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1
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Dubey SK, Dubey R, Jung K, Hernandez AG, Kleinman ME. Deciphering age-related transcriptomic changes in the mouse retinal pigment epithelium. Aging (Albany NY) 2025; 17:657-684. [PMID: 40042930 PMCID: PMC11984418 DOI: 10.18632/aging.206219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 02/18/2025] [Indexed: 04/08/2025]
Abstract
Aging of the retinal pigment epithelium (RPE) leads to a gradual decline in RPE homeostasis over time, significantly impacting retinal health. Understanding the mechanisms underlying RPE aging is crucial for elucidating the background in which many age-related retinal pathologies develop. In this study, we compared the transcriptomes of young and aged mouse RPE and observed a marked upregulation of immunogenic, proinflammatory, and oxidative stress genes in aging RPE. Additionally, aging RPE exhibited dysregulation of pathways associated with visual perception and extracellular matrix production. Research on aging in post-natal quiescent RPE is hindered by the absence of relevant in vitro models. Here, we evaluated an in vitro model of chronologically aged primary human RPE to address this gap and observed gene expression patterns comparable to native-aged RPE. Gene expression profiling in this model highlighted its potential utility in investigating cellular and molecular mechanisms of RPE aging and in screening of therapeutic compounds. In conclusion, our findings underscore the pivotal role of inflammation, immune activation, and oxidative stress in the aging RPE landscape and provide insights into why age increases the risk of retinal pathologies.
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Affiliation(s)
- Sushil K. Dubey
- Department of Surgery, East Tennessee State University, Johnson City, TN 37614, USA
| | - Rashmi Dubey
- Department of Surgery, East Tennessee State University, Johnson City, TN 37614, USA
| | - Kyungsik Jung
- Department of Surgery, East Tennessee State University, Johnson City, TN 37614, USA
| | - Alvaro G. Hernandez
- Roy J. Carver Biotechnology Center, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Mark E. Kleinman
- Department of Surgery, East Tennessee State University, Johnson City, TN 37614, USA
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2
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Gureev AP, Nesterova VV, Sadovnikova IS. Long-range PCR as a tool for evaluating mitochondrial DNA damage: Principles, benefits, and limitations of the technique. DNA Repair (Amst) 2025; 146:103812. [PMID: 39848024 DOI: 10.1016/j.dnarep.2025.103812] [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: 11/07/2024] [Revised: 01/14/2025] [Accepted: 01/16/2025] [Indexed: 01/25/2025]
Abstract
Mitochondrial DNA (mtDNA) is often more susceptible to damage compared to nuclear DNA. This is due to its localization in the mitochondrial matrix, where a large portion of reactive oxygen species are produced. Mitochondria do not have histones and mtDNA is only slightly protected by histone-like proteins and is believed to have less efficient repair mechanisms. In this review, we discuss the long-range PCR method, which allows for the effective detection of mtDNA damage. The method is based on the assumption that various types of DNA lesions can interfere the progress of DNA polymerase, resulting in reduced amplification efficiency. It can be used to estimate the number of additional (above background) lesions in mtDNA. The review outlines the evolution of the methodology, its variations, applications in a wide range of model organisms, the advantages of the method and its limitations, as well as ways to overcome these limitations. Over the past two decades, the use of long-range PCR has allowed the study of mtDNA repair mechanisms, the characteristics of mitochondrial genome damage in various neurodegenerative diseases, aging, ischemic and oncological processes, as well as in anticancer therapy. The assessment of mtDNA damage has also been proposed for use in environmental biomonitoring. This review provides a critical evaluation of the various variations of this method, summarizes the accumulated data, and discusses the role of mtDNA damage in different organs at the organismal level.
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Affiliation(s)
- Artem P Gureev
- Departments of Genetics, Cytology and Bioengineering, Voronezh State University, Voronezh, Russia.
| | - Veronika V Nesterova
- Departments of Genetics, Cytology and Bioengineering, Voronezh State University, Voronezh, Russia
| | - Irina S Sadovnikova
- Departments of Genetics, Cytology and Bioengineering, Voronezh State University, Voronezh, Russia
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3
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Parmar UPS, Surico PL, Mori T, Singh RB, Cutrupi F, Premkishore P, Gallo Afflitto G, Di Zazzo A, Coassin M, Romano F. Antioxidants in Age-Related Macular Degeneration: Lights and Shadows. Antioxidants (Basel) 2025; 14:152. [PMID: 40002339 PMCID: PMC11852319 DOI: 10.3390/antiox14020152] [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: 12/16/2024] [Revised: 01/13/2025] [Accepted: 01/23/2025] [Indexed: 02/27/2025] Open
Abstract
Age-related macular degeneration (AMD) is a leading cause of vision impairment worldwide, primarily driven by oxidative stress and inflammation. This review examines the role of antioxidants in mitigating oxidative damage, emphasizing both their therapeutic potential and limitations in AMD management. Key findings underscore the efficacy of specific antioxidants, including vitamins C and E, lutein, zeaxanthin, and Coenzyme Q10, in slowing AMD progression. Landmark studies such as AREDS and AREDS2 have shaped current antioxidant formulations, although challenges persist, including patient variability and long-term safety concerns. Emerging therapies, such as mitochondrial-targeted antioxidants and novel compounds like saffron and resveratrol, offer promising avenues for AMD treatment. Complementary lifestyle interventions, including antioxidant-rich diets and physical activity, further support holistic management approaches. This review highlights the critical role of antioxidants in AMD therapy, advocating for personalized strategies to optimize patient outcomes.
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Affiliation(s)
| | - Pier Luigi Surico
- Department of Ophthalmology, Campus Bio-Medico University Hospital, 00128 Rome, Italy
- Department of Sense Organs, La Sapienza University, 00185 Rome, Italy
| | - Tommaso Mori
- Department of Ophthalmology, Campus Bio-Medico University Hospital, 00128 Rome, Italy
| | - Rohan Bir Singh
- Department of Health and Medical Sciences, Adelaide Medical School, Adelaide, SA 5000, Australia
| | - Francesco Cutrupi
- Department of Ophthalmology, Campus Bio-Medico University Hospital, 00128 Rome, Italy
| | - Pramila Premkishore
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA
| | - Gabriele Gallo Afflitto
- Ophthalmology Unit, Department of Experimental Medicine, University of Rome “Tor Vergata”, 00128 Rome, Italy
| | - Antonio Di Zazzo
- Department of Ophthalmology, Campus Bio-Medico University Hospital, 00128 Rome, Italy
| | - Marco Coassin
- Department of Ophthalmology, Campus Bio-Medico University Hospital, 00128 Rome, Italy
| | - Francesco Romano
- Eye Clinic, Department of Biomedical and Clinical Sciences, Ospedale Luigi Sacco, University of Milan, 20157 Milan, Italy
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4
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Yadav DS, Tivig I, Savopol T, Moisescu MG. Dielectrophoretic characterization of peroxidized retinal pigment epithelial cells as a model of age-related macular degeneration. BMC Ophthalmol 2024; 24:340. [PMID: 39138426 PMCID: PMC11320855 DOI: 10.1186/s12886-024-03617-0] [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: 02/26/2024] [Accepted: 08/06/2024] [Indexed: 08/15/2024] Open
Abstract
BACKGROUND Age-related macular degeneration (AMD) is a prevalent ocular pathology affecting mostly the elderly population. AMD is characterized by a progressive retinal pigment epithelial (RPE) cell degeneration, mainly caused by an impaired antioxidative defense. One of the AMD therapeutic procedures involves injecting healthy RPE cells into the subretinal space, necessitating pure, healthy RPE cell suspensions. This study aims to electrically characterize RPE cells to demonstrate a possibility using simulations to separate healthy RPE cells from a mixture of healthy/oxidized cells by dielectrophoresis. METHODS BPEI-1 rat RPE cells were exposed to hydrogen peroxide to create an in-vitro AMD cellular model. Cell viability was evaluated using various methods, including microscopic imaging, impedance-based real-time cell analysis, and the MTS assay. Healthy and oxidized cells were characterized by recording their dielectrophoretic spectra, and electric cell parameters (crossover frequency, membrane conductivity and permittivity, and cytoplasm conductivity) were computed. A COMSOL simulation was performed on a theoretical microfluidic-based dielectrophoretic separation chip using these parameters. RESULTS Increasing the hydrogen peroxide concentration shifted the first crossover frequency toward lower values, and the cell membrane permittivity progressively increased. These changes were attributed to progressive membrane peroxidation, as they were diminished when measured on cells treated with the antioxidant N-acetylcysteine. The changes in the crossover frequency were sufficient for the efficient separation of healthy cells, as demonstrated by simulations. CONCLUSIONS The study demonstrates that dielectrophoresis can be used to separate healthy RPE cells from oxidized ones based on their electrical properties. This method could be a viable approach for obtaining pure, healthy RPE cell suspensions for AMD therapeutic procedures.
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Affiliation(s)
- Dharm Singh Yadav
- Biophysics and Cellular Biotechnology Department, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari blvd., Bucharest, 050474, Romania
| | - Ioan Tivig
- Biophysics and Cellular Biotechnology Department, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari blvd., Bucharest, 050474, Romania
- Excellence Center for Research in Biophysics and Cellular Biotechnology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Tudor Savopol
- Biophysics and Cellular Biotechnology Department, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari blvd., Bucharest, 050474, Romania.
- Excellence Center for Research in Biophysics and Cellular Biotechnology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
| | - Mihaela G Moisescu
- Biophysics and Cellular Biotechnology Department, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari blvd., Bucharest, 050474, Romania
- Excellence Center for Research in Biophysics and Cellular Biotechnology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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5
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Huang M, Li Y, Li Y, Liu S. C-Terminal Binding Protein: Regulator between Viral Infection and Tumorigenesis. Viruses 2024; 16:988. [PMID: 38932279 PMCID: PMC11209466 DOI: 10.3390/v16060988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 06/16/2024] [Accepted: 06/18/2024] [Indexed: 06/28/2024] Open
Abstract
C-terminal binding protein (CtBP), a transcriptional co-repressor, significantly influences cellular signaling, impacting various biological processes including cell proliferation, differentiation, apoptosis, and immune responses. The CtBP family comprises two highly conserved proteins, CtBP1 and CtBP2, which have been shown to play critical roles in both tumorigenesis and the regulation of viral infections. Elevated CtBP expression is noted in various tumor tissues, promoting tumorigenesis, invasiveness, and metastasis through multiple pathways. Additionally, CtBP's role in viral infections varies, exhibiting differing or even opposing effects depending on the virus. This review synthesizes the advances in CtBP's function research in viral infections and virus-associated tumorigenesis, offering new insights into potential antiviral and anticancer strategies.
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Affiliation(s)
- Meihui Huang
- Xiangya School of Medicine, Central South University, Changsha 410013, China; (M.H.); (Y.L.); (Y.L.)
| | - Yucong Li
- Xiangya School of Medicine, Central South University, Changsha 410013, China; (M.H.); (Y.L.); (Y.L.)
| | - Yuxiao Li
- Xiangya School of Medicine, Central South University, Changsha 410013, China; (M.H.); (Y.L.); (Y.L.)
| | - Shuiping Liu
- Xiangya School of Medicine, Central South University, Changsha 410013, China; (M.H.); (Y.L.); (Y.L.)
- Department of Microbiology, School of Basic Medical Science, Central South University, Changsha 410013, China
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6
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Jahan J, Joshi S, Oca IMD, Toelle A, Lopez-Yang C, Chacon CV, Beyer AM, Garcia CA, Jarajapu YP. The role of telomerase reverse transcriptase in the mitochondrial protective functions of Angiotensin-(1-7) in diabetic CD34 + cells. Biochem Pharmacol 2024; 222:116109. [PMID: 38458330 PMCID: PMC11007670 DOI: 10.1016/j.bcp.2024.116109] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 01/08/2024] [Accepted: 03/05/2024] [Indexed: 03/10/2024]
Abstract
Angiotensin (Ang)-(1-7) stimulates vasoprotective functions of diabetic (DB) CD34+ hematopoietic stem/progenitor cells partly by decreasing reactive oxygen species (ROS), increasing nitric oxide (NO) levels and decreasing TGFβ1 secretion. Telomerase reverse transcriptase (TERT) translocates to mitochondria and regulates ROS generation. Alternative splicing of TERT results in variants α-, β- and α-β-TERT, which may oppose functions of full-length (FL) TERT. This study tested if the protective functions of Ang-(1-7) or TGFβ1-silencing are mediated by mitoTERT and that diabetes decreases FL-TERT expression by inducing splicing. CD34+ cells were isolated from the peripheral blood mononuclear cells of nondiabetic (ND, n = 68) or DB (n = 74) subjects. NO and mitoROS levels were evaluated by flow cytometry. TERT splice variants and mitoDNA-lesions were characterized by qPCR. TRAP assay was used for telomerase activity. Decoy peptide was used to block mitochondrial translocation (mitoXTERT). TERT inhibitor or mitoXTERT prevented the effects of Ang-(1-7) on NO or mitoROS levels in DB-CD34+ cells. FL-TERT expression and telomerase activity were lower and mitoDNA-lesions were higher in DB cells compared to ND and were reversed by Ang-(1-7) or TGFβ1-silencing. The prevalence of TERT splice variants, with predominant β-TERT expression, was higher and the expression of FL-TERT was lower in DB cells (n = 25) compared to ND (n = 30). Ang-(1-7) or TGFβ1-silencing decreased TERT-splicing and increased FL-TERT. Blocking of β-splicing increased FL-TERT and protected mitoDNA in DB-cells. The findings suggest that diabetes induces TERT-splicing in CD34+ cells and that β-TERT splice variant largely contributes to the mitoDNA oxidative damage.
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Affiliation(s)
- Jesmin Jahan
- Department of Pharmaceutical Sciences, College of Health Professions, North Dakota State University, Fargo, ND, USA
| | - Shrinidh Joshi
- Department of Pharmaceutical Sciences, College of Health Professions, North Dakota State University, Fargo, ND, USA
| | | | - Andrew Toelle
- Department of Pharmaceutical Sciences, College of Health Professions, North Dakota State University, Fargo, ND, USA
| | | | | | - Andreas M Beyer
- Department of Medicine and Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
| | | | - Yagna Pr Jarajapu
- Department of Pharmaceutical Sciences, College of Health Professions, North Dakota State University, Fargo, ND, USA.
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7
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Ahsanuddin S, Rios HA, Otero-Marquez O, Macanian J, Zhou D, Rich C, Rosen RB. Flavoprotein fluorescence elevation is a marker of mitochondrial oxidative stress in patients with retinal disease. FRONTIERS IN OPHTHALMOLOGY 2023; 3:1110501. [PMID: 38983095 PMCID: PMC11182218 DOI: 10.3389/fopht.2023.1110501] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 01/27/2023] [Indexed: 07/11/2024]
Abstract
Purpose Recent studies of glaucoma, age-related macular degeneration, and diabetic retinopathy have demonstrated that flavoprotein fluorescence (FPF) can be utilized non-invasively as an indicator of mitochondrial oxidative stress in the retina. However, a comprehensive assessment of the validity and reliability of FPF in differentiating between healthy and diseased eyes across multiple disease states is lacking. Here, we evaluate the sensitivity and specificity of FPF in discriminating between healthy and diseased eyes in four leading causes of visual impairment worldwide, one of which has not been previously evaluated using FPF. We also evaluate the association between FPF and visual acuity. Methods A total of 88 eyes [21 eyes of 21 unaffected controls, 20 eyes from 20 retinal vein occlusion (RVO) patients, 20 eyes from 20 diabetic retinopathy (DR) patients, 17 eyes from 17 chronic exudative age-related macular degeneration (exudative AMD) patients, and 10 eyes from 10 central serous retinopathy (CSR) patients] were included in the present cross-sectional observational study. Eyes were imaged non-invasively using a specially configured fundus camera OcuMet Beacon® (OcuSciences, Ann Arbor, MI). The macula was illuminated using a narrow bandwidth blue light (455 - 470 nm) and fluorescence was recorded using a narrow notch filter to match the peak emission of flavoproteins from 520 to 540 nm. AUROC analysis was used to determine the sensitivity of FPF in discriminating between diseased eyes and healthy eyes. Nonparametric Kruskal-Wallis Tests with post-hoc Mann Whitney U tests with the Holm-Bonferroni correction were performed to assess differences in FPF intensity, FPF heterogeneity, and best corrected visual acuity (BCVA) between the five groups. Spearman rank correlation coefficients were calculated to assess the relationship between FPF and BCVA. Results AUROC analysis indicated that FPF intensity is highly sensitive for detecting disease, particularly for exudative AMD subjects (0.989; 95% CI = 0.963 - 1.000, p=3.0 x 107). A significant difference was detected between the FPF intensity, FPF heterogeneity, and BCVA in all four disease states compared to unaffected controls (Kruskal-Wallis Tests, p = 1.06 x 10-8, p = 0.002, p = 5.54 x 10-8, respectively). Compared to healthy controls, FPF intensity values were significantly higher in RVO, DR, exudative AMD, and CSR (p < 0.001, p < 0.001, p < 0.001, and p = 0.001, respectively). Spearman rank correlation coefficient between FPF intensity and BCVA was ρ = 0.595 (p = 9.62 x 10-10). Conclusions Despite variations in structural retinal findings, FPF was found to be highly sensitive for detecting retinal disease. Significant FPF elevation were seen in all four disease states, with the exudative AMD patients exhibiting the highest FPF values compared to DR, CSR, and RVO subjects. This is consistent with the hypothesis that there is elevated oxidative stress in all of these conditions as previously demonstrated by blood studies. FPF intensity is moderately correlated with the late-in disease-marker BCVA, which suggests that the degree of FPF elevation can be used as a metabolic indicator of disease severity.
