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Jawad M, Uthirapathy S, Altalbawy FMA, Oghenemaro EF, Rizaev J, Lal M, Eldesoqui M, Sharma N, Pramanik A, Al-Hamairy AK. Examining the role of antioxidant supplementation in mitigating oxidative stress markers in Alzheimer's disease: a comprehensive review. Inflammopharmacology 2025; 33:573-592. [PMID: 39699843 DOI: 10.1007/s10787-024-01622-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 11/30/2024] [Indexed: 12/20/2024]
Abstract
Alzheimer's disease is a devastating neurodegenerative disorder that affects millions of people worldwide. One of the key pathological features of Alzheimer's disease is oxidative stress, which is characterized by an imbalance between the production of reactive oxygen species and the body's ability to neutralize them with antioxidants. In recent years, there has been growing interest in the potential role of antioxidant supplementation in mitigating oxidative stress markers in Alzheimer's disease. This review paper aims to provide a comprehensive overview of the current research on antioxidant supplementation in Alzheimer's disease and its effects on oxidative stress markers. The paper will examine the underlying mechanisms of oxidative stress in Alzheimer's disease, the potential benefits of antioxidant supplementation, and the challenges and limitations of using antioxidants as a therapeutic strategy.
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Affiliation(s)
- Mahmood Jawad
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
| | - Subasini Uthirapathy
- Pharmacology Department, Tishk International University, Erbil, Kurdistan Region, Iraq.
| | - Farag M A Altalbawy
- Department of Chemistry, University College of Duba, University of Tabuk, Tabuk, Saudi Arabia
| | - Enwa Felix Oghenemaro
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Delta State University, PMB 1, Abraka, Delta State, Nigeria
| | - Jasur Rizaev
- Department of Public Health and Healthcare Management, Rector, Samarkand State Medical University, 18, Amir Temur Street, Samarkand, Uzbekistan
| | - Madan Lal
- Department of Medicine, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, India
| | - Mamdouh Eldesoqui
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Diriyah, 13713, Riyadh, Saudi Arabia.
| | - Naveen Sharma
- Chandigarh Pharmacy College, Chandigarh Group of Colleges-Jhanjeri, Mohali, Punjab, 140307, India
| | - Atreyi Pramanik
- School of Applied and Life Sciences, Division of Research and Innovation, Uttaranchal University, Dehradun, India
| | - Ahmed Khudhair Al-Hamairy
- Anesthesia Techniques Department, College of Health and Medical Techniques, Al-Mustaqbal University, Babylon, Iraq
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Lupu VV, Miron I, Trandafir LM, Jechel E, Starcea IM, Ioniuc I, Frasinariu OE, Mocanu A, Petrariu FD, Danielescu C, Nedelcu AH, Salaru DL, Revenco N, Lupu A. Challenging directions in pediatric diabetes - the place of oxidative stress and antioxidants in systemic decline. Front Pharmacol 2024; 15:1472670. [PMID: 39744134 PMCID: PMC11688324 DOI: 10.3389/fphar.2024.1472670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 12/04/2024] [Indexed: 01/06/2025] Open
Abstract
Diabetes is a complex condition with a rising global incidence, and its impact is equally evident in pediatric practice. Regardless of whether we are dealing with type 1 or type 2 diabetes, the development of complications following the onset of the disease is inevitable. Consequently, contemporary medicine must concentrate on understanding the pathophysiological mechanisms driving systemic decline and on finding ways to address them. We are particularly interested in the effects of oxidative stress on target cells and organs, such as pancreatic islets, the retina, kidneys, and the neurological or cardiovascular systems. Our goal is to explore, using the latest data from international scientific databases, the relationship between oxidative stress and the development or persistence of systemic damage associated with diabetes in children. Additionally, we highlight the beneficial roles of antioxidants such as vitamins, minerals, polyphenols, and other bioactive molecules; in mitigating the pathogenic cascade, detailing how they intervene and their bioactive properties. As a result, our study provides a comprehensive exploration of the key aspects of the oxidative stress-antioxidants-pediatric diabetes triad, expanding understanding of their significance in various systemic diseases.
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Affiliation(s)
- Vasile Valeriu Lupu
- Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
| | - Ingrith Miron
- Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
| | | | - Elena Jechel
- Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
| | | | - Ileana Ioniuc
- Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
| | | | - Adriana Mocanu
- Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
| | | | - Ciprian Danielescu
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
| | - Alin Horatiu Nedelcu
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
| | - Delia Lidia Salaru
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
| | - Ninel Revenco
- Pediatrics, “Nicolae Testemitanu” State University of Medicine and Pharmacy, Chisinau, Moldova
| | - Ancuta Lupu
- Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
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Olufunmilayo EO, Gerke-Duncan MB, Holsinger RMD. Oxidative Stress and Antioxidants in Neurodegenerative Disorders. Antioxidants (Basel) 2023; 12:antiox12020517. [PMID: 36830075 PMCID: PMC9952099 DOI: 10.3390/antiox12020517] [Citation(s) in RCA: 210] [Impact Index Per Article: 105.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/14/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Neurodegenerative disorders constitute a substantial proportion of neurological diseases with significant public health importance. The pathophysiology of neurodegenerative diseases is characterized by a complex interplay of various general and disease-specific factors that lead to the end point of neuronal degeneration and loss, and the eventual clinical manifestations. Oxidative stress is the result of an imbalance between pro-oxidant species and antioxidant systems, characterized by an elevation in the levels of reactive oxygen and reactive nitrogen species, and a reduction in the levels of endogenous antioxidants. Recent studies have increasingly highlighted oxidative stress and associated mitochondrial dysfunction to be important players in the pathophysiologic processes involved in neurodegenerative conditions. In this article, we review the current knowledge of the general effects of oxidative stress on the central nervous system, the different specific routes by which oxidative stress influences the pathophysiologic processes involved in Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis and Huntington's disease, and how oxidative stress may be therapeutically reversed/mitigated in order to stall the pathological progression of these neurodegenerative disorders to bring about clinical benefits.
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Affiliation(s)
- Edward O. Olufunmilayo
- Laboratory of Molecular Neuroscience and Dementia, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia
- Department of Medicine, University College Hospital, Queen Elizabeth Road, Oritamefa, Ibadan 5116, PMB, Nigeria
| | - Michelle B. Gerke-Duncan
- Education Innovation, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
| | - R. M. Damian Holsinger
- Laboratory of Molecular Neuroscience and Dementia, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia
- Neuroscience, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
- Correspondence:
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Hosseini A, Samadi M, Baeeri M, Rahimifard M, Haghi-Aminjan H. The neuroprotective effects of melatonin against diabetic neuropathy: A systematic review of non-clinical studies. Front Pharmacol 2022; 13:984499. [PMID: 36120309 PMCID: PMC9470957 DOI: 10.3389/fphar.2022.984499] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 08/05/2022] [Indexed: 11/30/2022] Open
Abstract
Backgrounds: Diabetes can cause diabetic neuropathy (DN), a nerve injury. High blood sugar (glucose) levels can harm nerves all over your body. The nerves in your legs and feet are the most commonly affected by DN. The purpose of this study was to conduct a review of melatonin’s potential neuroprotective properties against DN. Method: A full systematic search was conducted in several electronic databases (Scopus, PubMed, and Web of Science) up to March 2022 under the PRISMA guidelines. Forty-seven studies were screened using predefined inclusion and exclusion criteria. Finally, the current systematic review included nine publications that met the inclusion criteria. Result: According to in vivo findings, melatonin treatment reduces DN via inhibition of oxidative stress and inflammatory pathways. However, compared to the diabetes groups alone, melatonin treatment exhibited an anti-oxidant trend. According to other research, DN also significantly produces biochemical alterations in neuron cells/tissues. Additionally, histological alterations in neuron tissue following DN were detected. Conclusion: Nonetheless, in the majority of cases, these diabetes-induced biochemical and histological alterations were reversed when melatonin was administered. It is worth noting that the administration of melatonin ameliorates the neuropathy caused by diabetes. Melatonin exerts these neuroprotective effects via various anti-oxidant, anti-inflammatory, and other mechanisms.
