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Jimenez J, Dubey P, Carter B, Koomen JM, Markowitz J. A metabolic perspective on nitric oxide function in melanoma. Biochim Biophys Acta Rev Cancer 2024; 1879:189038. [PMID: 38061664 PMCID: PMC11380350 DOI: 10.1016/j.bbcan.2023.189038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 10/17/2023] [Accepted: 11/27/2023] [Indexed: 12/19/2023]
Abstract
Nitric oxide (NO) generated from nitric oxide synthase (NOS) exerts a dichotomous effect in melanoma, suppressing or promoting tumor progression. This dichotomy is thought to depend on the intracellular NO concentration and the cell type in which it is generated. Due to its central role in the metabolism of multiple critical constituents involved in signaling and stress, it is crucial to explore NO's contribution to the metabolic dysfunction of melanoma. This review will discuss many known metabolites linked to NO production in melanoma. We discuss the synthesis of these metabolites, their role in biochemical pathways, and how they alter the biological processes observed in the melanoma tumor microenvironment. The metabolic pathways altered by NO and the corresponding metabolites reinforce its dual role in melanoma and support investigating this effect for potential avenues of therapeutic intervention.
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Affiliation(s)
- John Jimenez
- Department of Cutaneous Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida Morsani School of Medicine, Tampa, FL 33612, USA
| | - Parul Dubey
- Department of Cutaneous Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - Bethany Carter
- Department of Cutaneous Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Flow Cytometry Core Facility, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - John M Koomen
- Molecular Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - Joseph Markowitz
- Department of Cutaneous Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida Morsani School of Medicine, Tampa, FL 33612, USA.
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Nitro Capsaicin Suppressed Microglial Activation and TNF-α-Induced Brain Microvascular Endothelial Cell Damage. Biomedicines 2022; 10:biomedicines10112680. [DOI: 10.3390/biomedicines10112680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/05/2022] [Accepted: 10/17/2022] [Indexed: 11/17/2022] Open
Abstract
Chronically activated microglia and brain vascular damage are major causes of neuroinflammation. The aim of this study was to determine the anti-inflammatory effects of nitro capsaicin, a newly modified capsaicin with less irritating characteristics, against microglial activation and brain microvascular endothelial cell damage. Using the SIMA9 microglia cell line, we found that nitro capsaicin reduced nitric oxide (NO) production in LPS-activated microglia better than its parent compound, capsaicin. Nitro capsaicin also decreased the expression of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) and enhanced the levels of anti-inflammatory factors, IL-4 and IL-10, both at the mRNA and protein levels. In the TNF-α-induced vascular damage model, nitro capsaicin decreased expression and secretion of the proinflammatory cytokines IL-1β and IL-6. Phosphorylated NF-κB p65, a key transcription factor that stimulates the signaling of inflammatory pathways, was also reduced in the presence of nitro capsaicin, suggesting that the anti-inflammatory effects of nitro capsaicin were created through reducing NF-κB activation. Together, we concluded that nitro capsaicin has the potential to be further developed as an anti-neuroinflammatory agent.
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Anti-Inflammatory Activity of Panduratin A against LPS-Induced Microglial Activation. Biomedicines 2022; 10:biomedicines10102587. [PMID: 36289849 PMCID: PMC9599841 DOI: 10.3390/biomedicines10102587] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/06/2022] [Accepted: 10/11/2022] [Indexed: 11/30/2022] Open
Abstract
Uncontrolled and excessive microglial activation is known to contribute to inflammation-mediated neurodegeneration. Therefore, reducing neurotoxic microglial activation may serve as a new approach to preventing neurodegeneration. Here, we investigated the anti-inflammatory effects of panduratin A against microglial activation induced by lipopolysaccharides (LPS) in the SIMA9 microglial cell line. We initially examined the anti-inflammatory properties of panduratin A by measuring LPS-induced nitric oxide (NO) production and the levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). Panduratin A significantly reduced NO levels and pro-inflammatory cytokines’ production and secretion. In addition, panduratin A enhanced the production of anti-inflammatory cytokines IL-4 and IL-10. The anti-inflammatory effects of panduratin A are related to the suppression of the NF-κB signaling pathway. Together, these results demonstrate the anti-inflammatory properties of panduratin A against LPS-induced microglial activation, suggesting panduratin A has the potential to be further developed as a new agent for the prevention of neuroinflammation-associated neurodegenerative diseases.
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Akhtar MJ, Ahamed M, Alhadlaq H, Alrokayan S. Pt-Coated Au Nanoparticle Toxicity Is Preferentially Triggered Via Mitochondrial Nitric Oxide/Reactive Oxygen Species in Human Liver Cancer (HepG2) Cells. ACS OMEGA 2021; 6:15431-15441. [PMID: 34151121 PMCID: PMC8210405 DOI: 10.1021/acsomega.1c01882] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 05/20/2021] [Indexed: 05/09/2023]
Abstract
Reactive nitrogen species (RNS) that are formed from the reaction of versatile nitric oxide (NO) with reactive oxygen species (ROS) have been less explored in potential cancer therapy. This may be partly due to the fewer available agents that could induce NO in cells. Here, we report platinum-coated gold nanoparticles (Pt-coated Au NPs; 27 ± 20 nm) as a strong inducer of NO (assessed by live-cell imaging under NO-specific DAR-1 probe labeling and indirectly using a Griess reagent) in human liver carcinoma (HepG2) cells. In addition to NO, this study found a critical role of ROS from mitochondrial sources in the mechanism of toxicity caused by Pt-coated Au NPs. Cotreatment with a thiol-replenishing general antioxidant NAC (N-acetyl cysteine) led to significant amelioration of oxidative stress against NP-induced toxicity. However, NAC did not exhibit as much ameliorative potential against NP-induced oxidative stress as the superoxide radical (O2•-)-scavenging mitochondrial specific antioxidant mito-TEMPO did. The higher protective potential of mito-TEMPO in comparison to NAC reveals mitochondrial ROS as an active mediator of NP-induced toxicity in HepG2 cells. Moreover, the relatively unaltered NP-induced NO concentration under cotreatment of GSH modulators NAC and buthionine sulfoximine (BSO) suggested that NO production due to NP treatment is rather independent of the cellular thiols at least in HepG2 cells. Moreover, toxicity potentiation by exogenous H2O2 again suggested a more direct involvement of ROS/RNS in comparison to the less potentiation of toxicity due to GSH-exhausting BSO. A steeper amelioration in NP-induced NO and ROS and, consequently, cytotoxicity by mito-TEMPO in comparison to NAC reveal a pronounced role of NO and ROS via the mitochondrial pathway in the toxicity of Pt-coated Au NPs in HepG2 cells.
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Affiliation(s)
- Mohd Javed Akhtar
- King
Abdullah Institute for Nanotechnology, King
Saud University, Riyadh 11451, Saudi Arabia
| | - Maqusood Ahamed
- King
Abdullah Institute for Nanotechnology, King
Saud University, Riyadh 11451, Saudi Arabia
| | - Hisham Alhadlaq
- King
Abdullah Institute for Nanotechnology, King
Saud University, Riyadh 11451, Saudi Arabia
- Department
of Physics and Astronomy, College of Sciences, King Saud University, Riyadh 11451, Saudi Arabia
| | - Salman Alrokayan
- Department
of Biochemistry, College of Science, King
Saud University, Riyadh 11451, Saudi Arabia
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Morris G, Walker AJ, Walder K, Berk M, Marx W, Carvalho AF, Maes M, Puri BK. Increasing Nrf2 Activity as a Treatment Approach in Neuropsychiatry. Mol Neurobiol 2021; 58:2158-2182. [PMID: 33411248 DOI: 10.1007/s12035-020-02212-w] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 11/16/2020] [Indexed: 02/07/2023]
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor encoded by NFE2L2. Under oxidative stress, Nrf2 does not undergo its normal cytoplasmic degradation but instead travels to the nucleus, where it binds to a DNA promoter and initiates transcription of anti-oxidative genes. Nrf2 upregulation is associated with increased cellular levels of glutathione disulfide, glutathione peroxidase, glutathione transferases, thioredoxin and thioredoxin reductase. Given its key role in governing the cellular antioxidant response, upregulation of Nrf2 has been suggested as a common therapeutic target in neuropsychiatric illnesses such as major depressive disorder, bipolar disorder and schizophrenia, which are associated with chronic oxidative and nitrosative stress, characterised by elevated levels of reactive oxygen species, nitric oxide and peroxynitrite. These processes lead to extensive lipid peroxidation, protein oxidation and carbonylation, and oxidative damage to nuclear and mitochondrial DNA. Intake of N-acetylcysteine, coenzyme Q10 and melatonin is accompanied by increased Nrf2 activity. N-acetylcysteine intake is associated with improved cerebral mitochondrial function, decreased central oxidative and nitrosative stress, reduced neuroinflammation, alleviation of endoplasmic reticular stress and suppression of the unfolded protein response. Coenzyme Q10, which acts as a superoxide scavenger in neuroglial mitochondria, instigates mitohormesis, ameliorates lipid peroxidation in the inner mitochondrial membrane, activates uncoupling proteins, promotes mitochondrial biogenesis and has positive effects on the plasma membrane redox system. Melatonin, which scavenges mitochondrial free radicals, inhibits mitochondrial nitric oxide synthase, restores mitochondrial calcium homeostasis, deacetylates and activates mitochondrial SIRT3, ameliorates increased permeability of the blood-brain barrier and intestine and counters neuroinflammation and glutamate excitotoxicity.
