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De la Fuente M, Joyera N, Félix J, Díaz-Del Cerro E, Linillos-Pradillo B, Rancan L, Tresguerres JAF. Cannabidiol, a Strategy in Aging to Improve Redox State and Immunity in Male Rats. Int J Mol Sci 2024; 25:12288. [PMID: 39596353 PMCID: PMC11595197 DOI: 10.3390/ijms252212288] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 11/08/2024] [Accepted: 11/14/2024] [Indexed: 11/28/2024] Open
Abstract
Aging is characterized by oxidative stress and immune function impairment, and is associated with increased morbidity. Cannabidiol (CBD) has anti-oxidant properties, but its role in aging has been scarcely studied. This work aims to test the effect of CBD on the redox state and immunity during aging in rats. In this study, 15-month-old male Long Evans rats received 10 mg/kg b.w/day of CBD in their diet for 10 weeks and were compared with same-age control and 2-month-old rats serving as a young control group, both following a standard diet. After treatment, they were sacrificed, and the spleen, thymus, and total blood cells were collected. Redox parameters such as glutathione reductase and peroxidase activities, reduced (GSH) and oxidized (GSSG) glutathione concentration, GSSG/GSH ratio, and lipid peroxidation were evaluated. Moreover, immune functions (chemotaxis, natural killer activity, and lymphoproliferation) were analyzed in the spleen. Results show that the 15-month-old control rats exhibited increased oxidative stress and immunosenescence compared to the 2-month-old rats. However, the CBD-treated animals showed higher anti-oxidant defenses, lower oxidants in the spleen, thymus, and blood cells, and better immunity in the spleen than the corresponding age-matched controls. Therefore, CBD administration neutralizes oxidative stress and improves immunity, suggesting it is a strategy for achieving healthy aging.
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Affiliation(s)
- Mónica De la Fuente
- Department of Genetics, Physiology and Microbiology (Animal Physiology Unit), Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain; (N.J.); (E.D.-D.C.)
- Institute of Investigation Hospital 12 Octubre (imas12), 28041 Madrid, Spain
| | - Noelia Joyera
- Department of Genetics, Physiology and Microbiology (Animal Physiology Unit), Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain; (N.J.); (E.D.-D.C.)
| | - Judith Félix
- Department of Genetics, Physiology and Microbiology (Animal Physiology Unit), Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain; (N.J.); (E.D.-D.C.)
- Institute of Investigation Hospital 12 Octubre (imas12), 28041 Madrid, Spain
| | - Estefanía Díaz-Del Cerro
- Department of Genetics, Physiology and Microbiology (Animal Physiology Unit), Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain; (N.J.); (E.D.-D.C.)
- Institute of Investigation Hospital 12 Octubre (imas12), 28041 Madrid, Spain
| | - Beatriz Linillos-Pradillo
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (B.L.-P.); (L.R.)
| | - Lisa Rancan
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (B.L.-P.); (L.R.)
| | - Jesús A. F. Tresguerres
- Department of Physiology, Faculty of Medicine, Complutense University of Madrid, 28040 Madrid, Spain;
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Huang ZH, Dong MQ, Liu FY, Zhou WJ. Dynamics of glutamine synthetase expression in hepatic ischemia-reperfusion injury: Implications for therapeutic interventions. World J Hepatol 2024; 16:1177-1184. [PMID: 39323976 PMCID: PMC11423427 DOI: 10.4254/wjh.v16.i8.1177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 07/09/2024] [Accepted: 07/25/2024] [Indexed: 08/21/2024] Open
Abstract
BACKGROUND Hepatic ischemia-reperfusion injury (IRI) poses a great challenge in liver surgery and transplantation because of oxidative stress and inflammatory responses. The changes in glutamine synthetase (GS) expression during hepatic IRI remain unclear. AIM To investigate the dynamic expression of GS during hepatic IRI. METHODS Following hepatic ischemia for 1 h and reperfusion, liver tissue samples were collected at 0.5, 6, and 24 hours postreperfusion for fixation, embedding, sectioning. Hematoxylin and eosin staining and GS staining were performed. RESULTS GS expression rapidly decreases in hepatocytes around the central vein after IRI, reaching its lowest point at 6 hours postreperfusion, and then gradually recovers. CONCLUSION GS is highly sensitive to IRI, highlighting its potential role as an indicator of liver injury states and a target for therapeutic intervention.
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Affiliation(s)
- Zhi-Hao Huang
- State Key Laboratory of Organ Failure Research, Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Meng-Qi Dong
- State Key Laboratory of Organ Failure Research, Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Feng-Yong Liu
- Department of Interventional Radiology, Senior Department of Oncology, Fifth Medical Center of PLA General Hospital, Beijing 100853, China
| | - Wei-Jie Zhou
- State Key Laboratory of Organ Failure Research, Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
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Martin LJ, Koh SJ, Price A, Park D, Kim BW. Nuclear Localization of Human SOD1 in Motor Neurons in Mouse Model and Patient Amyotrophic Lateral Sclerosis: Possible Links to Cholinergic Phenotype, NADPH Oxidase, Oxidative Stress, and DNA Damage. Int J Mol Sci 2024; 25:9106. [PMID: 39201793 PMCID: PMC11354607 DOI: 10.3390/ijms25169106] [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: 06/28/2024] [Revised: 08/13/2024] [Accepted: 08/21/2024] [Indexed: 09/03/2024] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal disease that causes degeneration of motor neurons (MNs) and paralysis. ALS can be caused by mutations in the gene that encodes copper/zinc superoxide dismutase (SOD1). SOD1 is known mostly as a cytosolic antioxidant protein, but SOD1 is also in the nucleus of non-transgenic (tg) and human SOD1 (hSOD1) tg mouse MNs. SOD1's nuclear presence in different cell types and subnuclear compartmentations are unknown, as are the nuclear functions of SOD1. We examined hSOD1 nuclear localization and DNA damage in tg mice expressing mutated and wildtype variants of hSOD1 (hSOD1-G93A and hSOD1-wildtype). We also studied ALS patient-derived induced pluripotent stem (iPS) cells to determine the nuclear presence of SOD1 in undifferentiated and differentiated MNs. In hSOD1-G93A and hSOD1-wildtype tg mice, choline acetyltransferase (ChAT)-positive MNs had nuclear hSOD1, but while hSOD1-wildtype mouse MNs also had nuclear ChAT, hSOD1-G93A mouse MNs showed symptom-related loss of nuclear ChAT. The interneurons had preserved parvalbumin nuclear positivity in hSOD1-G93A mice. hSOD1-G93A was seen less commonly in spinal cord astrocytes and, notably, oligodendrocytes, but as the disease emerged, the oligodendrocytes had increased mutant hSOD1 nuclear presence. Brain and spinal cord subcellular fractionation identified mutant hSOD1 in soluble nuclear extracts of the brain and spinal cord, but mutant hSOD1 was concentrated in the chromatin nuclear extract only in the spinal cord. Nuclear extracts from mutant hSOD1 tg mouse spinal cords had altered protein nitration, footprinting peroxynitrite presence, and the intact nuclear extracts had strongly increased superoxide production as well as the active NADPH oxidase marker, p47phox. The comet assay showed that MNs from hSOD1-G93A mice progressively (6-14 weeks of age) accumulated DNA single-strand breaks. Ablation of the NCF1 gene, encoding p47phox, and pharmacological inhibition of NADPH oxidase with systemic treatment of apocynin (10 mg/kg, ip) extended the mean lifespan of hSOD1-G93A mice by about 25% and mitigated genomic DNA damage progression. In human postmortem CNS, SOD1 was found in the nucleus of neurons and glia; nuclear SOD1 was increased in degenerating neurons in ALS cases and formed inclusions. Human iPS cells had nuclear SOD1 during directed differentiation to MNs, but mutant SOD1-expressing cells failed to establish wildtype MN nuclear SOD1 levels. We conclude that SOD1 has a prominent nuclear presence in the central nervous system, perhaps adopting aberrant contexts to participate in ALS pathobiology.
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Affiliation(s)
- Lee J. Martin
- Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA (D.P.)
- Pathobiology Graduate Program, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA
- Department of Neuroscience, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA
- Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA
| | - Shannon J. Koh
- Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA (D.P.)
- Texas Health Presbyterian Hospital, Dallas, TX 75231, USA
| | - Antionette Price
- Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA (D.P.)
| | - Dongseok Park
- Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA (D.P.)
| | - Byung Woo Kim
- Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA (D.P.)
- Pathobiology Graduate Program, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA
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Stadler K, Ilatovskaya DV. Renal Epithelial Mitochondria: Implications for Hypertensive Kidney Disease. Compr Physiol 2023; 14:5225-5242. [PMID: 38158371 PMCID: PMC11194858 DOI: 10.1002/cphy.c220033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2024]
Abstract
According to the Centers for Disease Control and Prevention, 1 in 2 U.S. adults have hypertension, and more than 1 in 7 chronic kidney disease. In fact, hypertension is the second leading cause of kidney failure in the United States; it is a complex disease characterized by, leading to, and caused by renal dysfunction. It is well-established that hypertensive renal damage is accompanied by mitochondrial damage and oxidative stress, which are differentially regulated and manifested along the nephron due to the diverse structure and functions of renal cells. This article provides a summary of the relevant knowledge of mitochondrial bioenergetics and metabolism, focuses on renal mitochondrial function, and discusses the evidence that has been accumulated regarding the role of epithelial mitochondrial bioenergetics in the development of renal tissue dysfunction in hypertension. © 2024 American Physiological Society. Compr Physiol 14:5225-5242, 2024.
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Affiliation(s)
- Krisztian Stadler
- Oxidative Stress and Disease Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - Daria V. Ilatovskaya
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
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Daehn IS, Ekperikpe US, Stadler K. Redox regulation in diabetic kidney disease. Am J Physiol Renal Physiol 2023; 325:F135-F149. [PMID: 37262088 PMCID: PMC10393330 DOI: 10.1152/ajprenal.00047.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 05/08/2023] [Accepted: 05/20/2023] [Indexed: 06/03/2023] Open
Abstract
Diabetic kidney disease (DKD) is one of the most devastating complications of diabetes mellitus, where currently there is no cure available. Several important mechanisms contribute to the pathogenesis of this complication, with oxidative stress being one of the key factors. The past decades have seen a large number of publications with various aspects of this topic; however, the specific details of redox regulation in DKD are still unclear. This is partly because redox biology is very complex, coupled with a complex and heterogeneous organ with numerous cell types. Furthermore, often times terms such as "oxidative stress" or reactive oxygen species are used as a general term to cover a wide and rich variety of reactive species and their differing reactions. However, no reactive species are the same, and not all of them are capable of biologically relevant reactions or "redox signaling." The goal of this review is to provide a biochemical background for an array of specific reactive oxygen species types with varying reactivity and specificity in the kidney as well as highlight some of the advances in redox biology that are paving the way to a better understanding of DKD development and risk.
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Affiliation(s)
- Ilse S Daehn
- Division of Nephrology, Department of Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, United States
| | - Ubong S Ekperikpe
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, United States
| | - Krisztian Stadler
- Oxidative Stress and Disease Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, United States
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de Souza PC, Corrêa AEDN, Gameiro JG, de Oliveira Júnior AG, Panagio LA, Venancio EJ, Almeida RS. Production of IgY against iron permease Ftr1 from Candida albicans and evaluation of its antifungal activity using Galleria mellonella as a model of systemic infection. Microb Pathog 2023:106166. [PMID: 37290729 DOI: 10.1016/j.micpath.2023.106166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/07/2023] [Accepted: 05/19/2023] [Indexed: 06/10/2023]
Abstract
Candida albicans is one of the leading pathological agents of mucosal and deep tissue infections. Considering that the variety of antifungals is restricted and that toxicity limits their use, immunotherapies against pathogenic fungi have been viewed as alternatives with reduced adverse effects. In this context, C. albicans has a protein used to capture iron from the environment and the host, known as the high-affinity iron permease Ftr1. This protein may be a new target of action for novel antifungal therapies, as it influences the virulence of this yeast. Thus, the aim of the present study was to produce and conduct the biological characterization of IgY antibodies against C. albicans Ftr1. Immunization of laying hens with an Ftr1-derived peptide resulted in IgY antibodies extracted from egg yolks capable of binding to the antigen with high affinity (avidity index = 66.6 ± 0.3%). These antibodies reduced the growth and even eliminated C. albicans under iron restriction, a favorable condition for the expression of Ftr1. This also occurred with a mutant strain that does not produce Ftr1 in the presence of iron, a circumstance in which the protein analog of iron permease, Ftr2, is expressed. Furthermore, the survival of G. mellonella larvae infected with C. albicans and treated with the antibodies was 90% higher than the control group, which did not receive treatment (p < 0.0001). Therefore, our data suggest that IgY antibodies against Ftr1 from C. albicans can inhibit yeast propagation by blocking iron uptake.