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Affiliation(s)
- Sofia Ahsanuddin
- Department of Ophthalmology, New York Eye and Ear Infirmary of Mount Sinai, New York, NY, United States
- Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Hernan A. Rios
- Department of Ophthalmology, New York Eye and Ear Infirmary of Mount Sinai, New York, NY, United States
- Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Oscar Otero-Marquez
- Department of Ophthalmology, New York Eye and Ear Infirmary of Mount Sinai, New York, NY, United States
- Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Jason Macanian
- Department of Medical Education, New York Medical College, Valhalla, NY, United States
| | - Davis Zhou
- Department of Ophthalmology, New York Eye and Ear Infirmary of Mount Sinai, New York, NY, United States
- Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Collin Rich
- OcuSciences Inc., Ann Arbor, MI, United States
| | - Richard B. Rosen
- Department of Ophthalmology, New York Eye and Ear Infirmary of Mount Sinai, New York, NY, United States
- Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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8
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Gilstrap SR, Hobson JM, Owens MA, White DM, Sammy MJ, Ballinger S, Sorge RE, Goodin BR. Mitochondrial reactivity following acute exposure to experimental pain testing in people with HIV and chronic pain. Mol Pain 2023; 19:17448069231195975. [PMID: 37542365 PMCID: PMC10467217 DOI: 10.1177/17448069231195975] [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: 04/24/2023] [Revised: 07/06/2023] [Accepted: 08/03/2023] [Indexed: 08/06/2023] Open
Abstract
Background: Physical stressors can cause a physiological response that can contribute to an increase in mitochondrial dysfunction and Mitochondrial DNA damage (mtDNA damage). People living with HIV (PWH) are more likely to suffer from chronic pain and may be more susceptible to mitochondrial dysfunction following exposure to a stressor. We used Quantitative Sensory Testing (QST) as an acute painful stressor in order to investigate whether PWH with/without chronic pain show differential mitochondrial physiological responses. Methods: The current study included PWH with (n = 26), and without (n = 29), chronic pain. Participants completed a single session that lasted approximately 180 min, including QST. Blood was taken prior to and following the QST battery for assays measuring mtDNA damage, mtDNA copy number, and mtDNA damage-associated molecular pattern (DAMP) levels (i.e., ND1 and ND6). Results: We examined differences between those with and without pain on various indicators of mitochondrial reactivity following exposure to QST. However, only ND6 and mtDNA damage were shown to be statistically significant between pain groups. Conclusion: PWH with chronic pain showed greater mitochondrial reactivity to laboratory stressors. Consequently, PWH and chronic pain may be more susceptible to conditions in which mitochondrial damage/dysfunction play a central role, such as cognitive decline.
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Affiliation(s)
- Shannon R Gilstrap
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Joanna M Hobson
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Michael A Owens
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA
| | - Dyan M White
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Melissa J Sammy
- Bio-Analytical Research Biology (BARB) Core, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Scott Ballinger
- Bio-Analytical Research Biology (BARB) Core, University of Alabama at Birmingham, Birmingham, AL, USA
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Robert E Sorge
- Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Burel R Goodin
- Department of Anesthesiology, Washington University, St Louis, MO, USA
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9
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Terao R, Ahmed T, Suzumura A, Terasaki H. Oxidative Stress-Induced Cellular Senescence in Aging Retina and Age-Related Macular Degeneration. Antioxidants (Basel) 2022; 11:2189. [PMID: 36358561 PMCID: PMC9686487 DOI: 10.3390/antiox11112189] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/02/2022] [Accepted: 11/03/2022] [Indexed: 07/30/2023] Open
Abstract
Aging leads to a gradual decline of function in multiple organs. Cataract, glaucoma, diabetic retinopathy, and age-related macular degeneration (AMD) are age-related ocular diseases. Because their pathogenesis is unclear, it is challenging to combat age-related diseases. Cellular senescence is a cellular response characterized by cell cycle arrest. Cellular senescence is an important contributor to aging and age-related diseases through the alteration of cellular function and the secretion of senescence-associated secretory phenotypes. As a driver of stress-induced premature senescence, oxidative stress triggers cellular senescence and age-related diseases by inducing senescence markers via reactive oxygen species and mitochondrial dysfunction. In this review, we focused on the mechanism of oxidative stress-induced senescence in retinal cells and its role in the pathogenesis of AMD.
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Affiliation(s)
- Ryo Terao
- Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8654, Japan
- Department of Ophthalmology & Visual Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA
| | - Tazbir Ahmed
- Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8654, Japan
| | - Ayana Suzumura
- Department of Ophthalmology, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan
| | - Hiroko Terasaki
- Institutes of Innovation for Future Society, Nagoya University, Nagoya 464-8601, Japan
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10
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Mohammadi A, Higazy R, Gauda EB. PGC-1α activity and mitochondrial dysfunction in preterm infants. Front Physiol 2022; 13:997619. [PMID: 36225305 PMCID: PMC9548560 DOI: 10.3389/fphys.2022.997619] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 09/09/2022] [Indexed: 11/26/2022] Open
Abstract
Extremely low gestational age neonates (ELGANs) are born in a relatively hyperoxic environment with weak antioxidant defenses, placing them at high risk for mitochondrial dysfunction affecting multiple organ systems including the nervous, respiratory, ocular, and gastrointestinal systems. The brain and lungs are highly affected by mitochondrial dysfunction and dysregulation in the neonate, causing white matter injury (WMI) and bronchopulmonary dysplasia (BPD), respectively. Adequate mitochondrial function is important in providing sufficient energy for organ development as it relates to alveolarization and axonal myelination and decreasing oxidative stress via reactive oxygen species (ROS) and reactive nitrogen species (RNS) detoxification. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a master regulator of mitochondrial biogenesis and function. Since mitochondrial dysfunction is at the root of WMI and BPD pathobiology, exploring therapies that can regulate PGC-1α activity may be beneficial. This review article describes several promising therapeutic agents that can mitigate mitochondrial dysfunction through direct and indirect activation and upregulation of the PGC-1α pathway. Metformin, resveratrol, omega 3 fatty acids, montelukast, L-citrulline, and adiponectin are promising candidates that require further pre-clinical and clinical studies to understand their efficacy in decreasing the burden of disease from WMI and BPD in preterm infants.
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Affiliation(s)
- Atefeh Mohammadi
- The Hospital for Sick Children, Division of Neonatology, Department of Pediatrics and Translational Medicine Program, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Randa Higazy
- The Hospital for Sick Children, Division of Neonatology, Department of Pediatrics and Translational Medicine Program, Toronto, ON, Canada
| | - Estelle B. Gauda
- The Hospital for Sick Children, Division of Neonatology, Department of Pediatrics and Translational Medicine Program, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
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11
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Zhang Z, Guo H, Liu B, Xian D, Liu X, Da B, Sun L. Understanding Complex Electron Radiolysis in Saline Solution by Big Data Analysis. ACS OMEGA 2022; 7:15113-15122. [PMID: 35572744 PMCID: PMC9089687 DOI: 10.1021/acsomega.2c01010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 04/08/2022] [Indexed: 06/15/2023]
Abstract
In this article, we developed a new method to analyze the complex chemical reactions induced by electron beam radiolysis based on big data analysis. At first, we built an element transport network to show the chemical reactions. Furthermore, the linearity between the species was quantified by Pearson correlation coefficient analysis. Based on the analysis, the mechanism of the high linearity between the special species pairs was interpreted by the element transport roadmap and chemical equations. The time variation of the pH of the solution and bubble formation in the solution were analyzed by simulation and data analysis. The simulation indicates that O2 and H2 can easily oversaturate and form bubbles. Finally, the radiolysis of high-energy electrons in pure water was analyzed as a reference for the radiolysis of high-energy electrons in saline solution. This work provides a new method for investigating a high-energy electron radiolysis process and for simplifying a complex chemical reaction based on quantitative analysis of the species variation in the reaction.
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Affiliation(s)
- Zhihao Zhang
- SEU-FEI
Nano-Pico Center, Key Laboratory of MEMS of Ministry of Education,
School of Electronic Science and Engineering, Southeast University, Nanjing 210096, People’s Republic
of China
| | - Hongxuan Guo
- SEU-FEI
Nano-Pico Center, Key Laboratory of MEMS of Ministry of Education,
School of Electronic Science and Engineering, Southeast University, Nanjing 210096, People’s Republic
of China
- Center
for Advanced Materials and Manufacture, Joint Research Institute of Southeast University and Monash University, Suzhou 215123, People’s Republic of China
| | - Bo Liu
- SEU-FEI
Nano-Pico Center, Key Laboratory of MEMS of Ministry of Education,
School of Electronic Science and Engineering, Southeast University, Nanjing 210096, People’s Republic
of China
| | - Dali Xian
- SEU-FEI
Nano-Pico Center, Key Laboratory of MEMS of Ministry of Education,
School of Electronic Science and Engineering, Southeast University, Nanjing 210096, People’s Republic
of China
| | - Xuanxuan Liu
- SEU-FEI
Nano-Pico Center, Key Laboratory of MEMS of Ministry of Education,
School of Electronic Science and Engineering, Southeast University, Nanjing 210096, People’s Republic
of China
| | - Bo Da
- Research
and Services Division of Materials Data and Integrated System, National Institute for Materials Science, 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan
| | - Litao Sun
- SEU-FEI
Nano-Pico Center, Key Laboratory of MEMS of Ministry of Education,
School of Electronic Science and Engineering, Southeast University, Nanjing 210096, People’s Republic
of China
- Center
for Advanced Materials and Manufacture, Joint Research Institute of Southeast University and Monash University, Suzhou 215123, People’s Republic of China
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12
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Navel V, Sapin V, Henrioux F, Blanchon L, Labbé A, Chiambaretta F, Baudouin C, Dutheil F. Oxidative and antioxidative stress markers in dry eye disease: A systematic review and meta-analysis. Acta Ophthalmol 2022; 100:45-57. [PMID: 33938134 DOI: 10.1111/aos.14892] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 04/10/2021] [Indexed: 12/11/2022]
Abstract
PURPOSE To conduct a systematic review and meta-analysis on the levels of oxidative stress markers and antioxidants in dry eye disease (DED) compared with healthy subject. METHOD The PubMed, Cochrane Library, Embase, Science Direct and Google Scholar databases were searched on 10 January 2021 for studies reporting oxidative and antioxidative stress markers in DED and healthy controls. Main meta-analysis was stratified by type of biomarkers, type of samples (tears, conjunctival cells or biopsies), Sjögren's syndrome (SS) (patients with or without SS) and by geographical zones (Asia or Europe). RESULTS We included nine articles, for a total of 333 patients (628 eye samples) with DED and 165 healthy controls (451 eye samples). There is an overall increase in oxidative stress markers in DED compared with healthy controls (standard mean deviation = 2.39, 95% confidence interval 1.85-2.94), with a significant increase in lipid peroxide (1.90, 0.69-3.11), myeloperoxidase (2.17, 1.06-3.28), nitric oxide synthase 3 (2.52, 0.95-4.08), xanthine oxidase/oxidoreductase (2.41, 1.40-5.43), 4-hydroxy-2-nonenal (4HNE) (4.75, 1.67-7.84), malondialdehyde (3.00, 2.55-3.45) and reactive oxygen species (1.31, 0.94-1.68). Oxidative stress markers were higher in tears, conjunctival cells and conjunctival biopsies of DED than controls. Even if small number of studies were included for antioxidants, catalase seemed to be decreased in DED compared with healthy controls (-2.17, -3.00 to -1.34), with an increase of antioxidants in tears of DED patients without SS (1.13, 0.76-1.49). CONCLUSION Oxidative stress markers, and probably antioxidants, were dysregulated in DED, establishing a local oxidative environment in tears, conjunctival cells and tissues.
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Affiliation(s)
- Valentin Navel
- University Hospital of Clermont‐Ferrand CHU Clermont‐Ferrand, Ophthalmology Clermont‐Ferrand France
- Université Clermont Auvergne CNRS UMR 6293 INSERM U1103 Genetic Reproduction and Development Laboratory (GReD) Translational Approach to Epithelial Injury and Repair Team Clermont‐Ferrand France
| | - Vincent Sapin
- Université Clermont Auvergne CNRS UMR 6293 INSERM U1103 Genetic Reproduction and Development Laboratory (GReD) Translational Approach to Epithelial Injury and Repair Team Clermont‐Ferrand France
- University Hospital of Clermont‐Ferrand CHU Clermont‐Ferrand, Biochemistry and Molecular Genetics Clermont‐Ferrand France
| | - Fanny Henrioux
- Université Clermont Auvergne CNRS UMR 6293 INSERM U1103 Genetic Reproduction and Development Laboratory (GReD) Translational Approach to Epithelial Injury and Repair Team Clermont‐Ferrand France
| | - Loïc Blanchon
- Université Clermont Auvergne CNRS UMR 6293 INSERM U1103 Genetic Reproduction and Development Laboratory (GReD) Translational Approach to Epithelial Injury and Repair Team Clermont‐Ferrand France
| | - Antoine Labbé
- Department of Ophthalmology III Quinze‐Vingts National Ophthalmology Hospital IHU FOReSIGHT Paris France
- Sorbonne Université INSERM CNRS Institut de la Vision Paris France
- Department of Ophthalmology Ambroise Paré Hospital APHP Université de Versailles Saint‐Quentin en Yvelines Versailles France
| | - Frédéric Chiambaretta
- University Hospital of Clermont‐Ferrand CHU Clermont‐Ferrand, Ophthalmology Clermont‐Ferrand France
- Université Clermont Auvergne CNRS UMR 6293 INSERM U1103 Genetic Reproduction and Development Laboratory (GReD) Translational Approach to Epithelial Injury and Repair Team Clermont‐Ferrand France
| | - Christophe Baudouin
- Department of Ophthalmology III Quinze‐Vingts National Ophthalmology Hospital IHU FOReSIGHT Paris France
- Sorbonne Université INSERM CNRS Institut de la Vision Paris France
- Department of Ophthalmology Ambroise Paré Hospital APHP Université de Versailles Saint‐Quentin en Yvelines Versailles France
| | - Frédéric Dutheil
- Université Clermont Auvergne CNRS LaPSCo Physiological and Psychosocial Stress CHU Clermont‐Ferrand University Hospital of Clermont‐Ferrand, Preventive and Occupational Medicine Witty Fit Clermont‐Ferrand France
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13
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Amadoro G, Latina V, Balzamino BO, Squitti R, Varano M, Calissano P, Micera A. Nerve Growth Factor-Based Therapy in Alzheimer's Disease and Age-Related Macular Degeneration. Front Neurosci 2021; 15:735928. [PMID: 34566573 PMCID: PMC8459906 DOI: 10.3389/fnins.2021.735928] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Accepted: 08/10/2021] [Indexed: 12/23/2022] Open
Abstract
Alzheimer's disease (AD) is an age-associated neurodegenerative disease which is the most common cause of dementia among the elderly. Imbalance in nerve growth factor (NGF) signaling, metabolism, and/or defect in NGF transport to the basal forebrain cholinergic neurons occurs in patients affected with AD. According to the cholinergic hypothesis, an early and progressive synaptic and neuronal loss in a vulnerable population of basal forebrain involved in memory and learning processes leads to degeneration of cortical and hippocampal projections followed by cognitive impairment with accumulation of misfolded/aggregated Aβ and tau protein. The neuroprotective and regenerative effects of NGF on cholinergic neurons have been largely demonstrated, both in animal models of AD and in living patients. However, the development of this neurotrophin as a disease-modifying therapy in humans is challenged by both delivery limitations (inability to cross the blood-brain barrier (BBB), poor pharmacokinetic profile) and unwanted side effects (pain and weight loss). Age-related macular degeneration (AMD) is a retinal disease which represents the major cause of blindness in developed countries and shares several clinical and pathological features with AD, including alterations in NGF transduction pathways. Interestingly, nerve fiber layer thinning, degeneration of retinal ganglion cells and changes of vascular parameters, aggregation of Aβ and tau protein, and apoptosis also occur in the retina of both AD and AMD. A protective effect of ocular administration of NGF on both photoreceptor and retinal ganglion cell degeneration has been recently described. Besides, the current knowledge about the detection of essential trace metals associated with AD and AMD and their changes depending on the severity of diseases, either systemic or locally detected, further pave the way for a promising diagnostic approach. This review is aimed at describing the employment of NGF as a common therapeutic approach to AMD and AD and the diagnostic power of detection of essential trace metals associated with both diseases. The multiple approaches employed to allow a sustained release/targeting of NGF to the brain and its neurosensorial ocular extensions will be also discussed, highlighting innovative technologies and future translational prospects.