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Affiliation(s)
- G Morris
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - A J Walker
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - K Walder
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - M Berk
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia.,CMMR Strategic Research Centre, School of Medicine, Deakin University, Geelong, VIC, Australia.,Orygen, The National Centre of Excellence in Youth Mental Health, The Department of Psychiatry and the Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - W Marx
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - A F Carvalho
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada.,Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada
| | - M Maes
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia.,Department of Psychiatry, Chulalongkorn University, Bangkok, Thailand
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The interplay between oxidative stress and bioenergetic failure in neuropsychiatric illnesses: can we explain it and can we treat it? Mol Biol Rep 2020; 47:5587-5620. [PMID: 32564227 DOI: 10.1007/s11033-020-05590-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 06/12/2020] [Indexed: 12/12/2022]
Abstract
Nitro-oxidative stress and lowered antioxidant defences play a key role in neuropsychiatric disorders such as major depression, bipolar disorder and schizophrenia. The first part of this paper details mitochondrial antioxidant mechanisms and their importance in reactive oxygen species (ROS) detoxification, including details of NO networks, the roles of H2O2 and the thioredoxin/peroxiredoxin system, and the relationship between mitochondrial respiration and NADPH production. The second part highlights and identifies the causes of the multiple pathological sequelae arising from self-amplifying increases in mitochondrial ROS production and bioenergetic failure. Particular attention is paid to NAD+ depletion as a core cause of pathology; detrimental effects of raised ROS and reactive nitrogen species on ATP and NADPH generation; detrimental effects of oxidative and nitrosative stress on the glutathione and thioredoxin systems; and the NAD+-induced signalling cascade, including the roles of SIRT1, SIRT3, PGC-1α, the FOXO family of transcription factors, Nrf1 and Nrf2. The third part discusses proposed therapeutic interventions aimed at mitigating such pathology, including the use of the NAD+ precursors nicotinamide mononucleotide and nicotinamide riboside, both of which rapidly elevate levels of NAD+ in the brain and periphery following oral administration; coenzyme Q10 which, when given with the aim of improving mitochondrial function and reducing nitro-oxidative stress in the brain, may be administered via the use of mitoquinone, which is in essence ubiquinone with an attached triphenylphosphonium cation; and N-acetylcysteine, which is associated with improved mitochondrial function in the brain and produces significant decreases in oxidative and nitrosative stress in a dose-dependent manner.
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Caissie MD, Gartley CJ, Scholtz EL, Hewson J, Johnson R, Chenier T. The Effects of Treatment with N-Acetyl Cysteine on Clinical Signs in Persistent Breeding-Induced Endometritis Susceptible Mares. J Equine Vet Sci 2020; 92:103142. [PMID: 32797774 DOI: 10.1016/j.jevs.2020.103142] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 05/06/2020] [Accepted: 05/25/2020] [Indexed: 11/28/2022]
Abstract
Persistent breeding-induced endometritis (PBIE) is a major cause of infertility in mares. Endometrial inflammation that persists until embryonic descent ultimately results in early embryonic death. A poor endometrial biopsy grade (IIb or III) has been identified as a risk factor for PBIE. Intrauterine fluid accumulation (>2 cm in depth), pathologic endometrial edema, and elevated intrauterine neutrophil levels are all clinical features of PBIE. Commonly applied treatment options include uterine lavage and oxytocin therapy. N-acetyl cysteine (NAC), a mucolytic used to treat bacterial endometritis in mares, has anti-inflammatory properties and was investigated as a potential treatment for PBIE. A randomized, blinded, cross-over design clinical trial used NAC before breeding in PBIE-susceptible mares (n = 9). Intrauterine infusion of 3.3% NAC was performed 12 hours before insemination, and endometrial cytology and endometrial biopsy samples were obtained at 12 and 60 hours after insemination. Endometrial biopsies were evaluated for the degree of inflammation present. Clinical signs of endometrial edema and intrauterine fluid volumes were assessed by transrectal ultrasound at 12 and then every 24 hours after breeding. Data were analyzed using repeated measures analysis of variance and a Mann Whitney Wilcoxon Test. Treatment with NAC did not improve clinical signs in PBIE-affected mares. However, endometrial biopsies from mares treated with NAC displayed more diffuse and severe neutrophil infiltration than control cycles. Further research using a larger population of mares is required to evaluate the effects of NAC treatment on the endometrium of PBIE-susceptible mares.
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Affiliation(s)
- Michelle D Caissie
- Department of Population Medicine, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada.
| | - Cathy J Gartley
- Department of Population Medicine, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada
| | - Elizabeth L Scholtz
- Department of Population Medicine, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada
| | - Joanne Hewson
- Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada
| | - Ronald Johnson
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada
| | - Tracey Chenier
- Department of Population Medicine, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada
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Zhou H, Sun Y, Wang Q, Li Z, Zhong W, Wang X, Dai X, Kong L. N-acetylcysteine alleviates liver injury by suppressing macrophage-mediated inflammatory response post microwave ablation. Int Immunopharmacol 2020; 85:106580. [PMID: 32438077 DOI: 10.1016/j.intimp.2020.106580] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 04/15/2020] [Accepted: 05/07/2020] [Indexed: 12/25/2022]
Abstract
OBJECT To investigate N-acetyl-cysteine (NAC) would able to alleviate liver injury and systemic inflammatory response caused by microwave ablation (MWA) in rats. MATERIALS AND METHODS Male Sprague-Dawley rats weighing 150-200 g were randomly divided into sham group (only anesthesia and laparotomy except MWA but with intraperitoneal PBS or NAC solution injection according to different situations), control group (intraperitoneal PBS injection for comparation 2 h prior to MWA), and NAC-treated group (intraperitoneal N-acetyl-cysteine (300 mg/kg) injection 2 h prior to MWA). Experimental rats were sacrificed at 4 h following operation in line with the liver injury severity curve. Liver tissue and serum samples were collected for determination of pathology, apoptosis, macrophages contents and protein expression. RESULTS The elevated serum level of liver enzymes, Myeloperoxidase (MPO) and inflammatory factors (TNF-α and CXCL1) in MWA-treated rats revealed injurious and pro- inflammatory effect of MVA. Macrophages aggregation was detected in MWA exposure rats similarly. and NAC pre-conditioning mitigate liver damage and hepatocyte apoptosis, besides macrophages accumulation and following inflammatory response in liver tissue. CONCLUSION Our results demonstrated that N-acetyl-cysteine application alleviate macrophages aggregation and inflammatory response in liver suffering microwave ablation, and mitigating liver injury and cell apoptosis.
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Affiliation(s)
- Haoming Zhou
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Yu Sun
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Qingyuan Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Zhi Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Weizhe Zhong
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Xuehao Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Xinzheng Dai
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
| | - Lianbao Kong
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
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Hwang I, Uddin MJ, Pak ES, Kang H, Jin EJ, Jo S, Kang D, Lee H, Ha H. The impaired redox balance in peroxisomes of catalase knockout mice accelerates nonalcoholic fatty liver disease through endoplasmic reticulum stress. Free Radic Biol Med 2020; 148:22-32. [PMID: 31877356 DOI: 10.1016/j.freeradbiomed.2019.12.025] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 11/29/2019] [Accepted: 12/20/2019] [Indexed: 12/21/2022]
Abstract
Peroxisomes are essential organelles for maintaining the homeostasis of lipids and reactive oxygen species (ROS). While oxidative stress-induced endoplasmic reticulum (ER) stress plays an important role in nonalcoholic fatty liver disease (NAFLD), the role of peroxisomes in ROS-mediated ER stress in the development of NAFLD remains elusive. We investigated whether an impaired peroxisomal redox state accelerates NAFLD by activating ER stress by inhibiting catalase, an antioxidant expressed exclusively in peroxisomes. Wild-type (WT) and catalase knockout (CKO) mice were fed either a normal diet or a high-fat diet (HFD) for 11 weeks. HFD-induced phenotype changes and liver injury accompanied by ER stress and peroxisomal dysfunction were accelerated in CKO mice compared to WT mice. Interestingly, these changes were also significantly increased in CKO mice fed a normal diet. Inhibition of catalase by 3-aminotriazole in hepatocytes resulted in the following effects: (i) increased peroxisomal H2O2 levels as measured by a peroxisome-targeted H2O2 probe (HyPer-P); (ii) elevated intracellular ROS; (iii) decreased peroxisomal biogenesis; (iv) activated ER stress; (v) induced lipogenic genes and neutral lipid accumulation; and (vi) suppressed insulin signaling cascade associated with JNK activation. N-acetylcysteine or 4-phenylbutyric acid effectively prevented those alterations. These results suggest that a redox imbalance in peroxisomes perturbs cellular metabolism through the activation of ER stress in the liver.
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Affiliation(s)
- Inah Hwang
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea
| | - Md Jamal Uddin
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea
| | - Eun Seon Pak
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea
| | - Hyeji Kang
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea
| | - Eun-Jung Jin
- Department of Biological Sciences, College of Natural Sciences, Wonkwang University, Iksan, Chunbuk, 54538, Republic of Korea
| | - Suin Jo
- Department of Life Science, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Dongmin Kang
- Department of Life Science, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Hyukjin Lee
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea
| | - Hunjoo Ha
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea.
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Morris G, Puri BK, Walker AJ, Berk M, Walder K, Bortolasci CC, Marx W, Carvalho AF, Maes M. The compensatory antioxidant response system with a focus on neuroprogressive disorders. Prog Neuropsychopharmacol Biol Psychiatry 2019; 95:109708. [PMID: 31351160 DOI: 10.1016/j.pnpbp.2019.109708] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 07/16/2019] [Accepted: 07/22/2019] [Indexed: 02/07/2023]
Abstract
Major antioxidant responses to increased levels of inflammatory, oxidative and nitrosative stress (ONS) are detailed. In response to increasing levels of nitric oxide, S-nitrosylation of cysteine thiol groups leads to post-transcriptional modification of many cellular proteins and thereby regulates their activity and allows cellular adaptation to increased levels of ONS. S-nitrosylation inhibits the function of nuclear factor kappa-light-chain-enhancer of activated B cells, toll-like receptor-mediated signalling and the activity of several mitogen-activated protein kinases, while activating nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2 or NFE2L2); in turn, the redox-regulated activation of Nrf2 leads to increased levels and/or activity of key enzymes and transporter systems involved in the glutathione system. The Nrf2/Kelch-like ECH-associated protein-1 axis is associated with upregulation of NAD(P)H:quinone oxidoreductase 1, which in turn has anti-inflammatory effects. Increased Nrf2 transcriptional activity also leads to activation of haem oxygenase-1, which is associated with upregulation of bilirubin, biliverdin and biliverdin reductase as well as increased carbon monoxide signalling, anti-inflammatory and antioxidant activity. Associated transcriptional responses, which may be mediated by retrograde signalling owing to elevated hydrogen peroxide, include the unfolded protein response (UPR), mitohormesis and the mitochondrial UPR; the UPR also results from increasing levels of mitochondrial and cytosolic reactive oxygen species and reactive nitrogen species leading to nitrosylation, glutathionylation, oxidation and nitration of crucial cysteine and tyrosine causing protein misfolding and the development of endoplasmic reticulum stress. It is shown how these mechanisms co-operate in forming a co-ordinated rapid and prolonged compensatory antioxidant response system.