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Affiliation(s)
- Patricia Canteri de Souza
- Department of Microbiology, Center of Biological Science, State University of Londrina, Rodovia Celso Garcia Cid, Pr 445, Km 380, Londrina, 86.057-970, Paraná, Brazil
| | - Alana Elke do Nascimento Corrêa
- Department of Microbiology, Center of Biological Science, State University of Londrina, Rodovia Celso Garcia Cid, Pr 445, Km 380, Londrina, 86.057-970, Paraná, Brazil
| | - Juliana Gutschow Gameiro
- Department of Pathology, Clinical and Toxicological Analysis, Center of Health Sciences, State University of Londrina, Rodovia Celso Garcia Cid, Pr 445, Km 380, Londrina, 86.057-970, Paraná, Brazil
| | - Admilton Gonçalves de Oliveira Júnior
- Department of Microbiology, Center of Biological Science, State University of Londrina, Rodovia Celso Garcia Cid, Pr 445, Km 380, Londrina, 86.057-970, Paraná, Brazil
| | - Luciano Aparecido Panagio
- Department of Microbiology, Center of Biological Science, State University of Londrina, Rodovia Celso Garcia Cid, Pr 445, Km 380, Londrina, 86.057-970, Paraná, Brazil
| | - Emerson José Venancio
- Department of Pathological Sciences, Center of Biological Science, State University of Londrina, Rodovia Celso Garcia Cid, Pr 445, Km 380, Londrina, 86.057-970, Paraná, Brazil
| | - Ricardo Sergio Almeida
- Department of Microbiology, Center of Biological Science, State University of Londrina, Rodovia Celso Garcia Cid, Pr 445, Km 380, Londrina, 86.057-970, Paraná, Brazil.
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Ataman MB, Aköz M, Dönmez N, Bodu M, Kul M, Bucak MN. The investigation of the effects of vitamin A, vitamin E, and β-carotene plus vitamin E on some fertility parameters in ewes. Trop Anim Health Prod 2023; 55:175. [PMID: 37099042 DOI: 10.1007/s11250-023-03586-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 04/12/2023] [Indexed: 04/27/2023]
Abstract
This study was aimed at investigating the effects of vitamin A (VITA), vitamin E (VITE), and combined β-carotene plus vitamin E (βCAR+VITE) injections on some fertility parameters in ewes. Estrus synchronization was performed by treating the ewes with intravaginal FGA sponges impregnated with 30 mg of fluorogestone acetate. On the days of the insertion and withdrawal of the intravaginal sponges, groups VITA, VITE, and βCAR+VITE were administered with 500 000 IU of vitamin A, 50 mg of vitamin E, and a combination of β-carotene plus vitamin E, respectively. The ewes in the control group (C) were maintained for control purposes. Statistically significant differences were determined between groups VITA and βCAR+VITE, groups VITE and βCAR+VITE, and groups C and βCAR+VITE, as well as groups VITE and C, groups VITA and C for the multiple birth rates. While significant differences were determined between groups VITA and C, groups VITE and C, and groups βCAR+VITE and C for the lambing rates, it was ascertained that the ratio of newborn lambs to delivered ewes (litter size) significantly differed between groups VITA and βCAR+VITE, groups VITA and C, groups VITE and βCAR+VITE, groups VITE and C, and groups βCAR+VITE and C. The highest MDA level and lowest GSH level were determined on day 20 after mating in the control group. In conclusion, it is suggested that both multiple birth rates and litter size can be increased by the combined administration of β-carotene and vitamin E.
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Affiliation(s)
- Mehmet Bozkurt Ataman
- Selçuk University, Faculty of Veterinary Medicine, Department of Reproduction and Artificial Insemination, Konya, Turkey.
| | - Mehmet Aköz
- Selçuk University, Vocational School of Health Services, Medical Services and Techniques, Medical Laboratory Techniques, Konya, Turkey
| | - Nurcan Dönmez
- Selçuk University, Faculty of Veterinary Medicine, Department of Physiology, Konya, Turkey
| | - Mustafa Bodu
- Selçuk University, Faculty of Veterinary Medicine, Department of Reproduction and Artificial Insemination, Konya, Turkey
| | - Mustafa Kul
- Selcuk University, Vocational School of Health Services, Medical Services and Techniques, Medical Imaging Techniques, Konya, Turkey
| | - Mustafa Numan Bucak
- Selçuk University, Faculty of Veterinary Medicine, Department of Reproduction and Artificial Insemination, Konya, Turkey
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8
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McCrimmon A, Corbin S, Shrestha B, Roman G, Dhungana S, Stadler K. Redox phospholipidomics analysis reveals specific oxidized phospholipids and regions in the diabetic mouse kidney. Redox Biol 2022; 58:102520. [PMID: 36334379 PMCID: PMC9640328 DOI: 10.1016/j.redox.2022.102520] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/18/2022] [Accepted: 10/22/2022] [Indexed: 11/08/2022] Open
Abstract
While it is generally accepted that oxidative stress impacts the diabetic kidney and contributes to pathogenesis, there is a substantial lack of knowledge about the molecular entity and anatomic location of a variety of reactive species. Here we provide a novel "oxidative stress map" of the diabetic kidney - the first of its kind, and identify specific, oxidized and other reactive lipids and their location. We used the db/db mouse model and Desorption Electrospray Ionization (DESI) mass spectrometry combined with heatmap image analysis. We analyzed a comprehensive array of phospholipid peroxide species in normal (db/m) and diabetic (db/db) kidneys using DESI imaging. Oxilipidomics heatmaps of the kidneys were generated focusing on phospholipids and their potential peroxidized products. We identified those lipids that undergo peroxidation in diabetic nephropathy. Several phospholipid peroxides and their spatial distribution were identified that were specific to the diabetic kidney, with significant enrichment in oxygenated phosphatidylethanolamines (PE) and lysophosphatidylethanolamine. Beyond qualitative and semi-quantitative information about the targets, the approach also reveals the anatomic location and the extent of lipid peroxide signal propagation across the kidney. Our approach provides novel, in-depth information of the location and molecular entity of reactive lipids in an organ with a very heterogeneous landscape. Many of these reactive lipids have been previously linked to programmed cell death mechanisms. Thus, the findings may be relevant to understand what impact phospholipid peroxidation has on cell and mitochondria membrane integrity and redox lipid signaling in diabetic nephropathy.
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Affiliation(s)
- Allison McCrimmon
- Oxidative Stress and Disease Laboratory, Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, 70808, LA, USA
| | - Sydney Corbin
- Oxidative Stress and Disease Laboratory, Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, 70808, LA, USA
| | | | | | | | - Krisztian Stadler
- Oxidative Stress and Disease Laboratory, Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, 70808, LA, USA.
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Nguyen-Powanda P, Robaire B. Aging and oxidative stress alter DNA repair mechanisms in male germ cells of superoxide dismutase-1 null mice. Biol Reprod 2021; 105:944-957. [PMID: 34098580 DOI: 10.1093/biolre/ioab114] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/17/2021] [Accepted: 05/29/2021] [Indexed: 11/13/2022] Open
Abstract
The efficiency of antioxidant defense system decreases with aging, thus resulting in high levels of reactive oxygen species (ROS) and DNA damage in spermatozoa. This damage can lead to genetic disorders in the offspring. There are limited studies investigating the effects of the total loss of antioxidants, such as superoxide dismutase-1 (SOD1), in male germ cells as they progress through spermatogenesis. In this study, we evaluated the effects of aging and removing SOD1 (in male germ cells of SOD1-null (Sod1-/-) mice) in order to determine the potential mechanism(s) of DNA damage in these cells. Immunohistochemical analysis showed an increase in lipid peroxidation and DNA damage in the germ cells of aged wild-type (WT) and Sod1-/- mice of all age. Immunostaining of OGG1, a marker of base excision repair (BER), increased in aged WT and young Sod1-/- mice. In contrast, immunostaining intensity of LIGIV and RAD51, markers of non-homologous end-joining (NHEJ) and homologous recombination (HR), respectively, decreased in aged and Sod1-/- mice. Gene expression analysis showed similar results with altered mRNA expression of these key DNA repair transcripts in pachytene spermatocytes and round spermatids of aged and Sod1-/- mice. Our study indicates that DNA repair pathway markers of BER, NHEJ, and HR are differentially regulated as a function of aging and oxidative stress in spermatocytes and spermatids, and aging enhances the repair response to increased oxidative DNA damage, whereas impairments in other DNA repair mechanisms may contribute to the increase in DNA damage caused by aging and the loss of SOD1.
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Affiliation(s)
| | - Bernard Robaire
- Department of Obstetrics & Gynecology, McGill University, Montreal, Quebec, Canada
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Jackson MJ. On the mechanisms underlying attenuated redox responses to exercise in older individuals: A hypothesis. Free Radic Biol Med 2020; 161:326-338. [PMID: 33099002 PMCID: PMC7754707 DOI: 10.1016/j.freeradbiomed.2020.10.026] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 10/08/2020] [Accepted: 10/18/2020] [Indexed: 12/12/2022]
Abstract
Responding appropriately to exercise is essential to maintenance of skeletal muscle mass and function at all ages and particularly during aging. Here, a hypothesis is presented that a key component of the inability of skeletal muscle to respond effectively to exercise in aging is a denervation-induced failure of muscle redox signalling. This novel hypothesis proposes that an initial increase in oxidation in muscle mitochondria leads to a paradoxical increase in the reductive state of specific cysteines of signalling proteins in the muscle cytosol that suppresses their ability to respond to normal oxidising redox signals during exercise. The following are presented for consideration:Transient loss of integrity of peripheral motor neurons occurs repeatedly throughout life and is normally rapidly repaired by reinnervation, but this repair process becomes less efficient with aging. Each transient loss of neuromuscular integrity leads to a rapid, large increase in mitochondrial peroxide production in the denervated muscle fibers and in neighbouring muscle fibers. This peroxide may initially act to stimulate axonal sprouting and regeneration, but also stimulates retrograde mitonuclear communication to increase expression of a range of cytoprotective proteins in an attempt to protect the fiber and neighbouring tissues against oxidative damage. The increased peroxide within mitochondria does not lead to an increased cytosolic peroxide, but the increases in adaptive cytoprotective proteins include some located to the muscle cytosol which modify the local cytosol redox environment to induce a more reductive state in key cysteines of specific signalling proteins. Key adaptations of skeletal muscle to exercise involve transient peroxiredoxin oxidation as effectors of redox signalling in the cytosol. This requires sensitive oxidation of key cysteine residues. In aging, the chronic change to a more reductive cytosolic environment prevents the transient oxidation of peroxiredoxin 2 and hence prevents essential adaptations to exercise, thus contributing to loss of muscle mass and function. Experimental approaches suitable for testing the hypothesis are also outlined.
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Affiliation(s)
- Malcolm J Jackson
- MRC-Versus Arthritis Centre for Integrated Research Into Musculoskeletal Ageing (CIMA), Department of Musculoskeletal and Ageing Biology, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, L7 8TX, UK.
