surface of the mucosa, whereas L-arginine maintained the partial volume of the epithelium and the epithelial surface, but not the total volume of the intestinal wall.
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Moreno C, Langlet P, Hittelet A, Lasser L, Degré D, Evrard S, Colle I, Lemmers A, Devière J, Le Moine O. Enteral nutrition with or without N-acetylcysteine in the treatment of severe acute alcoholic hepatitis: a randomized multicenter controlled trial. J Hepatol 2010; 53:1117-22. [PMID: 20801542 DOI: 10.1016/j.jhep.2010.05.030] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2010] [Revised: 05/13/2010] [Accepted: 05/28/2010] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Severe acute alcoholic hepatitis is associated with a high mortality rate. Oxidative stress is involved in the pathogenesis of acute alcoholic hepatitis. Previous findings had also suggested that enteral nutritional support might increase survival in patients with severe acute alcoholic hepatitis. Therefore, the aim of the present study was to evaluate the efficacy of N-acetylcysteine in combination with adequate nutritional support in patients with severe acute alcoholic hepatitis. METHODS Patients with biopsy-proven acute alcoholic hepatitis and mDF ≥32 were randomized to receive N-acetylcysteine intravenously or a placebo perfusion along with adequate nutritional support for 14 days. The primary endpoint was 6-month survival; secondary endpoints were biological parameter evolution and infection rate. RESULTS Fifty-two patients were randomized in the study (28 into the N-acetylcysteine arm, 24 into the control arm), and among them, five were excluded from the analysis for protocol violation. The two groups did not differ in baseline characteristics. Survival rates at 1 and 6 months in N-acetylcysteine and control groups were 70.2 vs. 83.8% (p=0.26) and 62.4 vs. 67.1% (p=0.60), respectively. Early biological changes, documented infection rate at 1 month, and incidence of hepatorenal syndrome did not differ between the two groups. CONCLUSIONS In this study, high doses of intravenous N-acetylcysteine therapy for 14 days conferred neither survival benefits nor early biological improvement in severe acute alcoholic hepatitis patients with adequate nutritional support. However, these results must be viewed with caution, since the study suffered from a lack of power.
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Affiliation(s)
- Christophe Moreno
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
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Cho SY, Yun JW, Park PJ, Sohn JH, Seo DB, Lim KM, Kim WG, Lee SJ. Effects of chitooligosaccharide lactate salt on activity of acetaldehyde dehydrogenase. J Med Food 2010; 13:1061-8. [PMID: 20828325 DOI: 10.1089/jmf.2009.1323] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Chitooligosaccharides (COS), a kind of oligosaccharide made from chitin or chitosan, have been used a popular remedy for hangovers. In this study we investigated the in vitro effect of COS lactate salt on ethanol-induced cytotoxicity and the in vivo effect of short-term COS lactate salt feeding on ethanol-induced hangover. Pretreatment of HepG2 cells with COS lactate salt significantly reduced ethanol-induced cytotoxicity and suppressed generation of reactive oxygen species. In addition, COS lactate salt dose-dependently increased acetaldehyde dehydrogenase (ALDH) activity in vitro and reversed the ALDH inhibition induced by daidzin. Furthermore, oral administration of COS lactate salt (200 mg/kg) for 5 days significantly decreased the blood levels of alcohol and acetaldehyde in ethanol-treated mice. It was also demonstrated that hepatic mitochondrial ALDH activity was significantly increased in COS lactate salt-treated mice. Taken together, these findings indicate that COS lactate salt may have efficacy for the management of alcoholic hangovers.