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Affiliation(s)
- Giuseppina Amadoro
- Institute of Translational Pharmacology (IFT)-CNR, Rome, Italy
- European Brain Research Institute, Rome, Italy
| | | | | | - Rosanna Squitti
- Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Monica Varano
- Research Laboratories in Ophthalmology, IRCCS-Fondazione Bietti, Rome, Italy
| | | | - Alessandra Micera
- Research Laboratories in Ophthalmology, IRCCS-Fondazione Bietti, Rome, Italy
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14
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Pravda J. Sepsis: Evidence-based pathogenesis and treatment. World J Crit Care Med 2021; 10:66-80. [PMID: 34316443 PMCID: PMC8291008 DOI: 10.5492/wjccm.v10.i4.66] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 04/13/2021] [Accepted: 06/02/2021] [Indexed: 02/06/2023] Open
Abstract
Sepsis can develop during the body’s response to a critical illness leading to multiple organ failure, irreversible shock, and death. Sepsis has been vexing health care providers for centuries due to its insidious onset, generalized metabolic dysfunction, and lack of specific therapy. A common factor underlying sepsis is the characteristic hypermetabolic response as the body ramps up every physiological system in its fight against the underlying critical illness. A hypermetabolic response requires supraphysiological amounts of energy, which is mostly supplied via oxidative phosphorylation generated ATP. A by-product of oxidative phosphorylation is hydrogen peroxide (H2O2), a toxic, membrane-permeable oxidizing agent that is produced in far greater amounts during a hypermetabolic state. Continued production of mitochondrial H2O2 can overwhelm cellular reductive (antioxidant) capacity leading to a build-up within cells and eventual diffusion into the bloodstream. H2O2 is a metabolic poison that can inhibit enzyme systems leading to organ failure, microangiopathic dysfunction, and irreversible septic shock. The toxic effects of H2O2 mirror the clinical and laboratory abnormalities observed in sepsis, and toxic levels of blood H2O2 have been reported in patients with septic shock. This review provides evidence to support a causal role for H2O2 in the pathogenesis of sepsis, and an evidence-based therapeutic intervention to reduce H2O2 levels in the body and restore redox homeostasis, which is necessary for normal organ function and vascular responsiveness.
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Affiliation(s)
- Jay Pravda
- Inflammatory Disease Research Centre, Therashock LLC, Palm Beach Gardens, FL 33410, United States
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15
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Blasiak J, Szczepanska J, Fila M, Pawlowska E, Kaarniranta K. Potential of Telomerase in Age-Related Macular Degeneration-Involvement of Senescence, DNA Damage Response and Autophagy and a Key Role of PGC-1α. Int J Mol Sci 2021; 22:ijms22137194. [PMID: 34281248 PMCID: PMC8268995 DOI: 10.3390/ijms22137194] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 06/29/2021] [Accepted: 07/01/2021] [Indexed: 02/07/2023] Open
Abstract
Age-related macular degeneration (AMD), the main cause of vision loss in the elderly, is associated with oxidation in the retina cells promoting telomere attrition. Activation of telomerase was reported to improve macular functions in AMD patients. The catalytic subunit of human telomerase (hTERT) may directly interact with proteins important for senescence, DNA damage response, and autophagy, which are impaired in AMD. hTERT interaction with mTORC1 (mTOR (mechanistic target of rapamycin) complex 1) and PINK1 (PTEN-induced kinase 1) activates macroautophagy and mitophagy, respectively, and removes cellular debris accumulated over AMD progression. Ectopic expression of telomerase in retinal pigment epithelium (RPE) cells lengthened telomeres, reduced senescence, and extended their lifespan. These effects provide evidence for the potential of telomerase in AMD therapy. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) may be involved in AMD pathogenesis through decreasing oxidative stress and senescence, regulation of vascular endothelial growth factor (VEGF), and improving autophagy. PGC-1α and TERT form an inhibitory positive feedback loop. In conclusion, telomerase activation and its ectopic expression in RPE cells, as well as controlled clinical trials on the effects of telomerase activation in AMD patients, are justified and should be assisted by PGC-1α modulators to increase the therapeutic potential of telomerase in AMD.
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Affiliation(s)
- Janusz Blasiak
- Department of Molecular Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland
- Correspondence: (J.B.); (K.K.)
| | - Joanna Szczepanska
- Department of Pediatric Dentistry, Medical University of Lodz, 92-216 Lodz, Poland;
| | - Michal Fila
- Department of Developmental Neurology and Epileptology, Polish Mother’s Memorial Hospital Research Institute, 93-338 Lodz, Poland;
| | - Elzbieta Pawlowska
- Department of Orthodontics, Medical University of Lodz, 92-217 Lodz, Poland;
| | - Kai Kaarniranta
- Department of Ophthalmology, University of Eastern Finland, 70210 Kuopio, Finland
- Department of Ophthalmology, Kuopio University Hospital, 70210 Kuopio, Finland
- Correspondence: (J.B.); (K.K.)
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16
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Zhang H, Liu X, Fan Y, Yu Y, Loor JJ, Elsabagh M, Peng A, Wang H. l-Arginine Alleviates Hydrogen Peroxide-Induced Oxidative Damage in Ovine Intestinal Epithelial Cells by Regulating Apoptosis, Mitochondrial Function, and Autophagy. J Nutr 2021; 151:1038-1046. [PMID: 33693729 DOI: 10.1093/jn/nxaa428] [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: 09/25/2020] [Revised: 11/05/2020] [Accepted: 12/08/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Previous studies demonstrated that dietary l-arginine (Arg) alters the equilibrium between reactive oxygen species (ROS) generation and biological defenses to resist oxidant-induced toxicity. Whether supplying Arg can protect ovine intestinal epithelial cells (OIECs) from hydrogen peroxide (H2O2)-induced oxidative damage is unclear. OBJECTIVES The current study aimed to examine the effect of Arg on mitophagy, mitochondrial dysfunction, and apoptosis induced by H2O2 in OIECs. METHODS The OIECs were incubated in Arg-free DMEM supplemented with 100 μM Arg (CON) or 350 μM Arg (ARG) alone or with 150 μM H2O2 (CON + H2O2, ARG + H2O2) for 24 h. Cellular apoptosis, mitochondrial function, autophagy, and the related categories of genes and proteins were determined. All data were analyzed by ANOVA using the general linear model procedures of SAS (SAS Institute) for a 2 × 2 factorial design. RESULTS Relative to the CON and ARG groups, H2O2 administration resulted in 44.9% and 26.5% lower (P < 0.05) cell viability but 34.7% and 61.8% greater (P < 0.05) ROS concentration in OIECs, respectively. Compared with the CON and CON + H2O2 groups, Arg supplementation led to 40.7% and 28.8% lower (P < 0.05) ROS concentration but 14.9%-49.0% and 29.3%-64.1% greater (P < 0.05) mitochondrial membrane potential, relative mitochondrial DNA content, and complex (I-IV) activity in OIECs, respectively. Compared with the CON and CON + H2O2 groups, Arg supplementation led to 33.9%-53.1% and 22.4%-49.1% lower (P < 0.05) mRNA abundance of proapoptotic genes, respectively. Relative to the CON and CON + H2O2 groups, Arg supplementation resulted in 33.0%-59.2% and 14.6%-37.7% lower (P < 0.05) abundance of proapoptotic, mitophagy, and cytoplasmic cytochrome c protein, respectively. CONCLUSIONS Supply of Arg protects OIECs against H2O2-induced damage partly by improving mitochondrial function and alleviating cellular apoptosis and autophagy.
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Affiliation(s)
- Hao Zhang
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety, Ministry of Education of China, Yangzhou University, Yangzhou, China
| | - Xiaoyun Liu
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety, Ministry of Education of China, Yangzhou University, Yangzhou, China
| | - Yaotian Fan
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety, Ministry of Education of China, Yangzhou University, Yangzhou, China
| | - Yin Yu
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety, Ministry of Education of China, Yangzhou University, Yangzhou, China
| | - Juan J Loor
- Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana, Illinois, USA
| | - Mabrouk Elsabagh
- Department of Animal Production and Technology, Faculty of Agricultural Sciences and Technologies, Niğde Ömer Halisdemir University, Niğde, Turkey.,Department of Nutrition and Clinical Nutrition, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh, Egypt
| | - Along Peng
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety, Ministry of Education of China, Yangzhou University, Yangzhou, China
| | - Hongrong Wang
- Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety, Ministry of Education of China, Yangzhou University, Yangzhou, China
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17
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Ruan Y, Jiang S, Gericke A. Age-Related Macular Degeneration: Role of Oxidative Stress and Blood Vessels. Int J Mol Sci 2021; 22:ijms22031296. [PMID: 33525498 PMCID: PMC7866075 DOI: 10.3390/ijms22031296] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/25/2021] [Accepted: 01/25/2021] [Indexed: 12/12/2022] Open
Abstract
Age-related macular degeneration (AMD) is a common irreversible ocular disease characterized by vision impairment among older people. Many risk factors are related to AMD and interact with each other in its pathogenesis. Notably, oxidative stress and choroidal vascular dysfunction were suggested to be critically involved in AMD pathogenesis. In this review, we give an overview on the factors contributing to the pathophysiology of this multifactorial disease and discuss the role of reactive oxygen species and vascular function in more detail. Moreover, we give an overview on therapeutic strategies for patients suffering from AMD.
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Affiliation(s)
- Yue Ruan
- Correspondence: (Y.R.); (A.G.); Tel.: +49-6131-178-276 (Y.R. & A.G.)
| | | | - Adrian Gericke
- Correspondence: (Y.R.); (A.G.); Tel.: +49-6131-178-276 (Y.R. & A.G.)
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18
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Arık YB, Buijsman W, Loessberg-Zahl J, Cuartas-Vélez C, Veenstra C, Logtenberg S, Grobbink AM, Bergveld P, Gagliardi G, den Hollander AI, Bosschaart N, van den Berg A, Passier R, van der Meer AD. Microfluidic organ-on-a-chip model of the outer blood-retinal barrier with clinically relevant read-outs for tissue permeability and vascular structure. LAB ON A CHIP 2021; 21:272-283. [PMID: 33346294 DOI: 10.1039/d0lc00639d] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
The outer blood-retinal barrier (oBRB) tightly controls the transport processes between the neural tissue of the retina and the underlying blood vessel network. The barrier is formed by the retinal pigment epithelium (RPE), its basal membrane and the underlying choroidal capillary bed. Realistic three-dimensional cell culture based models of the oBRB are needed to study mechanisms and potential treatments of visual disorders such as age-related macular degeneration that result from dysfunction of the barrier tissue. Ideally, such models should also include clinically relevant read-outs to enable translation of experimental findings in the context of pathophysiology. Here, we report a microfluidic organ-on-a-chip model of the oBRB that contains a monolayer of human immortalized RPE and a microvessel of human endothelial cells, separated by a semi-permeable membrane. Confluent monolayers of both cell types were confirmed by fluorescence microscopy. The three-dimensional vascular structures within the chip were imaged by optical coherence tomography: a medical imaging technique, which is routinely applied in ophthalmology. Differences in diameters and vessel density could be readily detected. Upon inducing oxidative stress by treating with hydrogen peroxide (H2O2), a dose dependent increase in barrier permeability was observed by using a dynamic assay for fluorescence tracing, analogous to the clinically used fluorescence angiography. This organ-on-a-chip of the oBRB will allow future studies of complex disease mechanisms and treatments for visual disorders using clinically relevant endpoints in vitro.
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Affiliation(s)
- Yusuf B Arık
- Applied Stem Cell Technologies, Technical Medical Centre, University of Twente, PO Box 217, 7500 AE, Enschede, The Netherlands.
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19
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Resveratrol and exercise combined to treat functional limitations in late life: A pilot randomized controlled trial. Exp Gerontol 2020; 143:111111. [PMID: 33068691 DOI: 10.1016/j.exger.2020.111111] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/17/2020] [Accepted: 10/04/2020] [Indexed: 12/26/2022]
Abstract
PURPOSE To evaluate the safety and feasibility of combining exercise (EX) and resveratrol to treat older adults with physical function limitations. METHODS Three-arm, two-site pilot randomized, controlled trial (RCT) for community-dwelling adults (N = 60), 71.8 ± 6.3 years of age with functional limitations. Participants were randomized to receive either 12 weeks of (1) EX + placebo [EX0], (2) EX + 500 mg/day resveratrol [EX500], or (3) EX + 1000 mg/day resveratrol [EX1000]. EX consisted of two sessions a week for 12 weeks of center-based walking and whole-body resistance training. Safety was assessed through adverse events and feasibility through exercise session and supplement (placebo, or resveratrol) protocol adherence. Outcome measures included a battery of indices of physical function as well as skeletal muscle mitchondrial function. Data were adjusted for age and gender using the Intent-To-Treat approach. RESULTS Adverse event frequency and type were similar between groups (n = 8 EX0, n = 12 EX500, and n = 7 EX1000). Overall, 85% of participants met the supplement adherence via pill counts while 82% met the exercise session adherence. Adjusted within group mean differences (95% confidence interval) from week 0 to 12 for gait speed ranged from -0.04 (EX0: -0.1, 0.03) m/s to 0.04 (EX1000: -0.02, 0.11) and the six-minute walk test mean differences were 9.45 (EX0: -9.02, 27.7), 22.9 (EX500: 4.18, 41.6), and 33.1 (EX1000: 13.8, 52.4) meters. Unadjusted mean differences for citrate synthase were -0.80 (EX0: -15.45, 13.84), -1.38 (EX500: -12.16, 9.39), and 7.75 (EX1000: -4.68, 20.18) mU/mg. COX activity mean within group changes ranged from -0.05 (EX0) to 0.06 (EX500) k/s/mg. Additional outcomes are detailed in the text. CONCLUSION The pilot RCT indicated that combined EX + resveratrol was safe and feasible for older adults with functional limitations and may improve skeletal muscle mitochondrial function and mobility-related indices of physical function. A larger trial appears warranted and is needed to formally test these hypotheses.