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Affiliation(s)
- Asieh Hosseini
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mahedeh Samadi
- Neuroscience Research Center, Iran University of Medical Science, Tehran, Iran
| | - Maryam Baeeri
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Mahban Rahimifard
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences (TUMS), Tehran, Iran
- *Correspondence: Mahban Rahimifard, ; Hamed Haghi-Aminjan,
| | - Hamed Haghi-Aminjan
- Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
- *Correspondence: Mahban Rahimifard, ; Hamed Haghi-Aminjan,
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Bartolome F, Carro E, Alquezar C. Oxidative Stress in Tauopathies: From Cause to Therapy. Antioxidants (Basel) 2022; 11:antiox11081421. [PMID: 35892623 PMCID: PMC9332496 DOI: 10.3390/antiox11081421] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 07/20/2022] [Indexed: 02/01/2023] Open
Abstract
Oxidative stress (OS) is the result of an imbalance between the production of reactive oxygen species (ROS) and the antioxidant capacity of cells. Due to its high oxygen demand, the human brain is highly susceptible to OS and, thus, it is not a surprise that OS has emerged as an essential component of the pathophysiology of several neurodegenerative diseases, including tauopathies. Tauopathies are a heterogeneous group of age-related neurodegenerative disorders characterized by the deposition of abnormal tau protein in the affected neurons. With the worldwide population aging, the prevalence of tauopathies is increasing, but effective therapies have not yet been developed. Since OS seems to play a key role in tauopathies, it has been proposed that the use of antioxidants might be beneficial for tau-related neurodegenerative diseases. Although antioxidant therapies looked promising in preclinical studies performed in cellular and animal models, the antioxidant clinical trials performed in tauopathy patients have been disappointing. To develop effective antioxidant therapies, the molecular mechanisms underlying OS in tauopathies should be completely understood. Here, we review the link between OS and tauopathies, emphasizing the causes of OS in these diseases and the role of OS in tau pathogenesis. We also summarize the antioxidant therapies proposed as a potential treatment for tauopathies and discuss why they have not been completely translated to clinical trials. This review aims to provide an integrated perspective of the role of OS and antioxidant therapies in tauopathies. In doing so, we hope to enable a more comprehensive understanding of OS in tauopathies that will positively impact future studies.
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Affiliation(s)
- Fernando Bartolome
- Group of Neurodegenerative Diseases, Hospital Universitario 12 de Octubre Research Institute (imas12), 28041 Madrid, Spain;
- Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Spain;
| | - Eva Carro
- Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Spain;
- Neurobiology of Alzheimer’s Disease Unit, Chronic Disease Program, Instituto de Salud Carlos III, 28222 Madrid, Spain
| | - Carolina Alquezar
- Group of Neurodegenerative Diseases, Hospital Universitario 12 de Octubre Research Institute (imas12), 28041 Madrid, Spain;
- Correspondence:
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Antioxidants in Alzheimer's Disease: Current Therapeutic Significance and Future Prospects. BIOLOGY 2022; 11:biology11020212. [PMID: 35205079 PMCID: PMC8869589 DOI: 10.3390/biology11020212] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/17/2022] [Accepted: 01/21/2022] [Indexed: 01/27/2023]
Abstract
Alzheimer's disease (AD) rate is accelerating with the increasing aging of the world's population. The World Health Organization (WHO) stated AD as a global health priority. According to the WHO report, around 82 million people in 2030 and 152 million in 2050 will develop dementia (AD contributes 60% to 70% of cases), considering the current scenario. AD is the most common neurodegenerative disease, intensifying impairments in cognition, behavior, and memory. Histopathological AD variations include extracellular senile plaques' formation, tangling of intracellular neurofibrils, and synaptic and neuronal loss in the brain. Multiple evidence directly indicates that oxidative stress participates in an early phase of AD before cytopathology. Moreover, oxidative stress is induced by almost all misfolded protein lumps like α-synuclein, amyloid-β, and others. Oxidative stress plays a crucial role in activating and causing various cell signaling pathways that result in lesion formations of toxic substances, which foster the development of the disease. Antioxidants are widely preferred to combat oxidative stress, and those derived from natural sources, which are often incorporated into dietary habits, can play an important role in delaying the onset as well as reducing the progression of AD. However, this approach has not been extensively explored yet. Moreover, there has been growing evidence that a combination of antioxidants in conjugation with a nutrient-rich diet might be more effective in tackling AD pathogenesis. Thus, considering the above-stated fact, this comprehensive review aims to elaborate the basics of AD and antioxidants, including the vitality of antioxidants in AD. Moreover, this review may help researchers to develop effectively and potentially improved antioxidant therapeutic strategies for this disease as it also deals with the clinical trials in the stated field.
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Li Y, Xu Z. Effects of Melatonin Supplementation on Insulin Levels and Insulin Resistance: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Horm Metab Res 2021; 53:616-624. [PMID: 34496412 DOI: 10.1055/a-1544-8181] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Insulin resistance (IR) is a pivotal process in various metabolic diseases. The well-known treatment is lifestyle modification and medication therapy, which may result in poor compliance and side effects. Melatonin has been suggested to have a role in glucose metabolism, yet the results across studies have been inconsistent. Therefore, we performed a systematic review to evaluate the effects of melatonin supplementation on insulin levels and IR. We searched PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov, and identified randomized controlled trials (RCTs) published prior to August 2020. Articles were reviewed, selected and extracted by two reviewers independently. In total, 8 RCTs of 376 participants were included. Data were pooled using a random-effects model, with mean differences (MDs) and 95% confidence intervals (CIs). Our results showed that melatonin administration significantly reduced insulin levels and homeostasis model assessment of insulin resistance (HOMA-IR), and increased the quantitative insulin sensitivity check index (QUICKI). We conclude that melatonin ameliorated hyperinsulinemia, insulin resistance, and insulin sensitivity, and the results are an update of a previous meta-analysis. Although more investigations are required, we clearly provide evidence for the use of melatonin as an adjuvant treatment for metabolic disorders involving IR.
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Affiliation(s)
- Yan Li
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Zhenbin Xu
- Department of Orthopaedics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
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Veisi S, Sarkheil M, Johari SA, Safari O. Dietary supplementation with melatonin: influence on growth performance, oxidative stress status, and amelioration of silver nanoparticles-induced toxicity in Nile tilapia (Oreochromis niloticus). Trop Anim Health Prod 2021; 53:314. [PMID: 33970357 DOI: 10.1007/s11250-021-02760-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 05/02/2021] [Indexed: 11/30/2022]
Abstract
Excessive use of silver nanoparticles (AgNPs) due to antibacterial properties can raise concerns about their release into environment and potential toxicity in aquatic organisms. Melatonin has several physiological functions especially antioxidant potential against oxidative stress. The current study was conducted to investigate the potential effects of two doses of dietary melatonin on growth performance, plasma biochemistry, and liver enzyme activity in Nile tilapia (Oreochromis niloticus) juveniles. We also investigated the potential ameliorative effect of melatonin in AgNPs-induced biochemical alterations in tilapia fish. The results showed that melatonin-supplemented diets had no significant effect on growth performance of fish (P>0.05). The liver GPx activity increased in fish fed melatonin-supplemented diets (P<0.05), but the SOD activity showed no significant difference in comparison with the control (P>0.05). The administration of melatonin-supplemented diets reduced the activity of liver MDA compared to the control (P<0.05). Feeding fish with high melatonin-supplemented diet (200 mg kg-1 of diet) decreased the plasma glucose, total protein, and AST levels (P<0.05). The liver GPx and SOD activities were higher in high melatonin-treated fish exposed to AgNPs than the control group (P<0.05). Dietary melatonin decreased the liver MDA activity in AgNPs-exposed fish. The plasma glucose, AST, and ALT levels in melatonin-treated fish exposed to AgNPs decreased compared to the untreated exposed fish (P<0.05). Melatonin-treated fish exposed to 0.05 and 0.5 mg L-1 of AgNPs had lower plasma LDH level than the control group (P<0.05). The results showed that consumption of melatonin-supplemented diets could modulate some of the biochemical indices of plasma and liver in Nile tilapia. The findings also indicated the ameliorative effect of dietary melatonin on AgNPs-induced toxicity in Nile tilapia.