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Affiliation(s)
- Gerwyn Morris
- IMPACT Strategic Research Centre, Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - Basant K Puri
- Department of Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom
| | - Adam J Walker
- IMPACT Strategic Research Centre, Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - Michael Berk
- IMPACT Strategic Research Centre, Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, The Department of Psychiatry, The Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia
| | - Ken Walder
- CMMR Strategic Research Centre, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - Chiara C Bortolasci
- CMMR Strategic Research Centre, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - Wolfgang Marx
- IMPACT Strategic Research Centre, Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - Andre F Carvalho
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada.
| | - Michael Maes
- IMPACT Strategic Research Centre, Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia
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Evaluation with endothelial nitric oxide synthase (eNOS) immunoreactivity of the protective role of astaxanthin on hepatorenal injury of remote organs caused by ischaemia reperfusion of the lower extremities. GASTROENTEROLOGY REVIEW 2019; 15:161-172. [PMID: 32550950 PMCID: PMC7294969 DOI: 10.5114/pg.2019.88620] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 08/09/2019] [Indexed: 02/07/2023]
Abstract
Introduction Ischemia and following reperfusion triggers local and systemic damage with the involvement of free oxygen radicals and inflammatory mediators. Although blood flow saves extremity from necrosis,multi organ dysfunction may progress and cause death of the patient. Aim The study aims to examine the effect of astaxanthin (AST) on the prevention of remote tissue injury resulting from lower extremity ischaemia–reperfusion (I/R). To elucidate the potential hepatoprotective and renoprotective effects of AST, in addition to histopathological findings, the intrahepatic and intrarenal kinetics of endothelial nitric oxide synthase (eNOS) during I/R were determined by using the immunohistochemical method. Material and methods Twenty-eight male Wistar albino rats were divided into four groups. For the control group, only the anaesthesia procedure (2 h) was conducted without I/R. In the I/R group, 2 h of reperfusion was conducted following ischaemia under anaesthesia. For the I/R group + AST, 7 days prior to ischaemia, 125 mg/kg AST was given with gavage, and 2 h of ischaemia and 2 h of reperfusion were conducted under anaesthesia. Following necropsy, liver and kidney tissue samples were fixed in 10% buffered formalin for 48 h for histopathological and immunohistochemical investigation. Results The histological analysis revealed that severe I/R hepatorenal injury such as inflammatory cell infiltration, dilatation in sinusoids and lumen of tubuli, congestion in glomerular capillaries, degeneration in hepatocyte and epithelial cells of tubuli, and necrosis was ameliorated by AST. Immunohistochemical studies showed that the I/R-induced elevation in eNOS expression was reduced by AST treatment. Conclusions In the case of acute lower extremity I/R, AST decreased the ischaemic injury in liver and renal tissues by protecting the microcirculation and providing a cytoprotective effect with vasodilatation.
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12
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Myalgic encephalomyelitis/chronic fatigue syndrome: From pathophysiological insights to novel therapeutic opportunities. Pharmacol Res 2019; 148:104450. [PMID: 31509764 DOI: 10.1016/j.phrs.2019.104450] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 08/26/2019] [Accepted: 09/06/2019] [Indexed: 12/12/2022]
Abstract
Myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) is a common and disabling condition with a paucity of effective and evidence-based therapies, reflecting a major unmet need. Cognitive behavioural therapy and graded exercise are of modest benefit for only some ME/CFS patients, and many sufferers report aggravation of symptoms of fatigue with exercise. The presence of a multiplicity of pathophysiological abnormalities in at least the subgroup of people with ME/CFS diagnosed with the current international consensus "Fukuda" criteria, points to numerous potential therapeutic targets. Such abnormalities include extensive data showing that at least a subgroup has a pro-inflammatory state, increased oxidative and nitrosative stress, disruption of gut mucosal barriers and mitochondrial dysfunction together with dysregulated bioenergetics. In this paper, these pathways are summarised, and data regarding promising therapeutic options that target these pathways are highlighted; they include coenzyme Q10, melatonin, curcumin, molecular hydrogen and N-acetylcysteine. These data are promising yet preliminary, suggesting hopeful avenues to address this major unmet burden of illness.
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Dhatwalia SK, Kumar M, Bhardwaj P, Dhawan D. White tea - A cost effective alternative to EGCG in fight against benzo(a)pyrene (BaP) induced lung toxicity in SD rats. Food Chem Toxicol 2019; 131:110551. [DOI: 10.1016/j.fct.2019.05.059] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 05/28/2019] [Accepted: 05/31/2019] [Indexed: 01/01/2023]
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Ahmed Abdel-Reheim M, Messiha BAS, Abo-Saif AA. Quillaja saponaria bark saponin protects Wistar rats against ferrous sulphate-induced oxidative and inflammatory liver damage. PHARMACEUTICAL BIOLOGY 2017; 55:1972-1983. [PMID: 28728456 PMCID: PMC6130630 DOI: 10.1080/13880209.2017.1345950] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 05/09/2017] [Accepted: 06/19/2017] [Indexed: 06/07/2023]
Abstract
CONTEXT Saponins from different sources are historically reported in Chinese medicine to possess many beneficial effects. However, insufficient experimental data are available regarding the hepatoprotective potential of Quillaja bark saponin. OBJECTIVE The protective effect of Quillaja saponaria Molina (Quillajaceae) bark triterpenoid saponin against iron-induced hepatotoxicity is compared to the standard N-acetylcysteine in adult male Wistar rats. MATERIALS AND METHODS Animals were divided into (six) groups, namely a normal control, an N-acetylcysteine control (300 mg/kg/day, p.o., 10 days), a saponin control (100 mg/kg/day, p.o., for 10 days), a hepatotoxicity control (two doses of ferrous sulphate, 30 mg/kg/day each, i.p., on 9th and 10th day), an N-acetylcysteine plus ferrous sulphate (standard treatment) and a saponin plus ferrous sulphate (test treatment) group. Hepatocyte integrity loss markers (serum ALT, AST, ALP, GGT and LDH), oxidative stress markers (hepatic MDA, GSH and NOx), dyslipidaemic markers (serum TC and TG) and hepatocyte functioning markers (serum bilirubin and albumin) were assessed. RESULTS Quillaja bark saponin decreased iron-induced elevation of ALT (reaching 57% of hepatotoxicity control), AST (66%), ALP (76%), GGT (60%), LDH (54%), MDA (65%), NOx (77%), TC (70%), TG (54%), and total (54%), direct (54%) and indirect (54%) bilirubin, coupled with increased GSH (219%) and albumin (159%) levels. Histopathological study strongly supported biochemical estimations, while immunohistochemical study showed marked effect on eNOS and iNOS expression. CONCLUSIONS Quillaja bark saponin has a good hepatoprotective effect. Amelioration of oxidative stress and suppression of NOS expression, with resultant maintenance of hepatocyte integrity and functioning, may explain this beneficial effect.
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Affiliation(s)
| | | | - Ali Ahmed Abo-Saif
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni Suef, Egypt
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Kumar M, Singh G, Bhardwaj P, Dhatwalia SK, Dhawan DK. Understanding the role of 3-O-Acetyl-11-keto-β-boswellic acid in conditions of oxidative-stress mediated hepatic dysfunction during benzo(a)pyrene induced toxicity. Food Chem Toxicol 2017; 109:871-878. [PMID: 28363852 DOI: 10.1016/j.fct.2017.03.058] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Revised: 03/23/2017] [Accepted: 03/27/2017] [Indexed: 01/14/2023]
Abstract
The present study was planned to see whether 3-O-Acetyl-11- keto-β-boswellic acid has any protective effects against benzo(a)pyrene (BaP) induced toxicity or not. In vitro studies show concentration dependent linear association of radical scavenging activity of AK which is comparable to ascorbic acid taken as reference compound. For in vivo studies, the animals were divided randomly into five groups which included a) normal control, b) vehicle treated (olive oil), c) BaP treated, d) AK treated and e) AK + BaP (combined treated). BaP was administered at a dose of 50mg/kg in olive oil twice a week orally for 4 weeks and AK (50mg/kg) was given in olive oil thrice a week for 4 weeks before and after BaP exposure. BaP treated animals showed a significant increase (p < 0.001) in lipid peroxidation (LPO) and protein carbonyl contents (PCC) in hepatic tissue. Further, a significant increase (p < 0.001) in the liver marker enzymes as well as citrulline and nitric oxide levels in the hepatic tissue was also observed. Interestingly, AK when supplemented to BaP treated animals ameliorated the above said biochemical indices appreciately. The histopathological observations also showed appreciable improvement when BaP treated animals were supplemented with AK, thus emphasing the protective potential of AK.
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Affiliation(s)
- Manoj Kumar
- Department of Biophysics, Panjab University Chandigarh, India
| | - Gurpreet Singh
- Department of Biophysics, Panjab University Chandigarh, India
| | - Priti Bhardwaj
- Department of Biophysics, Panjab University Chandigarh, India
| | | | - D K Dhawan
- Department of Biophysics, Panjab University Chandigarh, India.
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Abstract
Inducible NO synthase (iNOS/NOS2) protein expression is a well-studied predictor of poor outcome in multiple cancers, and it has also been associated with inflammatory and immunosuppressive processes in the tumor microenvironment. Immunotherapies are becoming increasingly key components in cancer treatment, and iNOS is receiving more attention as a potential regulator of treatment resistance. As we have reported in pancreatic cancer, by modulation of effector T-cell activity, iNOS overexpression may allow the tumor to escape the immune response through creating a microenvironment which causes recalcitrance to immunotherapy. Based on studies describing its role in the immune environment of multiple cancers, strategies that include iNOS inhibitors as combination partners may enhance immunotherapy approaches. The expression and the function of iNOS both depend on the tumor type and microenvironment, as well as on the patient's treatment history. Thus, enhancing immunotherapies, including adoptive T-cell therapies and checkpoint blockade, will require tailored cancer-specific approaches and additional levels of microenvironment regulation.