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Yuasa K, Shikata T, Ichikawa T, Tamura Y, Nishiyama Y. Nutrient deficiency stimulates the production of superoxide in the noxious red-tide-forming raphidophyte Chattonella antiqua. HARMFUL ALGAE 2020; 99:101938. [PMID: 33218451 DOI: 10.1016/j.hal.2020.101938] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 09/14/2020] [Accepted: 10/22/2020] [Indexed: 06/11/2023]
Abstract
The raphidophyte Chattonella antiqua is a single-celled alga that forms 'red tides' in coastal areas. C. antiqua produces superoxide anions (O2-), the excessive production of which has been associated with fish mortality. It is suggested that putative NADPH oxidase in the outer membrane oxidizes intracellular NADPH to produce O2- and secrete it externally. Earlier studies revealed that photosynthetic electron transport, a major producer of NADPH in photosynthetic organisms, is involved in the production of O2- in C. antiqua but the details of the O2- production mechanism have yet to be elucidated. Since nutrient deficiency adversely affects the formation of blooms of C. antiqua, in this study, we examined the effects of nutrient deficiency on O2- production in C. antiqua. When cells were grown under nitrogen (N)- or phosphorus (P)-deficient conditions, the production of O2- was stimulated. In particular, the extracellular levels of O2- under N- or P-deficient conditions were high during the dark period when photosynthetic activities in terms of actual quantum efficiency and photochemical quenching were low. The extracellular levels of O2- under the nutrient-deficient conditions were unaffected by the presence of 3-(3,4-dichlorophenyl)-1,1‑dimethylurea (DCMU), an inhibitor of photosynthetic electron transport, but decreased when the nutrients were present. Furthermore, the intracellular ratio of NADPH to NADP+ under N- or P-deficient conditions was higher than that under nutrient-replete conditions. These observations suggest that another metabolic pathway, independent of photosynthesis, provides NADPH for the production of O2- under nutrient deficiency.
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Affiliation(s)
- Koki Yuasa
- Department of Biochemistry and Molecular Biology, Graduate School of Science and Engineering, Saitama University, 255 Shimo-Okubo, Sakura-ku, Saitama 338-8570, Japan.
| | - Tomoyuki Shikata
- Fisheries Technology Institute, Japan Fisheries Research and Education Agency, 2-17-5 Maruishi, Hatsukaichi, Hiroshima 738-8635, Japan.
| | - Takayoshi Ichikawa
- Department of Biochemistry and Molecular Biology, Graduate School of Science and Engineering, Saitama University, 255 Shimo-Okubo, Sakura-ku, Saitama 338-8570, Japan.
| | - Yu Tamura
- Department of Biochemistry and Molecular Biology, Graduate School of Science and Engineering, Saitama University, 255 Shimo-Okubo, Sakura-ku, Saitama 338-8570, Japan.
| | - Yoshitaka Nishiyama
- Department of Biochemistry and Molecular Biology, Graduate School of Science and Engineering, Saitama University, 255 Shimo-Okubo, Sakura-ku, Saitama 338-8570, Japan.
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12
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Jackson MJ, Stretton C, McArdle A. Hydrogen peroxide as a signal for skeletal muscle adaptations to exercise: What do concentrations tell us about potential mechanisms? Redox Biol 2020; 35:101484. [PMID: 32184060 PMCID: PMC7284923 DOI: 10.1016/j.redox.2020.101484] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 02/24/2020] [Accepted: 02/28/2020] [Indexed: 12/26/2022] Open
Abstract
Hydrogen peroxide appears to be the key reactive oxygen species involved in redox signalling, but comparisons of the low concentrations of hydrogen peroxide that are calculated to exist within cells with those previously shown to activate common signalling events in vitro indicate that direct oxidation of key thiol groups on "redox-sensitive" signalling proteins is unlikely to occur. A number of potential mechanisms have been proposed to explain how cells overcome this block to hydrogen peroxide-stimulated redox signalling and these will be discussed in the context of the redox-stimulation of specific adaptations of skeletal muscle to contractile activity and exercise. It is argued that current data implicate a role for currently unidentified effector molecules (likely to be highly reactive peroxidases) in propagation of the redox signal from sites of hydrogen peroxide generation to common adaptive signalling pathways.
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Affiliation(s)
- Malcolm J Jackson
- MRC-Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing (CIMA), Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, L87TX, UK.
| | - Clare Stretton
- MRC-Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing (CIMA), Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, L87TX, UK
| | - Anne McArdle
- MRC-Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing (CIMA), Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, L87TX, UK
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13
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Jackson MJ. Mechanistic models to guide redox investigations and interventions in musculoskeletal ageing. Free Radic Biol Med 2020; 149:2-7. [PMID: 31981622 DOI: 10.1016/j.freeradbiomed.2020.01.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 01/16/2020] [Accepted: 01/17/2020] [Indexed: 10/25/2022]
Abstract
Age is the greatest risk factor for the major chronic musculoskeletal disorders, osteoarthritis, osteoporosis and age-related loss of skeletal muscle mass and function (sarcopenia). Dramatic advances in understanding of the fundamental mechanisms underlying the ageing process are being exploited to understand the causes of these age-related disorders and identify approaches to prevent or treat these disorders. This review will focus on one of these fundamental mechanisms, redox regulation, and the role of redox changes in age-related loss of skeletal muscle mass and function (sarcopenia). Key to understanding the role of such pathways has been the development and study of experimental models of musculoskeletal ageing that are designed to examine the effect of modification of ROS regulatory enzymes. These have primarily involved genetic deletion of regulatory enzymes for ROS in mice. Many of the models studied show increased oxidative damage in tissues, but no clear relationship with skeletal muscle aging has been seen The exception to this has been mice with disruption of the superoxide dismutases and, in particular, deletion of Cu,ZnSOD (SOD1) localised in the cytosol and mitochondrial intermembrane space. Studies of tissue specific models lacking SOD1 have highlighted the potential role that disrupted redox pathways can play in muscle loss and weakness and have demonstrated the need to study both motor neurons and muscle to understand age-related loss of skeletal muscle. The complex interplay that has been identified between changes in redox homeostasis in the motor neuron and skeletal muscle and their role in premature loss of muscle mass and function illustrates the utility of modifiable models to establish key pathways that may contribute to age-related changes and identify potential logical approaches to intervention.
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Affiliation(s)
- Malcolm J Jackson
- MRC-Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing (CIMA), Department of Musculoskeletal Biology, Institute of Ageing & Chronic Disease, University of Liverpool, Liverpool, L78TX, UK.
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14
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Yuasa K, Shikata T, Kitatsuji S, Yamasaki Y, Nishiyama Y. Extracellular secretion of superoxide is regulated by photosynthetic electron transport in the noxious red-tide-forming raphidophyte Chattonella antiqua. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2020; 205:111839. [PMID: 32146272 DOI: 10.1016/j.jphotobiol.2020.111839] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 02/11/2020] [Accepted: 02/21/2020] [Indexed: 12/28/2022]
Abstract
The raphidophyte Chattonella antiqua is a noxious red-tide-forming alga that harms fish culture and the aquatic environment. Chattonella antiqua produces and secretes superoxide anions (O2-), and excessive secretion of O2- into the water has been associated with fish mortality. It is known that strong light stimulates the production of O2- in Chattonella spp. but the mechanism of the light-induced production of O2- remains to be clarified. In the present study, we examined the effects of light on extracellular levels of O2- and photosynthesis in C. antiqua. Extracellular levels of O2- rose during growth under high-intensity light, and the level of O2- was correlated with the photosynthetic parameter qP, which reflects the rate of transport of electrons downstream of photosystem II. The production of O2- was inhibited in the presence of 3-(3,4-dichlorophenyl)-1,1-dimethylurea, an inhibitor of photosynthetic electron transport, suggesting that reducing power derived from electron transport might be required for the production of O2-. By contrast, the production of O2- was enhanced in the presence of glycolaldehyde, an inhibitor of the Calvin-Benson cycle, suggesting that the accumulation of NADPH might stimulate the production of O2-. Thus, it is likely that the production of O2- is regulated by photosynthesis in C. antiqua.
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Affiliation(s)
- Koki Yuasa
- Department of Biochemistry and Molecular Biology, Graduate School of Science and Engineering, Saitama University, 255 Shimo-Okubo, Sakura-ku, Saitama 338-8570, Japan
| | - Tomoyuki Shikata
- National Research Institute of Fisheries and Environment of Inland Sea, Fisheries Research and Education Agency, 2-17-5 Maruishi, Hatsukaichi, Hiroshima 738-8635, Japan
| | - Saho Kitatsuji
- National Research Institute of Fisheries and Environment of Inland Sea, Fisheries Research and Education Agency, 2-17-5 Maruishi, Hatsukaichi, Hiroshima 738-8635, Japan
| | - Yasuhiro Yamasaki
- Department of Applied Aquabiology, National Fisheries University, Fisheries Research and Education Agency, 2-7-1 Nagatahonmachi, Shimonoseki, Yamaguchi 759-6595, Japan
| | - Yoshitaka Nishiyama
- Department of Biochemistry and Molecular Biology, Graduate School of Science and Engineering, Saitama University, 255 Shimo-Okubo, Sakura-ku, Saitama 338-8570, Japan.
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15
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Çetin E, Güçlü BK. Effect of dietary l-carnitine supplementation and energy level on oxidant/antioxidant balance in laying hens subjected to high stocking density. J Anim Physiol Anim Nutr (Berl) 2019; 104:136-143. [PMID: 31544992 DOI: 10.1111/jpn.13210] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Revised: 07/25/2019] [Accepted: 08/24/2019] [Indexed: 12/01/2022]
Abstract
This study aimed to investigate the effect of l-carnitine and energy level and on oxidant/antioxidant balance in laying hens subjected to high stocking density. A total of 176, 32-week-old laying hens were assigned to eight groups with four replicates and hens in four groups were placed at the normal stocking densities of 500 cm2 /hen (four hens per cage) and in the remaining four groups were placed at the high stocking densities of 287.5 cm2 /hen (seven hens per cage). Hens received diets of high (2,850 kcal/kg ME) or normal (2,650 kcal/kg ME) energy which are supplemented with 0 or 200 mg/kg l-carnitine for 70 days. Results showed that exposure to high stocking density increased (p < .05) plasma malondialdehyde (MDA) and nitric oxide (NO) levels and decreased (p < .05) erythrocyte superoxide dismutase (SOD), catalase (CAT) and superoxide dismutase (GPx) activities. l-carnitine supplementation increased (p < .05) erythrocyte SOD, CAT and GPx activities, and decreased (p <.05) MDA and NO level in high stocking densities. The oxidan/antioxidan balance of birds was not influenced by increasing dietary energy level. The results of the present study indicate that the supplementation of l-carnitine to the birds subjected to high stocking density could effectively reverse the negative effects of high stocking density by improving oxidant/antioxidant balance. Therefore, l-carnitine supplementation at level of 200 mg/kg to diet may be as a favourable alternative to deal with oxidative stress caused by high stocking density in laying hens.