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20
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Gümüş S, Yarıktaş M, Nazıroğlu M, Cihangir Uğuz A, Aynali G, Başpınar Ş. Effect of corticosteroid (triamcinolone acetonide) and chlorhexidin on chemotherapy- induced oxidative stress in buccal mucosa of rats. EAR, NOSE & THROAT JOURNAL 2020:145561319894405. [PMID: 32921183 DOI: 10.1177/0145561319894405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Oral mucositis (OM) refers to erythematous and ulcerative lesions of the oral mucosa. This pathology can occur by various causes. Cancer therapy is one of the well-known causes of OM such as chemotherapy and/or with radiation therapy. It has been widely mentioned that oxidative stress parameters such as lipid peroxidation (LP) levels increase during cancer process. Glutathione (GSH) is one of the major intracellular enzymes to detoxify oxidant molecules. The aim of this study was to investigate and compare the effects of Triamcinolone Acetonide (TA), a synthetic steroid chlorhexidine (CHX), a chemical antiseptic, on 5- fluorouracil (5-FU), a chemotherapeutic agent and soft abrasion induced OM in buccal mucosa of rats.OM was induced in rats through a combination of 5-FU treatment and mild abrasion of the cheek pouch with a wire brush. Buccal mucosa lipid peroxidation (LP) levels were higher (p< 0.05) in 5-FU group than in control although LP levels were lower (p<0.05) in TA group than in control group. The reduced glutathione levels were lower (p<0.05) in 5-FU group than in the control group although its level was higher (p<0.05) in TA and CHX groups than in the 5-FU group. Glutathione peroxidase activity was also higher (p<0.05) in TA group than the 5- FU group. In histopathological analyses, treatment with TA reduced 5-FU induced inflammatory cell infiltration and ulceration (p<0.001) but not with CHX.In conclusion, we observed that TA and CHX treatment modulated chemotherapy induced oxidative injury in the rat OM. However, only TA histopathologically ameliorated the 5-FU induced OM of rats. These findings suggest that TA is a useful agent for management of experimental oxidative injury and OM caused by the chemotherapy.
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Affiliation(s)
- Sami Gümüş
- Department of Otorhinolaryngology, Faculty of Medicine, 52994Süleyman Demirel University, Isparta, Turkey
| | - Murat Yarıktaş
- Department of Otorhinolaryngology, Faculty of Medicine, 52994Süleyman Demirel University, Isparta, Turkey
| | - Mustafa Nazıroğlu
- Neuroscience Research Center, 52994Süleyman Demirel University, Isparta, Turkey
- Department of Biophysics, Faculty of Medicine, 52994Süleyman Demirel University, Isparta, Turkey
| | - Abdülhadi Cihangir Uğuz
- Department of Biophysics, Faculty of Medicine, 52994Süleyman Demirel University, Isparta, Turkey
| | - Giray Aynali
- Department of Otorhinolaryngology, Faculty of Medicine, 52994Süleyman Demirel University, Isparta, Turkey
| | - Şirin Başpınar
- Department of Pathology, Faculty of Medicine, 52994Süleyman Demirel University, Isparta, Turkey
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21
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Jiang P, Choi A, Swindle-Reilly KE. Controlled release of anti-VEGF by redox-responsive polydopamine nanoparticles. NANOSCALE 2020; 12:17298-17311. [PMID: 32789323 DOI: 10.1039/d0nr03710a] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Reactive oxidative species (ROS) are the primary mediator of angiogenesis by upregulating the expression of vascular endothelial growth factor (VEGF) in the development of wet age-related macular degeneration (AMD). However, the current treatment of AMD currently relies on monthly intravitreal injection of anti-angiogenic therapeutics to inhibit new choroidal angiogenesis. However, repeated injections have been associated with side-effects, are costly, and may lower patient compliance. Moreover, the intraocular oxidative stress-dependent angiogenesis is not alleviated by current treatments, which limits the overall efficacy of the treatment strategy. Recently, nanoparticle-based devices present potential in sustained delivery of angiogenesis inhibitors and excellent capability of scavenging reactive oxygen species (ROS). Nevertheless, limited efforts have been dedicated to the treatment of oxidative stress-related diseases via a combined anti-angiogenesis and anti-oxidization pathway. For this purpose, we developed anti-angiogenetic protein-loaded polydopamine (PDA) nanoparticles for the enhanced treatment of AMD. Remarkably, the PDA nanoparticles could efficiently scavenge ROS to reduce the expression of angiogenic agents. In parallel, the particles were able to controllably release loaded anti-angiogenic drugs in response to oxidative stress.
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Affiliation(s)
- Pengfei Jiang
- William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, 134-140 W Woodruff Ave, Columbus, OH 43210, USA.
| | - Andrew Choi
- Department of Biomedical Engineering, The Ohio State University, 1080 Carmack Rd, Columbus, OH 43210, USA
| | - Katelyn E Swindle-Reilly
- William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, 134-140 W Woodruff Ave, Columbus, OH 43210, USA. and Department of Biomedical Engineering, The Ohio State University, 1080 Carmack Rd, Columbus, OH 43210, USA and Department of Ophthalmology & Visual Science, The Ohio State University, 915 Olentangy River Rd, Columbus, OH 43212, USA
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Williamson J, Hughes CM, Cobley JN, Davison GW. The mitochondria-targeted antioxidant MitoQ, attenuates exercise-induced mitochondrial DNA damage. Redox Biol 2020; 36:101673. [PMID: 32810739 PMCID: PMC7452004 DOI: 10.1016/j.redox.2020.101673] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 07/21/2020] [Accepted: 08/02/2020] [Indexed: 12/23/2022] Open
Abstract
High-intensity exercise damages mitochondrial DNA (mtDNA) in skeletal muscle. Whether MitoQ - a redox active mitochondrial targeted quinone - can reduce exercise-induced mtDNA damage is unknown. In a double-blind, randomized, placebo-controlled design, twenty-four healthy male participants consisting of two groups (placebo; n = 12, MitoQ; n = 12) performed an exercise trial of 4 x 4-min bouts at 90–95% of heart rate max. Participants completed an acute (20 mg MitoQ or placebo 1-h pre-exercise) and chronic (21 days of supplementation) phase. Blood and skeletal muscle were sampled immediately pre- and post-exercise and analysed for nuclear and mtDNA damage, lipid hydroperoxides, lipid soluble antioxidants, and the ascorbyl free radical. Exercise significantly increased nuclear and mtDNA damage across lymphocytes and muscle (P < 0.05), which was accompanied with changes in lipid hydroperoxides, ascorbyl free radical, and α-tocopherol (P < 0.05). Acute MitoQ treatment failed to impact any biomarker likely due to insufficient initial bioavailability. However, chronic MitoQ treatment attenuated nuclear (P < 0.05) and mtDNA damage in lymphocytes and muscle tissue (P < 0.05). Our work is the first to show a protective effect of chronic MitoQ supplementation on the mitochondrial and nuclear genomes in lymphocytes and human muscle tissue following exercise, which is important for genome stability.
Exercise damages mitochondrial DNA in lymphocytes and muscle tissue. Acute MitoQ ingestion has no impact on biomarkers of oxidative stress. Chronic MitoQ supplementation protects mitochondrial and nuclear DNA.
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Affiliation(s)
- Josh Williamson
- Ulster University, Sport and Exercise Research Institute, Newtownabbey, Northern Ireland, UK
| | - Ciara M Hughes
- Ulster University, Nursing and Health Research Institute, Newtownabbey, Northern Ireland, UK
| | - James N Cobley
- Free Radical Research Group, University of the Highlands and Islands, Centre for Health Sciences, Inverness, IV2 3JH, UK
| | - Gareth W Davison
- Ulster University, Sport and Exercise Research Institute, Newtownabbey, Northern Ireland, UK.
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23
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Mesenchymal Stem Cell Secretome Enhancement by Nicotinamide and Vasoactive Intestinal Peptide: A New Therapeutic Approach for Retinal Degenerative Diseases. Stem Cells Int 2020; 2020:9463548. [PMID: 32676122 PMCID: PMC7336242 DOI: 10.1155/2020/9463548] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 04/16/2020] [Accepted: 06/04/2020] [Indexed: 12/24/2022] Open
Abstract
Mesenchymal stem cells (MSC) secrete neuroprotective molecules that may be useful as an alternative to cell transplantation itself. Our purpose was to develop different pharmaceutical compositions based on conditioned medium (CM) of adipose MSC (aMSC) stimulated by and/or combined with nicotinamide (NIC), vasoactive intestinal peptide (VIP), or both factors; and to evaluate in vitro their proliferative and neuroprotective potential. Nine pharmaceutical compositions were developed from 3 experimental approaches: (1) unstimulated aMSC-CM collected and combined with NIC, VIP, or both factors (NIC+VIP), referred to as the aMSC-CM combined composition; (2) aMSC-CM collected just after stimulation with the mentioned factors and containing them, referred to as the aMSC-CM stimulated-combined composition; and (3) aMSC-CM previously stimulated with the factors, referred to as the aMSC stimulated composition. The potential of the pharmaceutical compositions to increase cell proliferation under oxidative stress and neuroprotection were evaluated in vitro by using a subacute oxidative stress model of retinal pigment epithelium cells (line ARPE-19) and spontaneous degenerative neuroretina model. Results showed that oxidatively stressed ARPE-19 cells exposed to aMSC-CM stimulated and stimulated-combined with NIC or NIC+VIP tended to have better recovery from the oxidative stress status. Neuroretinal explants cultured with aMSC-CM stimulated-combined with NIC+VIP had better preservation of the neuroretinal morphology, mainly photoreceptors, and a lower degree of glial cell activation. In conclusion, aMSC-CM stimulated-combined with NIC+VIP contributed to improving the proliferative and neuroprotective properties of the aMSC secretome. Further studies are necessary to evaluate higher concentrations of the drugs and to characterize specifically the aMSC-secreted factors related to neuroprotection. However, this study supports the possibility of improving the potential of new effective pharmaceutical compositions based on the secretome of MSC plus exogenous factors or drugs without the need to inject cells into the eye, which can be very useful in retinal pathologies.
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24
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Al Sabaani N. Kaempferol Protects Against Hydrogen Peroxide-Induced Retinal Pigment Epithelium Cell Inflammation and Apoptosis by Activation of SIRT1 and Inhibition of PARP1. J Ocul Pharmacol Ther 2020; 36:563-577. [PMID: 32412821 DOI: 10.1089/jop.2019.0151] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Purpose: This study investigated the protective effect of Kaempferol against hydrogen peroxides (H2O2)-induced retinal pigment epithelium (RPE) cell oxidative stress, inflammation, and apoptosis and investigated if this protection involves modulation of poly(ADP-ribose) polymerase-1 (PARP1)/silent information regulator 1 (SIRT1) signaling pathway. Methods: ARPE-19 cells were pretreated with increasing doses of Kaempferol (10, 25, 50, 100 μM) for 24 h in Dulbecco's modified Eagle's medium/F-12 medium with or without postincubation with H2O2. Control cells remained untreated. Results: Kaempferol, in a dose-dependent manner, significantly increased cell survival and reduced levels of reactive oxygen species, malondialdehyde, single-stranded DNA (ssDNA), and lactate dehydrogenase but increased levels of glutathione (GSH) and manganese-superoxide dismutase (MnSOD) in H2O2-treated ARPE-19 cells. It also increased GSH and MnSOD in a dose-dependent manner in control + Kaempferol treated cells. At a dose of 50 μM, the most effective dose, Kaempferol also inhibited protein levels of tumor necrosis factor alpha and interleukin-6, nuclear activity and protein levels of total, acetylated, and cleaved PARP1, and increased nuclear levels and activity of SIRT1 in H2O2-treated cells. In parallel, it increased total nuclear levels of Nrf2 but reduced the acetylation of p53, Nrf2, nuclear factor-κB (NF-κB) p65, and forkhead transcriptional factor 1 (FOXO1). Of interest, the stimulatory role of Kaempferol in the nuclear accumulation and activation of SIRT1 and the nuclear levels of Nrf2, as well as in reducing the acetylation of Nrf2, NF-κB p65, and FOXO1, was shown in nuclei of control + Kaempferol-treated cells. Conclusion: Kaempferol protective effect against H2O2-induced ARPE-19 damage involves antioxidant and anti-inflammatory effects mediated, at least, by stimulating the nuclear accumulation, activation, and deacetylase ability of SIRT1 and concurrent inhibition of PARP1.
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Affiliation(s)
- Nasser Al Sabaani
- Opthalmology Department, College of Medicine, King Khalid University, Abha, Saudi Arabia
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25
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Pravda J. Hydrogen peroxide and disease: towards a unified system of pathogenesis and therapeutics. Mol Med 2020; 26:41. [PMID: 32380940 PMCID: PMC7204068 DOI: 10.1186/s10020-020-00165-3] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 04/07/2020] [Indexed: 02/07/2023] Open
Abstract
Although the immune response has a prominent role in the pathophysiology of ulcerative colitis, sepsis, and systemic lupus erythematosus, a primary immune causation has not been established to explain the pathogenesis of these diseases. However, studies have reported significantly elevated levels of colonic epithelial hydrogen peroxide (a known colitic agent) in ulcerative colitis prior to the appearance of colitis. And patients with sepsis are reported to have toxic levels of blood hydrogen peroxide, whose pathologic effects mirror the laboratory and clinical abnormalities observed in sepsis. More recently, evidence supports a causal role for cellular hydrogen peroxide (a potent apoptotic agent) in the enhanced apoptosis believed to be the driving force behind auto-antigenic exposure and chronic immune activation in systemic lupus erythematosus. The different biological properties of hydrogen peroxide exert distinct pathologic effects depending on the site of accumulation within the body resulting in a unique disease patho-phenotype. On a cellular level, the build-up of hydrogen peroxide triggers apoptosis resulting in systemic lupus erythematosus, on a tissue level (colonic epithelium) excess hydrogen peroxide leads to inflammation and ulcerative colitis, and on a systemic level the pathologic effects of toxic concentrations of blood hydrogen peroxide result in bioenergetic failure and microangiopathic dysfunction leading to multiple organ failure and circulatory shock, characteristic of advanced sepsis. The aim of this paper is to provide a unified evidence-based common causal role for hydrogen peroxide in the pathogenesis of ulcerative colitis, sepsis, and systemic lupus erythematosus. Based on this new theory of pathogenesis, a novel evidence-based treatment of sepsis is also discussed.
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26
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Picard E, Daruich A, Youale J, Courtois Y, Behar-Cohen F. From Rust to Quantum Biology: The Role of Iron in Retina Physiopathology. Cells 2020; 9:cells9030705. [PMID: 32183063 PMCID: PMC7140613 DOI: 10.3390/cells9030705] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 03/07/2020] [Accepted: 03/09/2020] [Indexed: 12/24/2022] Open
Abstract
Iron is essential for cell survival and function. It is a transition metal, that could change its oxidation state from Fe2+ to Fe3+ involving an electron transfer, the key of vital functions but also organ dysfunctions. The goal of this review is to illustrate the primordial role of iron and local iron homeostasis in retinal physiology and vision, as well as the pathological consequences of iron excess in animal models of retinal degeneration and in human retinal diseases. We summarize evidence of the potential therapeutic effect of iron chelation in retinal diseases and especially the interest of transferrin, a ubiquitous endogenous iron-binding protein, having the ability to treat or delay degenerative retinal diseases.
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Affiliation(s)
- Emilie Picard
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Team 17, F-75006 Paris, France; (A.D.); (J.Y.); (Y.C.); (F.B.-C.)
- Correspondence: ; Tel.: +331-44-27-81-82
| | - Alejandra Daruich
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Team 17, F-75006 Paris, France; (A.D.); (J.Y.); (Y.C.); (F.B.-C.)