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Affiliation(s)
- Suhendan Ekmekcioglu
- a Department of Melanoma Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Elizabeth A Grimm
- a Department of Melanoma Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Jason Roszik
- a Department of Melanoma Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.,b Department of Genomic Medicine , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
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Li Y, Wang Y, Wu Q, Li L, Shi Y, Bu H, Bao J. Comparison of methods for isolating primary hepatocytes from mini pigs. Xenotransplantation 2016; 23:414-420. [PMID: 27596934 DOI: 10.1111/xen.12259] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Revised: 07/07/2016] [Accepted: 08/12/2016] [Indexed: 02/05/2023]
Abstract
Successful porcine hepatocyte isolation is crucial for the development of bioartificial liver devices and hepatocyte transplantation. Serva collagenase NB grades are formulated collagenases that are suitable for various tissue isolation applications. N-acetylcysteine (NAC) can improve the viability of human hepatocytes. The aim of this study was to compare the effectiveness of two collagenases and effect of NAC on hepatocyte isolation from porcine liver tissue. Porcine hepatocytes were isolated using the perfusion method from Bama mini pigs assigned to the Serva NB 4 group (n=6), the Serva NB 8 group (n=6), or the NB 8+NAC group (n=6). Viability and yield were defined as fresh hepatocytes and their spheroids formation after 24-hour rocker culture in serum-free medium. Metabolic function was assessed by gene expression, albumin, and urea synthesis. All procedures resulted in successful hepatocyte isolation. Cells from the NB 8+NAC group had (97.8±1.9)% viability, which was higher than the NB 8 group with (94.4±2.4)% and the NB 4 group with (94.5±3.2)% (P<.001). The final cell yield reached (11.8±1.0)×10(9) cells in the NB 8+NAC group, compared to (9.5±2.1)×10(9) cells in the NB 8 group (P<.01) and (9.1±1.1) ×10(9) cells in the NB 4 group (P<.001). The secretion of albumin was superior in the NB 8+NAC group at a concentration of (425.8±35.3) ng/mL compared to the NB 8 group (339.1±32.6) ng/mL (P <.001) and NB 4 group (293.6±43.3) ng/mL (P <.01). The injury of hepatocytes also decreased in the NB 8+NAC group (P<.01). The data are presented as means ± SD. Formulated collagenase Serva NB 8 and NAC could improve the porcine hepatocyte isolation, resulting in higher yields of viable cells.
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Affiliation(s)
- Yi Li
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, China
| | - Yujia Wang
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, China
- Division of Transplant Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Qiong Wu
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, China
| | - Li Li
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, China
| | - Yujun Shi
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Bu
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, China
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ji Bao
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
- Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, China.
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Pharmacological Modulation of Ischemic-Reperfusion Injury during Pringle Maneuver in Hepatic Surgery. A Prospective Randomized Pilot Study. World J Surg 2016; 40:2202-12. [DOI: 10.1007/s00268-016-3506-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Quadros Gomes BA, da Silva LFD, Quadros Gomes AR, Moreira DR, Dolabela MF, Santos RS, Green MD, Carvalho EP, Percário S. N-acetyl cysteine and mushroom Agaricus sylvaticus supplementation decreased parasitaemia and pulmonary oxidative stress in a mice model of malaria. Malar J 2015; 14:202. [PMID: 25971771 PMCID: PMC4435846 DOI: 10.1186/s12936-015-0717-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 04/27/2015] [Indexed: 12/17/2022] Open
Abstract
Background Malaria infection can cause high oxidative stress, which could lead to the development of severe forms of malaria, such as pulmonary malaria. In recent years, the role of reactive oxygen species in the pathogenesis of the disease has been discussed, as well as the potential benefit of antioxidants supplementation. The aim of this study was to investigate the effects of N-acetyl cysteine (NAC) or mushroom Agaricus sylvaticus supplementation on the pulmonary oxidative changes in an experimental model of malaria caused by Plasmodium berghei strain ANKA. Methods Swiss male mice were infected with P. berghei and treated with NAC or AS. Samples of lung tissue and whole blood were collected after one, three, five, seven or ten days of infection for the assessment of thiobarbituric acid reactive substances (TBARS), trolox equivalent antioxidant capacity (TEAC), nitrites and nitrates (NN) and to assess the degree of parasitaemia. Results Although parasitaemia increased progressively with the evolution of the disease in all infected groups, there was a significant decrease from the seventh to the tenth day of infection in both antioxidant-supplemented groups. Results showed significant higher levels of TEAC in both supplemented groups, the highest occurring in the group supplemented with A. sylvaticus. In parallel, TBARS showed similar levels among all groups, while levels of NN were higher in animals supplemented with NAC in relation to the positive control groups and A. sylvaticus, whose levels were similar to the negative control group. Conclusion Oxidative stress arising from plasmodial infection was attenuated by supplementation of both antioxidants, but A. sylvaticus proved to be more effective and has the potential to become an important tool in the adjuvant therapy of malaria. Electronic supplementary material The online version of this article (doi:10.1186/s12936-015-0717-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Bruno A Quadros Gomes
- Oxidative Stress Research Laboratory, Institute of Biological Sciences, Federal University of Pará, Belém, Pará, Brazil.
| | - Lucio F D da Silva
- Oxidative Stress Research Laboratory, Institute of Biological Sciences, Federal University of Pará, Belém, Pará, Brazil.
| | - Antonio R Quadros Gomes
- Oxidative Stress Research Laboratory, Institute of Biological Sciences, Federal University of Pará, Belém, Pará, Brazil.
| | - Danilo R Moreira
- Oxidative Stress Research Laboratory, Institute of Biological Sciences, Federal University of Pará, Belém, Pará, Brazil.
| | - Maria Fani Dolabela
- Institute of Health Sciences, Federal University of Pará, Belém, Pará, Brazil.
| | - Rogério S Santos
- Oxidative Stress Research Laboratory, Institute of Biological Sciences, Federal University of Pará, Belém, Pará, Brazil.
| | - Michael D Green
- Division of Parasitic Diseases and Malaria, US Centers for Disease Control and Prevention, 1600 Clifton Rd. NE, Mailstop G49, Atlanta, GA, USA.
| | - Eliete P Carvalho
- Oxidative Stress Research Laboratory, Institute of Biological Sciences, Federal University of Pará, Belém, Pará, Brazil.
| | - Sandro Percário
- Oxidative Stress Research Laboratory, Institute of Biological Sciences, Federal University of Pará, Belém, Pará, Brazil.
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The Role of e-NOS in Chronic Cholestasis-Induced Liver and Renal Injury in Rats: The Effect of N-Acetyl Cysteine. Gastroenterol Res Pract 2014; 2014:564949. [PMID: 25431587 PMCID: PMC4241572 DOI: 10.1155/2014/564949] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2014] [Revised: 10/20/2014] [Accepted: 10/21/2014] [Indexed: 01/20/2023] Open
Abstract
Introduction. The role of chronic cholestasis (CC) in liver injury and fibrosis remains unclear. The aims of this study were to define the role of endothelial nitric oxide synthase (e-NOS) in CC and the protective effect of N-acetyl-L-cysteine (NAC) in liver and kidney injury. Materials and Methods. Group A (sham group); Group B (CBDL); and Group C (CBDL + NAC). Group C received daily dosage of NAC (100 mg/kg) intraperitoneally for up to 4 weeks. Results. The rate of bridging fibrosis was higher (100% versus 20%, P = .025), but the intensity of e-NOS in liver was lower in rats that received NAC (1.3 versus 2.7, P = .046). The necrotic area in the kidneys among rats that received NAC was lower at week 4 (48% versus 57%; P < .001). The numbers of e-NOS stained cells in kidney were similar in sham group and the two groups with CBDL. Discussion. NAC reduced the stimulus for liver fibrosis in this rat model of CC and attenuated liver and kidney injury. Our study showed that e-NOS expression increased in liver tissue of rats with CC and that this was reversed by NAC. Treatment with NAC might restore e-NOS protein expression and prevent liver injury in CC.
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He PY, Gao SM, Hou ZP, Ma LX, Li BQ. Resveratrol protects against alcohol-induced oxidative stress in human HepG2 cells. Shijie Huaren Xiaohua Zazhi 2014; 22:1928-1935. [DOI: 10.11569/wcjd.v22.i14.1928] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the effect of resveratrol as an antioxidant on alcohol-induced oxidative stress in HepG2 cells and to explore the possible mechanisms involved.
METHODS: HepG2 cells were pretreated with resveratrol for 24 h before treatment with alcohol to induce oxidative stress. MTT assay was performed to detect the viability of resveratrol-treated HepG2 cells and control cells. ELISA was used to detect the activity of superoxide dismutase (SOD) and the level of total intracellular reactive oxygen species (ROS). Finally, RT-PCR was performed to detect the expression levels of SOD1, SOD2 and catalase, which are key genes involved in anti-oxidation pathway.
RESULTS: In comparison with control cells (not treated with resveratrol), the toxicity of resveratrol (12.5, 25, 50, 100 μmol/L) towards HepG2 cells during pre-treatment was below 20%. Treatment with 300 mmol/L alcohol without pre-treatment with resveratrol resulted in the death of around 50% of cells. Resveratrol at concentrations ranging from 25 to 100 μmol/L had an antagonistic effect against cytotoxicity of 300 mmol/L alcohol to HepG2 cells. SOD activity was significantly higher in cells pre-treated with 100 mmol/L resveratrol (0.391 ± 0.011) compared to non-treated controls (0.391 ± 0.011 vs 0.286 ± 0.019, P < 0.05). After alcohol induction, non-treated cells showed a higher ROS level compared to cells treated with 25, 50, and 100 μmol/L resveratrol (29234.79 ± 2288.00 vs 18023.26 ± 1359.66, 13528.44 ± 1078.99, 8219.87 ± 635.99). Compared to cells induced with 300 mM alcohol, resveratrol increased the expression levels of SOD1 (0.5535 ± 0.0035, 0.586 ± 0.0113, 0.623 ± 0.0127), SOD2 (1.249 ± 0.011, 1.369 ± 0.028, 1.377 ± 0.021, 1.401 ± 0.0578) and catalase (0.1955 ± 0.004, 0.2275 ± 0.00707).
CONCLUSION: Resveratrol as an antioxidant protects against alcohol-induced oxidative stress by regulating the expression of genes involved in anti-oxidant pathways.
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Czaja AJ. Hepatic inflammation and progressive liver fibrosis in chronic liver disease. World J Gastroenterol 2014; 20:2515-32. [PMID: 24627588 PMCID: PMC3949261 DOI: 10.3748/wjg.v20.i10.2515] [Citation(s) in RCA: 255] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 10/24/2013] [Accepted: 11/12/2013] [Indexed: 02/06/2023] Open
Abstract
Chronic liver inflammation drives hepatic fibrosis, and current immunosuppressive, anti-inflammatory, and anti-viral therapies can weaken this driver. Hepatic fibrosis is reversed, stabilized, or prevented in 57%-79% of patients by conventional treatment regimens, mainly by their anti-inflammatory actions. Responses, however, are commonly incomplete and inconsistently achieved. The fibrotic mechanisms associated with liver inflammation have been clarified, and anti-fibrotic agents promise to improve outcomes as adjunctive therapies. Hepatitis C virus and immune-mediated responses can activate hepatic stellate cells by increasing oxidative stress within hepatocytes. Angiotensin can be synthesized by activated hepatic stellate cells and promote the production of reactive oxygen species. Anti-oxidants (N-acetylcysteine, S-adenosyl-L-methionine, and vitamin E) and angiotensin inhibitors (losartin) have had anti-fibrotic actions in preliminary human studies, and they may emerge as supplemental therapies. Anti-fibrotic agents presage a new era of supplemental treatment for chronic liver disease.
