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Salgado KDCB, Nascimento RGF, Albuquerque ALS, Oliveira LAM, Pinto Coelho Nogueira KDO. Melatonin protects mouse hippocampal neurons from neurotoxicity induced by amyloid β-peptide 25-35. Brain Res 2025; 1859:149637. [PMID: 40222698 DOI: 10.1016/j.brainres.2025.149637] [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: 02/05/2025] [Revised: 04/07/2025] [Accepted: 04/08/2025] [Indexed: 04/15/2025]
Abstract
Alzheimer's disease (AD) is a complex neurodegenerative disorder and the leading cause of dementia in the elderly, as classified by the WHO. Its neuropathological hallmarks include the accumulation of amyloid-β (Aβ) plaques and intracellular tau tangles, which contribute to oxidative stress, mitochondrial dysfunction, lipid peroxidation, and neuronal death. Emerging evidence suggests that melatonin, a potent antioxidant produced by the pineal gland, plays a neuroprotective role in AD, yet its precise mechanisms remain underexplored. In this study, we utilized a physiologically relevant primary culture of hippocampal neurons to investigate melatonin's protective effects against toxicity induced by Aβ25-35. Our findings demonstrate that melatonin significantly enhances cellular metabolism and viability while reducing reactive oxygen species (ROS) levels and lipid peroxidation, thereby mitigating Aβ-induced neurotoxicity. These results provide mechanistic insights into melatonin's antioxidative and neuroprotective properties, reinforcing its potential as a therapeutic agent against oxidative stress in AD. This study underscores the promise of melatonin-based interventions in the development of novel antioxidant-targeted therapies for AD.
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Affiliation(s)
- Karen Del Carmen B Salgado
- Department of Biological Sciences, Laboratory of Neurobiology and Biomaterials (LNBio), Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Rosiene G F Nascimento
- Department of Biological Sciences, Laboratory of Neurobiology and Biomaterials (LNBio), Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Ana Luiza S Albuquerque
- Department of Biological Sciences, Laboratory of Neurobiology and Biomaterials (LNBio), Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Laser A M Oliveira
- Department of Biological Sciences, Laboratory of Neurobiology and Biomaterials (LNBio), Federal University of Ouro Preto, Ouro Preto, Brazil
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2
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Abdelhameed NG, Ahmed YH, Yasin NAE, Mahmoud MY, El-Sakhawy MA. Effects of Aluminum Oxide Nanoparticles in the Spinal Cord of Male Wistar Rats and the Potential Ameliorative Role of Melatonin. ENVIRONMENTAL TOXICOLOGY 2025; 40:737-749. [PMID: 39705097 DOI: 10.1002/tox.24466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 11/26/2024] [Accepted: 12/08/2024] [Indexed: 12/22/2024]
Abstract
Aluminum oxide nanoparticles (Al2O3 NPs) are widely utilized in vaccine manufacturing and other medical preparations. Melatonin has numerous effects as an antioxidant and anti-apoptotic. The purpose of this study was to examine the beneficial impact of melatonin on Al2O3 NPs toxicity in the spinal cord. Forty male rats were divided into four groups: Group I, the negative controls (received standard diet and distilled water); Group II, Al2O3 NPs (received 30 mg/kg bw Al2O3 NPs); Group III, melatonin and Al2O3 NPs (received 30 mg/kg bw Al2O3 NPs + 10 mg/kg bw melatonin); Group IV, melatonin (received 10 mg/kg bw melatonin). All treatments were administered daily for 28 days by gastric gavage. After that, all rats were sacrificed, then, the samples from different spinal cords were subjected to histopathological, biochemical, and immunohistochemical analyses. Al2O3 NPs markedly elevated malondialdehyde and 8-hydroxydeoxyguanosine while inhibiting superoxide dismutase and catalase. Al2O3 NPs also induced histological alterations in both gray and white matter manifested by neuronal degeneration, vacuolation, axonal degeneration, ballooning, and fusion of myelin sheaths. Furthermore, immunohistochemical results displayed a strong positive expression of caspase-3. Conversely, melatonin significantly mitigated the effects of Al2O3 NPs by increasing the activities of antioxidant enzymes and inhibiting malondialdehyde and 8-hydroxydeoxyguanosine. Moreover, melatonin alleviated most histological alterations induced by Al2O3 NPs and reduced caspase-3 immunoreactivity. Collectively, melatonin could protect the spinal cord and mitigate Al2O3 NPs-induced neurotoxicity.
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Affiliation(s)
- Nermeen G Abdelhameed
- Cytology and Histology Department, Veterinary Medicine, Cairo University, Giza, Egypt
| | - Yasmine H Ahmed
- Cytology and Histology Department, Veterinary Medicine, Cairo University, Giza, Egypt
| | - Noha A E Yasin
- Cytology and Histology Department, Veterinary Medicine, Cairo University, Giza, Egypt
| | - Mohamed Y Mahmoud
- Toxicology and Forensic Medicine Department, Veterinary Medicine, Cairo University, Giza, Egypt
| | - Mohamed A El-Sakhawy
- Cytology and Histology Department, Veterinary Medicine, Cairo University, Giza, Egypt
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3
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Cong J, Li JY, Zou W. Mechanism and treatment of intracerebral hemorrhage focus on mitochondrial permeability transition pore. Front Mol Neurosci 2024; 17:1423132. [PMID: 39156127 PMCID: PMC11328408 DOI: 10.3389/fnmol.2024.1423132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 07/15/2024] [Indexed: 08/20/2024] Open
Abstract
Intracerebral hemorrhage (ICH) is the second most common subtype of stroke, characterized by high mortality and a poor prognosis. Despite various treatment methods, there has been limited improvement in the prognosis of ICH over the past decades. Therefore, it is imperative to identify a feasible treatment strategy for ICH. Mitochondria are organelles present in most eukaryotic cells and serve as the primary sites for aerobic respiration and energy production. Under unfavorable cellular conditions, mitochondria can induce changes in permeability through the opening of the mitochondrial permeability transition pore (mPTP), ultimately leading to mitochondrial dysfunction and contributing to various diseases. Recent studies have demonstrated that mPTP plays a role in the pathological processes associated with several neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, Huntington's disease, ischemic stroke and ischemia-reperfusion injury, among others. However, there is limited research on mPTP involvement specifically in ICH. Therefore, this study comprehensively examines the pathological processes associated with mPTP in terms of oxidative stress, apoptosis, necrosis, autophagy, ferroptosis, and other related mechanisms to elucidate the potential mechanism underlying mPTP involvement in ICH. This research aims to provide novel insights for the treatment of secondary injury after ICH.
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Affiliation(s)
- Jing Cong
- The First School of Clinical Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Jing-Yi Li
- The Second School of Clinical Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Wei Zou
- Molecular Biology Laboratory of Clinical Integrated of Traditional Chinese and Western Medicine of Heilong Jiang Province, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
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Reiter RJ, Sharma R, Tan DX, Chuffa LGDA, da Silva DGH, Slominski AT, Steinbrink K, Kleszczynski K. Dual sources of melatonin and evidence for different primary functions. Front Endocrinol (Lausanne) 2024; 15:1414463. [PMID: 38808108 PMCID: PMC11130361 DOI: 10.3389/fendo.2024.1414463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 04/30/2024] [Indexed: 05/30/2024] Open
Abstract
This article discusses data showing that mammals, including humans, have two sources of melatonin that exhibit different functions. The best-known source of melatonin, herein referred to as Source #1, is the pineal gland. In this organ, melatonin production is circadian with maximal synthesis and release into the blood and cerebrospinal fluid occurring during the night. Of the total amount of melatonin produced in mammals, we speculate that less than 5% is synthesized by the pineal gland. The melatonin rhythm has the primary function of influencing the circadian clock at the level of the suprachiasmatic nucleus (the CSF melatonin) and the clockwork in all peripheral organs (the blood melatonin) via receptor-mediated actions. A second source of melatonin (Source # 2) is from multiple tissues throughout the body, probably being synthesized in the mitochondria of these cells. This constitutes the bulk of the melatonin produced in mammals and is concerned with metabolic regulation. This review emphasizes the action of melatonin from peripheral sources in determining re-dox homeostasis, but it has other critical metabolic effects as well. Extrapineal melatonin synthesis does not exhibit a circadian rhythm and it is not released into the blood but acts locally in its cell of origin and possibly in a paracrine matter on adjacent cells. The factors that control/influence melatonin synthesis at extrapineal sites are unknown. We propose that the concentration of melatonin in these cells is determined by the subcellular redox state and that melatonin synthesis may be inducible under stressful conditions as in plant cells.
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Affiliation(s)
- Russel J. Reiter
- Department of Cell Systems and Anatomy, UT Health San Antonio, Long School of Medicine, San Antonio TX, United States
| | - Ramaswamy Sharma
- Applied Biomedical Sciences, University of the Incarnate Word, School of Osteopathic Medicine, San Antonio, TX, United States
| | - Dun-Xian Tan
- Department of Cell Systems and Anatomy, UT Health San Antonio, Long School of Medicine, San Antonio TX, United States
| | - Luiz Gustavo de Almieda Chuffa
- Departamento de Biologia Estrutural e Funcional, Setor de Anatomia - Instituto de Biociências, IBB/UNESP, Botucatu, São Paulo, Brazil
| | - Danilo Grunig Humberto da Silva
- Department of Biology, Universidade Estadual Paulista (UNESP), São Paulo, Brazil
- Department of Biology, Universidade Federal de Mato Grosso Do Sul, Três Lagoas, Mato Grosso Do Sul, Brazil
| | - Andrzej T. Slominski
- US and Pathology Laboratory Service, Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, United States
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Gill NB, Dowker-Key PD, Hedrick M, Bettaieb A. Unveiling the Role of Oxidative Stress in Cochlear Hair Cell Death: Prospective Phytochemical Therapeutics against Sensorineural Hearing Loss. Int J Mol Sci 2024; 25:4272. [PMID: 38673858 PMCID: PMC11050722 DOI: 10.3390/ijms25084272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 03/31/2024] [Accepted: 04/07/2024] [Indexed: 04/28/2024] Open
Abstract
Hearing loss represents a multifaceted and pervasive challenge that deeply impacts various aspects of an individual's life, spanning psychological, emotional, social, and economic realms. Understanding the molecular underpinnings that orchestrate hearing loss remains paramount in the quest for effective therapeutic strategies. This review aims to expound upon the physiological, biochemical, and molecular aspects of hearing loss, with a specific focus on its correlation with diabetes. Within this context, phytochemicals have surfaced as prospective contenders in the pursuit of potential adjuvant therapies. These compounds exhibit noteworthy antioxidant and anti-inflammatory properties, which hold the potential to counteract the detrimental effects induced by oxidative stress and inflammation-prominent contributors to hearing impairment. Furthermore, this review offers an up-to-date exploration of the diverse molecular pathways modulated by these compounds. However, the dynamic landscape of their efficacy warrants recognition as an ongoing investigative topic, inherently contingent upon specific experimental models. Ultimately, to ascertain the genuine potential of phytochemicals as agents in hearing loss treatment, a comprehensive grasp of the molecular mechanisms at play, coupled with rigorous clinical investigations, stands as an imperative quest.
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Affiliation(s)
- Nicholas B. Gill
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN 37996-0840, USA
| | - Presley D. Dowker-Key
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN 37996-0840, USA
| | - Mark Hedrick
- Department of Audiology & Speech Pathology, The University of Tennessee Health Science Center, Knoxville, TN 37996-0240, USA
| | - Ahmed Bettaieb
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN 37996-0840, USA
- Graduate School of Genome Science and Technology, University of Tennessee Knoxville, Knoxville, TN 37996-0840, USA
- Department of Biochemistry, Cellular and Molecular Biology, University of Tennessee Knoxville, Knoxville, TN 37996-0840, USA
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Volonte D, Benson CJ, Daugherty SL, Beckel JM, Trebak M, Galbiati F. Purinergic signaling promotes premature senescence. J Biol Chem 2024; 300:107145. [PMID: 38460941 PMCID: PMC11002311 DOI: 10.1016/j.jbc.2024.107145] [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: 01/24/2024] [Revised: 02/26/2024] [Accepted: 02/28/2024] [Indexed: 03/11/2024] Open
Abstract
Extracellular ATP activates P2 purinergic receptors. Whether purinergic signaling is functionally coupled to cellular senescence is largely unknown. We find that oxidative stress induced release of ATP and caused senescence in human lung fibroblasts. Inhibition of P2 receptors limited oxidative stress-induced senescence, while stimulation with exogenous ATP promoted premature senescence. Pharmacological inhibition of P2Y11 receptor (P2Y11R) inhibited premature senescence induced by either oxidative stress or ATP, while stimulation with a P2Y11R agonist was sufficient to induce cellular senescence. Our data show that both extracellular ATP and a P2Y11R agonist induced calcium (Ca++) release from the endoplasmic reticulum (ER) and that either inhibition of phospholipase C or intracellular Ca++ chelation impaired ATP-induced senescence. We also find that Ca++ that was released from the ER, following ATP-mediated activation of phospholipase C, entered mitochondria in a manner dependent on P2Y11R activation. Once in mitochondria, excessive Ca++ promoted the production of reactive oxygen species in a P2Y11R-dependent fashion, which drove development of premature senescence of lung fibroblasts. Finally, we show that conditioned medium derived from senescent lung fibroblasts, which were induced to senesce through the activation of ATP/P2Y11R-mediated signaling, promoted the proliferation of triple-negative breast cancer cells and their tumorigenic potential by secreting amphiregulin. Our study identifies the existence of a novel purinergic signaling pathway that links extracellular ATP to the development of a protumorigenic premature senescent phenotype in lung fibroblasts that is dependent on P2Y11R activation and ER-to-mitochondria calcium signaling.