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Affiliation(s)
- Ebru Çetin
- Departments of Physiology Faculty of Veterinary Medicine, University of Erciyes, Kayseri, Turkey
| | - Berrin Kocaoğlu Güçlü
- Animal Nutrition and Nutritional Diseases, Faculty of Veterinary Medicine, University of Erciyes, Kayseri, Turkey
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16
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Kruger C, Nguyen TT, Breaux C, Guillory A, Mangelli M, Fridianto KT, Kovalik JP, Burk DH, Noland RC, Mynatt R, Stadler K. Proximal Tubular Cell-Specific Ablation of Carnitine Acetyltransferase Causes Tubular Disease and Secondary Glomerulosclerosis. Diabetes 2019; 68:819-831. [PMID: 30728184 PMCID: PMC6425873 DOI: 10.2337/db18-0090] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 01/28/2019] [Indexed: 02/06/2023]
Abstract
Proximal tubular epithelial cells are highly energy demanding. Their energy need is covered mostly from mitochondrial fatty acid oxidation. Whether derailments in fatty acid metabolism and mitochondrial dysfunction are forerunners of tubular damage has been suggested but is not entirely clear. Here we modeled mitochondrial overload by creating mice lacking the enzyme carnitine acetyltransferase (CrAT) in the proximal tubules, thus limiting a primary mechanism to export carbons under conditions of substrate excess. Mice developed tubular disease and, interestingly, secondary glomerulosclerosis. This was accompanied by increased levels of apoptosis regulator and fibrosis markers, increased oxidative stress, and abnormal profiles of acylcarnitines and organic acids suggesting profound impairments in all major forms of nutrient metabolism. When mice with CrAT deletion were fed a high-fat diet, kidney disease was more severe and developed faster. Primary proximal tubular cells isolated from the knockout mice displayed energy deficit and impaired respiration before the onset of pathology, suggesting mitochondrial respiratory abnormalities as a potential underlying mechanism. Our findings support the hypothesis that derailments of mitochondrial energy metabolism may be causative to chronic kidney disease. Our results also suggest that tubular injury may be a primary event followed by secondary glomerulosclerosis, raising the possibility that focusing on normalizing tubular cell mitochondrial function and energy balance could be an important preventative strategy.
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Affiliation(s)
- Claudia Kruger
- Oxidative Stress and Disease Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA
| | - Trang-Tiffany Nguyen
- Oxidative Stress and Disease Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA
| | - Chelsea Breaux
- Oxidative Stress and Disease Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA
| | - Alana Guillory
- Oxidative Stress and Disease Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA
| | - Margaret Mangelli
- Oxidative Stress and Disease Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA
| | - Kevin T Fridianto
- Programme in Cardiovascular & Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, Singapore
| | - Jean-Paul Kovalik
- Programme in Cardiovascular & Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, Singapore
| | - David H Burk
- Cell Biology and Bioimaging Core, Pennington Biomedical Research Center, Baton Rouge, LA
| | - Robert C Noland
- Skeletal Muscle Metabolism Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA
| | - Randall Mynatt
- Transgenics Core, Pennington Biomedical Research Center, Baton Rouge, LA
| | - Krisztian Stadler
- Oxidative Stress and Disease Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA
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17
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Hameed S, Hans S, Singh S, Fatima Z. Harnessing Metal Homeostasis Offers Novel and Promising Targets Against Candida albicans. Curr Drug Discov Technol 2019; 17:415-429. [PMID: 30827249 DOI: 10.2174/1570163816666190227231437] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 01/08/2019] [Accepted: 01/30/2019] [Indexed: 11/22/2022]
Abstract
Fungal infections, particularly of Candida species, which are the commensal organisms of human, are one of the major debilitating diseases in immunocompromised patients. The limited number of antifungal drugs available to treat Candida infections, with the concomitant increasing incidence of multidrug-resistant (MDR) strains, further worsens the therapeutic options. Thus, there is an urgent need for the better understanding of MDR mechanisms, and their reversal, by employing new strategies to increase the efficacy and safety profiles of currently used therapies against the most prevalent human fungal pathogen, Candida albicans. Micronutrient availability during C. albicans infection is regarded as a critical factor that influences the progression and magnitude of the disease. Intracellular pathogens colonize a variety of anatomical locations that are likely to be scarce in micronutrients, as a defense strategy adopted by the host, known as nutritional immunity. Indispensable critical micronutrients are required both by the host and by C. albicans, especially as a cofactor in important metabolic functions. Since these micronutrients are not freely available, C. albicans need to exploit host reservoirs to adapt within the host for survival. The ability of pathogenic organisms, including C. albicans, to sense and adapt to limited micronutrients in the hostile environment is essential for survival and confers the basis of its success as a pathogen. This review describes that micronutrients availability to C. albicans is a key attribute that may be exploited when one considers designing strategies aimed at disrupting MDR in this pathogenic fungi. Here, we discuss recent advances that have been made in our understanding of fungal micronutrient acquisition and explore the probable pathways that may be utilized as targets.
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Affiliation(s)
- Saif Hameed
- Amity Institute of Biotechnology, Amity University Haryana, Gurugram (Manesar)-122413, India
| | - Sandeep Hans
- Amity Institute of Biotechnology, Amity University Haryana, Gurugram (Manesar)-122413, India
| | - Shweta Singh
- Amity Institute of Biotechnology, Amity University Haryana, Gurugram (Manesar)-122413, India
| | - Zeeshan Fatima
- Amity Institute of Biotechnology, Amity University Haryana, Gurugram (Manesar)-122413, India
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18
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Goswami G, Panda D, Samanta R, Boro RC, Modi MK, Bujarbaruah KM, Barooah M. Bacillus megaterium adapts to acid stress condition through a network of genes: Insight from a genome-wide transcriptome analysis. Sci Rep 2018; 8:16105. [PMID: 30382109 PMCID: PMC6208408 DOI: 10.1038/s41598-018-34221-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 10/05/2018] [Indexed: 11/18/2022] Open
Abstract
RNA-seq analysis of B. megaterium exposed to pH 7.0 and pH 4.5 showed differential expression of 207 genes related to several processes. Among the 207 genes, 11 genes displayed increased transcription exclusively in pH 4.5. Exposure to pH 4.5 induced the expression of genes related to maintenance of cell integrity, pH homeostasis, alternative energy generation and modification of metabolic processes. Metabolic processes like pentose phosphate pathway, fatty acid biosynthesis, cysteine and methionine metabolism and synthesis of arginine and proline were remodeled during acid stress. Genes associated with oxidative stress and osmotic stress were up-regulated at pH 4.5 indicating a link between acid stress and other stresses. Acid stress also induced expression of genes that encoded general stress-responsive proteins as well as several hypothetical proteins. Our study indicates that a network of genes aid B. megaterium G18 to adapt and survive in acid stress condition.
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Affiliation(s)
- Gunajit Goswami
- Department of Agricultural Biotechnology, Assam Agricultural University, Jorhat, 785013, India.,Department of Life-Sciences, Dibrugarh University, Dibrugarh, 786004, Assam, India
| | - Debashis Panda
- Distributed Information Centre, Department of Agricultural Biotechnology, Assam Agricultural University, Jorhat, 785013, India
| | - Ramkrishna Samanta
- Department of Life-Sciences, Dibrugarh University, Dibrugarh, 786004, Assam, India
| | - Robin Chandra Boro
- Department of Agricultural Biotechnology, Assam Agricultural University, Jorhat, 785013, India
| | - Mahendra Kumar Modi
- Department of Agricultural Biotechnology, Assam Agricultural University, Jorhat, 785013, India.,Distributed Information Centre, Department of Agricultural Biotechnology, Assam Agricultural University, Jorhat, 785013, India
| | - Kamal Malla Bujarbaruah
- Department of Agricultural Biotechnology, Assam Agricultural University, Jorhat, 785013, India
| | - Madhumita Barooah
- Department of Agricultural Biotechnology, Assam Agricultural University, Jorhat, 785013, India.
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19
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Keeney JTR, Ren X, Warrier G, Noel T, Powell DK, Brelsfoard JM, Sultana R, Saatman KE, Clair DKS, Butterfield DA. Doxorubicin-induced elevated oxidative stress and neurochemical alterations in brain and cognitive decline: protection by MESNA and insights into mechanisms of chemotherapy-induced cognitive impairment ("chemobrain"). Oncotarget 2018; 9:30324-30339. [PMID: 30100992 PMCID: PMC6084398 DOI: 10.18632/oncotarget.25718] [Citation(s) in RCA: 105] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 06/13/2018] [Indexed: 12/21/2022] Open
Abstract
Chemotherapy-induced cognitive impairment (CICI) is now widely recognized as a real and too common complication of cancer chemotherapy experienced by an ever-growing number of cancer survivors. Previously, we reported that doxorubicin (Dox), a prototypical reactive oxygen species (ROS)-producing anti-cancer drug, results in oxidation of plasma proteins, including apolipoprotein A-I (ApoA-I) leading to tumor necrosis factor-alpha (TNF-α)-mediated oxidative stress in plasma and brain. We also reported that co-administration of the antioxidant drug, 2-mercaptoethane sulfonate sodium (MESNA), prevents Dox-induced protein oxidation and subsequent TNF-α elevation in plasma. In this study, we measured oxidative stress in both brain and plasma of Dox-treated mice both with and without MESNA. MESNA ameliorated Dox-induced oxidative protein damage in plasma, confirming our prior studies, and in a new finding led to decreased oxidative stress in brain. This study also provides further functional and biochemical evidence of the mechanisms of CICI. Using novel object recognition (NOR), we demonstrated the Dox administration resulted in memory deficits, an effect that was rescued by MESNA. Using hydrogen magnetic resonance imaging spectroscopy (H1-MRS) techniques, we demonstrated that Dox administration led to a dramatic decrease in choline-containing compounds assessed by (Cho)/creatine ratios in the hippocampus in mice. To better elucidate a potential mechanism for this MRS observation, we tested the activities of the phospholipase enzymes known to act on phosphatidylcholine (PtdCho), a key component of phospholipid membranes and a source of choline for the neurotransmitter, acetylcholine (ACh). The activities of both phosphatidylcholine-specific phospholipase C (PC-PLC) and phospholipase D were severely diminished following Dox administration. The activity of PC-PLC was preserved when MESNA was co-administered with Dox; however, PLD activity was not protected. This study is the first to demonstrate the protective effects of MESNA on Dox-related protein oxidation, cognitive decline, phosphocholine (PCho) levels, and PC-PLC activity in brain and suggests novel potential therapeutic targets and strategies to mitigate CICI.
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Affiliation(s)
| | - Xiaojia Ren
- Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA
| | - Govind Warrier
- Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA
| | - Teresa Noel
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA
| | - David K. Powell
- Magnetic Resonance Imaging and Spectroscopy Center, University of Kentucky Medical Center, Lexington, KY 40536, USA
| | - Jennifer M. Brelsfoard
- Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536, USA
| | - Rukhsana Sultana
- Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA
| | - Kathryn E. Saatman
- Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536, USA
| | - Daret K. St. Clair
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA
- Department of Radiation Medicine, University of Kentucky, Lexington, KY 40502, USA
- Markey Cancer Center, University of Kentucky, Lexington, KY 40502, USA
| | - D. Allan Butterfield
- Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA
- Markey Cancer Center, University of Kentucky, Lexington, KY 40502, USA
- Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA
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20
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Wauchope OR, Mitchener MM, Beavers WN, Galligan JJ, Camarillo JM, Sanders WD, Kingsley PJ, Shim HN, Blackwell T, Luong T, deCaestecker M, Fessel JP, Marnett LJ. Oxidative stress increases M1dG, a major peroxidation-derived DNA adduct, in mitochondrial DNA. Nucleic Acids Res 2018; 46:3458-3467. [PMID: 29438559 PMCID: PMC5909422 DOI: 10.1093/nar/gky089] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 01/29/2018] [Accepted: 02/03/2018] [Indexed: 02/07/2023] Open
Abstract
Reactive oxygen species (ROS) are formed in mitochondria during electron transport and energy generation. Elevated levels of ROS lead to increased amounts of mitochondrial DNA (mtDNA) damage. We report that levels of M1dG, a major endogenous peroxidation-derived DNA adduct, are 50-100-fold higher in mtDNA than in nuclear DNA in several different human cell lines. Treatment of cells with agents that either increase or decrease mitochondrial superoxide levels leads to increased or decreased levels of M1dG in mtDNA, respectively. Sequence analysis of adducted mtDNA suggests that M1dG residues are randomly distributed throughout the mitochondrial genome. Basal levels of M1dG in mtDNA from pulmonary microvascular endothelial cells (PMVECs) from transgenic bone morphogenetic protein receptor 2 mutant mice (BMPR2R899X) (four adducts per 106 dG) are twice as high as adduct levels in wild-type cells. A similar increase was observed in mtDNA from heterozygous null (BMPR2+/-) compared to wild-type PMVECs. Pulmonary arterial hypertension is observed in the presence of BMPR2 signaling disruptions, which are also associated with mitochondrial dysfunction and oxidant injury to endothelial tissue. Persistence of M1dG adducts in mtDNA could have implications for mutagenesis and mitochondrial gene expression, thereby contributing to the role of mitochondrial dysfunction in diseases.