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Ahangarpour A, Heidari H, Fatemeh RAA, Pakmehr M, Shahbazian H, Ahmadi I, Mombeini Z, Mehrangiz BH. Effect of Boswellia serrata supplementation on blood lipid, hepatic enzymes and fructosamine levels in type2 diabetic patients. J Diabetes Metab Disord 2014; 13:29. [PMID: 24495344 PMCID: PMC3929136 DOI: 10.1186/2251-6581-13-29] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Accepted: 01/05/2014] [Indexed: 02/03/2023]
Abstract
BACKGROUND Type 2 diabetes is an endocrine disorder that affects a large percentage of patients. High blood glucose causes fatty deposits in the liver which is likely to increase in SGOT and SGPT activities. Significant increase in SGOT/SGPT and low HDL levels is observed in patients with diabetes. Serum fructosamine concentration reflects the degree of blood glucose control in diabetic patients. This study was aimed to investigate the antidiabetic, hypolipidemic and hepatoprotective effects of supplementation of Boswellia serrata in type2 diabetic patients. METHODS 60 type 2 diabetic patients from both sexes (30 males and 30 females) were dedicated to the control and intervention groups (30 subjects per group). Boswellia serrata gum resin in amount of 900 mg daily for 6 weeks were orally administered (as three 300 mg doses) in intervention group and the control group did not receive anything. Blood samples were taken at the beginning of the study and after 6 weeks. Blood levels of fructosamine, lipid profiles as well as hepatic enzyme in type 2 diabetic patients were measured. RESULTS Treatment of diabetic patient with Boswellia serrata was caused to significant increase in blood HDL levels as well as a remarkable decrease in cholesterol, LDL, fructosamine (p < 0.05) SGPT and SGOT levels after 6 weeks (p < 0.01). In spite of reduction of serum triglyceride, VLDL levels in intervention group, we did not detect a significant difference after 6 weeks. CONCLUSION This study showed that Boswellia serrata supplementation can be beneficial in controlling blood parameters in patients with type 2 diabetes. Therefore, its use can be useful in patients with medicines.
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Affiliation(s)
| | - Hamid Heidari
- Department of Physiology, School of Medicine, (Golestan Street), Jundishapur University of Medical Sciences, Ahvaz 61335-189, Iran.
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Czaja AJ. Review article: The prevention and reversal of hepatic fibrosis in autoimmune hepatitis. Aliment Pharmacol Ther 2014; 39:385-406. [PMID: 24387318 DOI: 10.1111/apt.12592] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Revised: 11/29/2013] [Accepted: 12/05/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Immunosuppressive treatment of autoimmune hepatitis can prevent or reverse hepatic fibrosis, but these anti-fibrotic effects are inconsistent secondary gains. AIM To describe the anti-fibrotic effects of current therapies for autoimmune hepatitis, discuss the pathogenic mechanisms of hepatic fibrosis that might be targeted by anti-fibrotic interventions, indicate the non-invasive diagnostic tests of hepatic fibrosis that must be validated in autoimmune hepatitis and to suggest promising treatment opportunities. METHODS Studies cited in PubMed from 1972 to 2013 for autoimmune hepatitis, hepatic fibrosis, cirrhosis, anti-fibrotic therapy and non-invasive tests of hepatic fibrosis were selected. RESULTS Hepatic fibrosis improves in 53-57% of corticosteroid-treated patients with autoimmune hepatitis; progressive fibrosis slows or is prevented in 79%; and cirrhosis may be reversed. Progressive hepatic fibrosis is associated with liver inflammation, and the inability to fully suppress inflammatory activity within 12 months is associated with progression to cirrhosis (54%) and death or need for liver transplantation (15%). Liver tissue examination remains the gold standard for assessing hepatic fibrosis, but laboratory and radiological tests may be useful non-invasive methods to measure the fibrotic response. Severe liver inflammation can confound radiological assessments, and the preferred non-invasive test in autoimmune hepatitis is uncertain. Individualised treatment adjustments and adjunctive anti-fibrotic therapies are poised for study in this disease. CONCLUSIONS The prevention and reversal of hepatic fibrosis are achievable objectives in autoimmune hepatitis. Strategies that evaluate individualised therapies adjusted to the rapidity and completeness of the inflammatory response, and the use of adjunctive anti-fibrotic interventions, must be evaluated.
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Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
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May oxidative stress contribute to autoimmune hepatitis pathogenesis, and can antioxidants be of value as adjuvant therapy for refractory patients? Dig Dis Sci 2013; 58:1440-1. [PMID: 23504353 DOI: 10.1007/s10620-013-2622-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Accepted: 02/25/2013] [Indexed: 02/06/2023]
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Senthil Kumar KJ, Liao JW, Xiao JH, Gokila Vani M, Wang SY. Hepatoprotective effect of lucidone against alcohol-induced oxidative stress in human hepatic HepG2 cells through the up-regulation of HO-1/Nrf-2 antioxidant genes. Toxicol In Vitro 2012; 26:700-8. [PMID: 22484158 DOI: 10.1016/j.tiv.2012.03.012] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2011] [Revised: 03/06/2012] [Accepted: 03/22/2012] [Indexed: 01/10/2023]
Abstract
Lucidone was previously reported to exhibit anti-inflammatory activity in vitro and in vivo. In the present study, we characterized the mechanisms underlying the hepatoprotective effect of lucidone against alcohol-induced oxidative stress in vitro. Human hepatoma (HepG2) cells were pretreated with lucidone (1-10μg/mL) and then hepatotoxicity was stimulated by the addition ethanol (100mM). With response to ethanol-challenge, increased amount of alanine aminotransferase (ALT) and aspirate aminotransferase (AST) release were observed, whereas lucidone pretreatment significantly inhibited the leakage of AST and ALT in HepG2 cells without appreciable cytotoxic effects. We also found that lucidone pretreatment significantly decreased ethanol-induced nitric oxide (NO), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), reactive oxygen species (ROS) and glutathione (GSH) depletion in HepG2 cells. Furthermore, Western blot and quantitative-PCR analyses showed that ethanol-exposure apparently down-regulated endogenous anti-oxidant hemoxygenase-1 (HO-1) expression, whereas pretreatment with lucidone significantly up-regulates HO-1 expression followed by the transcriptional activation of NF-E2 related factor-2 (Nrf-2). Interestingly, the profound up-regulation of HO-1 and Nrf-2 were observed in only ethanol-challenged cells, which evidenced that lucidone-induced induction of HO-/Nrf-2 were specific with oxidative stress. Thus, we concluded that lucidone-mediated up-regulation of phase-II enzymes and HO-1 via Nrf-2 signaling pathway may provide a pivotal mechanism for its hepatoprotective action.
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Affiliation(s)
- K J Senthil Kumar
- Department of Forestry, National Chung Hsing University, Kou Kung Road, Taichung 402, Taiwan
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Park CM, Jin KS, Cho CW, Lee YW, Huh GH, Cha YS, Song YS. Luteolin inhibits inflammatory responses by downregulating the JNK, NF-κB, and AP-1 pathways in TNF-α activated HepG2 cells. Food Sci Biotechnol 2012. [DOI: 10.1007/s10068-012-0037-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
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Protective effect of N-acetylcysteine on early outcomes of deceased renal transplantation. Transplant Proc 2011; 43:1443-9. [PMID: 21693215 DOI: 10.1016/j.transproceed.2011.02.020] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2011] [Accepted: 02/07/2011] [Indexed: 02/07/2023]
Abstract
We investigated the effects of the antioxidant N-acetylcysteine (NAC) on early outcomes of deceased donor renal transplantation. Between April 2005 and June 2008, adult primary graft recipients of deceased renal donors were assigned to treatment (n = 38) or control (n = 36) groups and evaluated for 90 days and one year after renal transplantation. The treatment group received NAC orally (600 mg twice daily) from day 0 to 7 postoperatively. Renal function was determined by serum creatinine, MDRD and Cockcroft-Gault estimated GFR (eGFR), delayed graft function (DGF) and dialysis free Kaplan-Meier estimate curve. Serum levels of thiobarbituric acid reactive substances (TBARS), were employed as markers of oxidative stress. The NAC group displayed a lower mean serum creatinine during the first 90 days (P = .026) and at 1 year after transplantation (P = .005). Furthermore, the NAC group showed a higher mean eGFR throughout the first 90 days and at 1 year. DGF was lower among the NAC group (P = .017) and these recipients required fewer days of dialysis (P = .012). Oxidative stress was significantly attenuated with NAC (P < .001). Our results suggested that NAC enhanced early outcomes of deceased donor renal transplantation by attenuating oxidative stress.
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Effect of rifampin on production of inflammatory mediators in HepG2 liver epithelial cells. Antimicrob Agents Chemother 2011; 55:5541-6. [PMID: 21930886 DOI: 10.1128/aac.05149-11] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Rifampin, a potent antibacterial agent, is one of the main drugs used in the treatment of mycobacterial infections. Hepatotoxicity is a well-documented adverse event. The aim of this study was to investigate the effect of rifampin on the production of inflammatory mediators in human epithelial HepG2 liver cells in the absence or presence of proinflammatory cytokines. Incubation of HepG2 cells with a cytokine mix plus rifampin was associated with a significant dose-dependent increase in the production of nitric oxide compared to incubation with the cytokine mix alone (P < 0.05) as well as with an increase in inducible nitric oxide synthase protein and mRNA expression. Rifampin significantly increased the secretion of interleukin 8 (IL-8) in both untreated cells (P < 0.001) and cytokine-treated cells (P < 0.006). An array screening assay revealed that rifampin stimulated the production of IL-1β and gamma interferon-induced protein-10 (IP-10) in untreated cells and increased the secretion of RANTES in cytokine-treated cells. Together, these results indicate that rifampin may exert proinflammatory effects on liver cells.