- Ophthalmology Department, Necker-Enfants Malades University Hospital, APHP, 75015 Paris, France
| | - Jenny Youale
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Team 17, F-75006 Paris, France; (A.D.); (J.Y.); (Y.C.); (F.B.-C.)
| | - Yves Courtois
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Team 17, F-75006 Paris, France; (A.D.); (J.Y.); (Y.C.); (F.B.-C.)
| | - Francine Behar-Cohen
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Team 17, F-75006 Paris, France; (A.D.); (J.Y.); (Y.C.); (F.B.-C.)
- Ophtalmopole, Cochin Hospital, AP-HP, Assistance Publique Hôpitaux de Paris, 24 rue du Faubourg Saint-Jacques, 75014 Paris, France
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27
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Mehrzadi S, Hemati K, Reiter RJ, Hosseinzadeh A. Mitochondrial dysfunction in age-related macular degeneration: melatonin as a potential treatment. Expert Opin Ther Targets 2020; 24:359-378. [PMID: 32116056 DOI: 10.1080/14728222.2020.1737015] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Introduction: Age-related Macular Degeneration (AMD), a retinal neurodegenerative disease is the most common cause of blindness among the elderly in developed countries. The impairment of mitochondrial biogenesis has been reported in human retinal pigment epithelium (RPE) cells affected by AMD. Oxidative/nitrosative stress plays an important role in AMD development. The mitochondrial respiratory system is considered a major site of reactive oxygen species (ROS) generation. During aging, insufficient free radical scavenger systems, impairment of DNA repair mechanisms and reduction of mitochondrial degradation and turnover contribute to the massive accumulation of ROS disrupting mitochondrial function. Impaired mitochondrial function leads to the decline in the autophagic capacity and induction of inflammation and apoptosis in human RPE cells affected by AMD.Areas covered: This article evaluates the ameliorative effect of melatonin on AMD and examines AMD pathogenesis with an emphasis on mitochondrial dysfunction. It also considers the potential effects of melatonin on mitochondrial function.Expert opinion: The effect of melatonin on mitochondrial function results in the reduction of oxidative stress, inflammation and apoptosis in the retina; these findings demonstrate that melatonin has the potential to prevent and treat AMD.
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Affiliation(s)
- Saeed Mehrzadi
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Karim Hemati
- Department of Anesthesiology, Iran University of Medical Sciences, Tehran, Iran
| | - Russel J Reiter
- Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA
| | - Azam Hosseinzadeh
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
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28
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Liu L, Wang F, Tong Y, Li LF, Liu Y, Gao WQ. Pentamidine inhibits prostate cancer progression via selectively inducing mitochondrial DNA depletion and dysfunction. Cell Prolif 2019; 53:e12718. [PMID: 31721355 PMCID: PMC6985668 DOI: 10.1111/cpr.12718] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 09/17/2019] [Accepted: 10/11/2019] [Indexed: 01/28/2023] Open
Abstract
Objectives We investigated the anti‐cancer activity of pentamidine, an anti‐protozoal cationic aromatic diamidine drug, in prostate cancer cells and aimed to provide valuable insights for improving the efficacy of prostate cancer treatment. Materials and methods Prostate cancer cell lines and epithelial RWPE‐1 cells were used in the study. Cell viability, wound‐healing, transwell and apoptosis assays were examined to evaluate the influences of pentamidine in vitro. RNA‐seq and qPCR were performed to analyse changes in gene transcription levels upon pentamidine treatment. Mitochondrial changes were assessed by measuring mitochondrial DNA content, morphology, membrane potential, cellular glucose uptake, ATP production and ROS generation. Nude mouse xenograft models were used to test anti‐tumour effects of pentamidine in vivo. Results Pentamidine exerted profound inhibitory effects on proliferation, colony formation, migration and invasion of prostate cancer cells. In addition, the drug suppressed growth of xenograft tumours without exhibiting any obvious toxicity in nude mice. Mechanistically, pentamidine caused mitochondrial DNA content reduction and induced mitochondrial morphological changes, mitochondrial membrane potential dissipation, ATP level reduction, ROS production elevation and apoptosis in prostate cancer cells. Conclusions Pentamidine can efficiently suppress prostate cancer progression and may serve as a novel mitochondria‐targeted therapeutic agent for prostate cancer.
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Affiliation(s)
- Lin Liu
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Fan Wang
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yu Tong
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lin-Feng Li
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yanfeng Liu
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wei-Qiang Gao
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
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29
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Yamaguchi MS, McCartney MM, Falcon AK, Linderholm AL, Ebeler SE, Kenyon NJ, Harper RH, Schivo M, Davis CE. Modeling cellular metabolomic effects of oxidative stress impacts from hydrogen peroxide and cigarette smoke on human lung epithelial cells. J Breath Res 2019; 13:036014. [PMID: 31063985 PMCID: PMC9798928 DOI: 10.1088/1752-7163/ab1fc4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The respiratory system is continuously exposed to variety of biological and chemical irritants that contain reactive oxygen species, and these are well known to cause oxidative stress responses in lung epithelial cells. There is a clinical need to identify biomarkers of oxidative stress which could potentially support early indicators of disease and health management. To identify volatile biomarkers of oxidative stress, we analyzed the headspace above human bronchial epithelial cell cultures (HBE1) before and after hydrogen peroxide (H2O2) and cigarette smoke extract (CSE) exposure. Using stir bar and headspace sorptive extraction-gas chromatography-mass spectrometry, we searched for volatile organic compounds (VOC) of these oxidative measures. In the H2O2 cell peroxidation experiments, four different H2O2 concentrations (0.1, 0.5, 10, 50 mM) were applied to the HBE1 cells, and VOCs were collected every 12 h over the time course of 48 h. In the CSE cell peroxidation experiments, four different smoke extract concentrations (0%, 10%, 30%, 60%) were applied to the cells, and VOCs were collected every 12 h over the time course of 48 h. We used partial-least squares (PLS) analysis to identify putative compounds from the mass spectrometry results that highly correlated with the known applied oxidative stress. We observed chemical emissions from the cells that related to both the intensity of the oxidative stress and followed distinct time courses. Additionally, some of these chemicals are aldehydes, which are thought to be non-invasive indicators of oxidative stress in exhaled human breath. Together, these results illustrate a powerful in situ cell culture model of oxidative stress that can be used to explore the putative biological genesis of exhaled breath biomarkers that are often observed in human clinical studies.
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Affiliation(s)
- Mei S. Yamaguchi
- Mechanical and Aerospace Engineering, University of California Davis, Davis, CA 95616, USA
| | - Mitchell M. McCartney
- Mechanical and Aerospace Engineering, University of California Davis, Davis, CA 95616, USA
| | - Alexandria K. Falcon
- Mechanical and Aerospace Engineering, University of California Davis, Davis, CA 95616, USA
| | - Angela L. Linderholm
- Center for Comparative Respiratory Biology and Medicine, UC Davis Medical School, Davis, CA 95616, USA
| | - Susan E. Ebeler
- Viticulture and Enology, University of California Davis, One Shields Avenue, Davis, California 95616, USA
| | - Nicholas J. Kenyon
- Center for Comparative Respiratory Biology and Medicine, UC Davis Medical School, Davis, CA 95616, USA,Department of Internal Medicine, 4150 V Street, Suite 3400, University of California, Davis, Sacramento, CA 95817, USA,VA Northern California Health Care System, 10535 Hospital Way, Mather, CA 95655, USA
| | - Richart H. Harper
- Center for Comparative Respiratory Biology and Medicine, UC Davis Medical School, Davis, CA 95616, USA,Department of Internal Medicine, 4150 V Street, Suite 3400, University of California, Davis, Sacramento, CA 95817, USA,VA Northern California Health Care System, 10535 Hospital Way, Mather, CA 95655, USA
| | - Michael Schivo
- Center for Comparative Respiratory Biology and Medicine, UC Davis Medical School, Davis, CA 95616, USA,Department of Internal Medicine, 4150 V Street, Suite 3400, University of California, Davis, Sacramento, CA 95817, USA,VA Northern California Health Care System, 10535 Hospital Way, Mather, CA 95655, USA
| | - Cristina E. Davis
- Mechanical and Aerospace Engineering, University of California Davis, Davis, CA 95616, USA,Corresponding author: Prof. Cristina E. Davis ()
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Role of Mitochondrial DNA Damage in ROS-Mediated Pathogenesis of Age-Related Macular Degeneration (AMD). Int J Mol Sci 2019; 20:ijms20102374. [PMID: 31091656 PMCID: PMC6566654 DOI: 10.3390/ijms20102374] [Citation(s) in RCA: 138] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 04/17/2019] [Accepted: 04/28/2019] [Indexed: 12/19/2022] Open
Abstract
Age-related macular degeneration (AMD) is a complex eye disease that affects millions of people worldwide and is the main reason for legal blindness and vision loss in the elderly in developed countries. Although the cause of AMD pathogenesis is not known, oxidative stress-related damage to retinal pigment epithelium (RPE) is considered an early event in AMD induction. However, the precise cause of such damage and of the induction of oxidative stress, including related oxidative effects occurring in RPE and the onset and progression of AMD, are not well understood. Many results point to mitochondria as a source of elevated levels of reactive oxygen species (ROS) in AMD. This ROS increase can be associated with aging and effects induced by other AMD risk factors and is correlated with damage to mitochondrial DNA. Therefore, mitochondrial DNA (mtDNA) damage can be an essential element of AMD pathogenesis. This is supported by many studies that show a greater susceptibility of mtDNA than nuclear DNA to DNA-damaging agents in AMD. Therefore, the mitochondrial DNA damage reaction (mtDDR) is important in AMD prevention and in slowing down its progression as is ROS-targeting AMD therapy. However, we know far less about mtDNA than its nuclear counterparts. Further research should measure DNA damage in order to compare it in mitochondria and the nucleus, as current methods have serious disadvantages.
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31
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Mitochondrial DNA Integrity: Role in Health and Disease. Cells 2019; 8:cells8020100. [PMID: 30700008 PMCID: PMC6406942 DOI: 10.3390/cells8020100] [Citation(s) in RCA: 165] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 01/25/2019] [Accepted: 01/28/2019] [Indexed: 01/06/2023] Open
Abstract
As the primary cellular location for respiration and energy production, mitochondria serve in a critical capacity to the cell. Yet, by virtue of this very function of respiration, mitochondria are subject to constant oxidative stress that can damage one of the unique features of this organelle, its distinct genome. Damage to mitochondrial DNA (mtDNA) and loss of mitochondrial genome integrity is increasingly understood to play a role in the development of both severe early-onset maladies and chronic age-related diseases. In this article, we review the processes by which mtDNA integrity is maintained, with an emphasis on the repair of oxidative DNA lesions, and the cellular consequences of diminished mitochondrial genome stability.
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Loukovitis E, Sfakianakis K, Syrmakesi P, Tsotridou E, Orfanidou M, Bakaloudi DR, Stoila M, Kozei A, Koronis S, Zachariadis Z, Tranos P, Kozeis N, Balidis M, Gatzioufas Z, Fiska A, Anogeianakis G. Genetic Aspects of Keratoconus: A Literature Review Exploring Potential Genetic Contributions and Possible Genetic Relationships with Comorbidities. Ophthalmol Ther 2018; 7:263-292. [PMID: 30191404 PMCID: PMC6258591 DOI: 10.1007/s40123-018-0144-8] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Indexed: 01/24/2023] Open
Abstract
INTRODUCTION Keratoconus (KC) is a complex, genetically heterogeneous, multifactorial degenerative disorder that is accompanied by corneal ectasia which usually progresses asymmetrically. With an incidence of approximately 1 per 2000 and 2 cases per 100,000 population presenting annually, KC follows an autosomal recessive or dominant pattern of inheritance and is, apparently, associated with genes that interact with environmental, genetic, and/or other factors. This is an important consideration in refractive surgery in the case of familial KC, given the association of KC with other genetic disorders and the imbalance between dizygotic twins. The present review attempts to identify the genetic loci contributing to the different KC clinical presentations and relate them to the common genetically determined comorbidities associated with KC. METHODS The PubMed, MEDLINE, Google Scholar, and GeneCards databases were screened for KC-related articles published in English between January 2006 and November 2017. Keyword combinations of "keratoconus," "risk factor(s)," "genetics," "genes," "genetic association(s)," and "cornea" were used. In total, 217 articles were retrieved and analyzed, with greater weight placed on the more recent literature. Further bibliographic research based on the 217 articles revealed another 124 relevant articles that were included in this review. Using the reviewed literature, an attempt was made to correlate genes and genetic risk factors with KC characteristics and genetically related comorbidities associated with KC based on genome-wide association studies, family-based linkage analysis, and candidate-gene approaches. RESULTS An association matrix between known KC-related genes and KC symptoms and/or clinical signs together with an association matrix between identified KC genes and genetically related KC comorbidities/syndromes were constructed. CONCLUSION Twenty-four genes were identified as potential contributors to KC and 49 KC-related comorbidities/syndromes were found. More than 85% of the known KC-related genes are involved in glaucoma, Down syndrome, connective tissue disorders, endothelial dystrophy, posterior polymorphous corneal dystrophy, and cataract.
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Affiliation(s)
| | - Konstantinos Sfakianakis
- Division of Surgical Anatomy, Laboratory of Anatomy, Medical School, Democritus University of Thrace, University Campus, Alexandroupolis, Greece
| | - Panagiota Syrmakesi
- AHEPA University Hospital, Thessaloníki, Greece
- Ophthalmica Eye Institute, Thessaloníki, Greece
| | - Eleni Tsotridou
- Ophthalmica Eye Institute, Thessaloníki, Greece
- Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Myrsini Orfanidou
- Ophthalmica Eye Institute, Thessaloníki, Greece
- Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Dimitra Rafailia Bakaloudi
- Ophthalmica Eye Institute, Thessaloníki, Greece
- Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Maria Stoila
- Ophthalmica Eye Institute, Thessaloníki, Greece
- Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloníki, Greece
| | - Athina Kozei
- Ophthalmica Eye Institute, Thessaloníki, Greece
- School of Pharmacology, University of Nicosia, Makedonitissis, Nicosia, Cyprus
| | | | | | | | | | | | - Zisis Gatzioufas
- Department of Ophthalmology, Cornea, Cataract and Refractive Surgery, University Hospital Basel, Basel, Switzerland
| | - Aliki Fiska
- Laboratory of Anatomy, Medical School, Democritus University of Thrace, University Campus, Alexandroupolis, Greece
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Loss of MICOS complex integrity and mitochondrial damage, but not TDP-43 mitochondrial localisation, are likely associated with severity of CHCHD10-related diseases. Neurobiol Dis 2018; 119:159-171. [PMID: 30092269 DOI: 10.1016/j.nbd.2018.07.027] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Revised: 07/20/2018] [Accepted: 07/28/2018] [Indexed: 12/12/2022] Open
Abstract
Following the involvement of CHCHD10 in FrontoTemporal-Dementia-Amyotrophic Lateral Sclerosis (FTD-ALS) clinical spectrum, a founder mutation (p.Gly66Val) in the same gene was identified in Finnish families with late-onset spinal motor neuronopathy (SMAJ). SMAJ is a slowly progressive form of spinal muscular atrophy with a life expectancy within normal range. In order to understand why the p.Ser59Leu mutation, responsible for severe FTD-ALS, and the p.Gly66Val mutation could lead to different levels of severity, we compared their effects in patient cells. Unlike affected individuals bearing the p.Ser59Leu mutation, patients presenting with SMAJ phenotype have neither mitochondrial myopathy nor mtDNA instability. The expression of CHCHD10S59L mutant allele leads to disassembly of mitochondrial contact site and cristae organizing system (MICOS) with mitochondrial dysfunction and loss of cristae in patient fibroblasts. We also show that G66V fibroblasts do not display the loss of MICOS complex integrity and mitochondrial damage found in S59L cells. However, S59L and G66V fibroblasts show comparable accumulation of phosphorylated mitochondrial TDP-43 suggesting that the severity of phenotype and mitochondrial damage do not depend on mitochondrial TDP-43 localization. The expression of the CHCHD10G66V allele is responsible for mitochondrial network fragmentation and decreased sensitivity towards apoptotic stimuli, but with a less severe effect than that found in cells expressing the CHCHD10S59L allele. Taken together, our data show that cellular phenotypes associated with p.Ser59Leu and p.Gly66Val mutations in CHCHD10 are different; loss of MICOS complex integrity and mitochondrial dysfunction, but not TDP-43 mitochondrial localization, being likely essential to develop a severe motor neuron disease.