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Affiliation(s)
- Daniela Volonte
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Cory J Benson
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Stephanie L Daugherty
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Jonathan M Beckel
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Mohamed Trebak
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Ferruccio Galbiati
- Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
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Deng Z, He M, Hu H, Zhang W, Zhang Y, Ge Y, Ma T, Wu J, Li L, Sun M, An S, Li J, Huang Q, Gong S, Zhang J, Chen Z, Zeng Z. Melatonin attenuates sepsis-induced acute kidney injury by promoting mitophagy through SIRT3-mediated TFAM deacetylation. Autophagy 2024; 20:151-165. [PMID: 37651673 PMCID: PMC10761103 DOI: 10.1080/15548627.2023.2252265] [Citation(s) in RCA: 61] [Impact Index Per Article: 61.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 08/14/2023] [Accepted: 08/21/2023] [Indexed: 09/02/2023] Open
Abstract
ABBREVIATIONS AKI: acute kidney injury; ATP: adenosine triphosphate; BUN: blood urea nitrogen; CLP: cecal ligation and puncture; eGFR: estimated glomerular filtration rate; H&E: hematoxylin and eosin staining; LCN2/NGAL: lipocalin 2; LPS: lipopolysaccharide; LTL: lotus tetragonolobus lectin; mKeima: mitochondria-targeted Keima; mtDNA: mitochondrial DNA; PAS: periodic acid - Schiff staining; RTECs: renal tubular epithelial cells; SAKI: sepsis-induced acute kidney injury; Scr: serum creatinine; SIRT3: sirtuin 3; TFAM: transcription factor A, mitochondrial; TMRE: tetramethylrhodamine.
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Affiliation(s)
- Zhiya Deng
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Man He
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Hongbin Hu
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Wenqian Zhang
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Yaoyuan Zhang
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yue Ge
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- School of Nursing, Southern Medical University, Guangzhou, Guangdong, China
| | - Tongtong Ma
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jie Wu
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Lulan Li
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Maomao Sun
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Sheng An
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Jiaxin Li
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Qiaobing Huang
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Shenhai Gong
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Jiaxing Zhang
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhongqing Chen
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhenhua Zeng
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
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Park H, Kim J. Activation of melatonin receptor 1 by CRISPR-Cas9 activator ameliorates cognitive deficits in an Alzheimer's disease mouse model. J Pineal Res 2022; 72:e12787. [PMID: 35133672 DOI: 10.1111/jpi.12787] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 01/26/2022] [Accepted: 01/28/2022] [Indexed: 12/01/2022]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of neurotoxic beta-amyloid (Aβ) in the brain. Melatonin receptors have been reported to associate with aging and AD, and their expression decreased with the progression of AD. As an alternative to AD treatment, overexpression of melatonin receptors may lead to melatonin-like effects to treat alleviate the symptoms of AD. Here, we successfully activated the type 1 melatonin receptor (Mt1) in vivo brain using a Cas9 activator as a novel AD therapeutic strategy. The Cas9 activator efficiently activated the endogenous Mt1 gene in the brain. Activation of Mt1 via Cas9 activators modulated anti-amyloidogenic and anti-inflammatory roles in 5xFAD AD mice brain. Moreover, activation of Mt1 with the CRISPR/Cas9 activator improved cognitive deficits in an AD model. These results demonstrated the therapeutic potential of melatonin receptor activation via CRISPR/Cas9 activator for AD.
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Affiliation(s)
- Hanseul Park
- Department of Chemistry, Laboratory of Stem Cells & Cell Reprogramming, Dongguk University, Seoul, Republic of Korea
| | - Jongpil Kim
- Department of Chemistry, Laboratory of Stem Cells & Cell Reprogramming, Dongguk University, Seoul, Republic of Korea
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Anghel L, Baroiu L, Popazu CR, Pătraș D, Fotea S, Nechifor A, Ciubara A, Nechita L, Mușat CL, Stefanopol IA, Tatu AL, Ciubara AB. Benefits and adverse events of melatonin use in the elderly (Review). Exp Ther Med 2022; 23:219. [PMID: 35126722 PMCID: PMC8796282 DOI: 10.3892/etm.2022.11142] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 10/05/2021] [Indexed: 12/11/2022] Open
Abstract
Melatonin is a hormone secreted by the pineal gland in accordance with the circadian rhythm when the light level decreases. Reduction of melatonin secretion with age may be associated with physiological aging in neurodegenerative diseases by affecting the suprachiasmatic nucleus or of the neuronal pathways of transmission to the pineal gland. A significant decrease in melatonin synthesis has been reported in various disorders and diseases, including cardiovascular diseases, metabolic disorders (particularly diabetes type 2), cancer and endocrine diseases. In addition to the fact, that melatonin is a sleep inducer, it also exerts cytoprotective properties as an antioxidant and free radical scavenger. The therapeutic role of melatonin has been demonstrated in sleep disorders, eye damage and cardiovascular disease. The association between melatonin and β-blockers has had a positive impact on sleep disorders in clinical trials. Previous studies have reported the anti-inflammatory effect of melatonin by adjusting levels of pro-inflammatory cytokines, including interleukin (IL)-6, IL-1β and tumor necrosis factor-α. Melatonin treatment has been demonstrated to decrease IL-6 and IL-10 expression levels and efficiently attenuate T-cell proliferation. Currently, there is an inconsistency of scientific data regarding the lowest optimal dose and safety of melatonin for long-term use. The aim of the present review was to summarize the evidence on the role of melatonin in various clinical conditions and highlight the future research in this area.
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Affiliation(s)
- Lucreția Anghel
- Clinical Medical Department, Faculty of Medicine and Pharmacy, ‘Dunărea de Jos’ University, 800008 Galați, Romania
| | - Liliana Baroiu
- Clinical Medical Department, Faculty of Medicine and Pharmacy, ‘Dunărea de Jos’ University, 800008 Galați, Romania
| | - Corina Rișcă Popazu
- Clinical Medical Department, Faculty of Medicine and Pharmacy, ‘Dunărea de Jos’ University, 800008 Galați, Romania
| | - Diana Pătraș
- Internal Medicine Department, St. Andrew The Apostle Clinical Emergency County Hospital, 800578 Galați, Romania
| | - Silvia Fotea
- Clinical Medical Department, Faculty of Medicine and Pharmacy, ‘Dunărea de Jos’ University, 800008 Galați, Romania
| | - Alexandru Nechifor
- Clinical Medical Department, Faculty of Medicine and Pharmacy, ‘Dunărea de Jos’ University, 800008 Galați, Romania
- Multidisciplinary Integrated Center of Dermatological Interface Research, ‘Dunărea de Jos’ University, 800008 Galați, Romania
| | - Anamaria Ciubara
- Clinical Medical Department, Faculty of Medicine and Pharmacy, ‘Dunărea de Jos’ University, 800008 Galați, Romania
| | - Luiza Nechita
- Clinical Medical Department, Faculty of Medicine and Pharmacy, ‘Dunărea de Jos’ University, 800008 Galați, Romania
| | - Carmina Liana Mușat
- Department of Morphological and Functional Sciences, Faculty of Medicine and Pharmacy, ‘Dunărea de Jos’ University, 800008 Galați, Romania
| | - Ioana Anca Stefanopol
- Department of Morphological and Functional Sciences, Faculty of Medicine and Pharmacy, ‘Dunărea de Jos’ University, 800008 Galați, Romania
| | - Alin Laurențiu Tatu
- Clinical Medical Department, Faculty of Medicine and Pharmacy, ‘Dunărea de Jos’ University, 800008 Galați, Romania
- Multidisciplinary Integrated Center of Dermatological Interface Research, ‘Dunărea de Jos’ University, 800008 Galați, Romania
- Research Center in The Field of Medical and Pharmaceutical Sciences, ‘Dunărea de Jos’ University, 800008 Galați, Romania
| | - Alexandru Bogdan Ciubara
- Department of Morphological and Functional Sciences, Faculty of Medicine and Pharmacy, ‘Dunărea de Jos’ University, 800008 Galați, Romania
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Xu J, Chen P, Zhao G, Wei S, Li Q, Guo C, Cao Q, Wu X, Di G. Copolymer micelle-administered melatonin ameliorates hyperosmolarity-induced ocular surface damage through regulating PINK1 mediated mitophagy. Curr Eye Res 2022; 47:688-703. [PMID: 35179400 DOI: 10.1080/02713683.2021.2022163] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE To investigate the role and mechanism of melatonin-loaded polymer polyvinyl caprolactam-polyvinyl acetate-polyethyleneglycol graft copolymer (PVCL-PVA-PEG) micelles (Mel-Mic) in dry eye disease (DED). METHODS In vitro, the apoptosis and reactive oxygen species (ROS) generation in HCECs were analyzed by immunostaining and flow cytometry (FCM). The effect of Mel-Mic on autophagy and mitophagy was evaluated by immunostaining and western blots. PINK1 knockdown was analyzed by small interfering RNA (siRNA). In vivo, sodium fluorescein staining, tear secretion test, and periodic acid-schiff (PAS) staining were used to determine whether Mel-Mic can alleviate the severity of DED. Small molecule antagonists were pretreated to investigate whether melatonin type 1 and/or 2 receptors (MT1/MT2) mediate the effects of Mel-Mic. RESULTS Mel-Mic improved the solubility and biological activities of Mel in aqueous solutions. Treatment with Mel-Mic decreased the apoptosis of HCECs exposed to hyperosmotic medium, accompanied by downregulation of cleaved Caspase-3 and upregulation of Bcl-2. In addition, Mel-Mic application suppressed ROS overproduction, rescued mitochondrial function, and decreased the level of oxidative stress associated biomarkers (COX-2 and 4-HNE) in HCECs. Interestingly, HCECs treated with Mel-Mic exhibited increased levels of mitophagy markers (PINK1, PARKIN, Beclin 1 and LC3B) and restored impaired mitophagic flux under hyperosmolarity. While PINK1 knock down largely abolished its protective effects. In vivo, compared to vehicle group, topical Mel-Mic solution treated mice showed significantly improved clinical parameters, increased tear production and decreased goblet cells loss in a dose-dependent manner. Also, TEM assay revealed increased autophagosome number in the corneal epithelium of Mel-Mic group. Moreover, luzindole, a non-selective MT1/MT2 antagonist, but not 4-P-PDOT, a selective MT2 antagonist, blocked the protective effect of Mel-Mic. CONCLUSIONS Our findings demonstrated that Mel-Mic ameliorates hyperosmolarity induced ocular surface damage via PINK1 mediated mitophagy and may represent an effective treatment for DED possibly through acting MT1 receptor.
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Affiliation(s)
- Jing Xu
- School of Basic Medicine, College of Medicine, Qingdao University, Qingdao, China
| | - Peng Chen
- School of Basic Medicine, College of Medicine, Qingdao University, Qingdao, China
| | - Guangfen Zhao
- Department of Medicine, The Liaocheng Third People's Hospital. Liaocheng, China
| | - Susu Wei
- School of Basic Medicine, College of Medicine, Qingdao University, Qingdao, China
| | - Qiqi Li
- College of Chemical Engineering, Qingdao University of Science and Technology. Qingdao, China
| | - Chuanlong Guo
- College of Chemical Engineering, Qingdao University of Science and Technology. Qingdao, China
| | - Qilong Cao
- Qingdao Haier Biotech Co.Ltd, Qingdao, China
| | - Xianggen Wu
- College of Chemical Engineering, Qingdao University of Science and Technology. Qingdao, China
| | - Guohu Di
- School of Basic Medicine, College of Medicine, Qingdao University, Qingdao, China
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Cengiz S, Velioğlu N, Cengiz Mİ, Çakmak Özlü F, Akbal AU, Çoban AY, Özcan M. Cytotoxicity of Acrylic Resins, Particulate Filler Composite Resin and Thermoplastic Material in Artificial Saliva with and without Melatonin. MATERIALS 2022; 15:ma15041457. [PMID: 35208000 PMCID: PMC8877573 DOI: 10.3390/ma15041457] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/05/2022] [Accepted: 02/11/2022] [Indexed: 12/10/2022]
Abstract
There is limited information on the effect of melatonin on the cytotoxicity of dental materials. The study evaluated the cytotoxic effects of heat- and auto-polymerized acrylic resin, particulate filler composite resin and a thermoplastic material on L-929 fibroblast cell viability at different incubation periods in artificial saliva without and with melatonin. Disk-shaped specimens were prepared according to each manufacturer’s instructions and divided into two groups to be stored either in artificial saliva (AS) and AS with melatonin (ASM). The measurements were performed using an MTT (3-(4,5)-dimethylthiazol-2-yl)-2,5-diphenyl tetrazoliumbromide) assay, in which the L-929 mouse fibroblasts cell culture was used. For the MTT test, extracts were examined at 1, 24, 72 h and 1 and 2 weeks. Data were analyzed using 3-way ANOVA and Tukey’s tests. No significant difference was found between groups AS and ASM (F = 0.796; p = 0.373). Incubation period significantly affected all materials tested (p < 0.001). Storing resin-based materials in artificial saliva with melatonin solution for 24 h may reduce cytotoxic effects on the fibroblast cells for which the highest effect was observed. Soaking resin prosthesis or orthodontic appliances in artificial saliva with melatonin at least 24 h before intraoral use or rinsing medium containing melatonin may be recommended for decreasing the cytotoxicity of dental resin materials.