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Affiliation(s)
- Shakila Veisi
- Department of Fisheries, Faculty of Natural Resources, University of Kurdistan, Sanandaj, Kurdistan, Iran
| | - Mehrdad Sarkheil
- Department of Fisheries, Faculty of Natural Resources and Environment, Ferdowsi University of Mashhad, P.B, Mashhad, 91773-1363, Iran.
| | - Seyed Ali Johari
- Department of Fisheries, Faculty of Natural Resources, University of Kurdistan, Sanandaj, Kurdistan, Iran
| | - Omid Safari
- Department of Fisheries, Faculty of Natural Resources and Environment, Ferdowsi University of Mashhad, P.B, Mashhad, 91773-1363, Iran
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Counteracting effects of heavy metals and antioxidants on male fertility. Biometals 2021; 34:439-491. [PMID: 33761043 DOI: 10.1007/s10534-021-00297-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 03/04/2021] [Indexed: 01/06/2023]
Abstract
Infertility is regarded as a global health problem affecting 8-12% of couples. Male factors are regarded as the main cause of infertility in 40% of infertile couples and contribute to this condition in combination with female factors in another 20% of cases. Abnormal sperm parameters such as oligospermia, asthenospermia, and teratozoospermia result in male factor infertility. Several studies have shown the deteriorative impact of heavy metals on sperm parameters and fertility in human subjects or animal models. Other studies have pointed to the role of antioxidants in counteracting the detrimental effects of heavy metals. In the currents study, we summarize the main outcomes of studies that assessed the counteracting impacts of heavy metal and antioxidants on male fertility. Based on the provided data from animal studies, it seems rational to administrate appropriate antioxidants in persons who suffer from abnormal sperm parameters and infertility due to exposure to toxic elements. Yet, further human studies are needed to approve the beneficial effects of these antioxidants.
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Wajid F, Poolacherla R, Mim FK, Bangash A, Rutkofsky IH. Therapeutic potential of melatonin as a chronobiotic and cytoprotective agent in diabetes mellitus. J Diabetes Metab Disord 2020; 19:1797-1825. [PMID: 33520862 PMCID: PMC7843808 DOI: 10.1007/s40200-020-00585-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 07/06/2020] [Indexed: 12/21/2022]
Abstract
PURPOSE Diabetes mellitus is a complex metabolic disorder characterized by hyperglycemia occurring as a result of dysregulation and balance of various metabolic pathways. In recent years, circadian misalignment (due to altered sleep/wake, feeding/fasting cycles), has been intimately linked with the development of diabetes mellitus. Herein, we review our knowledge of oxidative stress, circadian rhythms control of metabolism, and the effects of its disruption on homeostasis while emphasizing the importance of melatonin, a nocturnally peaking, pineal hormone, as a potential therapeutic drug for the prevention and treatment of diabetes. METHODS PubMed database was systematically searched for related articles and data from all types of studies, including clinical trials, review articles, and case reports were considered without limiting the study to one specific category. RESULTS Experimental and epidemiological evidence indicate melatonin's multifaceted effects in intermediary metabolism via resynchronization of the circadian rhythms and its deficiency is associated with metabolic derangements. As a chronobiotic, it cures insomnia and sleep disorders caused by shift work or jet lag. The antagonistic relationship between melatonin and insulin highlights its influence in regulating insulin secretion, its action, and melatonin treatment successfully improved glucose homeostasis, energy balance, and overall health in diabetes mellitus. Melatonin's cytoprotective role as an antioxidant and free radical scavenger, proved useful in combating oxidative stress, preserving beta-cell function, and influencing the development of diabetic complications. CONCLUSION The therapeutic application of melatonin as a chronobiotic and cytoprotective agent is of promising significance in diabetes mellitus. Future investigations are encouraged to fully explore the efficacy of this ubiquitous molecule in various metabolic disorders.
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Affiliation(s)
- Fareha Wajid
- California Institute of Behavioural Neuroscience and Psychology, Fairfield, CA USA
| | - Raju Poolacherla
- California Institute of Behavioural Neuroscience and Psychology, Fairfield, CA USA
| | - Fatiha Kabir Mim
- California Institute of Behavioural Neuroscience and Psychology, Fairfield, CA USA
| | - Amna Bangash
- California Institute of Behavioural Neuroscience and Psychology, Fairfield, CA USA
| | - Ian H. Rutkofsky
- California Institute of Behavioural Neuroscience and Psychology, Fairfield, CA USA
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Saleh DO, Jaleel GAA, Al-Awdan SW, Hassan A, Asaad GF. Melatonin suppresses the brain injury after cerebral ischemia/reperfusion in hyperglycaemic rats. Res Pharm Sci 2020; 15:418-428. [PMID: 33628283 PMCID: PMC7879790 DOI: 10.4103/1735-5362.297844] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 06/10/2020] [Accepted: 10/02/2020] [Indexed: 11/04/2022] Open
Abstract
Background and purpose Diabetes mellitus is a disorder accompanied by oxidative and inflammatory responses, that might exacerbate vascular complications. The purpose of this study was to investigate the potential antioxidant and anti-inflammatory effects of melatonin (MLN) on streptozotocin (STZ)-induced diabetic rats subjected to middle cerebral artery occlusion followed by reperfusion (MCAO/Re). Experimental approach Diabetes was induced in rats by a single injection of STZ (55 mg/kg; i.p.). The cerebral injury was then induced by MCAO/Re after six weeks. After 24 h of MCAO/Re the MLN (10 mg/kg) was administered orally for 14 days. Serum and tissue samples were extracted to determine malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), interleukin-1β (IL-1β), and the tumor necrosis factor- α (TNF-α). Part of the brain tissue was kept in formalin for pathological and immunohistochemical studies to determine nuclear factor kappa B (NF-kB) and cyclooxygenase-2 (COX-2) immune reactivity. Findings/Results MCAO/Re in STZ-induced hyperglycaemic rats caused a decrease in brain GSH, an increase in brain MDA, and NO was increased in both serum and brain tissue. Rats showed a prominent increase in the serum and brain inflammatory markers viz. IL-1β and TNF-α. Oral treatment with MLN (10 mg/kg) for two weeks reduced the brain levels of MDA, NO, IL-1β, and TNF-α. Impressive amelioration in pathological findings, as well as a significant decrease in NF-kB and COX2 immune stained cells of the cerebral cortex, hippocampus, and cerebellum, occurred after treatment with MLN. It also succeeded to suppress the exacerbation of damage in the brain of hyperglycaemic rats. Conclusion and implications Daily intake of MLN attenuates the exacerbation of cerebral ischemic injury in a diabetic state.