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Affiliation(s)
- Orrette R Wauchope
- A.B. Hancock, Jr., Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Michelle M Mitchener
- Department of Chemistry, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - William N Beavers
- Department of Chemistry, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - James J Galligan
- A.B. Hancock, Jr., Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Jeannie M Camarillo
- A.B. Hancock, Jr., Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - William D Sanders
- A.B. Hancock, Jr., Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Philip J Kingsley
- A.B. Hancock, Jr., Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Ha-Na Shim
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
- Department of Pharmacology, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Thomas Blackwell
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
- Department of Pharmacology, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Thong Luong
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
- Department of Pharmacology, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Mark deCaestecker
- Departments of Cell and Developmental Biology, Surgery and Medicine, USA
| | - Joshua P Fessel
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
- Department of Pharmacology, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Lawrence J Marnett
- A.B. Hancock, Jr., Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA
- Department of Chemistry, Vanderbilt University School of Medicine, Nashville, TN, USA
- Department of Pharmacology, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
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Kruger C, Burke SJ, Collier JJ, Nguyen TT, Salbaum JM, Stadler K. Lipid peroxidation regulates podocyte migration and cytoskeletal structure through redox sensitive RhoA signaling. Redox Biol 2018; 16:248-254. [PMID: 29547847 PMCID: PMC5854917 DOI: 10.1016/j.redox.2018.02.024] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 02/24/2018] [Accepted: 02/25/2018] [Indexed: 11/28/2022] Open
Abstract
Early podocyte loss is characteristic of chronic kidney diseases (CKD) in obesity and diabetes. Since treatments for hyperglycemia and hypertension do not prevent podocyte loss, there must be additional factors causing podocyte depletion. The role of oxidative stress has been implicated in CKD but it is not known how exactly free radicals affect podocyte physiology. To assess this relationship, we investigated the effects of lipid radicals on podocytes, as lipid peroxidation is a major form of oxidative stress in diabetes. We found that lipid radicals govern changes in podocyte homeostasis through redox sensitive RhoA signaling: lipid radicals inhibit migration and cause loss of F-actin fibers. These effects were prevented by mutating the redox sensitive cysteines of RhoA. We therefore suggest that in diseases associated with increased lipid peroxidation, lipid radicals can determine podocyte function with potentially pathogenic consequences for kidney physiology.
Lipid peroxyl radicals impact podocyte motility and cytoskeletal F-actin arrangement. Lipid peroxyl radicals activate the small GTPase RhoA. When the Cys residues of RhoA are mutated, lipid peroxyl radicals do not affect podocytes. Lipid peroxidation likely contributes to podocyte injury.
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Affiliation(s)
- Claudia Kruger
- Oxidative Stress and Disease Laboratory, Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, 70808 LA, USA
| | - Susan J Burke
- Immunogenetics Laboratory, Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, 70808 LA, USA
| | - J Jason Collier
- Islet Cell Biology Laboratory, Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, 70808 LA, USA
| | - Trang-Tiffany Nguyen
- Oxidative Stress and Disease Laboratory, Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, 70808 LA, USA
| | - J Michael Salbaum
- Regulation of Gene Expression Laboratory, Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, 70808 LA, USA
| | - Krisztian Stadler
- Oxidative Stress and Disease Laboratory, Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, 70808 LA, USA.
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22
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NADPH Oxidases: Insights into Selected Functions and Mechanisms of Action in Cancer and Stem Cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017. [PMID: 28626501 PMCID: PMC5463201 DOI: 10.1155/2017/9420539] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
NADPH oxidases (NOX) are reactive oxygen species- (ROS-) generating enzymes regulating numerous redox-dependent signaling pathways. NOX are important regulators of cell differentiation, growth, and proliferation and of mechanisms, important for a wide range of processes from embryonic development, through tissue regeneration to the development and spread of cancer. In this review, we discuss the roles of NOX and NOX-derived ROS in the functioning of stem cells and cancer stem cells and in selected aspects of cancer cell physiology. Understanding the functions and complex activities of NOX is important for the application of stem cells in tissue engineering, regenerative medicine, and development of new therapies toward invasive forms of cancers.
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23
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Demeyer D, Mertens B, De Smet S, Ulens M. Mechanisms Linking Colorectal Cancer to the Consumption of (Processed) Red Meat: A Review. Crit Rev Food Sci Nutr 2017; 56:2747-66. [PMID: 25975275 DOI: 10.1080/10408398.2013.873886] [Citation(s) in RCA: 132] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the world. The vast majority of CRC cases have been linked to environmental causes rather than to heritable genetic changes. Over the last decades, epidemiological evidence linking the consumption of red and, more convincingly, of processed red meat to CRC has accumulated. In parallel, hypotheses on carcinogenic mechanisms underlying an association between CRC and the intake of red and processed red meat have been proposed and investigated in biological studies. The hypotheses that have received most attention until now include (1) the presence of polycyclic aromatic hydrocarbons and heterocyclic aromatic amines, two groups of compounds recognized as carcinogenic, (2) the enhancing effect of (nitrosyl)heme on the formation of carcinogenic N-nitroso compounds and lipid peroxidation. However, none of these hypotheses completely explains the link between red and processed red meat intake and the CRC risk. Consequently, scientists have proposed additional mechanisms or refined their hypotheses. This review first briefly summarizes the development of CRC followed by an in-depth overview and critical discussion of the different potential carcinogenic mechanisms underlying the increased CRC risk associated with the consumption of red and processed red meat.
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Affiliation(s)
- Daniel Demeyer
- a Superior Health Council , Brussels , Belgium.,b Laboratory for Animal Nutrition and Animal Product Quality , Faculty of Bioscience Engineering, Ghent University , Melle , Belgium
| | - Birgit Mertens
- a Superior Health Council , Brussels , Belgium.,c Program Toxicology, Department of Food , Medicines and Consumer Safety, Scientific Institute of Public Health (Site Elsene) , Brussels , Belgium
| | - Stefaan De Smet
- a Superior Health Council , Brussels , Belgium.,b Laboratory for Animal Nutrition and Animal Product Quality , Faculty of Bioscience Engineering, Ghent University , Melle , Belgium
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24
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Selvaratnam J, Robaire B. Overexpression of catalase in mice reduces age-related oxidative stress and maintains sperm production. Exp Gerontol 2016; 84:12-20. [PMID: 27575890 DOI: 10.1016/j.exger.2016.08.012] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Revised: 08/22/2016] [Accepted: 08/25/2016] [Indexed: 11/18/2022]
Abstract
Advanced paternal age is associated with increased complications in pregnancy and genetic diseases in offspring. Oxidative stress is a major contributor to the damage accumulated in sperm during aging. Complex networks of antioxidants regulate reactive oxygen species (ROS) in the testis. While mounting evident shows that redox dysfunction compromises the quality of developing male germ cells, the mechanisms by which aging causes this remain unclear. Furthermore, therapies to successfully alleviate aging-associated loss in germ cell quality are limited. The antioxidant catalase (CAT) has been used in aging-associated pathologies to alleviate oxidative stress. We used mice overexpressing CAT (MCAT) to determine whether CAT overexpression alleviates the redox dysfunction observed with aging. We found that MCAT mice did not exhibit the age-dependent loss of spermatozoa, nor did they show aging associated loss in testicular germ and Sertoli cells seen in wild type (WT). Low overall ROS and reduced peroxynitrite levels were detected in spermatocytes from aged MCAT mice, following exposure to the pro-oxidant tert-butyl hydroperoxide. Germ cells from young MCATs showed elevated levels of DNA-damage repair markers, γ-H2AX and 53BP1, but this response was lost with aging. Finally, we found oxidative stress induced 8-oxodG lesions to increase in sperm with aging; these lesions were significantly reduced in aged MCAT and these mice showed no decrease in the age-dependent number of pups per litter. Thus we conclude that aged MCAT mice generate sperm at the same rate as young mice; these sperm are protected from oxidative stress associated damage.
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Affiliation(s)
- Johanna Selvaratnam
- Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec H3G 1Y6, Canada
| | - Bernard Robaire
- Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec H3G 1Y6, Canada; Obstetrics and Gynecology, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec H3G 1Y6, Canada.
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25
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Machado AK, Pan AY, da Silva TM, Duong A, Andreazza AC. Upstream Pathways Controlling Mitochondrial Function in Major Psychosis: A Focus on Bipolar Disorder. CANADIAN JOURNAL OF PSYCHIATRY. REVUE CANADIENNE DE PSYCHIATRIE 2016; 61:446-56. [PMID: 27310240 PMCID: PMC4959649 DOI: 10.1177/0706743716648297] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Mitochondrial dysfunction is commonly observed in bipolar disorder (BD) and schizophrenia (SCZ) and may be a central feature of psychosis. These illnesses are complex and heterogeneous, which is reflected by the complexity of the processes regulating mitochondrial function. Mitochondria are typically associated with energy production; however, dysfunction of mitochondria affects not only energy production but also vital cellular processes, including the formation of reactive oxygen species, cell cycle and survival, intracellular Ca(2+) homeostasis, and neurotransmission. In this review, we characterize the upstream components controlling mitochondrial function, including 1) mutations in nuclear and mitochondrial DNA, 2) mitochondrial dynamics, and 3) intracellular Ca(2+) homeostasis. Characterizing and understanding the upstream factors that regulate mitochondrial function is essential to understand progression of these illnesses and develop biomarkers and therapeutics.
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Affiliation(s)
- Alencar Kolinski Machado
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario Federal University of Santa Maria, Santa Maria, RS, Brazil Both authors contributed equally to this article
| | - Alexander Yongshuai Pan
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario Both authors contributed equally to this article
| | - Tatiane Morgana da Silva
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario Federal University of Pelotas, Pelotas, RS, Brazil
| | - Angela Duong
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario
| | - Ana Cristina Andreazza
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario Department of Psychiatry, University of Toronto, Toronto, Ontario Centre for Addiction and Mental Health, Toronto, Ontario
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26
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Selvaratnam JS, Robaire B. Effects of Aging and Oxidative Stress on Spermatozoa of Superoxide-Dismutase 1- and Catalase-Null Mice. Biol Reprod 2016; 95:60. [PMID: 27465136 PMCID: PMC5333935 DOI: 10.1095/biolreprod.116.141671] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Accepted: 07/22/2016] [Indexed: 12/28/2022] Open
Abstract
Advanced paternal age is linked to complications in pregnancy and genetic diseases in offspring. Aging results in excess reactive oxygen species (ROS) and DNA damage in spermatozoa; this damage can be transmitted to progeny with detrimental consequences. Although there is a loss of antioxidants with aging, the impact on aging male germ cells of the complete absence of either catalase (CAT) or superoxide dismutase 1 (SOD1) has not been investigated. We used CAT-null (Cat(-/-)) and SOD1-null (Sod(-/-)) mice to determine whether loss of these antioxidants increases germ cell susceptibility to redox dysfunction with aging. Aging reduced fertility and the numbers of Sertoli and germ cells in all mice. Aged Sod(-/-) mice displayed an increased loss of fertility compared to aged wild-type mice. Treatment with the pro-oxidant SIN-10 increased ROS in spermatocytes of aged wild-type and Sod(-/-) mice, while aged Cat(-/-) mice were able to neutralize this ROS. The antioxidant peroxiredoxin 1 (PRDX1) increased with age in wild-type and Cat(-/-) mice but was consistently low in young and aged Sod(-/-) mice. DNA damage and repair markers (γ-H2AX and 53BP1) were reduced with aging and lower in young Sod(-/-) and Cat(-/-) mice. Colocalization of γ-H2AX and 53BP1 suggested active repair in young wild-type mice but reduced in young Cat(-/-) and in Sod(-/-) mice and with age. Oxidative DNA damage (8-oxodG) increased in young Sod(-/-) mice and with age in all mice. These studies show that aged Sod(-/-) mice display severe redox dysfunction, while wild-type and Cat(-/-) mice have compensatory mechanisms to partially alleviate oxidative stress and reduce age-related DNA damage in spermatozoa. Thus, SOD1 but not CAT is critical to the maintenance of germ cell quality with aging.