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Affiliation(s)
- Seda Cengiz
- Department of Prosthodontics, Faculty of Dentistry, Zonguldak Bülent Ecevit University, Zonguldak 67600, Turkey
- Correspondence:
| | - Neslin Velioğlu
- Department of Prosthodontics, Navadent Oral and Dental Health Policlinic, Zonguldak 67000, Turkey;
| | - Murat İnanç Cengiz
- Department of Periodontology, Faculty of Dentistry, Zonguldak Bülent Ecevit University, Zonguldak 67600, Turkey;
| | - Fehiye Çakmak Özlü
- Department of Orthodontics, Faculty of Dentistry, Ondokuz Mayıs University, Samsun 55270, Turkey;
| | - Ahmet Ugur Akbal
- Unit of Infectious Diseases, Samsun Health Directorate, Samsun 55060, Turkey;
| | - Ahmet Yılmaz Çoban
- Department of Medical Biotechnology, Institute of Health Sciences, Akdeniz University, Antalya 07058, Turkey;
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Akdeniz University, Antalya 07058, Turkey
- Tuberculosis Research Center, Akdeniz University, Antalya 07058, Turkey
| | - Mutlu Özcan
- Center for Dental and Oral Medicine, Division of Dental Biomaterials, Clinic for Reconstructive Dentistry, University of Zurich, 8032 Zurich, Switzerland;
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12
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Melatonin and Pathological Cell Interactions: Mitochondrial Glucose Processing in Cancer Cells. Int J Mol Sci 2021; 22:ijms222212494. [PMID: 34830375 PMCID: PMC8621753 DOI: 10.3390/ijms222212494] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 10/06/2021] [Accepted: 11/17/2021] [Indexed: 12/18/2022] Open
Abstract
Melatonin is synthesized in the pineal gland at night. Since melatonin is produced in the mitochondria of all other cells in a non-circadian manner, the amount synthesized by the pineal gland is less than 5% of the total. Melatonin produced in mitochondria influences glucose metabolism in all cells. Many pathological cells adopt aerobic glycolysis (Warburg effect) in which pyruvate is excluded from the mitochondria and remains in the cytosol where it is metabolized to lactate. The entrance of pyruvate into the mitochondria of healthy cells allows it to be irreversibly decarboxylated by pyruvate dehydrogenase (PDH) to acetyl coenzyme A (acetyl-CoA). The exclusion of pyruvate from the mitochondria in pathological cells prevents the generation of acetyl-CoA from pyruvate. This is relevant to mitochondrial melatonin production, as acetyl-CoA is a required co-substrate/co-factor for melatonin synthesis. When PDH is inhibited during aerobic glycolysis or during intracellular hypoxia, the deficiency of acetyl-CoA likely prevents mitochondrial melatonin synthesis. When cells experiencing aerobic glycolysis or hypoxia with a diminished level of acetyl-CoA are supplemented with melatonin or receive it from another endogenous source (pineal-derived), pathological cells convert to a more normal phenotype and support the transport of pyruvate into the mitochondria, thereby re-establishing a healthier mitochondrial metabolic physiology.
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13
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Potentiating the Benefits of Melatonin through Chemical Functionalization: Possible Impact on Multifactorial Neurodegenerative Disorders. Int J Mol Sci 2021; 22:ijms222111584. [PMID: 34769013 PMCID: PMC8583879 DOI: 10.3390/ijms222111584] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/08/2021] [Accepted: 10/11/2021] [Indexed: 12/11/2022] Open
Abstract
Although melatonin is an astonishing molecule, it is possible that chemistry will help in the discovery of new compounds derived from it that may exceed our expectations regarding antioxidant protection and perhaps even neuroprotection. This review briefly summarizes the significant amount of data gathered to date regarding the multiple health benefits of melatonin and related compounds. This review also highlights some of the most recent directions in the discovery of multifunctional pharmaceuticals intended to act as one-molecule multiple-target drugs with potential use in multifactorial diseases, including neurodegenerative disorders. Herein, we discuss the beneficial activities of melatonin derivatives reported to date, in addition to computational strategies to rationally design new derivatives by functionalization of the melatonin molecular framework. It is hoped that this review will promote more investigations on the subject from both experimental and theoretical perspectives.
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14
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Atanasova D, Lazarov N, Stoyanov DS, Spassov RH, Tonchev AB, Tchekalarova J. Reduced neuroinflammation and enhanced neurogenesis following chronic agomelatine treatment in rats undergoing chronic constant light. Neuropharmacology 2021; 197:108706. [PMID: 34274352 DOI: 10.1016/j.neuropharm.2021.108706] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 07/03/2021] [Accepted: 07/05/2021] [Indexed: 10/20/2022]
Abstract
Experimental studies have revealed the involvement of neuroinflammation mediated by activated microglia in the pathophysiology of depression, suggesting a novel target for treatment. The atypical antidepressant Agomelatine (Ago) has an advantage compared to the classical antidepressants due to its chronobiotic activity and unique pharmacological profile as a selective agonist at the melatonin receptors and an antagonist at the 5HT2C receptors. We have recently revealed that Ago can exert a potent antidepressant effect in rats exposed to a chronic constant light (CCL). In the present study, we hypothesized that the anti-inflammatory activity of this melatonin analog on activated neuroglia in specific brain structures might contribute to its antidepressant effect in this model. Chronic Ago treatment (40 mg/kg, i.p. for 21 days) was executed during the last 3 weeks of a 6-week period of CCL exposure in rats. The CCL-vehicle-treated rats showed a profound neuroinflammation characterized by microgliosis and astrogliosis in the hippocampus, basolateral amygdala (BL) and partly in the piriform cortex (Pir) confirmed by immunohistochemistry. With the exception of the Pir, the CCL regime was accompanied by neuronal damage, identified by Nissl staining, in the hippocampus and basolateral amygdala and impaired neurogenesis with reduced dendritic complexity of hippocampal neuroprogenitor cells detected by doublecortin-positive cells in the dentate gyrus (DG) subgranular zone compared to the control group. Ago reversed the gliosis in a region-specific manner and partially restored the suppressed DG neurogenesis. Ago failed to produce neuroprotection in CCL exposed rats. The present results suggest that the beneficial effects of Ago represent an important mechanism underlying its antidepressant effect in models characterized by impaired circadian rhythms.
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Affiliation(s)
- Dimitrinka Atanasova
- Institute of Neurobiology, Bulgarian Academy of Sciences, 1113, Sofia, Bulgaria; Department of Anatomy, Faculty of Medicine, Trakia University, 6003, Stara Zagora, Bulgaria
| | - Nikolai Lazarov
- Institute of Neurobiology, Bulgarian Academy of Sciences, 1113, Sofia, Bulgaria; Department of Anatomy and Histology, Medical University of Sofia, 1431, Sofia, Bulgaria
| | - Dimo S Stoyanov
- Department of Anatomy and Cell Biology, Faculty of Medicine, Medical University - Varna "Prof. Dr. Paraskev Stoyanov", 9002, Varna, Bulgaria
| | - Radoslav H Spassov
- Department of Anatomy and Cell Biology, Faculty of Medicine, Medical University - Varna "Prof. Dr. Paraskev Stoyanov", 9002, Varna, Bulgaria
| | - Anton B Tonchev
- Department of Anatomy and Cell Biology, Faculty of Medicine, Medical University - Varna "Prof. Dr. Paraskev Stoyanov", 9002, Varna, Bulgaria
| | - Jana Tchekalarova
- Institute of Neurobiology, Bulgarian Academy of Sciences, 1113, Sofia, Bulgaria.
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15
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Morciano G, Naumova N, Koprowski P, Valente S, Sardão VA, Potes Y, Rimessi A, Wieckowski MR, Oliveira PJ. The mitochondrial permeability transition pore: an evolving concept critical for cell life and death. Biol Rev Camb Philos Soc 2021; 96:2489-2521. [PMID: 34155777 DOI: 10.1111/brv.12764] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 05/28/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023]
Abstract
In this review, we summarize current knowledge of perhaps one of the most intriguing phenomena in cell biology: the mitochondrial permeability transition pore (mPTP). This phenomenon, which was initially observed as a sudden loss of inner mitochondrial membrane impermeability caused by excessive calcium, has been studied for almost 50 years, and still no definitive answer has been provided regarding its mechanisms. From its initial consideration as an in vitro artifact to the current notion that the mPTP is a phenomenon with physiological and pathological implications, a long road has been travelled. We here summarize the role of mitochondria in cytosolic calcium control and the evolving concepts regarding the mitochondrial permeability transition (mPT) and the mPTP. We show how the evolving mPTP models and mechanisms, which involve many proposed mitochondrial protein components, have arisen from methodological advances and more complex biological models. We describe how scientific progress and methodological advances have allowed milestone discoveries on mPTP regulation and composition and its recognition as a valid target for drug development and a critical component of mitochondrial biology.
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Affiliation(s)
- Giampaolo Morciano
- Maria Cecilia Hospital, GVM Care & Research, Via Corriera 1, Cotignola, Ravenna, 48033, Italy.,Department of Medical Sciences, Section of Experimental Medicine, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Via Fossato di Mortara 70, Ferrara, 44121, Italy
| | - Natalia Naumova
- Department of Cardiac Thoracic and Vascular Sciences and Public Health, University of Padua Medical School, Via Giustiniani 2, Padova, 35128, Italy
| | - Piotr Koprowski
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, Warsaw, 02-093, Poland
| | - Sara Valente
- CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC Biotech, Biocant Park, Cantanhede, 3060-197, Portugal
| | - Vilma A Sardão
- CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC Biotech, Biocant Park, Cantanhede, 3060-197, Portugal
| | - Yaiza Potes
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, Warsaw, 02-093, Poland
| | - Alessandro Rimessi
- Department of Medical Sciences, Section of Experimental Medicine, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Via Fossato di Mortara 70, Ferrara, 44121, Italy
| | - Mariusz R Wieckowski
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, Warsaw, 02-093, Poland
| | - Paulo J Oliveira
- CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC Biotech, Biocant Park, Cantanhede, 3060-197, Portugal
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16
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Liang Z, Currais A, Soriano-Castell D, Schubert D, Maher P. Natural products targeting mitochondria: emerging therapeutics for age-associated neurological disorders. Pharmacol Ther 2021; 221:107749. [PMID: 33227325 PMCID: PMC8084865 DOI: 10.1016/j.pharmthera.2020.107749] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 11/16/2020] [Accepted: 11/17/2020] [Indexed: 12/17/2022]
Abstract
Mitochondria are the primary source of energy production in the brain thereby supporting most of its activity. However, mitochondria become inefficient and dysfunctional with age and to a greater extent in neurological disorders. Thus, mitochondria represent an emerging drug target for many age-associated neurological disorders. This review summarizes recent advances (covering from 2010 to May 2020) in the use of natural products from plant, animal, and microbial sources as potential neuroprotective agents to restore mitochondrial function. Natural products from diverse classes of chemical structures are discussed and organized according to their mechanism of action on mitochondria in terms of modulation of biogenesis, dynamics, bioenergetics, calcium homeostasis, and membrane potential, as well as inhibition of the oxytosis/ferroptosis pathway. This analysis emphasizes the significant value of natural products for mitochondrial pharmacology as well as the opportunities and challenges for the discovery and development of future neurotherapeutics.
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Affiliation(s)
- Zhibin Liang
- Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, United States; The Paul F. Glenn Center for Biology of Aging Research, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, United States.
| | - Antonio Currais
- Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, United States
| | - David Soriano-Castell
- Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, United States
| | - David Schubert
- Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, United States; The Paul F. Glenn Center for Biology of Aging Research, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, United States
| | - Pamela Maher
- Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, United States.
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17
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Hardeland R. Divergent Importance of Chronobiological Considerations in High- and Low-dose Melatonin Therapies. Diseases 2021; 9:18. [PMID: 33803450 PMCID: PMC8006026 DOI: 10.3390/diseases9010018] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 03/01/2021] [Indexed: 12/15/2022] Open
Abstract
Melatonin has been used preclinically and clinically for different purposes. Some applications are related to readjustment of circadian oscillators, others use doses that exceed the saturation of melatonin receptors MT1 and MT2 and are unsuitable for chronobiological purposes. Conditions are outlined for appropriately applying melatonin as a chronobiotic or for protective actions at elevated levels. Circadian readjustments require doses in the lower mg range, according to receptor affinities. However, this needs consideration of the phase response curve, which contains a silent zone, a delay part, a transition point and an advance part. Notably, the dim light melatonin onset (DLMO) is found in the silent zone. In this specific phase, melatonin can induce sleep onset, but does not shift the circadian master clock. Although sleep onset is also under circadian control, sleep and circadian susceptibility are dissociated at this point. Other limits of soporific effects concern dose, duration of action and poor individual responses. The use of high melatonin doses, up to several hundred mg, for purposes of antioxidative and anti-inflammatory protection, especially in sepsis and viral diseases, have to be seen in the context of melatonin's tissue levels, its formation in mitochondria, and detoxification of free radicals.