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Affiliation(s)
- Dalia O Saleh
- Pharmacology Department, National Research Centre, Dokki, Giza, Egypt
| | | | - Sally W Al-Awdan
- Pharmacology Department, National Research Centre, Dokki, Giza, Egypt
| | - Azza Hassan
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Gihan F Asaad
- Pharmacology Department, National Research Centre, Dokki, Giza, Egypt
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Farrokhian A, Tohidi M, Ahanchi NS, Khalili D, Niroomand M, Mahboubi A, Derakhshi A, Abbasinazari M, Hadaegh F. Effect of Bedtime Melatonin Administration in Patients with Type 2 Diabetes: A Triple-Blind, Placebo-Controlled, Randomized Trial. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2020; 18:258-268. [PMID: 32802105 PMCID: PMC7393042 DOI: 10.22037/ijpr.2019.112011.13485] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
Melatonin is widely available as over the counter product. Despite promising effects of melatonin supplementation on glycemic control, there is a significant heterogeneity between studies. The current study aimed at determining the effect of melatonin on fasting blood glucose (FBG), insulin resistance/sensitivity indices, glycosylated hemoglobin A1c (HbA1c), and high sensitivity C-reactive protein (hs-CRP) among type 2 diabetes mellitus (T2D) population during 8 weeks in a randomized, triple-blind, placebo-controlled trial. Thirty four subjects with the mean age ± standard deviation of 57.74 ± 8.57 years and 36 subjects with the mean age of 57.61 ± 9.11 years were allocated to 6 mg nightly melatonin and placebo groups, respectively. Melatonin and placebo groups were matched by age, gender, body mass index, and duration of diabetes. Also, there was no significant difference in laboratory findings except for HbA1c, which was lower in the placebo group (7.00 ± 0.89% vs 7.60 ± 1.47%, P=0.042). After trial completion, the increase of serum levels of melatonin was greater in the intervention than the placebo group (3.38 ± 1.33 vs 0.94 ± 1.28 ng/L, P=0.192). Moreover, compared to placebo group, among melatonin users, homeostasis model assessment of insulin resistance (HOMA1-IR) tended to be unfavorable at the end of follow-up [-0.51 (-1.76-0.81) vs. 0.28 (-1.24-1.74), P=0.20]; the similar trend was also shown for insulin sensitivity index (HOMA1-S) [2.33 (-3.59-12.46) vs. -2.33 (-10.61-9.16), P=0.148]. No differences were observed in FBG, HbA1C, and hs-CRP changes between the trial groups. The current study did not support the improving effect of melatonin on glucose homeostasis.
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Affiliation(s)
- Amir Farrokhian
- Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Tohidi
- Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Noushin Sadat Ahanchi
- Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Khalili
- Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran .,Department of Biostatistics and Epidemiology, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahtab Niroomand
- Internal Medicine Department, Endocrinology Division, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arash Mahboubi
- Food Safety Research Center, Department of Pharmaceutics, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arash Derakhshi
- Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Abbasinazari
- Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farzad Hadaegh
- Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Afsar B, Elsurer Afsar R, Sag AA, Kanbay A, Korkmaz H, Cipolla-Neto J, Covic A, Ortiz A, Kanbay M. Sweet dreams: therapeutic insights, targeting imaging and physiologic evidence linking sleep, melatonin and diabetic nephropathy. Clin Kidney J 2020; 13:522-530. [PMID: 32905249 PMCID: PMC7467577 DOI: 10.1093/ckj/sfz198] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 12/16/2019] [Indexed: 12/25/2022] Open
Abstract
Melatonin is the main biochronologic molecular mediator of circadian rhythm and sleep. It is also a powerful antioxidant and has roles in other physiologic pathways. Melatonin deficiency is associated with metabolic derangements including glucose and cholesterol dysregulation, hypertension, disordered sleep and even cancer, likely due to altered immunity. Diabetic nephropathy (DN) is a key microvascular complication of both type 1 and 2 diabetes. DN is the end result of a complex combination of metabolic, haemodynamic, oxidative and inflammatory factors. Interestingly, these same factors have been linked to melatonin deficiency. This report will collate in a clinician-oriented fashion the mechanistic link between melatonin deficiency and factors contributing to DN.
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Affiliation(s)
- Baris Afsar
- Division of Nephrology, Department of Medicine, Suleyman Demirel University School of Medicine, Isparta, Turkey
| | - Rengin Elsurer Afsar
- Division of Nephrology, Department of Medicine, Suleyman Demirel University School of Medicine, Isparta, Turkey
| | - Alan A Sag
- Division of Vascular and Interventional Radiology, Department of Radiology, Duke University Medical Center, Durham, NC, USA
| | - Asiye Kanbay
- Department of Pulmonary Medicine, Istanbul Medeniyet University School of Medicine, Istanbul, Turkey
| | - Hakan Korkmaz
- Division of Endocrinology, Department of Medicine, Suleyman Demirel University School of Medicine, Isparta, Turkey
| | - José Cipolla-Neto
- Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Adrian Covic
- Dialysis Unit, School of Medicine, IIS-Fundacion Jimenez Diaz, Universidad Autónoma de Madrid, Madrid, Spain
| | - Alberto Ortiz
- Nephrology Clinic, Dialysis and Renal Transplant Center, ‘C.I. PARHON’ University Hospital and ‘Grigore T. Popa’ University of Medicine, Iasi, Romania
| | - Mehmet Kanbay
- Division of Nephrology, Department of Medicine, Koç University School of Medicine, Istanbul, Turkey
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Melatonin regulates the expression of inflammatory cytokines, VEGF and apoptosis in diabetic retinopathy in rats. Chem Biol Interact 2020; 327:109183. [PMID: 32554039 DOI: 10.1016/j.cbi.2020.109183] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 05/23/2020] [Accepted: 06/15/2020] [Indexed: 02/06/2023]
Abstract
The present study analyzed whether melatonin could mediate the expression of VEGF, IL-6 and TNF-α, as well as the apoptotic index in rats with diabetic retinopathy. Fifty Wistar albino rats were divided into the following groups: GC: rats without induction of diabetes by streptozotocin; GD: rats induced to diabetes by streptozotocin and treated with placebo; GDM: rats induced to diabetes by streptozotocin and after confirmation treated with melatonin at a dose of 10 mg/kg for 20 days; GDMS: rats induced to diabetes by streptozotocin and treated simultaneously with melatonin at a dosage of 10 mg/kg for 20 days; GDI: rats induced to diabetes by streptozotocin and after confirmation treated with insulin for 20 days. Diabetes was induced by intraperitoneal injections of streptozotocin (60 mg/kg), and insulin (5 U/day) was administered subcutaneously. For apoptosis TUNEL was used, while for the analysis of VEGF, IL-6 and TNF-α. The results showed that the groups that were treated with melatonin decreased the expression of cytokines and VEGF, in addition to apoptosis. Thus, it is concluded that melatonin can regulate the expression of these factors by improving the condition of the retina in diabetic retinopathy.
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Espino J, Rodríguez AB, Pariente JA. Melatonin and Oxidative Stress in the Diabetic State: Clinical Implications and Potential Therapeutic Applications. Curr Med Chem 2019; 26:4178-4190. [PMID: 29637854 DOI: 10.2174/0929867325666180410094149] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 12/07/2017] [Accepted: 12/07/2017] [Indexed: 02/07/2023]
Abstract
All living organisms exhibit circadian rhythms, which govern the majority of biological functions, including metabolic processes. Misalignment of these circadian rhythms increases the risk of developing metabolic diseases. Thus, disruption of the circadian system has been proven to affect the onset of type 2 diabetes mellitus (T2DM). In this context, the pineal indoleamine melatonin is a signaling molecule able to entrain circadian rhythms. There is mounting evidence that suggests a link between disturbances in melatonin production and impaired insulin, glucose, lipid metabolism, and antioxidant capacity. Besides, several genetic association studies have causally associated various single nucleotide polymorphysms (SNPs) of the human MT2 receptor with increased risk of developing T2DM. Taken together, these data suggest that endogenous as well as exogenous melatonin may influence diabetes and associated metabolic disturbances not only by regulating insulin secretion but also by providing protection against reactive oxygen species (ROS) since pancreatic β-cells are very susceptible to oxidative stress due to their low antioxidant capacity.