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Affiliation(s)
- Si Young Cho
- Food Research Institute, R&D Center, AmorePacific Corporation, Giheung-gu, Gyeonggi-do, Republic of Korea
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Kaur J, Shalini S, Bansal MP. Influence of vitamin E on alcohol-induced changes in antioxidant defenses in mice liver. Toxicol Mech Methods 2010; 20:82-9. [PMID: 20067348 DOI: 10.3109/15376510903559950] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
It is widely accepted that oxidative stress plays a central role in alcohol-induced pathogenesis. Redox-sensitive transcription factors nuclear factor-kappaB (NFkappaB) and activator protein-1 (AP1) are involved in development of alcohol-related diseases. Because of its antioxidative properties, vitamin E is believed to prevent diseases associated with oxidative stress. The aim of the present study was to evaluate the molecular mechanism associated with alcohol-induced oxidative stress and its prevention with vitamin E supplementation. Male Balb/c mice were divided into three groups viz. group I (control), group II (alcohol-treated) and group III (alcohol-treated + Vitamin E supplemented). Group II received 8% alcohol as sole source of drinking fluid while group III was given Vitamin E orally as 5 IU/kg body weight along with 8% alcohol. After 15 days, increases in lipid peroxidation, catalase and GST activity and decreases in SOD activity as well as redox ratio were observed in group II. This was associated with increased apoptosis in this group. Vitamin E supplementation restored the redox status, reduced apoptosis and prevented oxidative stress. Further mRNA expression of cjun, cfos, p65 (NFkappaB) showed increased expression during oxidative stress in group II. Although inhibition in NFkappaB activation was observed with Vitamin E, on the contrary it stimulated AP1 expression. This study supports the fact that alcohol promoted oxidative stress and is the major cause of alcohol toxicity in liver. Vitamin E can mitigate the toxic effects of alcohol and can be suitably used as a potential therapeutic agent for alcohol-induced oxidative damage in liver.
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Affiliation(s)
- Jasmeet Kaur
- Department of Biophysics, Panjab University, Chandigarh 160014, India
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Chen ML, Ip SP, Tsai SH, Ko KM, Che CT. Biochemical mechanism of Wu-Zi-Yan-Zong-Wan, a traditional Chinese herbal formula, against alcohol-induced oxidative damage in CYP2E1 cDNA-transfected HepG2 (E47) cells. JOURNAL OF ETHNOPHARMACOLOGY 2010; 128:116-122. [PMID: 20051262 DOI: 10.1016/j.jep.2009.12.036] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2009] [Revised: 09/08/2009] [Accepted: 12/28/2009] [Indexed: 05/28/2023]
Abstract
AIM OF THE STUDY Wu-Zi-Yan-Zong-Wan (WZ) is a traditional Chinese herbal formula which is commonly used for treating patients with "Yang deficiency". In the present study, the effect of WZ on ethanol-induced toxicity in CYP2E1 cDNA-transfected HepG2 (E47) cells was investigated. MATERIALS AND METHODS WZ extract was obtained by extracting the herbal powder with 50% ethanol (v/v, in water) and the effect of the extract on ethanol-induced toxicity was investigated in cultured cells. RESULTS The treatment with WZ extract (12.5-200 microg/mL) for 24h dose-dependently protected against ethanol-induced toxicity in E47 cells, as evidenced by the enhanced cell viability and decreased extent of lactate dehydrogeanse leakage. The cytoprotection against ethanol-induced toxicity was associated with decreases in the extents of reactive oxygen species production and lipid peroxidation, as well as increases in mitochondrial reduced glutathione and membrane potential. In addition, WZ extract treatment also suppressed the formation of DNA fragments in ethanol-intoxicated E47 cells. CONCLUSIONS WZ extract was found to protect against the ethanol-induced toxicity in E47 cells, possibly by virtues of its antioxidant activity.