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Affiliation(s)
- Rüdiger Hardeland
- Johann Friedrich Blumenbach Institute of Zoology and Anthropology, University of Göttingen, 37073 Göttingen, Germany
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18
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Wang S, Liu W, Wen A, Yang B, Pang X. Luzindole and 4P-PDOT block the effect of melatonin on bovine granulosa cell apoptosis and cell cycle depending on its concentration. PeerJ 2021; 9:e10627. [PMID: 33732541 PMCID: PMC7950190 DOI: 10.7717/peerj.10627] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 11/30/2020] [Indexed: 01/16/2023] Open
Abstract
Granulosa cells play an essential physiological role in mediating the follicle development and survival or apoptosis of granulosa cells dictate the follicle development or atresia. The aim of this study was to investigate the role of high dose (10-5 M) and low dose (10-9 M) melatonin in bovine granulosa cells, and assess whether MT1 and MT2 inhibiter affect granulosa cells response to melatonin. We found that the high dose (10-5 M) and low dose (10-9 M) both could act as an essential role in modulating granulosa cells apoptosis, cell cycle and antioxidant. The beneficial effect could be related to that melatonin promoted the expression of Bcl2, Bcl-xl, SOD1 and GPX4, and inhibited Bax, caspase-3 and p53 expression. Moreover P21 expression was decreased in granulosa cells treated with the high dose (10-5 M) melatonin and increased in that treated with the low dose (10-9 M) melatonin. To further reveal the role of MT1 and MT2 in mediating the effect of melatonin on granulosa cells apoptosis, cell cycle and antioxidant, we found that the luzindole and 4P-PDOT did not affect the effect of high dose (10-5 M) melatonin on regulating Bcl2, Bax, caspase-3, SOD1, GPX4 and p53 expression, while blocked its effect on modulating Bcl-xl and P21expression. However, luzindole and 4P-PDOT disturbed the effect of low dose (10-9 M) melatonin on regulating Bcl2, Bax, caspase-3, Bcl-xl, SOD1, GPX4, and p53 expression. In conclusion, these results reveal that the effect of low dose (10-9 M) melatonin on granulosa cells apoptosis are mediated by MT1 and MT2, and the high dose (10-5 M) melatonin affect the granulosa cells apoptosis by other pathway, besides MT1 and MT2. Moreover MT1 and MT2 may work in concert to modulate bovine granulosa cells function by regulating cellular progression and apoptosis.
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Affiliation(s)
- Shujuan Wang
- College of Animal Science, Anhui Science and Technology University, Fengyang, China
- Anhui Province Key Laboratory of Animal Nutritional Regulation and Health, Fengyang, China
| | - Wenju Liu
- College of Life and Health Science, Anhui Science and Technology University, Fengyang, China
| | - Aiyou Wen
- College of Animal Science, Anhui Science and Technology University, Fengyang, China
| | - Bing Yang
- College of Animal Science, Anhui Science and Technology University, Fengyang, China
| | - Xunsheng Pang
- College of Animal Science, Anhui Science and Technology University, Fengyang, China
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19
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Hashem KS, Abdelazem AZ, Mohammed MA, Nagi AM, Aboulhoda BE, Mohammed ET, Abdel-Daim MM. Thymoquinone alleviates mitochondrial viability and apoptosis in diclofenac-induced acute kidney injury (AKI) via regulating Mfn2 and miR-34a mRNA expressions. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:10100-10113. [PMID: 33165700 DOI: 10.1007/s11356-020-11313-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 10/18/2020] [Indexed: 06/11/2023]
Abstract
The current study was prepared to assess the underlying mechanism of diclofenac (Diclo)-stimulated renal oxidative damage (50 mg/kg/day for two consecutive days I.P) and antioxidative, and antiapoptotic effects of Thymoquinone (20 mg/kg/day for 21 days P.O). Exposure of rats to Diclo significantly increased serum urea and creatinine, decreased GSH, catalase, and total antioxidant capacity with a concomitant increase of lipid peroxidation. Diclo significantly decreased renal mitochondrial viability %, increased DNA fragmentation %, caspase 3 activity, and cytochrome C (Cyt C) concentration. Molecular investigations revealed that Diclo administration caused a significant reduction of mitofusin-2 (Mfn2) and increase of microRNA-34a (miR-34a) mRNA expressions with a concomitant decrease of Nrf2 and HO-1 mRNA expressions/protein levels and increase of NF-κB mRNA expressions. Thymoquinone restored renal oxidative/antioxidant redox. Thymoquinone significantly increased the renal mitochondrial viability % and reduced renal DNA fragmentation %, caspase 3 activity, and Cyt C. Moreover, thymoquinone modulated renal Mfn2 and miR-34a as compared to Diclo group. Our findings were confirmed by immunohistochemical assays for detecting the iNOS and NOX4 in renal tissue as well as histopathological investigations. Obtained results demonstrated that thymoquinone possess a potential antioxidant, antiapoptotic defense and exhibited a strong nephroprotective activity against Diclo-induced toxicity.
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Affiliation(s)
- Khalid Shaaban Hashem
- Biochemistry Department, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef, 62511, Egypt.
| | - Ahmed Zakaria Abdelazem
- Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences, Beni-Suef University, Beni-Suef, Egypt
| | | | - Amr M Nagi
- Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences, Beni-Suef University, Beni-Suef, Egypt
| | - Basma Emad Aboulhoda
- Department of Anatomy and Embryology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Eman T Mohammed
- Biochemistry Department, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef, 62511, Egypt
| | - Mohamed M Abdel-Daim
- Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia
- Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, 41522, Ismailia, Egypt
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20
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Gonzalez A. Antioxidants and Neuron-Astrocyte Interplay in Brain Physiology: Melatonin, a Neighbor to Rely on. Neurochem Res 2021; 46:34-50. [PMID: 31989469 DOI: 10.1007/s11064-020-02972-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 01/19/2020] [Accepted: 01/21/2020] [Indexed: 12/19/2022]
Abstract
This manuscript is a review focused onto the role of astrocytes in the protection of neurons against oxidative stress and how melatonin can contribute to the maintenance of brain homeostasis. The first part of the review is dedicated to the dependence of neurons on astrocytes by terms of survival under oxidative stress conditions. Additionally, the effects of melatonin against oxidative stress in the brain and its putative role in the protection against diseases affecting the brain are highlighted. The effects of melatonin on the physiology of neurons and astrocytes also are reviewed.
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Affiliation(s)
- Antonio Gonzalez
- Department of Physiology, Institute of Molecular Pathology Biomarkers, University of Extremadura, Avenida de las Ciencias s/n, 10003, Cáceres, Spain.
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21
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Xu M, Sivak JG, McCanna DJ. Ocular toxicology: synergism of UV radiation and benzalkonium chloride. Cutan Ocul Toxicol 2020; 39:370-379. [PMID: 33019823 DOI: 10.1080/15569527.2020.1833027] [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: 10/23/2022]
Abstract
PURPOSE To investigate the combined toxic effect of ultraviolet (UV) radiation and benzalkonium chloride (BAK), a common preservative in ophthalmic eye drops, on human corneal epithelial cells (HCEC). METHODS Cultured HCEC were exposed to different combined and separate UV (280-400 nm) and BAK solutions at relevant human exposure levels. Human exposure to UV can occur before, during, or after eye drop installation, therefore, three different orders of ocular exposures were investigated: UV and BAK at the same time, UV first followed by BAK, and BAK first followed by UV. Control treatments included testing HCEC exposed to BAK alone and also HCEC exposed to UV alone. In addition, phosphate-buffered saline (PBS) was used as a negative control. After exposure, cell metabolic activity of the cultures was measured with PrestoBlue, and cell viability was determined using confocal microscopy with viability dyes. RESULTS BAK alone reduced the metabolic activity and cell viability of HCEC in a dose- and time-dependent manner. UV alone at a low dose (0.17 J/cm2) had little toxicity on HCEC and was not significantly different from PBS control. However, UV plus BAK showed combined effects that were either greater than (synergistic) or equal to (additive) the sum of their individual effects. The synergistic effects occurred between low dose UV radiation (0.17 J/cm2) and low concentrations of BAK (0.001%, 0.002%, 0.003%, and 0.004%). CONCLUSIONS This investigation determined that at relevant human exposure levels, the combination of UV radiation (280-400 nm) and BAK can cause synergistic and additive toxic effects on human corneal epithelial cells. This finding highlights the importance of considering the combined ocular toxicity of BAK and solar radiation in the risk assessment of BAK-preserved ophthalmic solutions.
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Affiliation(s)
- Manlong Xu
- School of Optometry and Vision Science, University of Waterloo, Waterloo, Canada
| | - Jacob G Sivak
- School of Optometry and Vision Science, University of Waterloo, Waterloo, Canada
| | - David J McCanna
- Centre for Ocular Research & Education, School of Optometry and Vision Science, University of Waterloo, Waterloo, Canada
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22
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Guo Y, Sun J, Bu S, Li B, Zhang Q, Wang Q, Lai D. Melatonin protects against chronic stress-induced oxidative meiotic defects in mice MII oocytes by regulating SIRT1. Cell Cycle 2020; 19:1677-1695. [PMID: 32453975 DOI: 10.1080/15384101.2020.1767403] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Chronic stress which is common in the current society can be harmful to female reproduction and is associated with oocyte defects. However, the underlying mechanisms remain largely unknown. Herein, by using a mouse model of chronic restraint stress, we demonstrated that chronic stress could induce meiotic spindle abnormalities, chromatin misalignment, mitochondrial dysfunction and elevated ROS levels in oocytes in vivo, all of which were normalized by the administration of melatonin. Consistently, melatonin treatment during in vitro maturation also attenuated the meiotic defects induced by H2O2 by regulating autophagy and SIRT1, which could be abolished by SIRT1 inhibitor, Ex527 and autophagy inhibitor Bafilomycin A1 (Baf A1). These data indicate that melatonin can mitigate chronic stress-induced oxidative meiotic defects in mice MII oocytes by regulating SIRT1 and autophagy, providing new understanding for stress-related meiotic errors in MII oocytes and suggesting melatonin and SIRT1 could be new targets for optimizing culture system of oocytes as well as fertility management.
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Affiliation(s)
- Ying Guo
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai, China.,Shanghai Key Laboratory of Embryo Original Diseases , Shanghai, China
| | - Junyan Sun
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai, China.,Shanghai Key Laboratory of Embryo Original Diseases , Shanghai, China
| | - Shixia Bu
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai, China.,Shanghai Key Laboratory of Embryo Original Diseases , Shanghai, China
| | - Boning Li
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai, China.,Shanghai Key Laboratory of Embryo Original Diseases , Shanghai, China
| | - Qiuwan Zhang
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai, China.,Shanghai Key Laboratory of Embryo Original Diseases , Shanghai, China
| | - Qian Wang
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai, China.,Shanghai Key Laboratory of Embryo Original Diseases , Shanghai, China
| | - Dongmei Lai
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai, China.,Shanghai Key Laboratory of Embryo Original Diseases , Shanghai, China
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Effect of endurance training on diurnal rhythms of superoxide dismutase activity, glutathione and lipid peroxidation in plasma of pinealectomized rats. Neurosci Lett 2020; 716:134637. [DOI: 10.1016/j.neulet.2019.134637] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 11/04/2019] [Accepted: 11/18/2019] [Indexed: 11/18/2022]
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Bizzarri M. Advances in Characterizing Recently-Identified Molecular Actions of Melatonin: Clinical Implications. APPROACHING COMPLEX DISEASES 2020. [PMCID: PMC7164543 DOI: 10.1007/978-3-030-32857-3_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Melatonin, N-acetyl-5-methoxy-tryptamine, was discovered to be a product of serotonin metabolism in the mammalian pineal gland where its synthesis is under control of the light:dark cycle. Besides its regulatory pathway involving ganglion cells in the retina, the neural connections between the eyes and the pineal gland include the master circadian clock, the suprachiasmatic nuclei, and the central and peripheral nervous systems. Since pineal melatonin is released into the blood and into the cerebrospinal fluid, it has access to every cell in an organism and it mediates system-wide effects. Subsequently, melatonin was found in several extrapineal organs and, more recently, perhaps in every cell of every organ. In contrast to the pinealocytes, non-pineal cells do not discharge melatonin into the blood; rather it is used locally in an intracrine, autocrine, or paracrine manner. Melatonin levels in non-pineal cells do not exhibit a circadian rhythm and do not depend on circulating melatonin concentrations although when animals are treated with exogenous melatonin it is taken up by presumably all cells. Mitochondria are the presumed site of melatonin synthesis in all cells; the enzymatic machinery for melatonin synthesis has been identified in mitochondria. The association of melatonin with mitochondria, because of its ability to inhibit oxidative stress, is very fortuitous since these organelles are a major site of damaging reactive oxygen species generation. In this review, some of the actions of non-pineal-derived melatonin are discussed in terms of cellular and subcellular physiology.
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Affiliation(s)
- Mariano Bizzarri
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
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25
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Bjørklund G, Rajib SA, Saffoon N, Pen JJ, Chirumbolo S. Insights on Melatonin as an Active Pharmacological Molecule in Cancer Prevention: What's New? Curr Med Chem 2019; 26:6304-6320. [PMID: 29714136 DOI: 10.2174/0929867325666180501094850] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 04/10/2018] [Accepted: 04/18/2018] [Indexed: 12/12/2022]
Abstract
Along with playing an important role in circadian rhythm, melatonin is thought to play a significant role in preventing cells from damage, as well as in the inhibition of growth and in triggering apoptosis in malignant cells. Its relationship with circadian rhythms, energetic homeostasis, diet, and metabolism, is fundamental to achieve a better comprehension of how melatonin has been considered a chemopreventive molecule, though very few papers dealing with this issue. In this article, we tried to review the most recent evidence regarding the protective as well as the antitumoral mechanisms of melatonin, as related to diet and metabolic balance. From different studies, it was evident that an intracellular antioxidant defense mechanism is activated by upregulating an antioxidant gene battery in the presence of high-dose melatonin in malignant cells. Like other broad-spectrum antioxidant molecules, melatonin plays a vital role in killing tumor cells, preventing metastasis, and simultaneously keeping normal cells protected from oxidative stress and other types of tissue damage.