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Affiliation(s)
- Javier Espino
- Department of Physiology (Neuroimmunophysiology and Chrononutrition Research Group), Faculty of Science, University of Extremadura, Badajoz, Spain
| | - Ana B Rodríguez
- Department of Physiology (Neuroimmunophysiology and Chrononutrition Research Group), Faculty of Science, University of Extremadura, Badajoz, Spain
| | - José A Pariente
- Department of Physiology (Neuroimmunophysiology and Chrononutrition Research Group), Faculty of Science, University of Extremadura, Badajoz, Spain
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Strohmaier S, Devore EE, Zhang Y, Schernhammer ES. A Review of Data of Findings on Night Shift Work and the Development of DM and CVD Events: a Synthesis of the Proposed Molecular Mechanisms. Curr Diab Rep 2018; 18:132. [PMID: 30343445 PMCID: PMC6209035 DOI: 10.1007/s11892-018-1102-5] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
PURPOSE OF REVIEW Night shift work has become highly prevalent in our 24/7 societies, with up to 18% of the US work force working alternate shift schedules. However, studies indicate that there may be adverse health effects of chronic night work across diverse populations. These effects are likely due to misalignment of the circadian system with work schedules, mediated by the system's primary marker melatonin as well as other downstream molecules. RECENT FINDINGS Melatonin has multiple biologic actions that are relevant to cardiometabolic disease, including modulation of oxidative stress, inflammation, and (via the melatonin receptor) vasoconstriction. Behavioral traits, such as chronotype and meal timing, have recently been shown to interact with the effects of night work on cardiometabolic health. Together with recent findings suggesting a role for circadian genes in cardiometabolic risk, the interactions of night shift work and behavioral traits are likely to facilitate novel treatment and prevention approaches for cardiovascular disease and type 2 diabetes, incorporating aspects of clock and timing.
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Affiliation(s)
- S. Strohmaier
- 0000 0000 9259 8492grid.22937.3dDepartment of Epidemiology, Center for Public Health, Medical University of Vienna, Kinderspitalgasse 15, 1090 Vienna, Austria
- 000000041936754Xgrid.38142.3cChanning Division of Network Medicine, Harvard Medical School, Boston, MA USA
| | - E. E. Devore
- 000000041936754Xgrid.38142.3cChanning Division of Network Medicine, Harvard Medical School, Boston, MA USA
| | - Y. Zhang
- 000000041936754Xgrid.38142.3cChanning Division of Network Medicine, Harvard Medical School, Boston, MA USA
| | - E. S. Schernhammer
- 0000 0000 9259 8492grid.22937.3dDepartment of Epidemiology, Center for Public Health, Medical University of Vienna, Kinderspitalgasse 15, 1090 Vienna, Austria
- 000000041936754Xgrid.38142.3cChanning Division of Network Medicine, Harvard Medical School, Boston, MA USA
- 000000041936754Xgrid.38142.3cDepartment of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA USA
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Onaolapo AY, Onaolapo OJ. Circadian dysrhythmia-linked diabetes mellitus: Examining melatonin’s roles in prophylaxis and management. World J Diabetes 2018; 9:99-114. [PMID: 30079146 PMCID: PMC6068738 DOI: 10.4239/wjd.v9.i7.99] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Revised: 06/01/2018] [Accepted: 06/08/2018] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus is a chronic, life-threatening metabolic disorder that occurs worldwide. Despite an increase in the knowledge of the risk factors that are associated with diabetes mellitus, its worldwide prevalence has continued to rise; thus, necessitating more research into its aetiology. Recent researches are beginning to link a dysregulation of the circadian rhythm to impairment of intermediary metabolism; with evidences that circadian rhythm dysfunction might play an important role in the aetiology, course or prognosis of some cases of diabetes mellitus. These evidences thereby suggest possible relationships between the circadian rhythm regulator melatonin, and diabetes mellitus. In this review, we discuss the roles of the circadian rhythm in the regulation of the metabolism of carbohydrates and other macronutrients; with emphasis on the importance of melatonin and the impacts of its deficiency on carbohydrate homeostasis. Also, the possibility of using melatonin and its analogs for the “prophylaxis” or management of diabetes mellitus is also considered.
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Affiliation(s)
- Adejoke Y Onaolapo
- Behavioural Neuroscience/Neurobiology Unit, Department of Anatomy, Ladoke Akintola University of Technology, Ogbomosho 210211, Oyo State, Nigeria
| | - Olakunle J Onaolapo
- Behavioural Neuroscience/Neuropharmacology Unit, Department of Pharmacology, Ladoke Akintola University of Technology, Osogbo 230263, Osun State, Nigeria
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The effect of melatonin on lipid peroxide oxidation, oxidative modification of proteins and mitochondria swelling in the skeletal muscle tissue of rats under alloxan diabetes. UKRAINIAN BIOCHEMICAL JOURNAL 2018. [DOI: 10.15407/ubj90.03.062] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
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Melatonin Supplementation Decreases Aerobic Exercise Training Induced-Lipid Peroxidation and Malondialdehyde in Sedentary Young Women. POL J FOOD NUTR SCI 2017. [DOI: 10.1515/pjfns-2017-0001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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Gubin DG, Nelaeva AA, Uzhakova AE, Hasanova YV, Cornelissen G, Weinert D. Disrupted circadian rhythms of body temperature, heart rate and fasting blood glucose in prediabetes and type 2 diabetes mellitus. Chronobiol Int 2017; 34:1136-1148. [PMID: 28759269 DOI: 10.1080/07420528.2017.1347670] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
We report a progressive disruption of 24-h rhythms in fasting blood glucose (FBG), body temperature (BT) and heart rate (HR) associated with metabolic dysfunction and the development of prediabetes (PD) and type 2 diabetes mellitus (T2DM) in overweight middle-aged (40-69 years old) humans. Increasing BT and HR mean values and declining 24-h BT and HR amplitudes accompany adverse changes in metabolic state. Increased nocturnal BT and a phase delay of the 24-h BT rhythm, deviant 24-h HR profile and a phase advance of the 24-h HR and FBG rhythms are early signs of the PD metabolic state. In T2DM, the 24-h FBG rhythm is no longer detectable, and the 24-h amplitudes of BT and HR are greatly diminished. In addition, lepton and creatinine values were lowered in T2DM. Moreover, positive correlations between FBG and body mass index, BMI, and negative correlations between the 24-h amplitude of FBG and BMI indicate that overweight is an additional factor causing disruption of the circadian rhythms. Further studies on circadian disruption as a consequence of metabolic dysfunction are necessary. The quantitative analysis of changing circadian BT and HR rhythms may provide prognostic markers of T2DM and therapeutic targets for its prevention and correction.
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Affiliation(s)
- D G Gubin
- a Department of Biology , Medical University , Tyumen , Russia
| | - A A Nelaeva
- b Department of Endocrinology , Medical University , Tyumen , Russia
| | - A E Uzhakova
- b Department of Endocrinology , Medical University , Tyumen , Russia
| | - Y V Hasanova
- b Department of Endocrinology , Medical University , Tyumen , Russia
| | - G Cornelissen
- c Halberg Chronobiology Center , University of Minnesota , Minneapolis , MN , USA
| | - D Weinert
- d Institute of Biology/Zoology , Martin Luther University , Halle-Wittenberg , Germany
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Elbe H, Esrefoglu M, Vardi N, Taslidere E, Ozerol E, Tanbek K. Melatonin, quercetin and resveratrol attenuates oxidative hepatocellular injury in streptozotocin-induced diabetic rats. Hum Exp Toxicol 2016; 34:859-68. [PMID: 26286521 DOI: 10.1177/0960327114559993] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
In this study, effects of melatonin, quercetin and resveratrol on hepatocellular injury in streptozotocin (STZ)-induced experimental diabetes were aimed to be investigated by histological and biochemical methods. Thirty-five male Wistar albino rats were divided into five groups, namely, control, diabetes (STZ 45 mg/kg/single dose/intraperitoneally (ip)), diabetes + melatonin (10 mg/kg/30 days/ip), diabetes + quercetin (25 mg/kg/30 days/ip) and diabetes + resveratrol (10 mg/kg/30 days/ip). Initial and final blood glucose levels and body weights (BWs) were measured. At the end of the experimentation, following routine tissue processing procedure, sections were stained with haematoxylin-eosin (H-E), periodic acid Schiff and Masson's trichrome. Tissue malondialdehyde (MDA) and glutathione (GSH) levels and superoxide dismutase (SOD) and catalase (CAT) activities were examined. The diabetic rats had significantly higher blood glucose levels than those of control rats (p = 0.0001). Mean BWs of diabetic rats were significantly decreased when compared with the control rats (p = 0.0013). Histopathological alterations including cellular glycogen depletion, congestion, sinusoidal dilatation, inflammation and fibrosis were detected in diabetes group. On the other hand, histopathological changes markedly reduced in all of the treatment groups (p = 0.001). Mean tissue MDA level was increased but mean tissue CAT and SOD activities and GSH levels were decreased in the diabetes group. Melatonin, quercetin and resveratrol administered diabetic rats showed an increase in CAT activities and GSH levels and a decrease in MDA levels (p < 0.05, for all). Melatonin, quercetin and resveratrol administrations markedly reduced hepatocellular injury in STZ-induced experimental diabetes.