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Affiliation(s)
- Meng-Li Chen
- School of Chinese Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong
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Saravanan N, Rajasankar S, Nalini N. Antioxidant effect of 2-hydroxy-4-methoxy benzoic acid on ethanol-induced hepatotoxicity in rats. J Pharm Pharmacol 2010; 59:445-53. [PMID: 17331349 DOI: 10.1211/jpp.59.3.0015] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Abstract
Alcoholic liver disease (ALD) is one of the most common diseases in society. A large number of studies are in progress to identify natural substances that are effective in reducing the severity of ALD. 2-Hydroxy-4-methoxy benzoic acid (HMBA), the active principle of Hemidesmus indicus, an indigenous Ayurvedic medicinal plant in India, is expected to significantly inhibit the development of liver injury in ethanol administration. It is expected to reduce the severity of liver damage in terms of body weight, hepatic marker enzymes, oxidative stress, antioxidant status and histological changes in ethanol-induced hepatotoxic rats. Hepatotoxicity was induced by administering 20% ethanol (5 g kg−1 daily) for 60 days to male Wistar rats, which resulted in significantly decreased body weight and an increase in liver-body weight ratio. The liver marker enzymes aspartate transaminase, alanine transaminase, alkaline phosphatase, γ-glutamyl transpeptidase and lactate dehydrogenase were elevated. In addition, the levels of plasma, erythrocyte and hepatic thiobarbituric acid reactive substances, hydroperoxides and conjugated dienes were also elevated in ethanol-fed rats as compared with those of the experimental control rats. Decreased activity of superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione, vitamin C and α-tocopherol was also observed on alcohol administration as compared with experimental control rats. HMBA was co-administered at a dose of 200 μgkg−1 daily for the last 30 days of the experiment to rats with alcohol-induced liver injury, which significantly increased body weight, significantly decreased the liver-body weight ratio, transaminases, alkaline phosphatase, γ-glutamyl transpeptidase and lactate dehydrogenase, significantly decreased the levels of lipid peroxidative markers, significantly elevated the activity of enzymic and non-enzymic antioxidants in plasma, erythrocytes and liver and also increased levels of plasma and liver vitamin C and α-tocopherol at the end of the experimental period as compared with untreated ethanol-administered rats. The histological changes were also in correlation with the biochemical findings. The results suggest that HMBA administration may afford protection against ethanol-induced liver injury in rats.
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Affiliation(s)
- Nadana Saravanan
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalai nagar-608 002, Tamilnadu, India
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Muriel P. Role of free radicals in liver diseases. Hepatol Int 2009; 3:526-36. [PMID: 19941170 DOI: 10.1007/s12072-009-9158-6] [Citation(s) in RCA: 258] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2009] [Revised: 09/23/2009] [Accepted: 11/11/2009] [Indexed: 12/16/2022]
Abstract
Reactive oxygen and nitrogen species (ROS and RNS) are produced by metabolism of normal cells. However, in liver diseases, redox is increased thereby damaging the hepatic tissue; the capability of ethanol to increase both ROS/RNS and peroxidation of lipids, DNA, and proteins was demonstrated in a variety of systems, cells, and species, including humans. ROS/RNS can activate hepatic stellate cells, which are characterized by the enhanced production of extracellular matrix and accelerated proliferation. Cross-talk between parenchymal and nonparenchymal cells is one of the most important events in liver injury and fibrogenesis; ROS play an important role in fibrogenesis throughout increasing platelet-derived growth factor. Most hepatocellular carcinomas occur in cirrhotic livers, and the common mechanism for hepatocarcinogenesis is chronic inflammation associated with severe oxidative stress; other risk factors are dietary aflatoxin B(1) consumption, cigarette smoking, and heavy drinking. Ischemia-reperfusion injury affects directly on hepatocyte viability, particularly during transplantation and hepatic surgery; ischemia activates Kupffer cells which are the main source of ROS during the reperfusion period. The toxic action mechanism of paracetamol is focused on metabolic activation of the drug, depletion of glutathione, and covalent binding of the reactive metabolite N-acetyl-p-benzoquinone imine to cellular proteins as the main cause of hepatic cell death; intracellular steps critical for cell death include mitochondrial dysfunction and, importantly, the formation of ROS and peroxynitrite. Infection with hepatitis C is associated with increased levels of ROS/RNS and decreased antioxidant levels. As a consequence, antioxidants have been proposed as an adjunct therapy for various liver diseases.
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Affiliation(s)
- Pablo Muriel
- Department of Pharmacology, Cinvestav-I.P.N., Apdo. Postal 14-740, Mexico, 07000 D.F. Mexico
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