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Affiliation(s)
- Geir Bjørklund
- Council for Nutritional and Environmental Medicine, Mo i Rana, Norway
| | | | - Nadia Saffoon
- Department of Pharmacy and Forensic Science, Faculty of Life Science and Medicine, King's College London, London, United Kingdom
| | - Joeri J Pen
- Diabetes Clinic, Department of Internal Medicine, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium.,Department of Nutrition, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Salvatore Chirumbolo
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
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26
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Raza Z, Naureen Z. Melatonin ameliorates the drug induced nephrotoxicity: Molecular insights. Nefrologia 2019; 40:12-25. [PMID: 31735377 DOI: 10.1016/j.nefro.2019.06.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Revised: 05/29/2019] [Accepted: 06/07/2019] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Drug-induced nephrotoxicity is a frequent adverse event that can lead to acute or chronic kidney disease and increase the healthcare expenditure. It has high morbidity and mortality incidence in 40-70% of renal injuries and accounts for 66% cases of renal failure in elderly population. OBJECTIVE Amelioration of drug-induced nephrotoxicity has been long soughed to improve the effectiveness of therapeutic drugs. This study was conducted to review the melatonin potential to prevent the pathogenesis of nephrotoxicity induced by important nephrotoxic drugs. METHODS We analyzed the relevant studies indexed in Pubmed, Medline, Scielo and Web of science to explain the molecular improvements following melatonin co-administration with special attention to oxidative stress, inflammation and apoptosis as key players of drug-induced nephrotoxicity. RESULTS A robust consensus among researchers of these studies suggested that melatonin efficiently eradicate the chain reaction of free radical production and induced the endogenous antioxidant enzymes which attenuate the lipid peroxidation of cellular membranes and subcellular oxidative stress in drug-induced nephrotoxicity. This agreement was further supported by the melatonin role in disintegration of inflammatory process through inhibition of principle pro-inflammatory or apoptotic cytokines such as TNF-α and NF-κB. These studies highlighted that alleviation of drug-induced renal toxicity is a function of melatonin potential to down regulate the cellular inflammatory and oxidative injury process and to stimulate the cellular repair or defensive mechanisms. CONCLUSION The comprehensive nephroprotection and safer profile suggests the melatonin to be a useful adjunct to improve the safety of nephrotoxic drugs.
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Affiliation(s)
- Zohaib Raza
- Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan.
| | - Zainab Naureen
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
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27
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Farfán-García ED, Márquez-Gómez R, Barrón-González M, Pérez-Capistran T, Rosales-Hernández MC, Pinto-Almazán R, Soriano-Ursúa MA. Monoamines and their Derivatives on GPCRs: Potential Therapy for Alzheimer's Disease. Curr Alzheimer Res 2019; 16:871-894. [PMID: 30963972 DOI: 10.2174/1570159x17666190409144558] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Revised: 03/18/2019] [Accepted: 04/01/2019] [Indexed: 02/07/2023]
Abstract
Albeit cholinergic depletion remains the key event in Alzheimer's Disease (AD), recent information describes stronger links between monoamines (trace amines, catecholamines, histamine, serotonin, and melatonin) and AD than those known in the past century. Therefore, new drug design strategies focus efforts to translate the scope on these topics and to offer new drugs which can be applied as therapeutic tools in AD. In the present work, we reviewed the state-of-art regarding genetic, neuropathology and neurochemistry of AD involving monoamine systems. Then, we compiled the effects of monoamines found in the brain of mammals as well as the reported effects of their derivatives and some structure-activity relationships. Recent derivatives have triggered exciting effects and pharmacokinetic properties in both murine models and humans. In some cases, the mechanism of action is clear, essentially through the interaction on G-protein-coupled receptors as revised in this manuscript. Additional mechanisms are inhibition of enzymes for their biotransformation, regulation of free-radicals in the central nervous system and others for the effects on Tau phosphorylation or amyloid-beta accumulation. All these data make the monoamines and their derivatives attractive potential elements for AD therapy.
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Affiliation(s)
- Eunice D Farfán-García
- Departamento de Fisiologia y Bioquimica. Seccion de Estudios de Posgrado e Investigacion, Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Diaz Miron s/n, 11340, Mexico City, Mexico
| | - Ricardo Márquez-Gómez
- MRC Anatomical Neuropharmacology Unit, Department of Pharmacology, University of Oxford, OX1 3TH, Oxford, United Kingdom
| | - Mónica Barrón-González
- Departamento de Fisiologia y Bioquimica. Seccion de Estudios de Posgrado e Investigacion, Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Diaz Miron s/n, 11340, Mexico City, Mexico
| | - Teresa Pérez-Capistran
- Departamento de Fisiologia y Bioquimica. Seccion de Estudios de Posgrado e Investigacion, Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Diaz Miron s/n, 11340, Mexico City, Mexico
| | - Martha C Rosales-Hernández
- Laboratorio de Biofisica y Biocatalisis, Seccion de Estudios de Posgrado e Investigacion Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Diaz Miron s/n, 11340, Mexico City, Mexico
| | - Rodolfo Pinto-Almazán
- Unidad de Investigacion Hospital Regional de Alta Especialidad Ixtapaluca, Carretera Federal Mexico-Puebla km 34.5, C.P. 56530. Ixtapaluca, State of Mexico, Mexico
| | - Marvin A Soriano-Ursúa
- Departamento de Fisiologia y Bioquimica. Seccion de Estudios de Posgrado e Investigacion, Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Diaz Miron s/n, 11340, Mexico City, Mexico
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28
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Jou MJ, Peng TI, Reiter RJ. Protective stabilization of mitochondrial permeability transition and mitochondrial oxidation during mitochondrial Ca 2+ stress by melatonin's cascade metabolites C3-OHM and AFMK in RBA1 astrocytes. J Pineal Res 2019; 66:e12538. [PMID: 30415481 DOI: 10.1111/jpi.12538] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 10/29/2018] [Accepted: 11/02/2018] [Indexed: 01/02/2023]
Abstract
Cyclic 3-hydroxymelatonin (C3-OHM) and N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) are two major cascade metabolites of melatonin. We previously showed melatonin provides multiple levels of mitochondria-targeted protection beyond as a mitochondrial antioxidant during ionomycin-induced mitochondrial Ca2+ (mCa2+ ) stress in RBA1 astrocytes. Using noninvasive laser scanning fluorescence coupled time-lapse digital imaging microscopy, this study investigated whether C3-OHM and AFMK also provide mitochondrial levels of protection during ionomycin-induced mCa2+ stress in RBA1 astrocytes. Interestingly, precise temporal and spatial dynamic live mitochondrial images revealed that C3-OHM and AFMK prevented specifically mCa2+ -mediated mitochondrial reactive oxygen species (mROS) formation and hence mROS-mediated depolarization of mitochondrial membrane potential (△Ψm ) and permanent lethal opening of the MPT (p-MPT). The antioxidative effects of AFMK, however, were less potent than that of C3-OHM. Whether C3-OHM and AFMK targeted directly the MPT was investigated under a condition of "oxidation free-Ca2+ stress" using a classic antioxidant vitamin E to remove mCa2+ -mediated mROS stress and the potential antioxidative effects of C3-OHM and AFMK. Intriguingly, two compounds still effectively postponed "oxidation free-Ca2+ stress"-mediated depolarization of △Ψm and p-MPT. Measurements using a MPT pore-specific indicator Calcein further identified that C3-OHM and AFMK, rather than inhibiting, stabilized the MPT in its transient protective opening mode (t-MPT), a critical mechanism to reduce overloaded mROS and mCa2+ . These multiple layers of mitochondrial protection provided by C3-OHM and AFMK thus crucially allow melatonin to extend its metabolic cascades of mitochondrial protection during mROS- and mCa2+ -mediated MPT-associated apoptotic stresses and may provide therapeutic benefits against astrocyte-mediated neurodegeneration in the CNS.
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Affiliation(s)
- Mei-Jie Jou
- Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan
- Department of Neurology, Chang Gung Memorial Hospital, Keelung Branch, Keelung, Taiwan
| | - Tsung-I Peng
- Department of Neurology, Chang Gung Memorial Hospital, Keelung Branch, Keelung, Taiwan
- Department of Medicine, Chang Gung University, Tao-Yuan, Taiwan
| | - Russel J Reiter
- Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas
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29
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Golabchi A, Wu B, Li X, Carlisle DL, Kozai TDY, Friedlander RM, Cui XT. Melatonin improves quality and longevity of chronic neural recording. Biomaterials 2018; 180:225-239. [PMID: 30053658 PMCID: PMC6179369 DOI: 10.1016/j.biomaterials.2018.07.026] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 07/06/2018] [Accepted: 07/13/2018] [Indexed: 12/17/2022]
Abstract
The chronic performance of implantable neural electrodes is hindered by inflammatory brain tissue responses, including microglia activation, glial scarring, and neuronal loss. Melatonin (MT) has shown remarkable neuroprotective and neurorestorative effects in treating central nervous system (CNS) injuries and degeneration by inhibiting caspase-1, -3, and -9 activation and mitochondrial cytochrome c release, as well as reducing oxidative stress and neuroinflammation. This study examined the effect of MT administration on the quality and longevity of neural recording from an implanted microelectrode in the visual cortex of mice for 16 weeks. MT (30 mg/kg) was administered via daily intraperitoneal injection for acute (3 days before and 14 days post-implantation) and chronic (3 days before and 16 weeks post-implantation) exposures. During the first 4 weeks, both MT groups showed significantly higher single-unit (SU) yield, signal-to-noise ratio (SNR), and amplitude compared to the vehicle control group. However, after 4 weeks of implantation, the SU yield of the acute treatment group dropped to the same level as the control group, while the chronic treatment group maintained significantly higher SU yield compared to both acute (week 5-16) and control (week 0-16) mice. Histological studies revealed a significant increase in neuronal viability and decrease in neuronal apoptosis around the implanted electrode at week 16 in the chronic group in comparison to control and acute subjects, which is correlated with reduced oxidative stress and increased number of pro-regeneration arginase-1 positive microglia cells. These results demonstrate the potent effect of MT treatment in maintaining a high-quality electrode-tissue interface and suggest that MT promotes neuroprotection possibly through its anti-apoptotic, anti-inflammatory, and anti-oxidative properties.
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Affiliation(s)
- Asiyeh Golabchi
- Department of Bioengineering, University of Pittsburgh, USA; Center for Neural Basis of Cognition, USA
| | - Bingchen Wu
- Department of Bioengineering, University of Pittsburgh, USA; Center for Neural Basis of Cognition, USA
| | - Xia Li
- Department of Bioengineering, University of Pittsburgh, USA
| | - Diane L Carlisle
- Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh School of Medicine, USA
| | - Takashi D Y Kozai
- Department of Bioengineering, University of Pittsburgh, USA; Center for Neural Basis of Cognition, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, USA; Neurotechnology Division of the University of Pittsburgh Brain Institute, USA
| | - Robert M Friedlander
- Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh School of Medicine, USA
| | - Xinyan Tracy Cui
- Department of Bioengineering, University of Pittsburgh, USA; Center for Neural Basis of Cognition, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, USA.
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30
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Reiter RJ, Tan DX, Rosales-Corral S, Galano A, Jou MJ, Acuna-Castroviejo D. Melatonin Mitigates Mitochondrial Meltdown: Interactions with SIRT3. Int J Mol Sci 2018; 19:E2439. [PMID: 30126181 PMCID: PMC6121285 DOI: 10.3390/ijms19082439] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 08/03/2018] [Accepted: 08/08/2018] [Indexed: 02/07/2023] Open
Abstract
Melatonin exhibits extraordinary diversity in terms of its functions and distribution. When discovered, it was thought to be uniquely of pineal gland origin. Subsequently, melatonin synthesis was identified in a variety of organs and recently it was shown to be produced in the mitochondria. Since mitochondria exist in every cell, with a few exceptions, it means that every vertebrate, invertebrate, and plant cell produces melatonin. The mitochondrial synthesis of melatonin is not photoperiod-dependent, but it may be inducible under conditions of stress. Mitochondria-produced melatonin is not released into the systemic circulation, but rather is used primarily in its cell of origin. Melatonin's functions in the mitochondria are highly diverse, not unlike those of sirtuin 3 (SIRT3). SIRT3 is an NAD+-dependent deacetylase which regulates, among many functions, the redox state of the mitochondria. Recent data proves that melatonin and SIRT3 post-translationally collaborate in regulating free radical generation and removal from mitochondria. Since melatonin and SIRT3 have cohabitated in the mitochondria for many eons, we predict that these molecules interact in many other ways to control mitochondrial physiology. It is predicted that these mutual functions will be intensely investigated in the next decade and importantly, we assume that the findings will have significant applications for preventing/delaying some age-related diseases and aging itself.
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Affiliation(s)
- Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX 78229, USA.
| | - Dun Xian Tan
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX 78229, USA.
| | - Sergio Rosales-Corral
- Centro de Investigacion Biomedica de Occidente, Instituto Mexicano del Seguro Social, Guardalajara, 4436 Jalisco, Mexico.
| | - Annia Galano
- Departamento de Quimica, Universidad Antonoma Metropolitana-Unidad Iztapalapa, San Rafael Atlixco 186, Col. Vicentina, Iztapalapa, C.P. 09340 Mexico D.F., Mexico.
| | - Mei-Jie Jou
- Department of Physiology and Pharmacology, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan 333, Taiwan.
| | - Dario Acuna-Castroviejo
- Departamento de Fisiologia, Instituto de Biotecnologia, Universidad de Granada, Avenida de Conocimiento S/U, 18016 Granada, Spain.