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Affiliation(s)
- H Elbe
- Department of Histology and Embryology, Faculty of Medicine, MUGLA SITKI KOÇMAN UNIVERSITY, MUGLA, TURKEY
| | - M Esrefoglu
- Department of Histology and Embryology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| | - N Vardi
- Department of Histology and Embryology, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - E Taslidere
- Department of Histology and Embryology, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - E Ozerol
- Department of Biochemistry, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - K Tanbek
- Department of Biochemistry, Faculty of Medicine, Inonu University, Malatya, Turkey
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Abstract
Sleep and energy balance are essential for health. The two processes act in concert to regulate central and peripheral homeostasis. During sleep, energy is conserved due to suspended activity, movement, and sensory responses, and is redirected to restore and replenish proteins and their assemblies into cellular structures. During wakefulness, various energy-demanding activities lead to hunger. Thus, hunger promotes arousal, and subsequent feeding, followed by satiety that promotes sleep via changes in neuroendocrine or neuropeptide signals. These signals overlap with circuits of sleep-wakefulness, feeding, and energy expenditure. Here, we will briefly review the literature that describes the interplay between the circadian system, sleep-wake, and feeding-fasting cycles that are needed to maintain energy balance and a healthy metabolic profile. In doing so, we describe the neuroendocrine, hormonal/peptide signals that integrate sleep and feeding behavior with energy metabolism.
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Affiliation(s)
- Charu Shukla
- Department of Psychiatry, VA Boston Healthcare System, Harvard Medical School, West Roxbury, MA, USA
| | - Radhika Basheer
- Department of Psychiatry, VA Boston Healthcare System, Harvard Medical School, West Roxbury, MA, USA
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Peschke E, Bähr I, Mühlbauer E. Experimental and clinical aspects of melatonin and clock genes in diabetes. J Pineal Res 2015; 59:1-23. [PMID: 25904189 DOI: 10.1111/jpi.12240] [Citation(s) in RCA: 81] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 04/20/2015] [Indexed: 12/15/2022]
Abstract
The pineal hormone melatonin influences insulin secretion, as well as glucagon and somatostatin secretion, both in vivo and in vitro. These effects are mediated by two specific, high-affinity, seven transmembrane, pertussis toxin-sensitive, Gi-protein-coupled melatonin receptors, MT1 and MT2. Both isoforms are expressed in the β-cells, α-cells as well as δ-cells of the pancreatic islets of Langerhans and are involved in the modulation of insulin secretion, leading to inhibition of the adenylate cyclase-dependent cyclic adenosine monophosphate as well as cyclic guanosine monophosphate formation in pancreatic β-cells by inhibiting the soluble guanylate cyclase, probably via MT2 receptors. In this way, melatonin also likely inhibits insulin secretion, whereas using the inositol triphosphate pathway after previous blocking of Gi-proteins by pertussis toxin, melatonin increases insulin secretion. Desynchrony of receptor signaling may lead to the development of type 2 diabetes. This notion has recently been supported by genomewide association studies pinpointing variances of the MT2 receptor as a risk factor for this rapidly spreading metabolic disturbance. As melatonin is secreted in a clearly diurnal fashion, it is safe to assume that it also has a diurnal impact on the blood-glucose-regulating function of the islet. Observations of the circadian expression of clock genes (Clock, Bmal1, Per1,2,3, and Cry1,2) in pancreatic islets, as well as in INS1 rat insulinoma cells, may indicate that circadian rhythms are generated in the β-cells themselves. The circadian secretion of insulin from pancreatic islets is clock-driven. Disruption of circadian rhythms and clock function leads to metabolic disturbances, for example, type 2 diabetes. The study of melatonin-insulin interactions in diabetic rat models has revealed an inverse relationship between these two hormones. Both type 2 diabetic rats and patients exhibit decreased melatonin levels and slightly increased insulin levels, whereas type 1 diabetic rats show extremely reduced levels or the absence of insulin, but statistically significant increases in melatonin levels. Briefly, an increase in melatonin levels leads to a decrease in stimulated insulin secretion and vice versa. Melatonin levels in blood plasma, as well as the activity of the key enzyme of melatonin synthesis, AA-NAT (arylalkylamine-N-acetyltransferase) in pineal, are lower in type 2 diabetic rats compared to controls. In contrast, melatonin and pineal AA-NAT mRNA are increased and insulin receptor mRNA is decreased in type 1 diabetic rats, which also indicates a close relationship between insulin and melatonin. As an explanation, it was hypothesized that catecholamines, which reduce insulin levels and stimulate melatonin synthesis, control insulin-melatonin interactions. This conviction stems from the observation that catecholamines are increased in type 1 but are diminished in type 2 diabetes. In this context, another important line of inquiry involves the fact that melatonin protects β-cells against functional overcharge and, consequently, hinders the development of type 2 diabetes.
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Affiliation(s)
| | - Ina Bähr
- Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle, Germany
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Hardeland R, Cardinali DP, Brown GM, Pandi-Perumal SR. Melatonin and brain inflammaging. Prog Neurobiol 2015; 127-128:46-63. [DOI: 10.1016/j.pneurobio.2015.02.001] [Citation(s) in RCA: 132] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2014] [Revised: 10/27/2014] [Accepted: 02/05/2015] [Indexed: 02/07/2023]
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Ramos-Lobo AM, Buonfiglio DC, Cipolla-Neto J. Streptozotocin-induced diabetes disrupts the body temperature daily rhythm in rats. Diabetol Metab Syndr 2015; 7:39. [PMID: 25960780 PMCID: PMC4424512 DOI: 10.1186/s13098-015-0035-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 04/16/2015] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND In mammals, the temperature rhythm is regulated by the circadian pacemaker located in the suprachiasmatic nuclei, and is considered a "marker rhythm". Melatonin, the pineal gland hormone, is a major regulator of the endogenous rhythms including body temperature. Its production is influenced by many factors, such as type 1 diabetes mellitus. In rats, diabetes leads to hypothermia and reduced melatonin synthesis; insulin treatment reestablishes both. AIM To study the body temperature daily rhythm of diabetic animals and the effects of insulin and/or melatonin treatment on its structure. METHODS We studied the effects of streptozotocin-induced diabetes (60 mg/kg) on the body temperature rhythm of Wistar rats and the possible modifications resulting from early and late treatments with insulin (6U/day) and/or melatonin (daily 0.5 mg/kg). We monitored the daily body temperature rhythm, its rhythmic parameters (MESOR, amplitude and acrophase), glycemia and body weight for 55 days. Data were classified by groups and expressed as mean ± SEM. One-way ANOVA analysis was performed followed by Bonferroni posttest. Statistical significance was set at p < 0.05. RESULTS Diabetes led to complete disruption of the temperature rhythm and hypothermia, which were accentuated over time. All early treatments (insulin or/and melatonin) prevented the temperature rhythm disruption and hypothermia. Insulin plus melatonin restored the body temperature rhythm whereas insulin alone resulted less efficient; melatonin alone did not restore any of the parameters studied; however, when supplemented close to diabetes onset, it maintained the temperature rhythmicity. All these corrective effects of the early treatments were dependent on the continuous maintenance of the treatment. CONCLUSIONS Taken together, our findings show the disruption of the body temperature daily rhythm, a new consequence of insulin-dependent diabetes, as well as the beneficial effect of the complementary action of melatonin and insulin restoring the normal rhythmicity.