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Kumar KJS, Chu FH, Hsieh HW, Liao JW, Li WH, Lin JCC, Shaw JF, Wang SY. Antroquinonol from ethanolic extract of mycelium of Antrodia cinnamomea protects hepatic cells from ethanol-induced oxidative stress through Nrf-2 activation. JOURNAL OF ETHNOPHARMACOLOGY 2011; 136:168-77. [PMID: 21540101 DOI: 10.1016/j.jep.2011.04.030] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2010] [Revised: 04/13/2011] [Accepted: 04/13/2011] [Indexed: 05/15/2023]
Abstract
AIM OF THE STUDY In recent years, the medicinal mushroom Antrodia cinnamomea, known as "niu-chang chih" has received much attention with regard to its possible health benefits; especially its hepatoprotective effects against various drugs, toxins, and alcohol induced liver diseases. However, the molecular mechanism underlying this protective effect of Antrodia cinnamomea and its active compound antroquinonol was poorly understood. In the present study we evaluated to understand the hepatoprotective efficacy of antroquinonol and ethanolic extracts of mycelia of Antrodia cinnamomea (EMAC) in vitro and in vivo. MATERIALS AND METHODS The protective mechanism of antroquinonol and EMAC against ethanol-induced oxidative stress was investigated in cultured human hepatoma HepG2 cells and ICR mice model, respectively. HepG2 cells were pretreated with antroquinonol (1-20μM) and oxidative stress was induced by ethanol (100mM). Meanwhile, male ICR mice were pretreated with EMAC for 10 days and hepatotoxicity was generated by the addition of ethanol (5g/kg). Hepatic enzymes, cytokines and chemokines were determined using commercially available assay kits. Western blotting and real-time PCR were subjected to analyze HO-1 and Nr-2 expression. EMSA was performed to monitor Nrf-2 ARE binding activity. Possible changes in hepatic lesion were observed using histopathological analysis. RESULTS Antroquinonol pretreatment significantly inhibited ethanol-induced AST, ALT, ROS, NO, MDA production and GSH depletion in HepG2 cells. Western blot and RT-PCR analysis showed that antroquinonol enhanced Nrf-2 activation and its downstream antioxidant gene HO-1 via MAPK pathway. This mechanism was then confirmed in vivo in an acute ethanol intoxicated mouse model: serum ALT and AST production, hepatocellular lipid peroxidation and GSH depletion was prevented by EMAC in a dose-dependent manner. EMAC significantly enhanced HO-1 and Nrf-2 activation via MAPKs consistent with in vitro studies. Ethanol-induced hepatic swelling and hydropic degeneration of hepatocytes was significantly inhibited by EMAC in a dose-dependent manner. CONCLUSIONS These results provide a scientific basis for the hepatoprotective effects of Antrodia cinnamomea. Data also imply that antroquinonol, a potent bioactive compound may be responsible for the hepatoprotective activity of Antrodia cinnamomea. Moreover, the present study highly supported our traditional knowledge that Antrodia cinnamomea as a potential candidate for the treatment of alcoholic liver diseases.
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Affiliation(s)
- K J Senthil Kumar
- Department of Forestry, National Chung Hsing University, Kou Kung Road, Taichung 402, Taiwan
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Shyur LF, Huang CC, Hsu YY, Cheng YW, Yang SD. A sesquiterpenol extract potently suppresses inflammation in macrophages and mice skin and prevents chronic liver damage in mice through JNK-dependent HO-1 expression. PHYTOCHEMISTRY 2011; 72:391-399. [PMID: 21292288 DOI: 10.1016/j.phytochem.2010.12.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2010] [Revised: 11/11/2010] [Accepted: 12/27/2010] [Indexed: 05/30/2023]
Abstract
This study aimed to elucidate the anti-inflammatory and hepatoprotective bioactivities of a sesquiterpenol, (1S,6R)-2,7(14),10-bisabolatrien-1-ol-4-one (BSL), isolated from Cryptomeria japonica (Taxodiaceae) wood extract. BSL markedly suppressed TNF-α and IL-6 secretion, PGE(2) production, and mRNA expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), in lipopolysaccharide (LPS)-stimulated mouse macrophages. BSL also potently inhibited the 12-O-tetradecanoylphorbol-13-acetate (TPA) induced protein levels of nitrotyrosine and COX-2 in mouse skin with dermatitis. Conversely, the stress protein heme oxygenase-1 (HO-1) was found upregulated in the same BSL-treated macrophages, probably through activation of the JNK-dependent pathway. LPS-induced activation of NF-κB and mitogen-activated protein kinase signaling pathways, however, was not responsive to BSL treatment. A BSL-enriched extract (BSL-E; 10mg/kg) significantly prevented CCl(4)-induced chronic liver injury, lipid accumulation, and cell necrosis and inhibited aminotransferase activities and iNOS and COX-2 overexpression in mice liver tissues, an effect comparable with that of silymarin, a hepatoprotective drug.
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Affiliation(s)
- Lie-Fen Shyur
- Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan, ROC.
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Moreno-Otero R, Trapero-Marugán M. Antioxidants for liver disease. Aliment Pharmacol Ther 2010; 32:1292-3; author reply 1293-4. [PMID: 20955448 DOI: 10.1111/j.1365-2036.2010.04441.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Casanova-González MJ, Trapero-Marugán M, Jones EA, Moreno-Otero R. Liver disease and erythropoietic protoporphyria: A concise review. World J Gastroenterol 2010; 16:4526-31. [PMID: 20857522 PMCID: PMC2945483 DOI: 10.3748/wjg.v16.i36.4526] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The porphyries are a group of metabolic disorders characterized by deficiencies in the activity of enzymes involved in the biosynthesis of heme. In erythropoietic protoporphyria (EPP), in the majority of cases an autosomal dominant disease, there is a mutation of the gene that encodes ferrochelatase (FECH). FECH deficiency is associated with increased concentrations of protoporphyrin in erythrocytes, plasma, skin and liver. The prevalence of this inherited disorder oscillates between 1:75 000 and 1:200 000. Clinical manifestations of EPP appear in early infancy upon first exposure to the sun. Nevertheless, approximately 5%-20% of patients with EPP develop liver manifestations. Retention of protoporphyrin in the liver is associated with cholestatic phenomena and oxidative stress that predisposes to hepatobiliary disease of varying degrees of severity, such as cholelithiasis, mild parenchymal liver disease, progressive hepatocellular disease with end-stage liver disease and acute liver failure. Liver damage is the major risk in EPP patients, so surveillance and frequent clinical and biochemical liver follow-up is mandatory. The diagnostic approach consists in detecting increased levels of protoporphyrin, decreased activity of FECH and genetic analysis of the FECH gene. A variety of non-surgical therapeutic approaches have been adopted for the management of EPP associated with liver disease, but none of these has been shown to be unequivocally efficacious. Nevertheless, some may have a place in preparing patients for liver transplantation. Liver transplantation does not correct the constitutional deficiency of FECH. Consequently, there is a risk of recurrence of liver disease after liver transplantation as a result of continuing overproduction of protoporphyrin. Some authors recommend that bone marrow transplantation should be considered in liver allograft recipients to prevent recurrence of hepatic disease.
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Ozgur E, Güler G, Seyhan N. Mobile phone radiation-induced free radical damage in the liver is inhibited by the antioxidants N-acetyl cysteine and epigallocatechin-gallate. Int J Radiat Biol 2010; 86:935-45. [PMID: 20807176 DOI: 10.3109/09553002.2010.496029] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
PURPOSE To investigate oxidative damage and antioxidant enzyme status in the liver of guinea pigs exposed to mobile phone-like radiofrequency radiation (RFR) and the potential protective effects of N-acetyl cysteine (NAC) and epigallocatechin-gallate (EGCG) on the oxidative damage. MATERIALS AND METHODS Nine groups of guinea pigs were used to study the effects of exposure to an 1800-MHz Global System for Mobile Communications (GSM)-modulated signal (average whole body Specific Absorption Rate (SAR) of 0.38 W/kg, 10 or 20 min per day for seven days) and treatment with antioxidants. RESULTS Significant increases in malondialdehyde (MDA) and total nitric oxide (NO(x)) levels and decreases in activities of superoxide dismutase (SOD), myeloperoxidase (MPO) and glutathione peroxidase (GSH-Px) were observed in the liver of guinea pigs after RFR exposure. Only NAC treatment induces increase in hepatic GSH-Px activities, whereas EGCG treatment alone attenuated MDA level. Extent of oxidative damage was found to be proportional to the duration of exposure (P < 0.05). CONCLUSION Mobile phone-like radiation induces oxidative damage and changes the activities of antioxidant enzymes in the liver. The adverse effect of RFR may be related to the duration of mobile phone use. NAC and EGCG protect the liver tissue against the RFR-induced oxidative damage and enhance antioxidant enzyme activities.
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Affiliation(s)
- Elcin Ozgur
- Department of Biophysics and Gazi Non-Ionizing Radiation Protection Center, Gazi University Medical Faculty, Ankara, Turkey
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Sagias FG, Mitry RR, Hughes RD, Lehec SC, Patel AG, Rela M, Mieli-Vergani G, Heaton ND, Dhawan A. N-acetylcysteine improves the viability of human hepatocytes isolated from severely steatotic donor liver tissue. Cell Transplant 2010; 19:1487-92. [PMID: 20587150 DOI: 10.3727/096368910x514620] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Hepatocyte transplantation is dependent on the availability of good quality human hepatocytes isolated from donor liver tissue. Hepatocytes obtained from livers rejected for transplantation on the grounds of steatosis are often of low viability and not suitable for clinical use. The aim of this study was to evaluate the effects of the antioxidant N-acetylcysteine (NAC) on the function of hepatocytes isolated from steatotic donor livers. Human hepatocytes were isolated from 10 severely steatotic (>60%) donor livers rejected for transplantation. The left lateral segment of the donor liver was dissected into two equal size pieces and randomized to NAC or control. NAC (5 mM) was added to the first perfusion buffer of the standard collagenase digestion technique. Cells from tissues perfused with NAC had a significantly higher mean viability (81.1 ± 1.7% vs. 66.0 ± 4.7%; p = 0.003) and cell attachment (1.08 ± 0.26 vs. 0.67 ± 0.18 OD units; p = 0.012). Addition of NAC during isolation of human hepatocytes from steatotic donor liver tissue significantly improved the outcome of cell isolation. Further studies are needed to investigate the mechanism(s) of this effect. Incorporation of NAC in the hepatocyte isolation protocol could increase the availability of hepatocytes for transplantation.
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Affiliation(s)
- Filippos G Sagias
- Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK
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Abstract
We have read with interest the paper published in issue 2, volume 16 of World Journal of Gastroenterology 2010 by Nakamura et al, demonstrating that the antioxidant resveratrol (RVT) enhances hepatitis C virus (HCV) replication, consequently, they conclude that RVT is not a suitable antioxidant therapy for HCV chronic infection. The data raise some concern regarding the use of complementary and alternative medicine since the most frequent supplements taken by these patients are antioxidants or agents that may be beneficial for different chronic liver diseases. A recent study by Vidali et al on oxidative stress and steatosis in the progression of chronic hepatitis C concludes that oxidative stress and insulin resistance contribute to steatosis, thus accelerating the progression of fibrosis. We are particularly interested in investigating how the oxidative and nitrosative stress mechanisms are involved in the pathogenesis of different chronic liver diseases.