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31
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Galano A, Reiter RJ. Melatonin and its metabolites vs oxidative stress: From individual actions to collective protection. J Pineal Res 2018; 65:e12514. [PMID: 29888508 DOI: 10.1111/jpi.12514] [Citation(s) in RCA: 226] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 06/05/2018] [Indexed: 12/11/2022]
Abstract
Oxidative stress (OS) represents a threat to the chemical integrity of biomolecules including lipids, proteins, and DNA. The associated molecular damage frequently results in serious health issues, which justifies our concern about this phenomenon. In addition to enzymatic defense mechanisms, there are compounds (usually referred to as antioxidants) that offer chemical protection against oxidative events. Among them, melatonin and its metabolites constitute a particularly efficient chemical family. They offer protection against OS as individual chemical entities through a wide variety of mechanisms including electron transfer, hydrogen transfer, radical adduct formation, and metal chelation, and by repairing biological targets. In fact, many of them including melatonin can be classified as multipurpose antioxidants. However, what seems to be unique to the melatonin's family is their collective effects. Because the members of this family are metabolically related, most of them are expected to be present in living organisms wherever melatonin is produced. Therefore, the protection exerted by melatonin against OS may be viewed as a result of the combined antioxidant effects of the parent molecule and its metabolites. Melatonin's family is rather exceptional in this regard, offering versatile and collective antioxidant protection against OS. It certainly seems that melatonin is one of the best nature's defenses against oxidative damage.
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Affiliation(s)
- Annia Galano
- Departamento de Química, Universidad Autónoma Metropolitana-Iztapalapa, México City, México
| | - Russel J Reiter
- Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX, USA
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32
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Liu W, Wang S, Zhou J, Pang X, Wang L. RNAi-mediated knockdown of MTNR1B without disrupting the effects of melatonin on apoptosis and cell cycle in bovine granulose cells. PeerJ 2018; 6:e4463. [PMID: 29707428 PMCID: PMC5918132 DOI: 10.7717/peerj.4463] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Accepted: 04/03/2018] [Indexed: 02/06/2023] Open
Abstract
Melatonin is well known as a powerful free radical scavenger and exhibits the ability to prevent cell apoptosis. In the present study, we investigated the role of melatonin and its receptor MTNR1B in regulating the function of bovine granulosa cells (GCs) and hypothesized the involvement of MTNR1B in mediating the effect of melatonin on GCs. Our results showed that MTNR1B knockdown significantly promoted GCs apoptosis but did not affect the cell cycle. These results were further verified by increasing the expression of pro-apoptosis genes (BAX and CASP3), decreasing expression of the anti-apoptosis genes (BCL2 and BCL-XL) and anti-oxidant genes (SOD1 and GPX4) without affecting cell cycle factors (CCND1, CCNE1 and CDKN1A) and TP53. In addition, MTNR1B knockdown did not disrupt the effects of melatonin in suppressing the GCs apoptosis or blocking the cell cycle. Moreover, MTNR1B knockdown did not affect the role of melatonin in increasing BCL2, BCL-XL, and CDKN1A expression, or decreasing BAX, CASP3, TP53, CCND1 and CCNE1 expression. The expression of MTNR1A was upregulated after MTNR1B knockdown, and melatonin promoted MTNR1A expression with or without MTNR1B knockdown. However, despite melatonin supplementation, the expression of SOD1 and GPX4 was still suppressed after MTNR1B knockdown. In conclusion, these findings indicate that melatonin and MTNR1B are involved in BCL2 family and CASP3-dependent apoptotic pathways in bovine GCs. MTNR1A and MTNR1B may coordinate the work of medicating the appropriate melatonin responses to GCs.
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Affiliation(s)
- Wenju Liu
- College of Animal Science, Anhui Science and Technology University, Fengyang, Anhui, China.,Cell and Molecular Biology Research Center, Anhui Science and Technology University, Fengyang, AnHui, China
| | - Shujuan Wang
- College of Animal Science, Anhui Science and Technology University, Fengyang, Anhui, China
| | - Jinxing Zhou
- College of Animal Science, Anhui Science and Technology University, Fengyang, Anhui, China.,Cell and Molecular Biology Research Center, Anhui Science and Technology University, Fengyang, AnHui, China
| | - Xunsheng Pang
- College of Animal Science, Anhui Science and Technology University, Fengyang, Anhui, China
| | - Like Wang
- College of Animal Science, Anhui Science and Technology University, Fengyang, Anhui, China
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Melatonin: A Versatile Protector against Oxidative DNA Damage. Molecules 2018; 23:molecules23030530. [PMID: 29495460 PMCID: PMC6017920 DOI: 10.3390/molecules23030530] [Citation(s) in RCA: 180] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 02/13/2018] [Accepted: 02/22/2018] [Indexed: 12/15/2022] Open
Abstract
Oxidative damage to DNA has important implications for human health and has been identified as a key factor in the onset and development of numerous diseases. Thus, it is evident that preventing DNA from oxidative damage is crucial for humans and for any living organism. Melatonin is an astonishingly versatile molecule in this context. It can offer both direct and indirect protection against a wide variety of damaging agents and through multiple pathways, which may (or may not) take place simultaneously. They include direct antioxidative protection, which is mediated by melatonin's free radical scavenging activity, and also indirect ways of action. The latter include, at least: (i) inhibition of metal-induced DNA damage; (ii) protection against non-radical triggers of oxidative DNA damage; (iii) continuous protection after being metabolized; (iv) activation of antioxidative enzymes; (v) inhibition of pro-oxidative enzymes; and (vi) boosting of the DNA repair machinery. The rather unique capability of melatonin to exhibit multiple neutralizing actions against diverse threatening factors, together with its low toxicity and its ability to cross biological barriers, are all significant to its efficiency for preventing oxidative damage to DNA.
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34
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Reiter RJ, Tan DX, Rosales-Corral S, Galano A, Zhou XJ, Xu B. Mitochondria: Central Organelles for Melatonin's Antioxidant and Anti-Aging Actions. Molecules 2018; 23:E509. [PMID: 29495303 PMCID: PMC6017324 DOI: 10.3390/molecules23020509] [Citation(s) in RCA: 258] [Impact Index Per Article: 36.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 02/13/2018] [Accepted: 02/16/2018] [Indexed: 02/07/2023] Open
Abstract
Melatonin, along with its metabolites, have long been known to significantly reduce the oxidative stress burden of aging cells or cells exposed to toxins. Oxidative damage is a result of free radicals produced in cells, especially in mitochondria. When measured, melatonin, a potent antioxidant, was found to be in higher concentrations in mitochondria than in other organelles or subcellular locations. Recent evidence indicates that mitochondrial membranes possess transporters that aid in the rapid uptake of melatonin by these organelles against a gradient. Moreover, we predicted several years ago that, because of their origin from melatonin-producing bacteria, mitochondria likely also synthesize melatonin. Data accumulated within the last year supports this prediction. A high content of melatonin in mitochondria would be fortuitous, since these organelles produce an abundance of free radicals. Thus, melatonin is optimally positioned to scavenge the radicals and reduce the degree of oxidative damage. In light of the "free radical theory of aging", including all of its iterations, high melatonin levels in mitochondria would be expected to protect against age-related organismal decline. Also, there are many age-associated diseases that have, as a contributing factor, free radical damage. These multiple diseases may likely be deferred in their onset or progression if mitochondrial levels of melatonin can be maintained into advanced age.
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Affiliation(s)
- Russel J Reiter
- Department of Cellular and Structural Biology UT Health San Antonio, San Antonio, SD 78229, USA.
| | - Dun Xian Tan
- Department of Cellular and Structural Biology UT Health San Antonio, San Antonio, SD 78229, USA.
| | - Sergio Rosales-Corral
- Centro de Investigacion Biomedica de Occidente, Instituo Mexicana del Seguro Social, Guadalajara 44346, Mexico.
| | - Annia Galano
- Departamento de Quimica, Universidad Autonoma Metropolitana-Iztapatapa, Mexico D.F. 09340, Mexico.
| | - Xin Jia Zhou
- Department of Cellular and Structural Biology UT Health San Antonio, San Antonio, SD 78229, USA.
| | - Bing Xu
- Department of Cellular and Structural Biology UT Health San Antonio, San Antonio, SD 78229, USA.
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35
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Huang GQ, Yi GG, Wu LW, Feng SF, Wu W, Peng L, Yi RW, Ma W, Lu X. Protective effect of histatin 1 against ultraviolet-induced damage to human corneal epithelial cells. Exp Ther Med 2018; 15:679-684. [PMID: 29399071 PMCID: PMC5772520 DOI: 10.3892/etm.2017.5503] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 06/22/2017] [Indexed: 01/18/2023] Open
Abstract
The aim of the present study was to investigate the role of histatin 1 (Hst1) in human corneal epithelial cells (HCECs) exposed to ultraviolet (UV) radiation. Prior to UV irradiation for various durations, HCECs were pre-treated with different concentrations of Hst1 and the effect on cell apoptosis and cell viability were examined by flow cytometry, alamarBlue® and MTT assays to determine the optimal concentration of Hst1 and UV dose. Cells were then subjected to quantitative PCR, ELISA and western blot analysis to determine the expression of cell damage-associated genes. HCECs exposed to UV light for 1 h displayed decreased viability when compared to that of control cells, and a 3 h UV exposure markedly increased the apoptotic rate of HECEs, while apoptosis was inhibited by pre-treatment with Hst1. UV radiation downregulated expression of insulin-like growth factor (IGF)-1 and B-cell lymphoma 2 (Bcl-2), while it upregulated Bcl-2-associated X protein (Bax) expression. Hst1 protected HCECs against UV-induced damage by upregulating the expression of IGF-1 protein and increasing the Bcl-2/Bax ratio. In conclusion, Hst1 may prevent UV-induced damage to corneal epithelial tissue injury and promote its healing.
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Affiliation(s)
- Guo-Qiang Huang
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
- Department of Ophthalmology, Meizhou People's Hospital, Meizhou, Guangdong 514031, P.R. China
| | - Guo-Guo Yi
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Lai-Wei Wu
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Song-Fu Feng
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Wei Wu
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Ling Peng
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Rui-Wen Yi
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Wenbei Ma
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Xiaohe Lu
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
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Effects of Scopolamine and Melatonin Cotreatment on Cognition, Neuronal Damage, and Neurogenesis in the Mouse Dentate Gyrus. Neurochem Res 2017; 43:600-608. [PMID: 29260493 DOI: 10.1007/s11064-017-2455-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Revised: 11/16/2017] [Accepted: 12/14/2017] [Indexed: 10/18/2022]
Abstract
It has been demonstrated that melatonin plays important roles in memory improvement and promotes neurogenesis in experimental animals. We examined effects of melatonin on cognitive deficits, neuronal damage, cell proliferation, neuroblast differentiation and neuronal maturation in the mouse dentate gyrus after cotreatment of scopolamine (anticholinergic agent) and melatonin. Scopolamine (1 mg/kg) and melatonin (10 mg/kg) were intraperitoneally injected for 2 and/or 4 weeks to 8-week-old mice. Scopolamine treatment induced significant cognitive deficits 2 and 4 weeks after scopolamine treatment, however, cotreatment of scopolamine and melatonin significantly improved spatial learning and short-term memory impairments. Two and 4 weeks after scopolamine treatment, neurons were not damaged/dead in the dentate gyrus, in addition, no neuronal damage/death was shown after cotreatment of scopolamine and melatonin. Ki67 (a marker for cell proliferation)- and doublecortin (a marker for neuroblast differentiation)-positive cells were significantly decreased in the dentate gyrus 2 and 4 weeks after scopolamine treatment, however, cotreatment of scopolamine and melatonin significantly increased Ki67- and doublecortin-positive cells compared with scopolamine-treated group. However, double immunofluorescence for NeuN/BrdU, which indicates newly-generated mature neurons, did not show double-labeled cells (adult neurogenesis) in the dentate gyrus 2 and 4 weeks after cotreatment of scopolamine and melatonin. Our results suggest that melatonin treatment recovers scopolamine-induced spatial learning and short-term memory impairments and restores or increases scopolamine-induced decrease of cell proliferation and neuroblast differentiation, but does not lead to adult neurogenesis (maturation of neurons) in the mouse dentate gyrus following scopolamine treatment.
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Paul R, Phukan BC, Justin Thenmozhi A, Manivasagam T, Bhattacharya P, Borah A. Melatonin protects against behavioral deficits, dopamine loss and oxidative stress in homocysteine model of Parkinson's disease. Life Sci 2017; 192:238-245. [PMID: 29138117 DOI: 10.1016/j.lfs.2017.11.016] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Accepted: 11/10/2017] [Indexed: 10/18/2022]
Abstract
AIM Hyperhomocysteinemia and homocysteine (Hcy) mediated dopaminergic neurotoxicity is a matter of concern in the pathophysiology of Parkinson's disease (PD). Our previous study established the involvement of oxidative stress in the substantia nigra (SN) of Hcy rat model of PD; however, the role of antioxidants, such as melatonin, was not tested in this model. MAIN METHODS Melatonin (10, 20 and 30mg/kg, i.p.) was administered to rats injected with Hcy in right SN (1.0μmol in 2μl saline) to investigate its potency in attenuating the behavioral abnormalities, dopamine depletion and oxidative stress prompted by Hcy. KEY FINDINGS Treatment of melatonin protected against nigral dopamine loss and replenished the striatal dopamine loss that resulted in amelioration of rotational behavioral bias in Hcy denervated animals. Melatonin administration significantly improved mitochondrial complex-I activity and protected the SN neurons from the toxic insults of oxidative stress induced by Hcy. Amelioration of oxidative stress by melatonin in Hcy-infused SN was bought by dose-dependently scavenging of hydroxyl radicals, restoration of glutathione level and elevation in the activity of antioxidant enzymes. SIGNIFICANCE The observations bring into light the significant neuroprotective potentials of melatonin in Hcy model of PD which is attributed to the attenuation of oxidative stress in SN.
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Affiliation(s)
- Rajib Paul
- Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India; Department of Zoology, Pandit Deendayal Upadhyaya Adarsha Mahavidyalaya (PDUAM), Eraligool-788723, Karimganj, Assam, India
| | - Banashree Chetia Phukan
- Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India
| | - Arokiasamy Justin Thenmozhi
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, Tamil Nadu, India
| | - Thamilarasan Manivasagam
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, Tamil Nadu, India
| | - Pallab Bhattacharya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar-382355, Gujarat, India
| | - Anupom Borah
- Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India.