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Miller VJ, Villamena FA, Volek JS. Nutritional Ketosis and Mitohormesis: Potential Implications for Mitochondrial Function and Human Health. J Nutr Metab 2018; 2018:5157645. [PMID: 29607218 PMCID: PMC5828461 DOI: 10.1155/2018/5157645] [Citation(s) in RCA: 132] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 12/27/2017] [Indexed: 02/07/2023] Open
Abstract
Impaired mitochondrial function often results in excessive production of reactive oxygen species (ROS) and is involved in the etiology of many chronic diseases, including cardiovascular disease, diabetes, neurodegenerative disorders, and cancer. Moderate levels of mitochondrial ROS, however, can protect against chronic disease by inducing upregulation of mitochondrial capacity and endogenous antioxidant defense. This phenomenon, referred to as mitohormesis, is induced through increased reliance on mitochondrial respiration, which can occur through diet or exercise. Nutritional ketosis is a safe and physiological metabolic state induced through a ketogenic diet low in carbohydrate and moderate in protein. Such a diet increases reliance on mitochondrial respiration and may, therefore, induce mitohormesis. Furthermore, the ketone β-hydroxybutyrate (BHB), which is elevated during nutritional ketosis to levels no greater than those resulting from fasting, acts as a signaling molecule in addition to its traditionally known role as an energy substrate. BHB signaling induces adaptations similar to mitohormesis, thereby expanding the potential benefit of nutritional ketosis beyond carbohydrate restriction. This review describes the evidence supporting enhancement of mitochondrial function and endogenous antioxidant defense in response to nutritional ketosis, as well as the potential mechanisms leading to these adaptations.
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Affiliation(s)
- Vincent J. Miller
- Department of Human Sciences, College of Education and Human Ecology, The Ohio State University, Columbus, OH, USA
| | - Frederick A. Villamena
- Department of Biological Chemistry and Pharmacology, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Jeff S. Volek
- Department of Human Sciences, College of Education and Human Ecology, The Ohio State University, Columbus, OH, USA
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RAD51C/XRCC3 Facilitates Mitochondrial DNA Replication and Maintains Integrity of the Mitochondrial Genome. Mol Cell Biol 2018; 38:MCB.00489-17. [PMID: 29158291 DOI: 10.1128/mcb.00489-17] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 11/10/2017] [Indexed: 12/12/2022] Open
Abstract
Mechanisms underlying mitochondrial genome maintenance have recently gained wide attention, as mutations in mitochondrial DNA (mtDNA) lead to inherited muscular and neurological diseases, which are linked to aging and cancer. It was previously reported that human RAD51, RAD51C, and XRCC3 localize to mitochondria upon oxidative stress and are required for the maintenance of mtDNA stability. Since RAD51 and RAD51 paralogs are spontaneously imported into mitochondria, their precise role in mtDNA maintenance under unperturbed conditions remains elusive. Here, we show that RAD51C/XRCC3 is an additional component of the mitochondrial nucleoid having nucleus-independent roles in mtDNA maintenance. RAD51C/XRCC3 localizes to the mtDNA regulatory regions in the D-loop along with the mitochondrial polymerase POLG, and this recruitment is dependent upon Twinkle helicase. Moreover, upon replication stress, RAD51C and XRCC3 are further enriched at the mtDNA mutation hot spot region D310. Notably, the absence of RAD51C/XRCC3 affects the stability of POLG on mtDNA. As a consequence, RAD51C/XRCC3-deficient cells exhibit reduced mtDNA synthesis and increased lesions in the mitochondrial genome, leading to overall unhealthy mitochondria. Together, these findings lead to the proposal of a mechanism for a direct role of RAD51C/XRCC3 in maintaining mtDNA integrity under replication stress conditions.
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Ao J, Wood JP, Chidlow G, Gillies MC, Casson RJ. Retinal pigment epithelium in the pathogenesis of age-related macular degeneration and photobiomodulation as a potential therapy? Clin Exp Ophthalmol 2018; 46:670-686. [PMID: 29205705 DOI: 10.1111/ceo.13121] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 11/27/2017] [Accepted: 11/28/2017] [Indexed: 12/11/2022]
Abstract
The retinal pigment epithelium (RPE) comprises a monolayer of cells located between the neuroretina and the choriocapillaries. The RPE serves several important functions in the eye: formation of the blood-retinal barrier, protection of the retina from oxidative stress, nutrient delivery and waste disposal, ionic homeostasis, phagocytosis of photoreceptor outer segments, synthesis and release of growth factors, reisomerization of all-trans-retinal during the visual cycle, and establishment of ocular immune privilege. Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. Dysfunction of the RPE has been associated with the pathogenesis of AMD in relation to increased oxidative stress, mitochondrial destabilization and complement dysregulation. Photobiomodulation or near infrared light therapy which refers to non-invasive irradiation of tissue with light in the far-red to near-infrared light spectrum (630-1000 nm), is an intervention that specifically targets key mechanisms of RPE dysfunction that are implicated in AMD pathogenesis. The current evidence for the efficacy of photobiomodulation in AMD is poor but its safety profile and proposed mechanisms of action motivate further research as a novel therapy for AMD.
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Affiliation(s)
- Jack Ao
- South Australian Institute of Ophthalmology, University of Adelaide, Adelaide, South Australia, Australia
| | - John Pm Wood
- South Australian Institute of Ophthalmology, University of Adelaide, Adelaide, South Australia, Australia
| | - Glyn Chidlow
- South Australian Institute of Ophthalmology, University of Adelaide, Adelaide, South Australia, Australia
| | - Mark C Gillies
- The Save Sight Institute, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia
| | - Robert J Casson
- South Australian Institute of Ophthalmology, University of Adelaide, Adelaide, South Australia, Australia
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Liu H, Peng H, Xiang H, Guo L, Chen R, Zhao S, Chen W, Chen P, Lu H, Chen S. TWEAK/Fn14 promotes oxidative stress through AMPK/PGC‑1α/MnSOD signaling pathway in endothelial cells. Mol Med Rep 2017; 17:1998-2004. [PMID: 29257217 DOI: 10.3892/mmr.2017.8090] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Accepted: 11/09/2017] [Indexed: 11/06/2022] Open
Abstract
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) contributes to dysfunction of endothelial cells via its receptor, Fn14. However, its role in the production of reactive oxygen species (ROS), particularly mitochondrial ROS (mtROS) and the subsequent decrease in nitric oxide (NO) in endothelial cells remains unclear. In this study, the effect of TWEAK/Fn14 on generation of ROS, mtROS and NO in endothelial cells and its potential mechanism was investigated. Human umbilical vein endothelial cells (HUVECs) were treated with TWEAK with Fn14 small interfering (si)RNA or negative control RNA. It was demonstrated that TWEAK induced the production of ROS and mtROS in HUVECs, which were detected by fluorescent microscope, and flow cytometry. In addition, TWEAK decreased the generation of NO as indicated using the Nitric Oxide Assay kit. Furthermore, TWEAK aggravated mtDNA damage as measured by quantitative polymerase chain reaction analysis. Inhibition of Fn14 by Fn14 siRNA decreased TWEAK‑induced ROS and mtROS production, as well as mtDNA damage, while it increased the production of NO in endothelial cells. In addition, TWEAK inhibited the expression of active AMP‑activated protein kinase (AMPK) and its downstream protein peroxisome proliferator‑activated receptor‑γ coactivator-1α (PGC‑1α) and manganese superoxide dismutase (MnSOD). Notably, Fn14 siRNA enhanced the expression of the aforementioned proteins. Taken together, TWEAK/Fn14 contributes to endothelial dysfunction through modulation of ROS and mtROS. In addition, the underlying mechanism is implicated in the AMPK/PGC‑1α/MnSOD signaling pathway.
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Affiliation(s)
- Hengdao Liu
- Center for Experimental Medical Research, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Hui Peng
- Center for Experimental Medical Research, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Hong Xiang
- Center for Experimental Medical Research, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Lingli Guo
- Department of Critical Care Medicine, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453100, P.R. China
| | - Ruifang Chen
- Center for Experimental Medical Research, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Shaoli Zhao
- Center for Experimental Medical Research, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Wei Chen
- Center for Experimental Medical Research, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Pan Chen
- Center for Experimental Medical Research, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Hongwei Lu
- Center for Experimental Medical Research, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Shuhua Chen
- Department of Biochemistry, School of Life Sciences, Central South University, Changsha, Hunan 410013, P.R. China
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Cellular Senescence in Age-Related Macular Degeneration: Can Autophagy and DNA Damage Response Play a Role? OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:5293258. [PMID: 29225722 PMCID: PMC5687149 DOI: 10.1155/2017/5293258] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 05/29/2017] [Accepted: 06/28/2017] [Indexed: 12/14/2022]
Abstract
Age-related macular degeneration (AMD) is the main reason of blindness in developed countries. Aging is the main AMD risk factor. Oxidative stress, inflammation and some genetic factors play a role in AMD pathogenesis. AMD is associated with the degradation of retinal pigment epithelium (RPE) cells, photoreceptors, and choriocapillaris. Lost RPE cells in the central retina can be replaced by their peripheral counterparts. However, if they are senescent, degenerated regions in the macula cannot be regenerated. Oxidative stress, a main factor of AMD pathogenesis, can induce DNA damage response (DDR), autophagy, and cell senescence. Moreover, cell senescence is involved in the pathogenesis of many age-related diseases. Cell senescence is the state of permanent cellular division arrest and concerns only mitotic cells. RPE cells, although quiescent in the retina, can proliferate in vitro. They can also undergo oxidative stress-induced senescence. Therefore, cellular senescence can be considered as an important molecular pathway of AMD pathology, resulting in an inability of the macula to regenerate after degeneration of RPE cells caused by a factor inducing DDR and autophagy. It is too early to speculate about the role of the mutual interplay between cell senescence, autophagy, and DDR, but this subject is worth further studies.
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Kandasamy J, Olave N, Ballinger SW, Ambalavanan N. Vascular Endothelial Mitochondrial Function Predicts Death or Pulmonary Outcomes in Preterm Infants. Am J Respir Crit Care Med 2017; 196:1040-1049. [PMID: 28485984 DOI: 10.1164/rccm.201702-0353oc] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
RATIONALE Vascular endothelial mitochondrial dysfunction contributes to the pathogenesis of several oxidant stress-associated disorders. Oxidant stress is a major contributor to the pathogenesis of bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurity that often leads to sequelae in adult survivors. OBJECTIVES This study was conducted to identify whether differences in mitochondrial bioenergetic function and oxidant generation in human umbilical vein endothelial cells (HUVECs) obtained from extremely preterm infants were associated with risk for BPD or death before 36 weeks postmenstrual age. METHODS HUVEC oxygen consumption and superoxide and hydrogen peroxide generation were measured in 69 infants. MEASUREMENTS AND MAIN RESULTS Compared with HUVECs from infants who survived without BPD, HUVECs obtained from infants who developed BPD or died had a lower maximal oxygen consumption rate (mean ± SEM, 107 ± 8 vs. 235 ± 22 pmol/min/30,000 cells; P < 0.001), produced more superoxide after exposure to hyperoxia (mean ± SEM, 89,807 ± 16,616 vs. 162,706 ± 25,321 MitoSOX Red fluorescence units; P < 0.05), and released more hydrogen peroxide into the supernatant after hyperoxia exposure (mean ± SEM, 1,879 ± 278 vs. 842 ± 119 resorufin arbitrary fluorescence units; P < 0.001). CONCLUSIONS Our results indicating that endothelial cells of premature infants who later develop BPD or die have impaired mitochondrial bioenergetic capacity and produce more oxidants at birth suggest that the vascular endothelial mitochondrial dysfunction seen at birth in these infants persists through their postnatal life and contributes to adverse pulmonary outcomes and increased early mortality.
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Affiliation(s)
| | | | - Scott W Ballinger
- 2 Department of Pathology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama
| | - Namasivayam Ambalavanan
- 1 Department of Pediatrics and.,2 Department of Pathology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama
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Vallabh NA, Romano V, Willoughby CE. Mitochondrial dysfunction and oxidative stress in corneal disease. Mitochondrion 2017; 36:103-113. [PMID: 28549842 DOI: 10.1016/j.mito.2017.05.009] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Revised: 01/23/2017] [Accepted: 05/18/2017] [Indexed: 12/13/2022]
Abstract
The cornea is the anterior transparent surface and the main refracting structure of the eye. Mitochondrial dysfunction and oxidative stress are implicated in the pathogenesis of inherited (e.g. Kearns Sayre Syndrome) and acquired corneal diseases (e.g. keratoconus and Fuchs endothelial corneal dystrophy). Both antioxidants and reactive oxygen species are found in the healthy cornea. There is increasing evidence of imbalance in the oxidative balance and mitochondrial function in the cornea in disease states. The cornea is vulnerable to mitochondrial dysfunction and oxidative stress due to its highly exposed position to ultraviolet radiation and high oxygen tension. The corneal endothelium is vulnerable to accumulating mitochondrial DNA (mtDNA) damage due to the post- mitotic nature of endothelial cells, yet their mitochondrial genome is continually replicating and mtDNA mutations can develop and accumulate with age. The unique physiology of the cornea predisposes this structure to oxidative damage, and there is interplay between inherited and acquired mitochondrial dysfunction, oxidative damage and a number of corneal diseases. By targeting mitochondrial dysfunction in corneal disease, emerging treatments may prevent or reduce visual loss.
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Affiliation(s)
- Neeru A Vallabh
- Corneal and External Eye Service, St. Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool, United Kingdom; Institute of Ageing and Chronic Disease, Department of Eye and Vision Science, University of Liverpool, Liverpool, United Kingdom
| | - Vito Romano
- Corneal and External Eye Service, St. Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool, United Kingdom
| | - Colin E Willoughby
- Corneal and External Eye Service, St. Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool, United Kingdom; Institute of Ageing and Chronic Disease, Department of Eye and Vision Science, University of Liverpool, Liverpool, United Kingdom.
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Gümüş S, Yarıktaş M, Nazıroğlu M, Uğuz AC, Aynali G, Başpınar Ş. Effect of a corticosteroid (triamcinolone) and chlorhexidine on chemotherapy-induced oxidative stress in the buccal mucosa of rats. EAR, NOSE & THROAT JOURNAL 2017; 95:E36-E43. [PMID: 27929606 DOI: 10.1177/014556131609501211] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Oral mucositis manifests as erythematous and ulcerative lesions of the oral mucosa. Among its various causes, cancer treatment (e.g., chemotherapy with or without radiation therapy) is one of the more well known. It has been widely mentioned that oxidative stress parameters such as lipid peroxidation levels increase during the cancer process. Glutathione is one of the major intracellular enzymes used to detoxify oxidant molecules; it exists in both a reduced and oxidized state. Reduced glutathione is used as a substrate to synthesize glutathione peroxidase. We conducted a study to investigate and compare the effects of triamcinolone (a synthetic steroid) and chlorhexidine (a chemical antiseptic) on 5-fluorouracil (5-FU; a chemotherapeutic agent)-induced oral mucositis in the buccal mucosa of 36 rats. Oral mucositis was induced through a combination of 5-FU treatment and mild abrasion of the cheek pouch with a wire brush. The rats were treated with one of four regimens: saline placebo (group I), 5-FU only (group II), 5-FU plus triamcinolone (group III), and 5-FU plus chlorhexidine (group IV). Three rats in the triamcinolone group died of unknown causes on days 7 and 8, and 3 rats in the chlorhexidine group died on days 7 and 9. On day 9, the remaining 30 rats were sacrificed and examined. Buccal mucosa lipid peroxidation levels were significantly higher in the 5-FU-only group than in the control group and significantly higher in the control group than in the triamcinolone group (p < 0.05 for both). Levels of reduced glutathione were significantly lower in the 5-FU-only group than in both the triamcinolone group and the chlorhexidine group (p < 0.05). Glutathione peroxidase activity was significantly higher in the triamcinolone group than in the 5-FU-only group (p < 0.01). Histopathologic analysis revealed that treatment with triamcinolone significantly reduced 5-FU-induced inflammatory cell infiltration and ulceration (p < 0.001); no such reduction was seen with chlorhexidine. In conclusion, we observed that triamcinolone and chlorhexidine treatment modulated chemotherapy-induced oxidative injury in rat oral mucositis. However, only triamcinolone histopathologically ameliorated 5-FU-induced oral mucositis. These findings suggest that triamcinolone is a useful agent for the management of experimental oxidative injury and oral mucositis caused by 5-FU chemotherapy.