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Affiliation(s)
- Johanna S Selvaratnam
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Bernard Robaire
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada Department of Obstetrics and Gynecology, McGill University, Montréal, Québec, Canada
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27
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Vonder Haar C, Peterson TC, Martens KM, Hoane MR. Vitamins and nutrients as primary treatments in experimental brain injury: Clinical implications for nutraceutical therapies. Brain Res 2016; 1640:114-129. [PMID: 26723564 PMCID: PMC4870112 DOI: 10.1016/j.brainres.2015.12.030] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Revised: 12/14/2015] [Accepted: 12/15/2015] [Indexed: 02/07/2023]
Abstract
With the numerous failures of pharmaceuticals to treat traumatic brain injury in humans, more researchers have become interested in combination therapies. This is largely due to the multimodal nature of damage from injury, which causes excitotoxicity, oxidative stress, edema, neuroinflammation and cell death. Polydrug treatments have the potential to target multiple aspects of the secondary injury cascade, while many previous therapies focused on one particular aspect. Of specific note are vitamins, minerals and nutrients that can be utilized to supplement other therapies. Many of these have low toxicity, are already FDA approved and have minimal interactions with other drugs, making them attractive targets for therapeutics. Over the past 20 years, interest in supplementation and supraphysiologic dosing of nutrients for brain injury has increased and indeed many vitamins and nutrients now have a considerable body of the literature backing their use. Here, we review several of the prominent therapies in the category of nutraceutical treatment for brain injury in experimental models, including vitamins (B2, B3, B6, B9, C, D, E), herbs and traditional medicines (ginseng, Gingko biloba), flavonoids, and other nutrients (magnesium, zinc, carnitine, omega-3 fatty acids). While there is still much work to be done, several of these have strong potential for clinical therapies, particularly with regard to polydrug regimens. This article is part of a Special Issue entitled SI:Brain injury and recovery.
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28
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Budachetri K, Karim S. An insight into the functional role of thioredoxin reductase, a selenoprotein, in maintaining normal native microbiota in the Gulf Coast tick (Amblyomma maculatum). INSECT MOLECULAR BIOLOGY 2015; 24:570-81. [PMID: 26184979 PMCID: PMC4560682 DOI: 10.1111/imb.12184] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
Tick selenoproteins have been associated with antioxidant activity in ticks. Thioredoxin reductase (TrxR), also a selenoprotein, belongs to the pyridine nucleotide-disulphide oxidoreductase family of proteins and is an important antioxidant. Molecular interactions between native microbiota and tick hosts have barely been investigated to date. In this study, we determined the functional role of TrxR in tick feeding and in maintenance of the native microbial community. TrxR transcript levels remained high and microbial load was reduced throughout tick attachment to the vertebrate host. RNA interference (RNAi) showed that depletion of TrxR activity did not interfere with tick haematophagy or phenotype but did reduce the viability of the microbiome within the tick tissues, presumably by perturbing redox homeostasis. The transcriptional activity of various antioxidant genes remained unaffected whereas the antioxidant genes Manganese superoxide dismutase (MnSOD), copper/zinc superoxide dismutase (Cu/Zn SOD) and selenoprotein M (SelM) were significantly down-regulated in salivary glands of the ticks subjected to RNAi. The perturbed TrxR enzymatic activity in the knocked-down tick tissues negatively affected the bacterial load as well. Furthermore, we observed the altered bacterial profiles in TrxR-silenced tick tissues. Taken together, these results indicate an essential functional role for TrxR in maintaining the bacterial community associated with ticks.
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Affiliation(s)
- K Budachetri
- Department of Biological Sciences, The University of Southern Mississippi, Hattiesburg, MS, USA
| | - S Karim
- Department of Biological Sciences, The University of Southern Mississippi, Hattiesburg, MS, USA
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29
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Akhmedov AT, Marín-García J. Mitochondrial DNA maintenance: an appraisal. Mol Cell Biochem 2015; 409:283-305. [DOI: 10.1007/s11010-015-2532-x] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 08/06/2015] [Indexed: 12/13/2022]
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30
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Selvaratnam J, Paul C, Robaire B. Male Rat Germ Cells Display Age-Dependent and Cell-Specific Susceptibility in Response to Oxidative Stress Challenges. Biol Reprod 2015. [PMID: 26224006 DOI: 10.1095/biolreprod.115.131318] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
For decades male germ cells were considered unaffected by aging, due to the fact that males continue to generate sperm into old age; however, evidence indicates that germ cells from aged males are of lower quality than those of young males. The current study examines the effects of aging on pachytene spermatocytes and round spermatids, and is the first study to culture these cells in isolation for an extended period. Our objective is to determine the cell-specific responses germ cells have to aging and oxidative insult. Culturing isolated germ cells from young and aged Brown Norway rats revealed that germ cells from aged males displayed an earlier decline in viability, elevated levels of reactive oxygen species (ROS), and increased spermatocyte DNA damage, compared to young males. Furthermore, oxidative insult by prooxidant 3-morpholinosydnonimine provides insight into how spermatocytes and spermatids manage excess ROS. Genome-wide microarray analyses revealed that several transcripts for antioxidants, Sod1, Cat, and Prdxs, were up-regulated in response to ROS in germ cells from young males while being expressed at lower levels in the aged. In contrast, the expression of DNA damage repair genes Rad50 and Atm were increased in the germ cells from aged animals. Our data indicate that as germ cells undergo spermatogenesis, they adapt and respond to oxidative stress differently, depending on their phase of development, and the process of aging results in redox dysfunction. Thus, even at early stages of spermatogenesis, germ cells from aged males are unable to mount an appropriate response to manage oxidative stress.
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Affiliation(s)
- Johanna Selvaratnam
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Catriona Paul
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Bernard Robaire
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada Department of Obstetrics and Gynecology, McGill University, Montréal, Québec, Canada
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31
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Wei X, Yin H. Covalent modification of DNA by α, β-unsaturated aldehydes derived from lipid peroxidation: Recent progress and challenges. Free Radic Res 2015; 49:905-17. [PMID: 25968945 DOI: 10.3109/10715762.2015.1040009] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Oxidative stress-induced lipid peroxidation (LPO) has been associated with human physiology and pathophysiology. LPO generates an array of oxidation products and among them reactive lipid aldehydes have received intensive research attentions due to their roles in modulating functions of biomolecules through covalent modification. Thus, covalent modification of DNA by these reactive lipid electrophiles has been postulated to be partially responsible for the biological roles of LPO. In this review, we summarized recent progress and challenges in studying the roles of covalent modification of DNA including nuclear and mitochondrial DNA by reactive lipid metabolites from LPO. We focused on the novel mechanistic insights into generation of lipid aldehydes from cellular membranes especially mitochondria through LPO. Recent advances in the technological front using mass spectrometry have also been highlighted in the settings of studying DNA damage caused by LPO and its biological relevance.
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Affiliation(s)
- X Wei
- Key Laboratory of Food Safety Research, Institute for Nutritional Sciences (INS), Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) , Shanghai , China
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32
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Cheng J, Liu Q, Shuhendler AJ, Rauth AM, Wu XY. Optimizing the design and in vitro evaluation of bioreactive glucose oxidase-microspheres for enhanced cytotoxicity against multidrug resistant breast cancer cells. Colloids Surf B Biointerfaces 2015; 130:164-72. [PMID: 25896537 DOI: 10.1016/j.colsurfb.2015.04.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Revised: 03/31/2015] [Accepted: 04/01/2015] [Indexed: 01/11/2023]
Abstract
Glucose oxidase (GOX) encapsulated in alginate-chitosan microspheres (GOX-MS) was shown in our previous work to produce reactive oxygen species (ROS) in situ and exhibit anticancer effects in vitro and in vivo. The purpose of present work was to optimize the design and thus enhance the efficacy of GOX-MS against multidrug resistant (MDR) cancer cells. GOX-MS with different mean diameters of 4, 20 or 140 μm were prepared using an emulsification-internal gelation-adsorption-chitosan coating method with varying compositions and conditions. The GOX loading efficiency, loading level, relative bioactivity of GOX-MS, and GOX leakage were determined and optimal chitosan concentrations in the coating solution were identified. The influence of particle size on cellular uptake, ROS generation, cytotoxicity and their underlying mechanisms was investigated. At the same GOX dose and incubation time, smaller sized GOX-MS produced larger amounts of H2O2 in cell culture medium and greater cytotoxicity toward murine breast cancer MDR (EMT6/AR1.0) and wild type (EMT6/WT) cells. Fluorescence and confocal laser scanning microscopy revealed significant uptake of small sized (4 μm) GOX-MS by both MDR and WT cells, but no cellular uptake of large (140 μm) GOX-MS. The GOX-MS were equally effective in killing both MDR cells and WT cells. The cytotoxicity of the GOX formulations was positively correlated with membrane damage and lipid peroxidation. GOX-MS induced greater membrane damage and lipid peroxidation in MDR cells than the WT cells. These results suggest that the optimized, small micron-sized GOX-MS are highly effective against MDR breast cancer cells.
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Affiliation(s)
- Ji Cheng
- Advanced Pharmaceutics & Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, Canada M5S 3M2
| | - Qun Liu
- Advanced Pharmaceutics & Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, Canada M5S 3M2
| | - Adam J Shuhendler
- Advanced Pharmaceutics & Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, Canada M5S 3M2
| | - Andrew M Rauth
- Departments of Medical Biophysics and Radiation Oncology, University of Toronto, 610 University Ave, Toronto, Ontario, Canada M5G 2M9
| | - Xiao Yu Wu
- Advanced Pharmaceutics & Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, Canada M5S 3M2.
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Wauquier F, Léotoing L, Philippe C, Spilmont M, Coxam V, Wittrant Y. Pros and cons of fatty acids in bone biology. Prog Lipid Res 2015; 58:121-45. [PMID: 25835096 DOI: 10.1016/j.plipres.2015.03.001] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Revised: 03/06/2015] [Accepted: 03/23/2015] [Indexed: 12/12/2022]
Abstract
Despite the growing interest in deciphering the causes and consequences of obesity-related disorders, the mechanisms linking fat intake to bone behaviour remain unclear. Since bone fractures are widely associated with increased morbidity and mortality, most notably in elderly and obese people, bone health has become a major social and economic issue. Consistently, public health system guidelines have encouraged low-fat diets in order to reduce associated complications. However, from a bone point of view, mechanisms linking fat intake to bone alteration remain quite controversial. Thus, after more than a decade of dedicated studies, this timely review offers a comprehensive overview of the relationships between bone and fatty acids. Using clinical evidences as a starting-point to more complex molecular elucidation, this work highlights the complexity of the system and reveals that bone alteration that cannot be solved simply by taking ω-3 pills. Fatty acid effects on bone metabolism can be both direct and indirect and require integrated investigations. Furthermore, even at the level of a single cell, one fatty acid is able to trigger several different independent pathways (receptors, metabolites…) which may all have a say in the final cellular metabolic response.
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Affiliation(s)
- Fabien Wauquier
- INRA, UMR 1019, UNH, CRNH Auvergne, F-63009 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France; Equipe Alimentation, Squelette et Métabolismes, France
| | - Laurent Léotoing
- INRA, UMR 1019, UNH, CRNH Auvergne, F-63009 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France; Equipe Alimentation, Squelette et Métabolismes, France
| | - Claire Philippe
- INRA, UMR 1019, UNH, CRNH Auvergne, F-63009 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France; Equipe Alimentation, Squelette et Métabolismes, France
| | - Mélanie Spilmont
- INRA, UMR 1019, UNH, CRNH Auvergne, F-63009 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France; Equipe Alimentation, Squelette et Métabolismes, France
| | - Véronique Coxam
- INRA, UMR 1019, UNH, CRNH Auvergne, F-63009 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France; Equipe Alimentation, Squelette et Métabolismes, France
| | - Yohann Wittrant
- INRA, UMR 1019, UNH, CRNH Auvergne, F-63009 Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France; Equipe Alimentation, Squelette et Métabolismes, France.