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Reiter RJ, Rosales-Corral S, Tan DX, Jou MJ, Galano A, Xu B. Melatonin as a mitochondria-targeted antioxidant: one of evolution's best ideas. Cell Mol Life Sci 2017; 74:3863-3881. [PMID: 28864909 PMCID: PMC11107735 DOI: 10.1007/s00018-017-2609-7] [Citation(s) in RCA: 378] [Impact Index Per Article: 47.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 08/03/2017] [Indexed: 01/27/2023]
Abstract
Melatonin is an ancient antioxidant. After its initial development in bacteria, it has been retained throughout evolution such that it may be or may have been present in every species that have existed. Even though it has been maintained throughout evolution during the diversification of species, melatonin's chemical structure has never changed; thus, the melatonin present in currently living humans is identical to that present in cyanobacteria that have existed on Earth for billions of years. Melatonin in the systemic circulation of mammals quickly disappears from the blood presumably due to its uptake by cells, particularly when they are under high oxidative stress conditions. The measurement of the subcellular distribution of melatonin has shown that the concentration of this indole in the mitochondria greatly exceeds that in the blood. Melatonin presumably enters mitochondria through oligopeptide transporters, PEPT1, and PEPT2. Thus, melatonin is specifically targeted to the mitochondria where it seems to function as an apex antioxidant. In addition to being taken up from the circulation, melatonin may be produced in the mitochondria as well. During evolution, mitochondria likely originated when melatonin-forming bacteria were engulfed as food by ancestral prokaryotes. Over time, engulfed bacteria evolved into mitochondria; this is known as the endosymbiotic theory of the origin of mitochondria. When they did so, the mitochondria retained the ability to synthesize melatonin. Thus, melatonin is not only taken up by mitochondria but these organelles, in addition to many other functions, also probably produce melatonin as well. Melatonin's high concentrations and multiple actions as an antioxidant provide potent antioxidant protection to these organelles which are exposed to abundant free radicals.
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Affiliation(s)
- Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, 78229, USA.
| | - Sergio Rosales-Corral
- Centro de Investigacion Biomedica de Occidente, Del Instituto Mexicana del Seguro Social, 44340, Guadalajara, Mexico
| | - Dun Xian Tan
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, 78229, USA
| | - Mei Jie Jou
- Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyüan, Taiwan
- Department of Neurology, Kee-Lung Medical Center, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Annia Galano
- Departemento de Quimica, Uninversidad Autonoma Metropolitana-Iztapalapa, 09340, Mexico City, Mexico
| | - Bing Xu
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, 78229, USA
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Han L, Wang H, Li L, Li X, Ge J, Reiter RJ, Wang Q. Melatonin protects against maternal obesity-associated oxidative stress and meiotic defects in oocytes via the SIRT3-SOD2-dependent pathway. J Pineal Res 2017; 63. [PMID: 28658527 DOI: 10.1111/jpi.12431] [Citation(s) in RCA: 130] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 06/23/2017] [Indexed: 12/12/2022]
Abstract
Maternal obesity in humans is associated with poor outcomes across the reproductive spectrum. Emerging evidence indicates that these defects are likely attributed to factors within the oocyte. Although various molecules and pathways may contribute to impaired oocyte quality, prevention of fertility issues associated with maternal obesity is a challenge. Using mice fed a high-fat diet (HFD) as an obesity model, we document spindle disorganization, chromosome misalignment, and elevated reactive oxygen species (ROS) levels in oocytes from obese mice. Oral administration of melatonin to HFD mice not only reduces ROS generation, but also prevents spindle/chromosome anomalies in oocytes, consequently promoting the developmental potential of early embryos. Consistent with this finding, we find that melatonin supplement during in vitro maturation also markedly attenuates oxidative stress and meiotic defects in HFD oocytes. Finally, by performing morpholino knockdown and acetylation-mimetic mutant overexpression assays, we reveal that melatonin ameliorates maternal obesity-induced defective phenotypes in oocytes through the SIRT3-SOD2-dependent mechanism. In sum, our data uncover the marked beneficial effects of melatonin on oocyte quality from obese females; this opens a new area for optimizing culture system as well as fertility management.
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Affiliation(s)
- Longsen Han
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| | - Haichao Wang
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| | - Ling Li
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| | - Xiaoyan Li
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Juan Ge
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| | - Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health, San Antonio, TX, USA
| | - Qiang Wang
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
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Choi SI, Lee E, Akuzum B, Jeong JB, Maeng YS, Kim TI, Kim EK. Melatonin reduces endoplasmic reticulum stress and corneal dystrophy-associated TGFBIp through activation of endoplasmic reticulum-associated protein degradation. J Pineal Res 2017; 63. [PMID: 28580641 DOI: 10.1111/jpi.12426] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 05/31/2017] [Indexed: 02/06/2023]
Abstract
Endoplasmic reticulum (ER) stress is emerging as a factor for the pathogenesis of granular corneal dystrophy type 2 (GCD2). This study was designed to investigate the molecular mechanisms underlying the protective effects of melatonin on ER stress in GCD2. Our results showed that GCD2 corneal fibroblasts were more susceptible to ER stress-induced death than were wild-type cells. Melatonin significantly inhibited GCD2 corneal cell death, caspase-3 activation, and poly (ADP-ribose) polymerase 1 cleavage caused by the ER stress inducer, tunicamycin. Under ER stress, melatonin significantly suppressed the induction of immunoglobulin heavy-chain-binding protein (BiP) and activation of inositol-requiring enzyme 1α (IRE1α), and their downstream target, alternative splicing of X-box binding protein 1(XBP1). Notably, the reduction in BiP and IRE1α by melatonin was suppressed by the ubiquitin-proteasome inhibitor, MG132, but not by the autophagy inhibitor, bafilomycin A1, indicating involvement of the ER-associated protein degradation (ERAD) system. Melatonin treatment reduced the levels of transforming growth factor-β-induced protein (TGFBIp) significantly, and this reduction was suppressed by MG132. We also found reduced mRNA expression of the ERAD system components HRD1 and SEL1L, and a reduced level of SEL1L protein in GCD2 cells. Interestingly, melatonin treatments enhanced SEL1L levels and suppressed the inhibition of SEL1L N-glycosylation caused by tunicamycin. In conclusion, this study provides new insights into the mechanisms by which melatonin confers its protective actions during ER stress. The results also indicate that melatonin might have potential as a therapeutic agent for ER stress-related diseases including GCD2.
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Affiliation(s)
- Seung-Il Choi
- Department of Ophthalmology, Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Eunhee Lee
- Department of Ophthalmology, Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Begum Akuzum
- Department of Ophthalmology, Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Jang Bin Jeong
- Department of Ophthalmology, Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Yong-Sun Maeng
- Department of Ophthalmology, Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Tae-Im Kim
- Department of Ophthalmology, Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Korea
- Institute of Vision Research, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Eung Kweon Kim
- Department of Ophthalmology, Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Korea
- Institute of Vision Research, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
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Reiter RJ, Rosales-Corral SA, Tan DX, Acuna-Castroviejo D, Qin L, Yang SF, Xu K. Melatonin, a Full Service Anti-Cancer Agent: Inhibition of Initiation, Progression and Metastasis. Int J Mol Sci 2017; 18:E843. [PMID: 28420185 PMCID: PMC5412427 DOI: 10.3390/ijms18040843] [Citation(s) in RCA: 326] [Impact Index Per Article: 40.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 04/05/2017] [Accepted: 04/06/2017] [Indexed: 12/21/2022] Open
Abstract
There is highly credible evidence that melatonin mitigates cancer at the initiation, progression and metastasis phases. In many cases, the molecular mechanisms underpinning these inhibitory actions have been proposed. What is rather perplexing, however, is the large number of processes by which melatonin reportedly restrains cancer development and growth. These diverse actions suggest that what is being observed are merely epiphenomena of an underlying more fundamental action of melatonin that remains to be disclosed. Some of the arresting actions of melatonin on cancer are clearly membrane receptor-mediated while others are membrane receptor-independent and involve direct intracellular actions of this ubiquitously-distributed molecule. While the emphasis of melatonin/cancer research has been on the role of the indoleamine in restraining breast cancer, this is changing quickly with many cancer types having been shown to be susceptible to inhibition by melatonin. There are several facets of this research which could have immediate applications at the clinical level. Many studies have shown that melatonin's co-administration improves the sensitivity of cancers to inhibition by conventional drugs. Even more important are the findings that melatonin renders cancers previously totally resistant to treatment sensitive to these same therapies. Melatonin also inhibits molecular processes associated with metastasis by limiting the entrance of cancer cells into the vascular system and preventing them from establishing secondary growths at distant sites. This is of particular importance since cancer metastasis often significantly contributes to death of the patient. Another area that deserves additional consideration is related to the capacity of melatonin in reducing the toxic consequences of anti-cancer drugs while increasing their efficacy. Although this information has been available for more than a decade, it has not been adequately exploited at the clinical level. Even if the only beneficial actions of melatonin in cancer patients are its ability to attenuate acute and long-term drug toxicity, melatonin should be used to improve the physical wellbeing of the patients. The experimental findings, however, suggest that the advantages of using melatonin as a co-treatment with conventional cancer therapies would far exceed improvements in the wellbeing of the patients.
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Affiliation(s)
- Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health, San Antonio, TX 78229, USA.
| | - Sergio A Rosales-Corral
- Centro de Investigacion Biomedica de Occidente, Del Instituto Mexicano del Seguro Social, Guadalajara 44340, Mexico.
| | - Dun-Xian Tan
- Department of Cell Systems and Anatomy, UT Health, San Antonio, TX 78229, USA.
| | | | - Lilan Qin
- Department of Cell Systems and Anatomy, UT Health, San Antonio, TX 78229, USA.
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan, Medical University, Taichung 40201, Taiwan.
| | - Kexin Xu
- Department of Molecular Medicine, UT Health, San Antonio, TX 78229, USA.
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Sharif R, Aghsami M, Gharghabi M, Sanati M, Khorshidahmad T, Vakilzadeh G, Mehdizadeh H, Gholizadeh S, Taghizadeh G, Sharifzadeh M. Melatonin reverses H-89 induced spatial memory deficit: Involvement of oxidative stress and mitochondrial function. Behav Brain Res 2017; 316:115-124. [PMID: 27555536 DOI: 10.1016/j.bbr.2016.08.040] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 08/11/2016] [Accepted: 08/20/2016] [Indexed: 01/08/2023]
Abstract
Oxidative stress and mitochondrial dysfunction play indispensable role in memory and learning impairment. Growing evidences have shed light on anti-oxidative role for melatonin in memory deficit. We have previously reported that inhibition of protein kinase A by H-89 can induce memory impairment. Here, we investigated the effect of melatonin on H-89 induced spatial memory deficit and pursued their interactive consequences on oxidative stress and mitochondrial function in Morris Water Maze model. Rats received melatonin (50 and 100μg/kg/side) and H-89(10μM) intra-hippocampally 30min before each day of training. Animals were trained for 4 consecutive days, each containing one block from four trials. Oxidative stress indices, including thiobarbituric acid (TBARS), reactive oxygen species (ROS), thiol groups, and ferric reducing antioxidant power (FRAP) were assessed using spectrophotometer. Mitochondrial function was evaluated through measuring ROS production, mitochondrial membrane potential (MMP), swelling, outer membrane damage, and cytochrome c release. As expected from our previous report, H-89 remarkably impaired memory by increasing the escape latency and traveled distance. Intriguingly, H-89 significantly augmented TBARS and ROS levels, caused mitochondrial ROS production, swelling, outer membrane damage, and cytochrome c release. Moreover, H-89 lowered thiol, FRAP, and MMP values. Intriguingly, melatonin pre-treatment not only effectively hampered H-89-mediated spatial memory deficit at both doses, but also reversed the H-89 effects on mitochondrial and biochemical indices upon higher dose. Collectively, these findings highlight a protective role for melatonin against H-89-induced memory impairment and indicate that melatonin may play a therapeutic role in the treatment of oxidative- related neurodegenerative disorders.
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Affiliation(s)
- Rojin Sharif
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran
| | - Mehdi Aghsami
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran
| | - Mehdi Gharghabi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran
| | - Mehdi Sanati
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran
| | - Tina Khorshidahmad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran; College of Pharmacy, University of Manitoba, 750 McDermot Avenue, Winnipeg, R3E 0T5, MB, Canada; Manitoba Multiple Sclerosis Research Network Organization (MMSRNO), Winnipeg, Canada
| | - Gelareh Vakilzadeh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran
| | - Hajar Mehdizadeh
- Department of Neuroscience, School of Advanced Science and Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Shervin Gholizadeh
- Leslie Dan Faculty of Pharmacy, Department of Pharmaceutical Sciences, University of Toronto, M5S 3M2, Toronto, ON, Canada
| | - Ghorban Taghizadeh
- Department of Neuroscience, School of Advanced Science and Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Sharifzadeh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran.