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Affiliation(s)
- Sami Gümüş
- Department of Otorhinolaryngology Süleyman Demirel University Faculty of Medicine, Isparta, Turkey
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Mitochondrial dysfunction underlying outer retinal diseases. Mitochondrion 2017; 36:66-76. [PMID: 28365408 DOI: 10.1016/j.mito.2017.03.006] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 03/06/2017] [Accepted: 03/27/2017] [Indexed: 01/21/2023]
Abstract
Dysfunction of photoreceptors, retinal pigment epithelium (RPE) or both contribute to the initiation and progression of several outer retinal disorders. Disrupted Müller glia function might additionally subsidize to these diseases. Mitochondrial malfunctioning is importantly associated with outer retina pathologies, which can be classified as primary and secondary mitochondrial disorders. This review highlights the importance of oxidative stress and mitochondrial DNA damage, underlying outer retinal disorders. Indeed, the metabolically active photoreceptors/RPE are highly prone to these hallmarks of mitochondrial dysfunction, indicating that mitochondria represent a weak link in the antioxidant defenses of outer retinal cells.
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Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium. Proc Natl Acad Sci U S A 2016; 113:14710-14715. [PMID: 27911769 DOI: 10.1073/pnas.1604572113] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The retinal pigment epithelium (RPE) is a monolayer of pigmented cells that requires an active metabolism to maintain outer retinal homeostasis and compensate for oxidative stress. Using 13C metabolic flux analysis in human RPE cells, we found that RPE has an exceptionally high capacity for reductive carboxylation, a metabolic pathway that has recently garnered significant interest because of its role in cancer cell survival. The capacity for reductive carboxylation in RPE exceeds that of all other cells tested, including retina, neural tissue, glial cells, and a cancer cell line. Loss of reductive carboxylation disrupts redox balance and increases RPE sensitivity to oxidative damage, suggesting that deficiencies of reductive carboxylation may contribute to RPE cell death. Supporting reductive carboxylation by supplementation with an NAD+ precursor or its substrate α-ketoglutarate or treatment with a poly(ADP ribose) polymerase inhibitor protects reductive carboxylation and RPE viability from excessive oxidative stress. The ability of these treatments to rescue RPE could be the basis for an effective strategy to treat blinding diseases caused by RPE dysfunction.
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Genin EC, Plutino M, Bannwarth S, Villa E, Cisneros-Barroso E, Roy M, Ortega-Vila B, Fragaki K, Lespinasse F, Pinero-Martos E, Augé G, Moore D, Burté F, Lacas-Gervais S, Kageyama Y, Itoh K, Yu-Wai-Man P, Sesaki H, Ricci JE, Vives-Bauza C, Paquis-Flucklinger V. CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis. EMBO Mol Med 2016; 8:58-72. [PMID: 26666268 PMCID: PMC4718158 DOI: 10.15252/emmm.201505496] [Citation(s) in RCA: 137] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
CHCHD10-related diseases include mitochondrial DNA instability disorder, frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) clinical spectrum, late-onset spinal motor neuropathy (SMAJ), and Charcot-Marie-Tooth disease type 2 (CMT2). Here, we show that CHCHD10 resides with mitofilin, CHCHD3 and CHCHD6 within the "mitochondrial contact site and cristae organizing system" (MICOS) complex. CHCHD10 mutations lead to MICOS complex disassembly and loss of mitochondrial cristae with a decrease in nucleoid number and nucleoid disorganization. Repair of the mitochondrial genome after oxidative stress is impaired in CHCHD10 mutant fibroblasts and this likely explains the accumulation of deleted mtDNA molecules in patient muscle. CHCHD10 mutant fibroblasts are not defective in the delivery of mitochondria to lysosomes suggesting that impaired mitophagy does not contribute to mtDNA instability. Interestingly, the expression of CHCHD10 mutant alleles inhibits apoptosis by preventing cytochrome c release.
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Affiliation(s)
- Emmanuelle C Genin
- IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, Nice Cedex 2, France
| | - Morgane Plutino
- IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, Nice Cedex 2, France
| | - Sylvie Bannwarth
- IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, Nice Cedex 2, France Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, Nice Cedex 2, France
| | - Elodie Villa
- INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe "contrôle métabolique des morts cellulaires", Nice Sophia-Antipolis University, Nice Cedex 2, France
| | - Eugenia Cisneros-Barroso
- Research Health Institute of Palma (IdISPa), Research Unit, Son Espases University Hospital, Palma de Mallorca, Spain
| | - Madhuparna Roy
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Bernardo Ortega-Vila
- Research Health Institute of Palma (IdISPa), Research Unit, Son Espases University Hospital, Palma de Mallorca, Spain
| | - Konstantina Fragaki
- IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, Nice Cedex 2, France Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, Nice Cedex 2, France
| | - Françoise Lespinasse
- IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, Nice Cedex 2, France
| | - Estefania Pinero-Martos
- Research Health Institute of Palma (IdISPa), Research Unit, Son Espases University Hospital, Palma de Mallorca, Spain
| | - Gaëlle Augé
- IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, Nice Cedex 2, France Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, Nice Cedex 2, France
| | - David Moore
- Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, International Centre for Life Newcastle University, Newcastle upon Tyne, UK Newcastle Eye Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UK
| | - Florence Burté
- Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, International Centre for Life Newcastle University, Newcastle upon Tyne, UK Newcastle Eye Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UK
| | - Sandra Lacas-Gervais
- Joint Center for Applied Electron Microscopy, Nice Sophia-Antipolis University, Nice Cedex 2, France
| | - Yusuke Kageyama
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kie Itoh
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Patrick Yu-Wai-Man
- Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, International Centre for Life Newcastle University, Newcastle upon Tyne, UK Newcastle Eye Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UK
| | - Hiromi Sesaki
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jean-Ehrland Ricci
- INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe "contrôle métabolique des morts cellulaires", Nice Sophia-Antipolis University, Nice Cedex 2, France
| | - Cristofol Vives-Bauza
- Research Health Institute of Palma (IdISPa), Research Unit, Son Espases University Hospital, Palma de Mallorca, Spain
| | - Véronique Paquis-Flucklinger
- IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, Nice Cedex 2, France Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, Nice Cedex 2, France
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Zhou Y, Zhou L, Ruan Z, Mi S, Jiang M, Li X, Wu X, Deng Z, Yin Y. Chlorogenic acid ameliorates intestinal mitochondrial injury by increasing antioxidant effects and activity of respiratory complexes. Biosci Biotechnol Biochem 2016; 80:962-71. [DOI: 10.1080/09168451.2015.1127130] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Abstract
Dietary polyphenols are thought to be beneficial for human health by acting as antioxidants. Chlorogenic acid (CGA) is abundant in plant-based foods as an ester of caffeic acid and quinic acid. In this study, we investigated the effects of CGA on mitochondrial protection. Our results demonstrated that pretreatment with CGA ameliorated the intestinal mitochondrial injury induced by H2O2; membrane potential was increased, mitochondrial swelling, levels of reactive oxygen species, contents of 8-hydroxy-2-deoxyguanosine, and cytochrome c released were decreased. The beneficial effects of CGA were accompanied by an increase in antioxidant and respiratory-chain complex I, IV, and V activities. In trinitrobenzene-sulfonic acid-induced colitic rats indicated that CGA supplementation improved mitochondria ultrastructure and decreased mitochondrial injury. Our results suggest a promising role for CGA as a mitochondria-targeted antioxidant in combating intestinal oxidative injury. Daily intake of diets containing CGA, such as coffee and honeysuckle, may be useful for prevention of intestinal diseases.
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Affiliation(s)
- Yan Zhou
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
- College of Food Science and Technology, Nanchang University, Nanchang, China
| | - Lili Zhou
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
- College of Food Science and Technology, Nanchang University, Nanchang, China
| | - Zheng Ruan
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
- College of Food Science and Technology, Nanchang University, Nanchang, China
| | - Shumei Mi
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
- College of Food Science and Technology, Nanchang University, Nanchang, China
| | - Min Jiang
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
- College of Food Science and Technology, Nanchang University, Nanchang, China
| | - Xiaolan Li
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
- College of Food Science and Technology, Nanchang University, Nanchang, China
| | - Xin Wu
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China
| | - Zeyuan Deng
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
- College of Food Science and Technology, Nanchang University, Nanchang, China
| | - Yulong Yin
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
- College of Food Science and Technology, Nanchang University, Nanchang, China
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China
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Fetterman JL, Holbrook M, Westbrook DG, Brown JA, Feeley KP, Bretón-Romero R, Linder EA, Berk BD, Weisbrod RM, Widlansky ME, Gokce N, Ballinger SW, Hamburg NM. Mitochondrial DNA damage and vascular function in patients with diabetes mellitus and atherosclerotic cardiovascular disease. Cardiovasc Diabetol 2016; 15:53. [PMID: 27036979 PMCID: PMC4818501 DOI: 10.1186/s12933-016-0372-y] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2015] [Accepted: 03/22/2016] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE Prior studies demonstrate mitochondrial dysfunction with increased reactive oxygen species generation in peripheral blood mononuclear cells in diabetes mellitus. Oxidative stress-mediated damage to mitochondrial DNA promotes atherosclerosis in animal models. Thus, we evaluated the relation of mitochondrial DNA damage in peripheral blood mononuclear cells s with vascular function in patients with diabetes mellitus and with atherosclerotic cardiovascular disease. APPROACH AND RESULTS We assessed non-invasive vascular function and mitochondrial DNA damage in 275 patients (age 57 ± 9 years, 60 % women) with atherosclerotic cardiovascular disease alone (N = 55), diabetes mellitus alone (N = 74), combined atherosclerotic cardiovascular disease and diabetes mellitus (N = 48), and controls age >45 without diabetes mellitus or atherosclerotic cardiovascular disease (N = 98). Mitochondrial DNA damage measured by quantitative PCR in peripheral blood mononuclear cells was higher with clinical atherosclerosis alone (0.55 ± 0.65), diabetes mellitus alone (0.65 ± 1.0), and combined clinical atherosclerosis and diabetes mellitus (0.89 ± 1.32) as compared to control subjects (0.23 ± 0.64, P < 0.0001). In multivariable models adjusting for age, sex, and relevant cardiovascular risk factors, clinical atherosclerosis and diabetes mellitus remained associated with higher mitochondrial DNA damage levels (β = 0.14 ± 0.13, P = 0.04 and β = 0.21 ± 0.13, P = 0.002, respectively). Higher mitochondrial DNA damage was associated with higher baseline pulse amplitude, a measure of arterial pulsatility, but not with flow-mediated dilation or hyperemic response, measures of vasodilator function. CONCLUSIONS We found greater mitochondrial DNA damage in patients with diabetes mellitus and clinical atherosclerosis. The association of mitochondrial DNA damage and baseline pulse amplitude may suggest a link between mitochondrial dysfunction and excessive small artery pulsatility with potentially adverse microvascular impact.
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Affiliation(s)
- Jessica L Fetterman
- Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, 72 East Concord Street, E-784, Boston, MA, 02118, USA.
| | - Monica Holbrook
- Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, 72 East Concord Street, E-784, Boston, MA, 02118, USA
| | - David G Westbrook
- Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jamelle A Brown
- Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Kyle P Feeley
- Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Rosa Bretón-Romero
- Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, 72 East Concord Street, E-784, Boston, MA, 02118, USA
| | - Erika A Linder
- Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, 72 East Concord Street, E-784, Boston, MA, 02118, USA
| | - Brittany D Berk
- Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, 72 East Concord Street, E-784, Boston, MA, 02118, USA
| | - Robert M Weisbrod
- Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, 72 East Concord Street, E-784, Boston, MA, 02118, USA
| | - Michael E Widlansky
- Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Noyan Gokce
- Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, 72 East Concord Street, E-784, Boston, MA, 02118, USA
| | - Scott W Ballinger
- Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Naomi M Hamburg
- Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, 72 East Concord Street, E-784, Boston, MA, 02118, USA
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Redmann M, Darley-Usmar V, Zhang J. The Role of Autophagy, Mitophagy and Lysosomal Functions in Modulating Bioenergetics and Survival in the Context of Redox and Proteotoxic Damage: Implications for Neurodegenerative Diseases. Aging Dis 2016; 7:150-62. [PMID: 27114848 PMCID: PMC4809607 DOI: 10.14336/ad.2015.0820] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Accepted: 08/20/2015] [Indexed: 12/21/2022] Open
Abstract
Redox and proteotoxic stress contributes to age-dependent accumulation of dysfunctional mitochondria and protein aggregates, and is associated with neurodegeneration. The free radical theory of aging inspired many studies using reactive species scavengers such as alpha-tocopherol, ascorbate and coenzyme Q to suppress the initiation of oxidative stress. However, clinical trials have had limited success in the treatment of neurodegenerative diseases. We ascribe this to the emerging literature which suggests that the oxidative stress hypothesis does not encompass the role of reactive species in cell signaling and therefore the interception with reactive species with antioxidant supplementation may result in disruption of redox signaling. In addition, the accumulation of redox modified proteins or organelles cannot be reversed by oxidant intercepting antioxidants and must then be removed by alternative mechanisms. We have proposed that autophagy serves this essential function in removing damaged or dysfunctional proteins and organelles thus preserving neuronal function and survival. In this review, we will highlight observations regarding the impact of autophagy regulation on cellular bioenergetics and survival in response to reactive species or reactive species generating compounds, and in response to proteotoxic stress.
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Affiliation(s)
- Matthew Redmann
- Center for Free Radical Biology,; Department of Pathology, University of Alabama at Birmingham
| | - Victor Darley-Usmar
- Center for Free Radical Biology,; Department of Pathology, University of Alabama at Birmingham
| | - Jianhua Zhang
- Center for Free Radical Biology,; Department of Pathology, University of Alabama at Birmingham,; Department of Veterans Affairs, Birmingham VA Medical Center, Birmingham, Alabama 35294, USA
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Krzywanski DM, Moellering DR, Westbrook DG, Dunham-Snary KJ, Brown J, Bray AW, Feeley KP, Sammy MJ, Smith MR, Schurr TG, Vita JA, Ambalavanan N, Calhoun D, Dell'Italia L, Ballinger SW. Endothelial Cell Bioenergetics and Mitochondrial DNA Damage Differ in Humans Having African or West Eurasian Maternal Ancestry. ACTA ACUST UNITED AC 2016; 9:26-36. [PMID: 26787433 DOI: 10.1161/circgenetics.115.001308] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 01/13/2016] [Indexed: 01/09/2023]
Abstract
BACKGROUND We hypothesized that endothelial cells having distinct mitochondrial genetic backgrounds would show variation in mitochondrial function and oxidative stress markers concordant with known differential cardiovascular disease susceptibilities. To test this hypothesis, mitochondrial bioenergetics were determined in endothelial cells from healthy individuals with African versus European maternal ancestries. METHODS AND RESULTS Bioenergetics and mitochondrial DNA (mtDNA) damage were assessed in single-donor human umbilical vein endothelial cells belonging to mtDNA haplogroups H and L, representing West Eurasian and African maternal ancestries, respectively. Human umbilical vein endothelial cells from haplogroup L used less oxygen for ATP production and had increased levels of mtDNA damage compared with those in haplogroup H. Differences in bioenergetic capacity were also observed in that human umbilical vein endothelial cells belonging to haplogroup L had decreased maximal bioenergetic capacities compared with haplogroup H. Analysis of peripheral blood mononuclear cells from age-matched healthy controls with West Eurasian or African maternal ancestries showed that haplogroups sharing an A to G mtDNA mutation at nucleotide pair 10398 had increased mtDNA damage compared with those lacking this mutation. Further study of angiographically proven patients with coronary artery disease and age-matched healthy controls revealed that mtDNA damage was associated with vascular function and remodeling and that age of disease onset was later in individuals from haplogroups lacking the A to G mutation at nucleotide pair 10398. CONCLUSIONS Differences in mitochondrial bioenergetics and mtDNA damage associated with maternal ancestry may contribute to endothelial dysfunction and vascular disease.