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Abdekhodaie M, Cheng J, Wu X. Effect of formulation factors on the bioactivity of glucose oxidase encapsulated chitosan–alginate microspheres: In vitro investigation and mathematical model prediction. Chem Eng Sci 2015. [DOI: 10.1016/j.ces.2014.11.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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35
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Reiss LK, Fragoulis A, Siegl S, Platen C, Kan YW, Nautiyal J, Parker M, Pufe T, Uhlig U, Martin C, Uhlig S, Wruck CJ. Interplay between nuclear factor erythroid 2-related factor 2 and amphiregulin during mechanical ventilation. Am J Respir Cell Mol Biol 2015; 51:668-77. [PMID: 24921206 DOI: 10.1165/rcmb.2013-0279oc] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Mechanical ventilation (MV) elicits complex and clinically relevant cellular responses in the lungs. The current study was designed to define the role of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), a major regulator of the cellular antioxidant defense system, in the pulmonary response to MV. Nrf2 activity was quantified in ventilated isolated perfused mouse lungs (IPL). Regulation of amphiregulin (AREG) was investigated in BEAS-2B cells with inactivated Nrf2 or Keap1, the inhibitor of Nrf2, using a luciferase vector with AREG promoter. AREG-dependent Nrf2 activity was examined in BEAS-2B cells, murine precision-cut lung slices (PCLS), and IPL. Finally, Nrf2 knockout and wild-type mice were ventilated to investigate the interplay between Nrf2 and AREG during MV in vivo. Lung functions and inflammatory parameters were measured. Nrf2 was activated in a ventilation-dependent manner. The knockdown of Nrf2 and Keap1 via short hairpin RNA in BEAS-2B cells and an EMSA with lung tissue revealed that AREG is regulated by Nrf2. Conversely, AREG application induced a significant Nrf2 activation in BEAS-2B cells, PCLS, and IPL. The signal transduction of ventilation-induced Nrf2 activation was shown to be p38 MAP kinase-dependent. In vivo ventilation experiments indicated that AREG is regulated by Nrf2 during MV. We conclude that Areg expression is regulated by Nrf2. During high-pressure ventilation, Nrf2 becomes activated and induces AREG, leading to a positive feedback loop between Nrf2 and AREG, which involves the p38 MAPK and results in the expression of cytoprotective genes.
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Sohal RS, Forster MJ. Caloric restriction and the aging process: a critique. Free Radic Biol Med 2014; 73:366-82. [PMID: 24941891 PMCID: PMC4111977 DOI: 10.1016/j.freeradbiomed.2014.05.015] [Citation(s) in RCA: 118] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Revised: 05/16/2014] [Accepted: 05/17/2014] [Indexed: 01/06/2023]
Abstract
The main objective of this review is to provide an appraisal of the current status of the relationship between energy intake and the life span of animals. The concept that a reduction in food intake, or caloric restriction (CR), retards the aging process, delays the age-associated decline in physiological fitness, and extends the life span of organisms of diverse phylogenetic groups is one of the leading paradigms in gerontology. However, emerging evidence disputes some of the primary tenets of this conception. One disparity is that the CR-related increase in longevity is not universal and may not even be shared among different strains of the same species. A further misgiving is that the control animals, fed ad libitum (AL), become overweight and prone to early onset of diseases and death, and thus may not be the ideal control animals for studies concerned with comparisons of longevity. Reexamination of body weight and longevity data from a study involving over 60,000 mice and rats, conducted by a National Institute on Aging-sponsored project, suggests that CR-related increase in life span of specific genotypes is directly related to the gain in body weight under the AL feeding regimen. Additionally, CR in mammals and "dietary restriction" in organisms such as Drosophila are dissimilar phenomena, albeit they are often presented to be the very same. The latter involves a reduction in yeast rather than caloric intake, which is inconsistent with the notion of a common, conserved mechanism of CR action in different species. Although specific mechanisms by which CR affects longevity are not well understood, existing evidence supports the view that CR increases the life span of those particular genotypes that develop energy imbalance owing to AL feeding. In such groups, CR lowers body temperature, rate of metabolism, and oxidant production and retards the age-related pro-oxidizing shift in the redox state.
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Affiliation(s)
- Rajindar S Sohal
- Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA.
| | - Michael J Forster
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
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Argüello G, Martinez P, Peña J, Chen O, Platt F, Zanlungo S, González M. Hepatic metabolic response to restricted copper intake in a Niemann–Pick C murine model. Metallomics 2014; 6:1527-39. [DOI: 10.1039/c4mt00056k] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Niemann–Pick C disease (NPC) is a vesicular trafficking disorder primarily caused by mutations in theNpc1gene and characterized by liver dysfunction and neuropathology.
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Affiliation(s)
- Graciela Argüello
- INTA
- Laboratorio de Bioinformática y Expresión Génica
- Universidad de Chile
- Santiago, Chile
- FONDAP-Center of Genome Regulation (CGR)
| | - Pablo Martinez
- Departamento de Gastroenterología
- Facultad de Medicina
- Pontificia Universidad Católica de Chile
- Santiago, Chile
| | - Juan Peña
- INTA
- Laboratorio de Bioinformática y Expresión Génica
- Universidad de Chile
- Santiago, Chile
| | - Oscar Chen
- Department of Pharmacology
- University of Oxford
- Oxford OX1 3QT, UK
| | - Frances Platt
- Department of Pharmacology
- University of Oxford
- Oxford OX1 3QT, UK
| | - Silvana Zanlungo
- FONDAP-Center of Genome Regulation (CGR)
- Santiago, Chile
- Departamento de Gastroenterología
- Facultad de Medicina
- Pontificia Universidad Católica de Chile
| | - Mauricio González
- INTA
- Laboratorio de Bioinformática y Expresión Génica
- Universidad de Chile
- Santiago, Chile
- FONDAP-Center of Genome Regulation (CGR)
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Krogenæs AK, Ropstad E, Gutleb AC, Hårdnes N, Berg V, Dahl E, Fowler PA. In utero exposure to environmentally relevant concentrations of PCB 153 and PCB 118 disrupts fetal testis development in sheep. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2014; 77:628-649. [PMID: 24754397 DOI: 10.1080/15287394.2014.887426] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Polychlorinated biphenyls (PCB) are environmental pollutants linked to adverse health effects including endocrine disruption and disturbance of reproductive development. This study aimed to determine whether exposure of pregnant sheep to three different mixtures of PCB 153 and PCB 118 affected fetal testis development. Ewes were treated by oral gavage from mating until euthanasia (d 134), producing three groups of fetuses with distinct adipose tissue PCB levels: high PCB 153/low PCB 118 (n = 13), high PCB 118/low PCB 153 (n = 14), and low PCB 153/low PCB 118 (n = 14). Fetal testes and blood samples were collected for investigation of testosterone, testis morphology, and testis proteome. The body weight of the offspring was lower in the high PCB compared to the low PCB group, but there were no significant differences in testis weight between groups when corrected for body weight. PCB exposure did not markedly affect circulating testosterone. There were no significant differences between groups in number of seminiferous tubules, Sertoli cell only tubules, and ratio between relative areas of seminiferous tubules and interstitium. Two-dimensional (2D) gel-based proteomics was used to screen for proteomic alterations in the high exposed groups relative to low PCB 153/low PCB 118 group. Twenty-six significantly altered spots were identified by liquid chromatography (LC)-mass spectroscopy (MS)/MS. Changes in protein regulation affected cellular processes as stress response, protein synthesis, and cytoskeleton regulation. The study demonstrates that in utero exposure to different environmental relevant PCB mixtures exerted subtle effects on developing fetal testis proteome but did not significantly disturb testis morphology and testosterone production.
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Affiliation(s)
- Anette K Krogenæs
- a Department of Production Animal Sciences , Norwegian School Veterinary Science , Oslo , Norway
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Andreazza AC, Wang JF, Salmasi F, Shao L, Young LT. Specific subcellular changes in oxidative stress in prefrontal cortex from patients with bipolar disorder. J Neurochem 2013; 127:552-61. [DOI: 10.1111/jnc.12316] [Citation(s) in RCA: 110] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Revised: 05/14/2013] [Accepted: 05/15/2013] [Indexed: 12/25/2022]
Affiliation(s)
- Ana C. Andreazza
- Departments of Psychiatry and Pharmacology; University of Toronto; Toronto Ontario Canada
- Centre for Addiction and Mental Health; Toronto Ontario Canada
| | - Jun-Feng Wang
- Department of Pharmacology and Therapeutics; University of Manitoba; Winnipeg Manitoba Canada
| | - Faraz Salmasi
- Departments of Psychiatry and Pharmacology; University of Toronto; Toronto Ontario Canada
| | - Li Shao
- Department of Psychiatry; University of British Columbia; Vancouver British Columbia Canada
| | - Lionel T. Young
- Departments of Psychiatry and Pharmacology; University of Toronto; Toronto Ontario Canada
- Centre for Addiction and Mental Health; Toronto Ontario Canada
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Zhang SC, Shi Q, Feng YN, Fang J. Tissue-Protective Effect of Glutamine on Hepatic Ischemia-Reperfusion Injury via Induction of Heme Oxygenase-1. Pharmacology 2013; 91:59-68. [DOI: 10.1159/000343809] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2012] [Accepted: 09/27/2012] [Indexed: 12/30/2022]
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Fredriksson MI. Effect of Priming in Subpopulations of Peripheral Neutrophils From Patients with Chronic Periodontitis. J Periodontol 2012; 83:1192-9. [DOI: 10.1902/jop.2012.110584] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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Acid stress response and protein induction in Campylobacter jejuni isolates with different acid tolerance. BMC Microbiol 2012; 12:174. [PMID: 22889088 PMCID: PMC3528441 DOI: 10.1186/1471-2180-12-174] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2012] [Accepted: 07/20/2012] [Indexed: 11/23/2022] Open
Abstract
Background During the transmission route from poultry to the human host, the major foodborne pathogen C. jejuni may experience many types of stresses, including low pH caused by different acids. However, not all strains are equally sensitive to the stresses. The aim of this study was to investigate the response to acid stress of three sequenced C. jejuni strains with different acid tolerances using HCl and acetic acid. Results Two-dimensional gel electrophoresis was used for proteomic analysis and proteins were radioactively labelled with methionine to identify proteins only related to acid exposure. To allow added radioactive methionine to be incorporated into induced proteins, a modified chemically defined broth was developed with the minimal amount of methionine necessary for satisfactory growth of all strains. Protein spots were analyzed using image software and identification was done with MALDI-TOF-TOF. The most acid-sensitive isolate was C. jejuni 327, followed by NCTC 11168 and isolate 305 as the most tolerant. Overall, induction of five proteins was observed within the pI range investigated: 19 kDa periplasmic protein (p19), thioredoxin-disulfide (TrxB), a hypothetical protein Cj0706 (Cj0706), molybdenum cofactor biosynthesis protein (MogA), and bacterioferritin (Dps). Strain and acid type dependent differences in the level of response were observed. For strain NCTC 11168, the induced proteins and the regulator fur were analysed at the transcriptomic level using qRT-PCR. In this transcriptomic analysis, only up-regulation of trxB and p19 was observed. Conclusions A defined medium that supports the growth of a range of Campylobacter strains and suitable for proteomic analysis was developed. Mainly proteins normally involved in iron control and oxidative stress defence were induced during acid stress of C. jejuni. Both strain and acid type affected sensitivity and response.