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Hu J, Zhang L, Yang Y, Guo Y, Fan Y, Zhang M, Man W, Gao E, Hu W, Reiter RJ, Wang H, Sun D. Melatonin alleviates postinfarction cardiac remodeling and dysfunction by inhibiting Mst1. J Pineal Res 2017; 62. [PMID: 27696525 DOI: 10.1111/jpi.12368] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 09/27/2016] [Indexed: 12/20/2022]
Abstract
Melatonin reportedly protects against several cardiovascular diseases including ischemia/reperfusion (I/R), atherosclerosis, and hypertension. The present study investigated the effects and mechanisms of melatonin on cardiomyocyte autophagy, apoptosis, and mitochondrial injury in the context of myocardial infarction (MI). We demonstrated that melatonin significantly alleviated cardiac dysfunction after MI. Four weeks after MI, echocardiography and Masson staining indicated that melatonin notably mitigated adverse left ventricle remodeling. The mechanism may be associated with increased autophagy, reduced apoptosis, and alleviated mitochondrial dysfunction. Furthermore, melatonin significantly inhibited Mst1 phosphorylation while promoting Sirt1 expression after MI, which indicates that Mst1/Sirt1 signaling may serve as the downstream target of melatonin. We thus constructed a MI model using Mst1 transgenic (Mst1 Tg) and Mst1 knockout (Mst1-/- ) mice. The absence of Mst1 abolished the favorable effects of melatonin on cardiac injury after MI. Consistently, melatonin administration did not further increase autophagy, decrease apoptosis, or alleviate mitochondrial integrity and biogenesis in Mst1 knockout mice subjected to MI injury. These results suggest that melatonin alleviates postinfarction cardiac remodeling and dysfunction by upregulating autophagy, decreasing apoptosis, and modulating mitochondrial integrity and biogenesis. The attributed mechanism involved, at least in part, Mst1/Sirt1 signaling.
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Affiliation(s)
- Jianqiang Hu
- Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Lei Zhang
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yang Yang
- Department of Biomedical Engineering, Fourth Military Medical University, Xi'an, China
| | - Yanjie Guo
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yanhong Fan
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Mingming Zhang
- Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Wanrong Man
- Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Erhe Gao
- Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA
| | - Wei Hu
- Department of Biomedical Engineering, Fourth Military Medical University, Xi'an, China
| | - Russel J Reiter
- Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX, USA
| | - Haichang Wang
- Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Dongdong Sun
- Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
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Coto-Montes A, Boga JA, Tan DX, Reiter RJ. Melatonin as a Potential Agent in the Treatment of Sarcopenia. Int J Mol Sci 2016; 17:ijms17101771. [PMID: 27783055 PMCID: PMC5085795 DOI: 10.3390/ijms17101771] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Revised: 10/17/2016] [Accepted: 10/17/2016] [Indexed: 12/31/2022] Open
Abstract
Considering the increased speed at which the world population is aging, sarcopenia could become an epidemic in this century. This condition currently has no means of prevention or treatment. Melatonin is a highly effective and ubiquitously acting antioxidant and free radical scavenger that is normally produced in all organisms. This molecule has been implicated in a huge number of biological processes, from anticonvulsant properties in children to protective effects on the lung in chronic obstructive pulmonary disease. In this review, we summarize the data which suggest that melatonin may be beneficial in attenuating, reducing or preventing each of the symptoms that characterize sarcopenia. The findings are not limited to sarcopenia, but also apply to osteoporosis-related sarcopenia and to age-related neuromuscular junction dysfunction. Since melatonin has a high safety profile and is drastically reduced in advanced age, its potential utility in the treatment of sarcopenic patients and related dysfunctions should be considered.
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Affiliation(s)
- Ana Coto-Montes
- Department of Morphology and Cellular Biology, Medicine Faculty, University of Oviedo, Julian Claveria, s/n, Oviedo 33006, Spain.
- Department of Cellular and Structural Biology, UTHSCSA, San Antonio, TX 78229, USA.
| | - Jose A Boga
- Department of Cellular and Structural Biology, UTHSCSA, San Antonio, TX 78229, USA.
- Service of Microbiology, Hospital Universitario Central de Asturias, Avenida de Roma, s/n, Oviedo 33011, Spain.
| | - Dun X Tan
- Department of Cellular and Structural Biology, UTHSCSA, San Antonio, TX 78229, USA.
| | - Russel J Reiter
- Department of Cellular and Structural Biology, UTHSCSA, San Antonio, TX 78229, USA.
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45
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Bai C, Li X, Gao Y, Yuan Z, Hu P, Wang H, Liu C, Guan W, Ma Y. Melatonin improves reprogramming efficiency and proliferation of bovine-induced pluripotent stem cells. J Pineal Res 2016; 61:154-67. [PMID: 27090494 DOI: 10.1111/jpi.12334] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 04/12/2016] [Indexed: 12/18/2022]
Abstract
Melatonin can modulate neural stem cell (NSC) functions such as proliferation and differentiation into NSC-derived pluripotent stem cells (N-iPS) in brain tissue, but the effect and mechanism underlying this are unclear. Thus, we studied how primary cultured bovine NSCs isolated from the retinal neural layer could transform into N-iPS cell. NSCs were exposed to 0.01, 0.1, 1, 10, or 100 μm melatonin, and cell viability studies indicated that 10 μm melatonin can significantly increase cell viability and promote cell proliferation in NSCs in vitro. Thus, 10 μm melatonin was used to study miR-302/367-mediated cell reprogramming of NSCs. We noted that this concentration of melatonin increased reprogramming efficiency of N-iPS cell generation from primary cultured bovine NSCs and that this was mediated by downregulation of apoptosis-related genes p53 and p21. Then, N-iPS cells were treated with 1, 10, 100, or 500 μm melatonin, and N-iPS (M-N-iPS) cell proliferation was measured. We noted that 100 μm melatonin increased proliferation of N-iPS cells via increased phosphorylation of intracellular ERK1/2 via activation of its pathway in M-N-iPS via melatonin receptors 1 (MT1). Finally, we verified that N-iPS cells and M-N-iPS cells are similar to typical embryonic stem cells including the expression of pluripotency markers (Oct4 and Nanog), the ability to form teratomas in vivo, and the capacity to differentiate into all three embryonic germ layers.
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Affiliation(s)
- Chunyu Bai
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Xiangchen Li
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Yuhua Gao
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
- College of Wildlife Resources, Northeast Forestry University, Harbin, China
| | - Ziao Yuan
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
- College of Wildlife Resources, Northeast Forestry University, Harbin, China
| | - Pengfei Hu
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Hui Wang
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
- Department of Food Science and Engineering, Liaoning Medical University, Jinzhou, China
| | - Changqing Liu
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
- Department of Bioscience, Bengbu Medical College, Bengbu, China
| | - Weijun Guan
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Yuehui Ma
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
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46
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Kurganova YM, Danilov AB. The Role of Melatonin in the Treatment of Chronic Back Pain. ACTA ACUST UNITED AC 2016. [DOI: 10.1007/s11055-016-0303-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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47
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Pahrudin Arrozi A, Wan Ngah WZ, Mohd Yusof YA, Ahmad Damanhuri MH, Makpol S. Antioxidant modulation in restoring mitochondrial function in neurodegeneration. Int J Neurosci 2016; 127:218-235. [PMID: 27074540 DOI: 10.1080/00207454.2016.1178261] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Alzheimer's disease (AD) and Parkinson's disease (PD) are the leading causes of disability associated with neurodegeneration worldwide. These diseases are influenced by multiple genetic and environmental factors and share similar mechanisms as both are characterized by accumulation and aggregation of misfolded proteins - amyloid-beta (Aβ) in AD and α-synuclein in PD. Over the past decade, increasing evidence has shown that mitochondrial dysfunction and the generation of reactive oxygen species (ROS) are involved in the pathology of these diseases, and the contributions of these defects to the cellular and molecular changes that eventually cause neuronal death have been explored. Using mitochondrial protective agents, such as antioxidants, to combat ROS provides a new strategy for neurodegenerative treatment. In this review, we highlight the potential of multiple types of antioxidants, including vitamins, phytochemicals, fatty acids and minerals, as well as synthetic antioxidants specifically targeting the mitochondria, which can restore mitochondrial function, in the treatment of neurodegenerative disorders at both the pre-clinical and clinical stages by focusing on AD and PD.
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Affiliation(s)
- Aslina Pahrudin Arrozi
- a Department of Biochemistry , Universiti Kebangsaan Malaysia Medical Center , Kuala Lumpur , Malaysia
| | - Wan Zurinah Wan Ngah
- a Department of Biochemistry , Universiti Kebangsaan Malaysia Medical Center , Kuala Lumpur , Malaysia
| | - Yasmin Anum Mohd Yusof
- a Department of Biochemistry , Universiti Kebangsaan Malaysia Medical Center , Kuala Lumpur , Malaysia
| | | | - Suzana Makpol
- a Department of Biochemistry , Universiti Kebangsaan Malaysia Medical Center , Kuala Lumpur , Malaysia
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48
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Kurganova YM, Danilov AB. [A role of melatonin in the treatment of low back pain]. Zh Nevrol Psikhiatr Im S S Korsakova 2015; 115:30-35. [PMID: 26288285 DOI: 10.17116/jnevro20151154130-35] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
OBJECTIVE To study an analgesic role of melatonin in the treatment of low back pain. MATERIAL AND METHODS A study included 178 patients, aged from 40 to 65 years, with low back pain during at least 12 weeks and the VAS score > 3. Patients were stratified into 6 groups (3 pairs of comparison). In the first pair, patients of the main group (n = 31) received APTPA (a combination of 500 mg of glucosamine hydrochloride and 500 mg of chondroitin sulfate) in dosage 1 tablet twice a day during 1 month and then 1 tablet during 2 months plus melaxen (3 mg of melatonin 30-40 min before sleep), patients of the control group (n = 29) received only APTPA. In the second pair, patients of the comparison group (n = 30) received APTPA in dosage 1 tablet twice a day and diclofenac in dosage 25 mg 2-3 times a day, patients of the main group (n = 30) received additionally melaxen (3 mg of melatonin 30-40 min before sleep). In the third pair, patients of the main group (n = 29) received APTPA in dosage 1 tablet twice a day, diclofenac in dosage 25 mg 2-3 times a day and melaxen (3 mg of melatonin 30-40 min before sleep), patients of the comparison group (n = 29) did not receive melaxen. Treatment results were assessed after 3 months for the first pair and after 1 month for the second and third pairs. RESULTS A significant reduction in pain intensity at movement and resting state was noted in the main groups compared to controls. CONCLUSION Possible mechanisms of analgesic properties of melatonin and world experience in chronic low back pain treatment are discussed.
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Affiliation(s)
| | - A B Danilov
- Sechenov First Moscow State Medical University, Moscow
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49
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Paul R, Borah A. The potential physiological crosstalk and interrelationship between two sovereign endogenous amines, melatonin and homocysteine. Life Sci 2015; 139:97-107. [PMID: 26281918 DOI: 10.1016/j.lfs.2015.07.031] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 07/07/2015] [Accepted: 07/31/2015] [Indexed: 12/13/2022]
Abstract
The antioxidant melatonin and the non-proteinogenic excitotoxic amino acid homocysteine (Hcy) are very distinct but related reciprocally to each other in their mode of action. The elevated Hcy level has been implicated in several disease pathologies ranging from cardio- and cerebro-vascular diseases to neurodegeneration owing largely to its free radical generating potency. Interestingly, melatonin administration potentially normalizes the elevated Hcy level, thereby protecting the cells from the undesired Hcy-induced excitotoxicity and cell death. However, the exact mechanism and between them remain obscure. Through literature survey we have found an indistinct but a vital link between melatonin and Hcy i.e., the existence of reciprocal regulation between them, and this aspect has been thoroughly described herein. In this review, we focus on all the possibilities of co-regulation of melatonin and Hcy at the level of their production and metabolism both in basal and in pathological conditions, and appraised the potential of melatonin in ameliorating homocysteinemia-induced cellular stresses. Also, we have summarized the differential mode of action of melatonin and Hcy on health and disease states.
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Affiliation(s)
- Rajib Paul
- Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India
| | - Anupom Borah
- Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India.
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50
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Mukherjee D, Ghosh AK, Dutta M, Mitra E, Mallick S, Saha B, Reiter RJ, Bandyopadhyay D. Mechanisms of isoproterenol-induced cardiac mitochondrial damage: protective actions of melatonin. J Pineal Res 2015; 58:275-90. [PMID: 25652673 DOI: 10.1111/jpi.12213] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2014] [Accepted: 01/30/2015] [Indexed: 12/20/2022]
Abstract
Mitochondrial dysfunction due to oxidative damage is the key feature of several diseases. We have earlier reported mitochondrial damage resulting from the generation of oxidative stress as a major pathophysiological effect of isoproterenol (ISO)-induced myocardial ischemia in rats. That melatonin is an antioxidant that ameliorates oxidative stress in experimental animals as well as in humans is well established. We previously demonstrated that melatonin provides cardioprotection against ISO-induced myocardial injury as a result of its antioxidant properties. The mechanism of ISO-induced cardiac mitochondrial damage and protection by melatonin, however, remains to be elucidated in vitro. In this study, we provide evidence that ISO causes dysfunction of isolated goat heart mitochondria. Incubation of cardiac mitochondria with increasing concentrations of ISO decreased mitochondrial succinate dehydrogenase (SDH) activity, which plays a pivotal role in mitochondrial bioenergetics, as well as altered the activities of other key enzymes of the Kreb's cycle and the respiratory chain. Co-incubation of ISO-challenged mitochondria with melatonin prevented the alterations in enzyme activity. That these changes in mitochondrial energy metabolism were due to the perpetration of oxidative stress by ISO was evident from the increased levels of lipid peroxidation and decreased reduced glutathione/oxidized glutathione ratio. ISO-induced oxidative stress also altered mitochondrial redox potential and brought about changes in the activity of the antioxidant enzymes manganese superoxide dismutase and glutathione peroxidase, eventually leading to alterations in total ATPase activity and membrane potential. Melatonin ameliorated these changes likely through its antioxidant abilities suggesting a possible mechanism of cardioprotection by this indole against ISO-induced myocardial injury.
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Affiliation(s)
- Debasri Mukherjee
- Oxidative stress and Free Radical Biology Laboratory, Department of Physiology, University College of Science and Technology, University of Calcutta, Kolkata, India; National Centre for Cell Science, Ganeshkhind, Pune, India
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