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Junior RFM, Kubrusly MS, Bellodi-Privato M, Molan NAT, Machado MCC, D'Albuquerque LAC. Beneficial effects of N-acetyl cysteine on pancreas and kidney following experimental pancreatic ischemia-reperfusion in rats. Clinics (Sao Paulo) 2010; 65:311-6. [PMID: 20360923 PMCID: PMC2845773 DOI: 10.1590/s1807-59322010000300012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2009] [Accepted: 12/17/2009] [Indexed: 11/29/2022] Open
Abstract
OBJECTIVE To evaluate the protective effects of N-acetyl cysteine on the pancreas and kidney after pancreatic ischemia reperfusion injury in a rat model. METHODS AND MATERIALS Pancreatic ischemia reperfusion was performed in Wistar rats for 1 hour. Revascularization was achieved followed by 4 h of reperfusion. A total of 24 animals were divided into four groups: Group 1: sham; Group 2: pancreatic ischemia reperfusion without treatment; Group 3: pancreatic ischemia reperfusion plus N-acetyl cysteine intravenously; and Group 4: pancreatic ischemia reperfusion plus N-acetyl cysteine per os. Blood and tissue samples were collected after reperfusion. RESULTS There were significant differences in amylase levels between Group 1 (6.11+/-0.55) and Group 2 (10.30+/-0.50) [p=0.0002] as well as between Group 2 (10.30+/-0.50) and Group 4 (7.82+/-0.38) [p=0.003]; creatinine levels between Group 1 (0.52 +/- 0.07) and Group 2 (0.77+/-0.18) [p=0.035] as well as between Group 2 (0.77+/-0.18) and Group 3 (0.48+/-0.13) [p=0.012]; and pancreatic tissue thiobarbituric acid reactive substance levels between Group 1 (1.27+/-0.96) and Group 2 (2.60+/-3.01) [p=0.026] as well as between Group 2 (2.60+/-3.01) and Group 4 (0.52+/-0.56) [p=0.002]. A decrease in pancreatic tissue GST-alpha3 gene expression was observed in Group 2 in comparison to Group 1 (p =0.006), and an increase was observed in Groups 3 and 4 when compared to Group 2 (p= 0.025 and p=0.010, respectively). CONCLUSION This study provides evidence that N-acetyl cysteine has a beneficial effect on pancreatic ischemia reperfusion injury and renal function in a rat model.
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Güler G, Turkozer Z, Tomruk A, Seyhan N. The protective effects of N-acetyl-L-cysteine and Epigallocatechin-3-gallate on electric field-induced hepatic oxidative stress. Int J Radiat Biol 2009; 84:669-80. [DOI: 10.1080/09553000802241747] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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McKay A, Cassidy D, Sutherland F, Dixon E. Clinical results of N-acetylcysteine after major hepatic surgery: a review. ACTA ACUST UNITED AC 2008; 15:473-8. [PMID: 18836799 DOI: 10.1007/s00534-007-1306-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2007] [Accepted: 09/22/2007] [Indexed: 12/18/2022]
Abstract
BACKGROUND/PURPOSE Ischemia/reperfusion injury is thought to play an important role in postoperative liver dysfunction and morbidity following major liver surgery. N-acetylcysteine may be protective by serving as a precursor to glutathione and replenishing intracellular stores, in addition to other mechanisms. The purpose of this review is to summarize the clinical evidence that N-acetylcysteine may reduce liver dysfunction and the postoperative complications following major liver surgery. METHODS A PubMed (MEDLINE) search was performed using the search terms "N-acetylcysteine", "Mucomyst", "liver", and "surgery" to identify all relevant articles published in English prior to February 2007. RESULTS Seventy-three articles were identified, and of these, there were seven studies that involved human patients undergoing orthotopic liver transplantation (six randomized controlled trials and one retrospective study). CONCLUSIONS The evidence that routine use of N-acetylcysteine reduces ischemia/reperfusion injury and prevents complications after major liver surgery is not conclusive. The available studies may have been limited by small sample sizes, and heterogeneous outcome measures prevent conclusions being made across studies and prevent pooling of the data. Further study with more relevant clinical endpoints and larger sample sizes is warranted.
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Affiliation(s)
- Andrew McKay
- Division of Surgical Oncology, University of Calgary Tom Baker Cancer Centre, 1331-29th Street NW, Calgary, Alberta, Canada
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Mansour HH, Hafez HF, Fahmy NM, Hanafi N. Protective effect of N-acetylcysteine against radiation induced DNA damage and hepatic toxicity in rats. Biochem Pharmacol 2007; 75:773-80. [PMID: 18028880 DOI: 10.1016/j.bcp.2007.09.018] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2007] [Revised: 09/16/2007] [Accepted: 09/18/2007] [Indexed: 11/19/2022]
Abstract
The present study was designed to evaluate the radioprotective effect of N- acetylcysteine (NAC) on gamma-radiation induced toxicity in hepatic tissue in rat. The cellular changes were estimated using malondialdehyde (MDA, an index of lipid peroxidation), superoxide dismutase (SOD), glutathione peroxidase (GSHPx), reduced glutathione (GSH), and total nitrate/nitrite (NO(x)) as markers of hepatic oxidative stress in rats following gamma-irradiation. The DNA damage was determined by agarose gel electrophoresis. To achieve the ultimate goal of this study, 40 adult rats were randomly divided into 4 groups of 10 animals each. Group I was injected intraperitoneally with saline solution for 7 consecutive days and served as control group. Group II was irradiated with a single dose of 6Gy gamma-radiation. Group III was daily injected with NAC (1g/kg, i.p.) for 7 consecutive days. Group IV received a daily i.p. injection of NAC (1g/kg, i.p.) for 7 consecutive days and 1h after the last dose, rats were irradiated with a single dose (6Gy) gamma-radiation. The animals were sacrificed after 24h. DNA damage was observed in tissue after total body irradiation with a single dose of 6Gy. Malondialdehyde and total nitrate/nitrite were increased significantly whereas the levels of GSH and antioxidant enzymes were significantly decreased in gamma-irradiated group. Pretreatment with NAC showed a significant decrease in the levels of MDA, NO(x) and DNA damage. The antioxidant enzymes increased significantly along with the levels of GSH. Moreover, histopathological examination of liver tissues confirmed the biochemical data. Thus, our results show that pretreatment with N-acetylcysteine offers protection against gamma-radiation induced cellular damage.
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Affiliation(s)
- Heba H Mansour
- Health Radiation Research Department, National Center for Radiation Research and Technology, Nasr City, Cairo, Egypt.
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San-Miguel B, Alvarez M, Culebras JM, González-Gallego J, Tuñón MJ. N-acetyl-cysteine protects liver from apoptotic death in an animal model of fulminant hepatic failure. Apoptosis 2007; 11:1945-57. [PMID: 17021698 DOI: 10.1007/s10495-006-0090-0] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND This work was undertaken to investigate whether treatment with N-acetyl-cysteine (NAC) prevents oxidative stress and inhibits the apoptotic pathways in an animal model of fulminant hepatic failure. METHODS Rabbits were experimentally infected with 2x10(4) hemagglutination units of a rabbit hemorrhagic disease virus isolate. RESULTS The spontaneous mortality rate of infected animals was 67% at 36 h post infection (pi) and 90% at 48 h pi. This percentage decreased significantly in animals receiving an i.p. injection of NAC (150 mg/kg body way/daily), for 7 days prior to infection. From 36 h pi marked increases were detected in blood levels of transaminases, lactate dehydrogenase, bilirubin and the oxidised/reduced glutathione ratio. All these effects were significantly prevented by NAC treatment. The Bax to Bcl-2 relative expression, the expression of FasL, cytochrome c and PARP-1, and the activity of caspase 3 were significantly increased at 36 and 48 h pi in infected animals. These changes were markedly reduced in animals treated with NAC, with the exception of FasL. CONCLUSION Our results suggest a potential hepatoprotective role of NAC in fulminant hepatic failure, mediated partially through the modulation of the intrinsic pathway of apoptosis.
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Affiliation(s)
- B San-Miguel
- Department of Physiology, University of León, 24071, León, Spain
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Yen HW, Lee HC, Lai WT, Sheu SH. Effects of Acetylcysteine and Probucol on Contrast Medium-induced Depression of Intrinsic Renal Glutathione Peroxidase Activity in Diabetic Rats. Arch Med Res 2007; 38:291-6. [PMID: 17350478 DOI: 10.1016/j.arcmed.2006.11.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2006] [Accepted: 11/10/2006] [Indexed: 10/23/2022]
Abstract
BACKGROUND Antioxidants such as N-acetylcysteine and probucol have been used to protect patients from contrast media-induced nephrotoxicity. The mechanisms underlying these protective effects are not well understood. We hypothesized that acetylcysteine and probucol alter the activity of endogenous antioxidant enzyme activity. METHODS Four weeks after induction of diabetes with streptozotocin, diabetic and nondiabetic rats were divided into three groups. Group 1 rats did not receive any antioxidant agents. Group 2 rats were treated with acetylcysteine and group 3 rats with probucol for 1 week before injection of the contrast medium diatrizoate (DTZ). RESULTS We found that diabetic rats had higher renal glutathione peroxidase (GPx) activity than normal rats. DTZ suppressed renal GPx activity significantly in both group 1 diabetic and normal rats. Interestingly, renal GPx activity in both diabetic and normal rats pretreated with acetylcysteine or probucol was not inhibited by DTZ. Renal superoxide dismutase (SOD) increased significantly in normal rats after DTZ injection, but not in diabetic rats. Finally, acetylcysteine or probucol did not significantly influence renal SOD. CONCLUSIONS These findings suggest that the renal protective effects of acetylcysteine and probucol against contrast-induced oxidative stress and nephrotoxicity may be mediated by altering endogenous GPx activity.