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Affiliation(s)
- Angela M Ramos-Lobo
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Av. Lineu Prestes, 1524, São Paulo, SP 05508-000 Brazil
| | - Daniella C Buonfiglio
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Av. Lineu Prestes, 1524, São Paulo, SP 05508-000 Brazil
| | - José Cipolla-Neto
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Av. Lineu Prestes, 1524, São Paulo, SP 05508-000 Brazil
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Laudon M, Frydman-Marom A. Therapeutic effects of melatonin receptor agonists on sleep and comorbid disorders. Int J Mol Sci 2014; 15:15924-50. [PMID: 25207602 PMCID: PMC4200764 DOI: 10.3390/ijms150915924] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2014] [Revised: 08/20/2014] [Accepted: 08/27/2014] [Indexed: 12/12/2022] Open
Abstract
Several melatonin receptors agonists (ramelteon, prolonged-release melatonin, agomelatine and tasimelteon) have recently become available for the treatment of insomnia, depression and circadian rhythms sleep-wake disorders. The efficacy and safety profiles of these compounds in the treatment of the indicated disorders are reviewed. Accumulating evidence indicates that sleep-wake disorders and co-existing medical conditions are mutually exacerbating. This understanding has now been incorporated into the new Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). Therefore, when evaluating the risk/benefit ratio of sleep drugs, it is pertinent to also evaluate their effects on wake and comorbid condition. Beneficial effects of melatonin receptor agonists on comorbid neurological, psychiatric, cardiovascular and metabolic symptomatology beyond sleep regulation are also described. The review underlines the beneficial value of enhancing physiological sleep in comorbid conditions.
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Affiliation(s)
- Moshe Laudon
- Neurim Pharmaceuticals Ltd., 27 Habarzel St. Tel-Aviv 6971039, Israel.
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27
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Elbe H, Vardi N, Esrefoglu M, Ates B, Yologlu S, Taskapan C. Amelioration of streptozotocin-induced diabetic nephropathy by melatonin, quercetin, and resveratrol in rats. Hum Exp Toxicol 2014; 34:100-13. [DOI: 10.1177/0960327114531995] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The role of oxygen radicals are known for the pathogenesis of kidney damage. The aim of the present study was to investigate the antioxidative effects of melatonin, quercetin, and resveratrol on streptozotocin (STZ)-induced diabetic nephropathy in rats. A total of 35 male Wistar rats were divided into 5 groups as follows: control, diabetes mellitus (DM), DM + melatonin, DM + quercetin, and DM + resveratrol. All the injections started on the same day of single-dose STZ injection and continued for 30 days. At the end of this period, kidneys were removed and processed for routine histological procedures. Biochemical parameters and morphological changes were examined. In DM group, blood glucose levels were significantly increased, whereas body weights were decreased compared with the control group. Significant increases in blood urea nitrogen and tissue malondialdehyde (MDA) levels and decreases in superoxide dismutase and catalase activities were detected in DM group. Administration of melatonin, quercetin, and resveratrol significantly reduced these values. Melatonin was more efficient in reducing MDA levels than other antioxidants ( p < 0.05). STZ-induced histopathological alterations including epithelial desquamation, swelling, intracytoplasmic vacuolization, brush border loss and peritubular infiltration. Additionally, basement membrane thickening and sclerotic changes were observed in glomerulus. Transforming growth factor-β1 positive cells were also increased. Melatonin, quercetin, and resveratrol significantly reduced these histopathological changes. Our results indicate that melatonin, quercetin, and resveratrol might be helpful in reducing diabetes-induced renal damage
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Affiliation(s)
- H Elbe
- Department of Histology and Embryology, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - N Vardi
- Department of Histology and Embryology, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - M Esrefoglu
- Department of Histology and Embryology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| | - B Ates
- Department of Chemistry, Faculty of Science and Art, Inonu University, Malatya, Turkey
| | - S Yologlu
- Department of Biostatistics, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - C Taskapan
- Department of Biochemistry, Faculty of Medicine, Inonu University, Malatya, Turkey
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Weeda S, Zhang N, Zhao X, Ndip G, Guo Y, Buck GA, Fu C, Ren S. Arabidopsis transcriptome analysis reveals key roles of melatonin in plant defense systems. PLoS One 2014; 9:e93462. [PMID: 24682084 PMCID: PMC3969325 DOI: 10.1371/journal.pone.0093462] [Citation(s) in RCA: 191] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Accepted: 03/06/2014] [Indexed: 02/03/2023] Open
Abstract
Melatonin is a ubiquitous molecule and exists across kingdoms including plant species. Studies on melatonin in plants have mainly focused on its physiological influence on growth and development, and on its biosynthesis. Much less attention has been drawn to its affect on genome-wide gene expression. To comprehensively investigate the role(s) of melatonin at the genomics level, we utilized mRNA-seq technology to analyze Arabidopsis plants subjected to a 16-hour 100 pM (low) and 1 mM (high) melatonin treatment. The expression profiles were analyzed to identify differentially expressed genes. 100 pM melatonin treatment significantly affected the expression of only 81 genes with 51 down-regulated and 30 up-regulated. However, 1 mM melatonin significantly altered 1308 genes with 566 up-regulated and 742 down-regulated. Not all genes altered by low melatonin were affected by high melatonin, indicating different roles of melatonin in regulation of plant growth and development under low and high concentrations. Furthermore, a large number of genes altered by melatonin were involved in plant stress defense. Transcript levels for many stress receptors, kinases, and stress-associated calcium signals were up-regulated. The majority of transcription factors identified were also involved in plant stress defense. Additionally, most identified genes in ABA, ET, SA and JA pathways were up-regulated, while genes pertaining to auxin responses and signaling, peroxidases, and those associated with cell wall synthesis and modifications were mostly down-regulated. Our results indicate critical roles of melatonin in plant defense against various environmental stresses, and provide a framework for functional analysis of genes in melatonin-mediated signaling pathways.
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Affiliation(s)
- Sarah Weeda
- Agriculture Research Station, Virginia State University, Petersburg, Virginia, United States of America
| | - Na Zhang
- College of Agriculture and Biotechnology, China Agricultural University, Beijing, P. R. China
| | - Xiaolei Zhao
- Tianjin Crop Science Institute, Tianjin Academy of Agricultural Science, Tianjin, P. R. China
| | - Grace Ndip
- Department of Chemistry, Virginia State University, Petersburg, Virginia, United States of America
| | - Yangdong Guo
- College of Agriculture and Biotechnology, China Agricultural University, Beijing, P. R. China
| | - Gregory A. Buck
- Center of the Study of Biological Complexity, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Conggui Fu
- Tianjin Crop Science Institute, Tianjin Academy of Agricultural Science, Tianjin, P. R. China
| | - Shuxin Ren
- Agriculture Research Station, Virginia State University, Petersburg, Virginia, United States of America
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Hepatoprotective effects of melatonin against pronecrotic cellular events in streptozotocin-induced diabetic rats. J Physiol Biochem 2014; 70:441-50. [PMID: 24604251 DOI: 10.1007/s13105-014-0322-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Accepted: 02/04/2014] [Indexed: 12/18/2022]
Abstract
Oxidative stress-mediated damage to liver tissue underlies the pathological alterations in liver morphology and function that are observed in diabetes. We examined the effects of the antioxidant action of melatonin against necrosis-inducing DNA damage in hepatocytes of streptozotocin (STZ)-induced diabetic rats. Daily administration of melatonin (0.2 mg/kg) was initiated 3 days before diabetes induction and maintained for 4 weeks. Melatonin-treated diabetic rats exhibited improved markers of liver injury (P < 0.05), alkaline phosphatase, and alanine and aspartate aminotransferases. Melatonin prevented the diabetes-related morphological deterioration of hepatocytes, DNA damage (P < 0.05), and hepatocellular necrosis. The improvement was due to containment of the pronecrotic oxygen radical load, observed as inhibition (P < 0.05) of the diabetes-induced rise in lipid peroxidation and hydrogen peroxide increase in the liver. This was accompanied by improved necrotic markers of cellular damage: a significant reduction in cleavage of the DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP-1) into necrotic 55- and 62-kDa fragments, and inhibition of nucleus-to-cytoplasm translocation and accumulation in the serum of the high-mobility group box 1 (HMGB1) protein. We conclude that melatonin is hepatoprotective in diabetes. It reduces extensive DNA damage and resulting necrotic processes. Melatonin application could thus present a viable therapeutic option in the management of diabetes-induced liver injury.