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Affiliation(s)
- David M Krzywanski
- From the Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport (D.M.K.); Department of Nutrition Sciences (D.R.M.), Center for Free Radical Biology and Medicine (D.R.M., D.G.W., K.J.D.-S., J.B., A.W.B., K.P.F., M.J.S., M.R.S., L.D., S.W.B.), Division of Molecular and Cellular Pathology, Department of Pathology (D.G.W., J.B., A.W.B., K.P.F., M.J.S., M.R.S., S.W.B.), Department of Pediatrics (N.A.), Department of Medicine (D.C., L.D.), University of Alabama at Birmingham; Department of Medicine, Queen's University, Kingston, Ontario, Canada (K.J.D.-S.); Department of Anthropology, University of Pennsylvania, Philadelphia (T.G.S.); and Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, MA (J.A.V.)
| | - Douglas R Moellering
- From the Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport (D.M.K.); Department of Nutrition Sciences (D.R.M.), Center for Free Radical Biology and Medicine (D.R.M., D.G.W., K.J.D.-S., J.B., A.W.B., K.P.F., M.J.S., M.R.S., L.D., S.W.B.), Division of Molecular and Cellular Pathology, Department of Pathology (D.G.W., J.B., A.W.B., K.P.F., M.J.S., M.R.S., S.W.B.), Department of Pediatrics (N.A.), Department of Medicine (D.C., L.D.), University of Alabama at Birmingham; Department of Medicine, Queen's University, Kingston, Ontario, Canada (K.J.D.-S.); Department of Anthropology, University of Pennsylvania, Philadelphia (T.G.S.); and Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, MA (J.A.V.)
| | - David G Westbrook
- From the Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport (D.M.K.); Department of Nutrition Sciences (D.R.M.), Center for Free Radical Biology and Medicine (D.R.M., D.G.W., K.J.D.-S., J.B., A.W.B., K.P.F., M.J.S., M.R.S., L.D., S.W.B.), Division of Molecular and Cellular Pathology, Department of Pathology (D.G.W., J.B., A.W.B., K.P.F., M.J.S., M.R.S., S.W.B.), Department of Pediatrics (N.A.), Department of Medicine (D.C., L.D.), University of Alabama at Birmingham; Department of Medicine, Queen's University, Kingston, Ontario, Canada (K.J.D.-S.); Department of Anthropology, University of Pennsylvania, Philadelphia (T.G.S.); and Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, MA (J.A.V.)
| | - Kimberly J Dunham-Snary
- From the Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport (D.M.K.); Department of Nutrition Sciences (D.R.M.), Center for Free Radical Biology and Medicine (D.R.M., D.G.W., K.J.D.-S., J.B., A.W.B., K.P.F., M.J.S., M.R.S., L.D., S.W.B.), Division of Molecular and Cellular Pathology, Department of Pathology (D.G.W., J.B., A.W.B., K.P.F., M.J.S., M.R.S., S.W.B.), Department of Pediatrics (N.A.), Department of Medicine (D.C., L.D.), University of Alabama at Birmingham; Department of Medicine, Queen's University, Kingston, Ontario, Canada (K.J.D.-S.); Department of Anthropology, University of Pennsylvania, Philadelphia (T.G.S.); and Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, MA (J.A.V.)
| | - Jamelle Brown
- From the Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport (D.M.K.); Department of Nutrition Sciences (D.R.M.), Center for Free Radical Biology and Medicine (D.R.M., D.G.W., K.J.D.-S., J.B., A.W.B., K.P.F., M.J.S., M.R.S., L.D., S.W.B.), Division of Molecular and Cellular Pathology, Department of Pathology (D.G.W., J.B., A.W.B., K.P.F., M.J.S., M.R.S., S.W.B.), Department of Pediatrics (N.A.), Department of Medicine (D.C., L.D.), University of Alabama at Birmingham; Department of Medicine, Queen's University, Kingston, Ontario, Canada (K.J.D.-S.); Department of Anthropology, University of Pennsylvania, Philadelphia (T.G.S.); and Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, MA (J.A.V.)
| | - Alexander W Bray
- From the Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport (D.M.K.); Department of Nutrition Sciences (D.R.M.), Center for Free Radical Biology and Medicine (D.R.M., D.G.W., K.J.D.-S., J.B., A.W.B., K.P.F., M.J.S., M.R.S., L.D., S.W.B.), Division of Molecular and Cellular Pathology, Department of Pathology (D.G.W., J.B., A.W.B., K.P.F., M.J.S., M.R.S., S.W.B.), Department of Pediatrics (N.A.), Department of Medicine (D.C., L.D.), University of Alabama at Birmingham; Department of Medicine, Queen's University, Kingston, Ontario, Canada (K.J.D.-S.); Department of Anthropology, University of Pennsylvania, Philadelphia (T.G.S.); and Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, MA (J.A.V.)
| | - Kyle P Feeley
- From the Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport (D.M.K.); Department of Nutrition Sciences (D.R.M.), Center for Free Radical Biology and Medicine (D.R.M., D.G.W., K.J.D.-S., J.B., A.W.B., K.P.F., M.J.S., M.R.S., L.D., S.W.B.), Division of Molecular and Cellular Pathology, Department of Pathology (D.G.W., J.B., A.W.B., K.P.F., M.J.S., M.R.S., S.W.B.), Department of Pediatrics (N.A.), Department of Medicine (D.C., L.D.), University of Alabama at Birmingham; Department of Medicine, Queen's University, Kingston, Ontario, Canada (K.J.D.-S.); Department of Anthropology, University of Pennsylvania, Philadelphia (T.G.S.); and Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, MA (J.A.V.)
| | - Melissa J Sammy
- From the Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport (D.M.K.); Department of Nutrition Sciences (D.R.M.), Center for Free Radical Biology and Medicine (D.R.M., D.G.W., K.J.D.-S., J.B., A.W.B., K.P.F., M.J.S., M.R.S., L.D., S.W.B.), Division of Molecular and Cellular Pathology, Department of Pathology (D.G.W., J.B., A.W.B., K.P.F., M.J.S., M.R.S., S.W.B.), Department of Pediatrics (N.A.), Department of Medicine (D.C., L.D.), University of Alabama at Birmingham; Department of Medicine, Queen's University, Kingston, Ontario, Canada (K.J.D.-S.); Department of Anthropology, University of Pennsylvania, Philadelphia (T.G.S.); and Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, MA (J.A.V.)
| | - Matthew R Smith
- From the Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport (D.M.K.); Department of Nutrition Sciences (D.R.M.), Center for Free Radical Biology and Medicine (D.R.M., D.G.W., K.J.D.-S., J.B., A.W.B., K.P.F., M.J.S., M.R.S., L.D., S.W.B.), Division of Molecular and Cellular Pathology, Department of Pathology (D.G.W., J.B., A.W.B., K.P.F., M.J.S., M.R.S., S.W.B.), Department of Pediatrics (N.A.), Department of Medicine (D.C., L.D.), University of Alabama at Birmingham; Department of Medicine, Queen's University, Kingston, Ontario, Canada (K.J.D.-S.); Department of Anthropology, University of Pennsylvania, Philadelphia (T.G.S.); and Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, MA (J.A.V.)
| | - Theodore G Schurr
- From the Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport (D.M.K.); Department of Nutrition Sciences (D.R.M.), Center for Free Radical Biology and Medicine (D.R.M., D.G.W., K.J.D.-S., J.B., A.W.B., K.P.F., M.J.S., M.R.S., L.D., S.W.B.), Division of Molecular and Cellular Pathology, Department of Pathology (D.G.W., J.B., A.W.B., K.P.F., M.J.S., M.R.S., S.W.B.), Department of Pediatrics (N.A.), Department of Medicine (D.C., L.D.), University of Alabama at Birmingham; Department of Medicine, Queen's University, Kingston, Ontario, Canada (K.J.D.-S.); Department of Anthropology, University of Pennsylvania, Philadelphia (T.G.S.); and Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, MA (J.A.V.)
| | - Joseph A Vita
- From the Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport (D.M.K.); Department of Nutrition Sciences (D.R.M.), Center for Free Radical Biology and Medicine (D.R.M., D.G.W., K.J.D.-S., J.B., A.W.B., K.P.F., M.J.S., M.R.S., L.D., S.W.B.), Division of Molecular and Cellular Pathology, Department of Pathology (D.G.W., J.B., A.W.B., K.P.F., M.J.S., M.R.S., S.W.B.), Department of Pediatrics (N.A.), Department of Medicine (D.C., L.D.), University of Alabama at Birmingham; Department of Medicine, Queen's University, Kingston, Ontario, Canada (K.J.D.-S.); Department of Anthropology, University of Pennsylvania, Philadelphia (T.G.S.); and Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, MA (J.A.V.)
| | - Namasivayam Ambalavanan
- From the Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport (D.M.K.); Department of Nutrition Sciences (D.R.M.), Center for Free Radical Biology and Medicine (D.R.M., D.G.W., K.J.D.-S., J.B., A.W.B., K.P.F., M.J.S., M.R.S., L.D., S.W.B.), Division of Molecular and Cellular Pathology, Department of Pathology (D.G.W., J.B., A.W.B., K.P.F., M.J.S., M.R.S., S.W.B.), Department of Pediatrics (N.A.), Department of Medicine (D.C., L.D.), University of Alabama at Birmingham; Department of Medicine, Queen's University, Kingston, Ontario, Canada (K.J.D.-S.); Department of Anthropology, University of Pennsylvania, Philadelphia (T.G.S.); and Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, MA (J.A.V.)
| | - David Calhoun
- From the Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport (D.M.K.); Department of Nutrition Sciences (D.R.M.), Center for Free Radical Biology and Medicine (D.R.M., D.G.W., K.J.D.-S., J.B., A.W.B., K.P.F., M.J.S., M.R.S., L.D., S.W.B.), Division of Molecular and Cellular Pathology, Department of Pathology (D.G.W., J.B., A.W.B., K.P.F., M.J.S., M.R.S., S.W.B.), Department of Pediatrics (N.A.), Department of Medicine (D.C., L.D.), University of Alabama at Birmingham; Department of Medicine, Queen's University, Kingston, Ontario, Canada (K.J.D.-S.); Department of Anthropology, University of Pennsylvania, Philadelphia (T.G.S.); and Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, MA (J.A.V.)
| | - Louis Dell'Italia
- From the Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport (D.M.K.); Department of Nutrition Sciences (D.R.M.), Center for Free Radical Biology and Medicine (D.R.M., D.G.W., K.J.D.-S., J.B., A.W.B., K.P.F., M.J.S., M.R.S., L.D., S.W.B.), Division of Molecular and Cellular Pathology, Department of Pathology (D.G.W., J.B., A.W.B., K.P.F., M.J.S., M.R.S., S.W.B.), Department of Pediatrics (N.A.), Department of Medicine (D.C., L.D.), University of Alabama at Birmingham; Department of Medicine, Queen's University, Kingston, Ontario, Canada (K.J.D.-S.); Department of Anthropology, University of Pennsylvania, Philadelphia (T.G.S.); and Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, MA (J.A.V.)
| | - Scott W Ballinger
- From the Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport (D.M.K.); Department of Nutrition Sciences (D.R.M.), Center for Free Radical Biology and Medicine (D.R.M., D.G.W., K.J.D.-S., J.B., A.W.B., K.P.F., M.J.S., M.R.S., L.D., S.W.B.), Division of Molecular and Cellular Pathology, Department of Pathology (D.G.W., J.B., A.W.B., K.P.F., M.J.S., M.R.S., S.W.B.), Department of Pediatrics (N.A.), Department of Medicine (D.C., L.D.), University of Alabama at Birmingham; Department of Medicine, Queen's University, Kingston, Ontario, Canada (K.J.D.-S.); Department of Anthropology, University of Pennsylvania, Philadelphia (T.G.S.); and Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, MA (J.A.V.).
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Jeung IC, Jee D, Rho CR, Kang S. Melissa Officinalis L. Extracts Protect Human Retinal Pigment Epithelial Cells against Oxidative Stress-Induced Apoptosis. Int J Med Sci 2016; 13:139-46. [PMID: 26941573 PMCID: PMC4764781 DOI: 10.7150/ijms.13861] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 12/10/2015] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND We evaluated the protective effect of ALS-L1023, an extract of Melissa officinalis L. (Labiatae; lemon balm) against oxidative stress-induced apoptosis in human retinal pigment epithelial cells (ARPE-19 cells). METHODS ARPE-19 cells were incubated with ALS-L1023 for 24 h and then treated with hydrogen peroxide (H2O2). Oxidative stress-induced apoptosis and intracellular generation of reactive oxygen species (ROS) were assessed by flow cytometry. Caspase-3/7 activation and cleaved poly ADP-ribose polymerase (PARP) were measured to investigate the protective role of ALS-L1023 against apoptosis. The protective effect of ALS-L1023 against oxidative stress through activation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) was evaluated by Western blot analysis. RESULTS ALS-L1023 clearly reduced H2O2-induced cell apoptosis and intracellular production of ROS. H2O2-induced oxidative stress increased caspase-3/7 activity and apoptotic PARP cleavage, which were significantly inhibited by ALS-L1023. Activation of the PI3K/Akt pathway was associated with the protective effect of ALS-L1023 on ARPE-19 cells. CONCLUSIONS ALS-L1023 protected human RPE cells against oxidative damage. This suggests that ALS-L1023 has therapeutic potential for the prevention of dry age-related macular degeneration.
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Affiliation(s)
- In Cheul Jeung
- 1. Clinical Research Institute, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon 301-012, Republic of Korea;; 2. Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, 137-701, Republic of Korea
| | - Donghyun Jee
- 3. Department of Ophthalmology and Visual Science, College of Medicine, The Catholic University of Korea, Seoul, 137-701, Republic of Korea
| | - Chang-Rae Rho
- 1. Clinical Research Institute, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon 301-012, Republic of Korea;; 3. Department of Ophthalmology and Visual Science, College of Medicine, The Catholic University of Korea, Seoul, 137-701, Republic of Korea
| | - Seungbum Kang
- 1. Clinical Research Institute, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon 301-012, Republic of Korea;; 3. Department of Ophthalmology and Visual Science, College of Medicine, The Catholic University of Korea, Seoul, 137-701, Republic of Korea
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50
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Toward understanding the selective anticancer capacity of cold atmospheric plasma--a model based on aquaporins (Review). Biointerphases 2015; 10:040801. [PMID: 26700469 DOI: 10.1116/1.4938020] [Citation(s) in RCA: 114] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Selectively treating tumor cells is the ongoing challenge of modern cancer therapy. Recently, cold atmospheric plasma (CAP), a near room-temperature ionized gas, has been demonstrated to exhibit selective anticancer behavior. However, the mechanism governing such selectivity is still largely unknown. In this review, the authors first summarize the progress that has been made applying CAP as a selective tool for cancer treatment. Then, the key role of aquaporins in the H2O2 transmembrane diffusion is discussed. Finally, a novel model, based on the expression of aquaporins, is proposed to explain why cancer cells respond to CAP treatment with a greater rise in reactive oxygen species than homologous normal cells. Cancer cells tend to express more aquaporins on their cytoplasmic membranes, which may cause the H2O2 uptake speed in cancer cells to be faster than in normal cells. As a result, CAP treatment kills cancer cells more easily than normal cells. Our preliminary observations indicated that glioblastoma cells consumed H2O2 much faster than did astrocytes in either the CAP-treated or H2O2-rich media, which supported the selective model based on aquaporins.
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