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Affiliation(s)
- Hsueh-Wei Yen
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University, Chung-Ho Memorial Hospital, Kaohsiung, Taiwan
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Martin H, Abadie C, Heyd B, Mantion G, Richert L, Berthelot A. N-Acetylcysteine Partially Reverses Oxidative Stress and Apoptosis Exacerbated by Mg-Deficiency Culturing Conditions in Primary Cultures of Rat and Human Hepatocytes. J Am Coll Nutr 2006; 25:363-9. [PMID: 17031004 DOI: 10.1080/07315724.2006.10719547] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
OBJECTIVE The effects of magnesium (Mg) deficiency on the rate of oxidative stress and apoptosis in primary cultures of human hepatocytes were compared to cultured rat hepatocytes. The possible reversion by N-acetylcysteine (NAC) in Mg-deficient culturing conditions was evaluated. METHODS Incubations were conducted for up to 72 h in media containing a deficient (0-0.4 mM) or a physiological (0.8 mM) Mg concentration, and in the presence or absence of NAC after 24 h of culture in these Mg concentration conditions. RESULTS We obtained similar profiles in terms of apoptosis and oxidative stress in primary cultures of human hepatocytes, as compared to rat hepatocytes, i.e. a Mg concentration-dependent effect on the caspase-3 activity and GSH levels after 72 h of culture, caspase-3 activity being highest and GSH levels being lowest in Mg-free cultures. The addition of NAC to culture media after the first 24 h of culture increased GSH concentrations. This was accompanied in Mg-deficient cultures by a decrease in both the caspase-3 activity and the lipid peroxidation. However, when culturing hepatocytes with physiological Mg concentrations, an increase in both caspase-3 activity and lipid peroxidation was observed. CONCLUSIONS Our results indicate that Mg deficiency exacerbates the rate of apoptosis in cultured hepatocytes, associated with an increase in oxidative stress, the sensitivity of human hepatocytes being equivalent to that of rat hepatocytes. They also indicate a dual role of NAC and/or GSH, i.e. protective for hepatocytes placed in a Mg-deficient environment, while deleterious for hepatocytes placed in a Mg-physiological environment.
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Affiliation(s)
- Hélène Martin
- Laboratoire de Biologie Cellulaire, EA 3921, UFR des Sciences Médicales et Pharmaceutiques, Place Saint-Jacques, 25030 Besançon cedex, France.
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Medina J, Moreno-Otero R. Antioxidant therapy in liver ischemia-reperfusion injury. Liver Transpl 2006; 12:890-1; author reply 892-3. [PMID: 16628705 DOI: 10.1002/lt.20769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Xia Z, Nagareddy PR, Guo Z, Zhang W, McNeill JH. Antioxidant N-acetylcysteine restores systemic nitric oxide availability and corrects depressions in arterial blood pressure and heart rate in diabetic rats. Free Radic Res 2006; 40:175-84. [PMID: 16390827 DOI: 10.1080/10715760500484336] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Increased oxidative stress and reduced nitric oxide (NO) bioactivity are key features of diabetes mellitus that eventually result in cardiovascular abnormalities. We assessed whether N-acetylcysteine (NAC), an antioxidant and glutathione precursor, could prevent the hyperglycaemia induced increase in oxidative stress, restore NO availability and prevent depression of arterial blood pressure and heart rate in vivo in experimental diabetes. Control (C) and streptozotocin-induced diabetic (D) rats were treated or not treated with NAC in drinking water for 8 weeks, initiated 1 week after induction of diabetes. At termination, plasma levels of free 15-F2t-isoprostane, a specific marker of oxygen free radical induced lipid peroxidation, was increased while the plasma total antioxidant concentration was decreased in untreated diabetic rats as compared to control rats (P<0.05). This was accompanied by a significant reduction of plasma levels of nitrate and nitrite, stable metabolites of NO, (P<0.05, D vs. C) and a reduced endothelial NO synthase protein expression in the heart and in aortic and mesenteric artery tissues. Systolic, diastolic and mean arterial blood pressures (SBP, DBP and MAP) and heart rate (HR) were reduced in diabetic rats (P<0.05 vs. C) and NAC normalised the changes that occurred in the diabetic rats. The protective effects may be attributable to restoration of NO bioavailability in the circulation.
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Affiliation(s)
- Zhengyuan Xia
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Division of Pharmacology, 2146 East mall, Vancouver BC, V6T 1Z3, Canada
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Abstract
Oxidative stress is a common pathogenetic mechanism contributing to initiation and progression of hepatic damage in a variety of liver disorders. Cell damage occurs when there is an excess of reactive species derived from oxygen and nitrogen, or a defect of antioxidant molecules. Experimental research on the delicately regulated molecular strategies whereby cells control the balance between oxidant and antioxidant molecules has progressed in recent years. On the basis of this evidence, antioxidants represent a logical therapeutic strategy for the treatment of chronic liver disease. Clinical studies with large numbers of patients have not yet been performed. However, results from several pilot trials support this concept and indicate that it may be worth performing multicentre studies, particularly combining antioxidants with anti-inflammatory and/or antiviral therapy. Oxidative stress plays a pathogenetic role in liver diseases such as alcoholic liver disease, chronic viral hepatitis, autoimmune liver diseases and non-alcoholic steatohepatitis. The use of antioxidants (e.g. S-adenosylmethionine [SAMe; ademetionine], tocopherol [vitamin E], polyenylphosphatidylcholine or silymarin) has already shown promising results in some of these pathologies.
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Affiliation(s)
- Jesús Medina
- Unidad de Hepatología, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Spain
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Pae HO, Oh GS, Jeong SO, Jeong GS, Lee BS, Choi BM, Lee HS, Chung HT. 1,2,3,4,6-penta-O-galloyl-β-D-glucose up-regulates heme oxygenase-1 expression by stimulating Nrf2 nuclear translocation in an extracellular signal-regulated kinase-dependent manner in HepG2 cells. World J Gastroenterol 2006; 12:214-21. [PMID: 16482620 PMCID: PMC4066029 DOI: 10.3748/wjg.v12.i2.214] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the potency of 1,2,3,4,6-penta-O-galloyl-β-D-glucose (PGG) as a hepatic heme oxygenase-1 (HO-1) inducer and its regulation in HepG2 cells.
METHODS: Expression of HO-1 and NF-E2-related factor 2 (Nrf2) and activation of mitogen-activated protein (MAP) kinases were analyzed by Western blot, immunofluorescence assay, and flow cytometry. Transfections of HO-1 gene, small interfering RNAs for HO-1 and Nrf2, and dominant-negative gene for MAP/extracellular signal-regulated kinase (ERK) were carried out to dissect the signaling pathways leading to HO-1 expression in HepG 2 cells.
RESULTS: PGG up-regulated HO-1 expression and this expression conferred cytoprotection against oxidative injury induced by t-butyl hydroperoxide. Moreover, PGG induced Nrf2 nuclear translocation, which was found to be an upstream step of PGG-induced HO-1 expression, and ERK activation, of which pathway was involved in PGG-induced Nrf2 nuclear translocation, HO-1 expression and cytoprotection.
CONCLUSION: PGG up-regulates HO-1 expression by stimulating Nrf2 nuclear translocation in an ERK-dependent manner, and HO-1 expression by PGG may serve as one of the important mechanisms for its hepatoprotective effects.
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Affiliation(s)
- Hyun-Ock Pae
- Medicinal Resources Research Institute, Wonkwang University, Iksan-Shi, Chonbug, 570-749, Republic of Korea
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de Araujo M, Andrade L, Coimbra TM, Rodrigues AC, Seguro AC. Magnesium Supplementation Combined with N-Acetylcysteine Protects against Postischemic Acute Renal Failure. J Am Soc Nephrol 2005; 16:3339-49. [PMID: 16177005 DOI: 10.1681/asn.2004100832] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Magnesium is a potent vasodilator whose effects have not been evaluated in renal ischemia. The antioxidant properties of N-acetylcysteine (NAC) partially protect animals from ischemic/reperfusion injury. This study was designed to evaluate magnesium supplementation, alone or combined with NAC, on ischemic acute renal failure. Rats were maintained on normal diets, supplemented or not with MgCl(2).6H(2)O (1% in drinking water) for 23 d, and some rats received NAC (440 mg/kg body wt) on days 20 to 23. On day 21, ischemia was induced by clamping both renal arteries for 30 min. Five groups were studied: Normal, ischemia, ischemia+magnesium, ischemia+NAC, and ischemia+magnesium+NAC. GFR (inulin clearance), renal blood flow (RBF), FEH(2)O, and FENa were determined. Serum magnesium was decreased in ischemia-only rats. Magnesium prevented postischemia GFR and RBF decreases but did not protect against tubular damage. However, NAC completely restored the tubular damage induced by ischemia/reperfusion. Semiquantitative immunoblotting showed that NAC prevented the decreased expression of Na-K-2Cl co-transporter and aquaporin 2 after renal ischemia/reperfusion. Untreated rats with acute renal failure demonstrated markedly decreased endothelial nitric oxide synthase expression. Significantly, treatment with NAC, magnesium, or both completely inhibited downregulation of endothelial nitric oxide synthase. The tubular necrosis scores were lower in rats that were treated with NAC alone or with the magnesium-NAC combination. Magnesium prevented postischemia GFR and RBF decreases but did not protect against tubular damage. The NAC protected tubules from ischemia, decreased infiltrating macrophages/lymphocytes, and had a mild protective effect on GFR. In ischemic/reperfusion injury, renal function benefits more from the magnesium-NAC combination than from magnesium alone.
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Affiliation(s)
- Magali de Araujo
- Department of Nephrology, Laboratory of Basic Research, University of São Paulo School of Medicine, São Paulo, Brazil
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Kleinert H, Pautz A, Linker K, Schwarz PM. Regulation of the expression of inducible nitric oxide synthase. Eur J Pharmacol 2005; 500:255-66. [PMID: 15464038 DOI: 10.1016/j.ejphar.2004.07.030] [Citation(s) in RCA: 454] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/01/2004] [Indexed: 01/24/2023]
Abstract
The role of nitric oxide (NO) generated by the inducible isoform of nitric oxide synthase (iNOS) is very complex. Induction of iNOS expression and hence NO production has been described to have beneficial antiviral, antiparasital, microbicidal, immunomodulatory, and antitumoral effects. However, induced at the wrong place or at the wrong time, iNOS has detrimental consequences and seems to be involved in the pathophysiology of different human diseases. The pathways regulating iNOS expression seem to vary in different cells or different species. In general, activation of the transcription factors nuclear factor (NF)-kappaB and signal transducer and activator of transcription (STAT)-1alpha and thereby activation of the iNOS promoter seems to be an essential step in the regulation of iNOS expression in most cells. Also, post-transcriptional mechanisms are critically involved in the regulation of iNOS expression.
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Affiliation(s)
- Hartmut Kleinert
- Department of Pharmacology, Johannes Gutenberg University, Obere Zahlbacher Strasse 67, D-55101 Mainz, Germany.
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