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Le TTT, Mawatari K, Maetani M, Yamamoto T, Hayashida S, Iba H, Aihara M, Hirata A, Shimohata T, Uebanso T, Takahashi A. VP2118 has major roles in Vibrio parahaemolyticus response to oxidative stress. Biochim Biophys Acta Gen Subj 2012; 1820:1686-92. [PMID: 22771831 DOI: 10.1016/j.bbagen.2012.06.019] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2012] [Revised: 06/11/2012] [Accepted: 06/26/2012] [Indexed: 11/17/2022]
Abstract
BACKGROUND Reactive oxygen species (ROS), including superoxide anion radical, induce chronic risk of oxidative damage to many cellular macromolecules resulting in damage to cells. Superoxide dismutases (SODs) catalyze the dismutation of superoxide to oxygen and hydrogen peroxide and are a primary defense against ROS. Vibrio parahaemolyticus, a marine bacterium that causes acute gastroenteritis following consumption of raw or undercooked seafood, can survive ROS generated by intestinal inflammatory cells. However, there is little information concerning SODs in V. parahaemolyticus. This study aims to clarify the role of V. parahaemolyticus SODs against ROS. METHODS V. parahaemolyticus SOD gene promoter activities were measured by a GFP reporter assay. Mutants of V. parahaemolyticus SOD genes were constructed and their SOD activity and resistance to oxidative stresses were measured. RESULTS Bioinformatic analysis showed that V. parahaemolyticus SODs were distinguished by their metal cofactors, FeSOD (VP2118), MnSOD (VP2860), and CuZnSOD (VPA1514). VP2118 gene promoter activity was significantly higher than the other SOD genes. In a VP2118 gene deletion mutant, SOD activity was significantly decreased and could be recovered by VP2118 gene complementation. The absence of VP2118 resulted in significantly lowered resistance to ROS generated by hydrogen peroxide, hypoxanthine-xanthine oxidase, or Paraquat. Furthermore, both the N- and C-terminal SOD domains of VP2118 were necessary for ROS resistance. CONCLUSION VP2118 is the primary V. parahaemolyticus SOD and is vital for anti-oxidative stress responses. GENERAL SIGNIFICANCE The V. parahaemolyticus FeSOD VP2118 may enhance ROS resistance and could promote its survival in the intestinal tract to facilitate host tissue infection.
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Affiliation(s)
- Tam Thi Thanh Le
- Department of Preventive Environment and Nutrition, Institute of Health Bioscience, The University of Tokushima Graduate School, Kuramoto-cho, Tokushima-City, Tokushima, Japan
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Mitochondrial DNA damage and its consequences for mitochondrial gene expression. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2012; 1819:979-91. [PMID: 22728831 DOI: 10.1016/j.bbagrm.2012.06.002] [Citation(s) in RCA: 142] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2012] [Revised: 06/06/2012] [Accepted: 06/14/2012] [Indexed: 12/11/2022]
Abstract
How mitochondria process DNA damage and whether a change in the steady-state level of mitochondrial DNA damage (mtDNA) contributes to mitochondrial dysfunction are questions that fuel burgeoning areas of research into aging and disease pathogenesis. Over the past decade, researchers have identified and measured various forms of endogenous and environmental mtDNA damage and have elucidated mtDNA repair pathways. Interestingly, mitochondria do not appear to contain the full range of DNA repair mechanisms that operate in the nucleus, although mtDNA contains types of damage that are targets of each nuclear DNA repair pathway. The reduced repair capacity may, in part, explain the high mutation frequency of the mitochondrial chromosome. Since mtDNA replication is dependent on transcription, mtDNA damage may alter mitochondrial gene expression at three levels: by causing DNA polymerase γ nucleotide incorporation errors leading to mutations, by interfering with the priming of mtDNA replication by the mitochondrial RNA polymerase, or by inducing transcriptional mutagenesis or premature transcript termination. This review summarizes our current knowledge of mtDNA damage, its repair, and its effects on mtDNA integrity and gene expression. This article is part of a special issue entitled: Mitochondrial Gene Expression.
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Li DD, Han RM, Liang R, Chen CH, Lai W, Zhang JP, Skibsted LH. Hydroxyl radical reaction with trans-resveratrol: initial carbon radical adduct formation followed by rearrangement to phenoxyl radical. J Phys Chem B 2012; 116:7154-61. [PMID: 22650146 DOI: 10.1021/jp3033337] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
In the reaction between trans-resveratrol (resveratrol) and the hydroxyl radical, kinetic product control leads to a short-lived hydroxyl radical adduct with an absorption maximum at 420 nm and a lifetime of 0.21 ± 0.01 μs (anaerobic acetonitrile at 25 °C) as shown by laser flash photolysis using N-hydroxypyridine-2(1H)-thione (N-HPT) as a "photo-Fenton" reagent. The transient spectra of the radical adduct are in agreement with density functional theory (DFT) calculations showing an absorption maximum at 442 or 422 nm for C2 and C6 hydroxyl adducts, respectively, and showing the lowest energy for the transition state leading to the C2 adduct compared to other radical products. From this initial product, the relative long-lived 4'-phenoxyl radical of resveratrol (τ = 9.9 ± 0.9 μs) with an absorption maximum at 390 nm is formed in a process with a time constant (τ = 0.21 ± 0.01 μs) similar to the decay constant for the C2 hydroxyl adduct (or a C2/C6 hydroxyl adduct mixture) and in agreement with thermodynamics identifying this product as the most stable resveratrol radical. The hydroxyl radical adduct to phenoxyl radical conversion with concomitant water dissociation has a rate constant of 5 × 10(6) s(-1) and may occur by intramolecular hydrogen atom transfer or by stepwise proton-assisted electron transfer. Photolysis of N-HPT also leads to a thiyl radical which adds to resveratrol in a parallel reaction forming a sulfur radical adduct with a lifetime of 0.28 ± 0.04 μs and an absorption maximum at 483 nm.
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Affiliation(s)
- Dan-Dan Li
- Department of Chemistry, Renmin University of China, Beijing 100872, PR China
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Fang J, Qin H, Seki T, Nakamura H, Tsukigawa K, Shin T, Maeda H. Therapeutic potential of pegylated hemin for reactive oxygen species-related diseases via induction of heme oxygenase-1: results from a rat hepatic ischemia/reperfusion injury model. J Pharmacol Exp Ther 2011; 339:779-89. [PMID: 21890508 DOI: 10.1124/jpet.111.185348] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Many diseases and pathological conditions, including ischemia/reperfusion (I/R) injury, are the consequence of the actions of reactive oxygen species (ROS). Controlling ROS generation or its level may thus hold promise as a standard therapeutic modality for ROS-related diseases. Here, we assessed heme oxygenase-1 (HO-1), which is a crucial antioxidative, antiapoptotic molecule against intracellular stresses, for its therapeutic potential via its inducer, hemin. To improve the solubility and in vivo pharmacokinetics of hemin for clinical applications, we developed a micellar hemin by conjugating it with poly(ethylene glycol) (PEG) (PEG-hemin). PEG-hemin showed higher solubility in water and significantly prolonged plasma half-life than free hemin, which resulted from its micellar nature with molecular mass of 126 kDa in aqueous media. In a rat I/R model, administration of PEG-hemin significantly elevated HO-1 expression and enzymatic activity. This induction of HO-1 led to significantly improved liver function, reduced apoptosis and thiobarbituric acid reactive substances of the liver, and decreased inflammatory cytokine production. PEG-hemin administration also markedly improved hepatic blood flow. These results suggest that PEG-hemin exerted a significant cytoprotective effect against I/R injury in rat liver by inducing HO-1 and thus seems to be a potential therapeutic for ROS-related diseases, including I/R injury.
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Affiliation(s)
- Jun Fang
- Laboratory of Microbiology and Oncology, Faculty of Pharmaceutical Sciences, DDS Research Institute, Sojo University, Kumamoto 860-0082, Japan
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Peuser V, Glaeser J, Klug G. The RSP_2889 gene product of Rhodobacter sphaeroides is a CueR homologue controlling copper-responsive genes. Microbiology (Reading) 2011; 157:3306-3313. [DOI: 10.1099/mic.0.051607-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Metal homeostasis is important in all living cells in order to provide sufficient amounts of metal ions for biological processes but to prevent toxic effects by excess amounts. Here we show that the gene product of RSP_2889 of the facultatively photosynthetic bacterium Rhodobacter sphaeroides is homologous to CueR, a regulator of copper metabolism in Escherichia coli and other bacteria. CueR binds to the promoter regions of genes for a copper-translocating ATPase and for a copper chaperone and is responsible for their high expression when cells are exposed to elevated levels of copper ions. While deletion of RSP_2889 has no significant effect on copper resistance, expression from a low-copy-number plasmid mediates increased sensitivity to copper.
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Affiliation(s)
- Verena Peuser
- Institut für Mikrobiologie und Molekularbiologie, University of Giessen, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany
| | - Jens Glaeser
- Institut für Mikrobiologie und Molekularbiologie, University of Giessen, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany
| | - Gabriele Klug
- Institut für Mikrobiologie und Molekularbiologie, University of Giessen, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany
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Barreto TO, Cleto LS, Gioda CR, Silva RS, Campi-Azevedo AC, de Sousa-Franco J, de Magalhães JC, Penaforte CL, Pinto KMDC, Cruz JDS, Rocha-Vieira E. Swim training does not protect mice from skeletal muscle oxidative damage following a maximum exercise test. Eur J Appl Physiol 2011; 112:2523-30. [PMID: 22075638 DOI: 10.1007/s00421-011-2211-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2011] [Accepted: 10/12/2011] [Indexed: 11/27/2022]
Abstract
We investigated whether swim training protects skeletal muscle from oxidative damage in response to a maximum progressive exercise. First, we investigated the effect of swim training on the activities of the antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), in the gastrocnemius muscle of C57Bl/6 mice, 48 h after the last training session. Mice swam for 90 min, twice a day, for 5 weeks at 31°C (± 1°C). The activities of SOD and CAT were increased in trained mice (P < 0.05) compared to untrained group. However, no effect of training was observed in the activity of GPx. In a second experiment, trained and untrained mice were submitted to a maximum progressive swim test. Compared to control mice (untrained, not acutely exercised), malondialdehyde (MDA) levels were increased in the skeletal muscle of both trained and untrained mice after maximum swim. The activity of GPx was increased in the skeletal muscle of both trained and untrained mice, while SOD activity was increased only in trained mice after maximum swimming. CAT activity was increased only in the untrained compared to the control group. Although the trained mice showed increased activity of citrate synthase in skeletal muscle, swim performance was not different compared to untrained mice. Our results show an imbalance in the activities of SOD, CAT and GPx in response to swim training, which could account for the oxidative damage observed in the skeletal muscle of trained mice in response to maximum swim, resulting in the absence of improved exercise performance.
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Affiliation(s)
- Tatiane Oliveira Barreto
- Department of Biological, Environmental and Health Sciences, University Center of Belo Horizonte, Prof. Mario Werneck Av, 1685, Belo Horizonte, MG, 30455-610, Brazil
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The efficacy of antioxidants in functional recovery of spinal cord injured rats: an experimental study. Neurol Sci 2011; 33:785-91. [PMID: 22068217 DOI: 10.1007/s10072-011-0829-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2011] [Accepted: 10/20/2011] [Indexed: 02/08/2023]
Abstract
A total of 30 female Sprague-Dawley rats (180-220 g) subjected to spinal cord injury (SCI) were divided into three groups of ten rats each. Group 1 served as control (SCI + Saline), Group 2 received daily dose of ascorbic acid 2,000 mg/kg body weight and group 3 rats received alpha tocopherol daily with the dose of 2,000 mg/kg body weight for 14 days. The Spontaneous coordinate activity (SCA), Basso, Beattie, and Bresnahan (BBB) and Tarlov locomotor scores were used to assess functional recovery of SCI rats. Compared to group 1, group 2 showed statistically insignificant improvement in the SCA, BBB and Tarlov scores at the end of the study. Compared to group 1, group 3 showed statistically significant improvement in the SCA (P < 0.001), BBB (P < 0.001) and Tarlov (P < 0.01) scores at the end of the study. In conclusion, the administration of alpha-tocopherol enhances the reparative effects against SCI and it is more effective than ascorbic acid.
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