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Zanuto R, Siqueira-Filho MA, Caperuto LC, Bacurau RFP, Hirata E, Peliciari-Garcia RA, do Amaral FG, Marçal AC, Ribeiro LM, Camporez JPG, Carpinelli AR, Bordin S, Cipolla-Neto J, Carvalho CRO. Melatonin improves insulin sensitivity independently of weight loss in old obese rats. J Pineal Res 2013; 55:156-65. [PMID: 23565768 DOI: 10.1111/jpi.12056] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Accepted: 03/22/2013] [Indexed: 12/29/2022]
Abstract
In aged rats, insulin signaling pathway (ISP) is impaired in tissues that play a pivotal role in glucose homeostasis, such as liver, skeletal muscle, and adipose tissue. Moreover, the aging process is also associated with obesity and reduction in melatonin synthesis from the pineal gland and other organs. The aim of the present work was to evaluate, in male old obese Wistar rats, the effect of melatonin supplementation in the ISP, analyzing the total protein amount and the phosphorylated status (immunoprecipitation and immunoblotting) of the insulin cascade components in the rat hypothalamus, liver, skeletal muscle, and periepididymal adipose tissue. Melatonin was administered in the drinking water for 8- and 12 wk during the night period. Food and water intake and fasting blood glucose remained unchanged. The insulin sensitivity presented a 2.1-fold increase both after 8- and 12 wk of melatonin supplementation. Animals supplemented with melatonin for 12 wk also presented a reduction in body mass. The acute insulin-induced phosphorylation of the analyzed ISP proteins increased 1.3- and 2.3-fold after 8- and 12 wk of melatonin supplementation. The total protein content of the insulin receptor (IR) and the IR substrates (IRS-1, 2) remained unchanged in all investigated tissues, except for the 2-fold increase in the total amount of IRS-1 in the periepididymal adipose tissue. Therefore, the known age-related melatonin synthesis reduction may also be involved in the development of insulin resistance and the adequate supplementation could be an important alternative for the prevention of insulin signaling impairment in aged organisms.
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Affiliation(s)
- Ricardo Zanuto
- Department of Physiology and Biophysics, Institute of Biomedical Sciences-I, University of São Paulo USP, São Paulo, SP, Brazil
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31
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Dato S, Crocco P, D'Aquila P, de Rango F, Bellizzi D, Rose G, Passarino G. Exploring the role of genetic variability and lifestyle in oxidative stress response for healthy aging and longevity. Int J Mol Sci 2013; 14:16443-72. [PMID: 23965963 PMCID: PMC3759920 DOI: 10.3390/ijms140816443] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Revised: 07/30/2013] [Accepted: 07/31/2013] [Indexed: 01/04/2023] Open
Abstract
Oxidative stress is both the cause and consequence of impaired functional homeostasis characterizing human aging. The worsening efficiency of stress response with age represents a health risk and leads to the onset and accrual of major age-related diseases. In contrast, centenarians seem to have evolved conservative stress response mechanisms, probably derived from a combination of a diet rich in natural antioxidants, an active lifestyle and a favorable genetic background, particularly rich in genetic variants able to counteract the stress overload at the level of both nuclear and mitochondrial DNA. The integration of these factors could allow centenarians to maintain moderate levels of free radicals that exert beneficial signaling and modulator effects on cellular metabolism. Considering the hot debate on the efficacy of antioxidant supplementation in promoting healthy aging, in this review we gathered the existing information regarding genetic variability and lifestyle factors which potentially modulate the stress response at old age. Evidence reported here suggests that the integration of lifestyle factors (moderate physical activity and healthy nutrition) and genetic background could shift the balance in favor of the antioxidant cellular machinery by activating appropriate defense mechanisms in response to exceeding external and internal stress levels, and thus possibly achieving the prospect of living a longer life.
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Affiliation(s)
- Serena Dato
- Department of Biology, Ecology and Heart Science, University of Calabria, Ponte Pietro Bucci cubo 4c, Rende 87036, CS, Italy.
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Piromelatine decreases triglyceride accumulation in insulin resistant 3T3-L1 adipocytes: Role of ATGL and HSL. Biochimie 2013; 95:1650-4. [DOI: 10.1016/j.biochi.2013.05.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2012] [Accepted: 05/14/2013] [Indexed: 11/21/2022]
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Melatonin and pancreatic islets: interrelationships between melatonin, insulin and glucagon. Int J Mol Sci 2013; 14:6981-7015. [PMID: 23535335 PMCID: PMC3645673 DOI: 10.3390/ijms14046981] [Citation(s) in RCA: 115] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2013] [Revised: 03/07/2013] [Accepted: 03/11/2013] [Indexed: 12/15/2022] Open
Abstract
The pineal hormone melatonin exerts its influence in the periphery through activation of two specific trans-membrane receptors: MT1 and MT2. Both isoforms are expressed in the islet of Langerhans and are involved in the modulation of insulin secretion from β-cells and in glucagon secretion from α-cells. De-synchrony of receptor signaling may lead to the development of type 2 diabetes. This notion has recently been supported by genome-wide association studies identifying particularly the MT2 as a risk factor for this rapidly spreading metabolic disturbance. Since melatonin is secreted in a clearly diurnal fashion, it is safe to assume that it also has a diurnal impact on the blood-glucose-regulating function of the islet. This factor has hitherto been underestimated; the disruption of diurnal signaling within the islet may be one of the most important mechanisms leading to metabolic disturbances. The study of melatonin–insulin interactions in diabetic rat models has revealed an inverse relationship: an increase in melatonin levels leads to a down-regulation of insulin secretion and vice versa. Elucidation of the possible inverse interrelationship in man may open new avenues in the therapy of diabetes.
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Antioxidant therapies for Alzheimer's disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2012; 2012:472932. [PMID: 22888398 PMCID: PMC3410354 DOI: 10.1155/2012/472932] [Citation(s) in RCA: 248] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2012] [Accepted: 04/17/2012] [Indexed: 12/28/2022]
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease featuring progressive impairments in memory, cognition, and behavior and ultimately leads to death. The histopathological changes of Alzheimer's disease include neuronal and synaptic loss, formation of extracellular senile plaques and intracellular neurofibrillary tangles in brain. Multiple lines of evidence indicate that oxidative stress not only strongly participates in an early stage of Alzheimer's disease prior to cytopathology, but plays an important role in inducing and activating multiple cell signaling pathways that contribute to the lesion formations of toxic substances and then promotes the development of Alzheimer's disease. Many years of studies show that antioxidant therapies have enjoyed general success in preclinical studies. Therefore, this paper mainly focuses on the recent developments of common used antioxidant therapies for Alzheimer's disease and thus provides indications for future potential antioxidant therapeutic strategies of neurodegenerative diseases.
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Nduhirabandi F, du Toit EF, Lochner A. Melatonin and the metabolic syndrome: a tool for effective therapy in obesity-associated abnormalities? Acta Physiol (Oxf) 2012; 205:209-23. [PMID: 22226301 DOI: 10.1111/j.1748-1716.2012.02410.x] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2011] [Revised: 09/20/2011] [Accepted: 01/04/2012] [Indexed: 12/20/2022]
Abstract
The metabolic syndrome (MetS) is a cluster of metabolic abnormalities associated with increased risk for cardiovascular diseases. Apart from its powerful antioxidant properties, the pineal gland hormone melatonin has recently attracted the interest of various investigators as a multifunctional molecule. Melatonin has been shown to have beneficial effects in cardiovascular disorders including ischaemic heart disease and hypertension. However, its role in cardiovascular risk factors including obesity and other related metabolic abnormalities is not yet established, particularly in humans. New emerging data show that melatonin may play an important role in body weight regulation and energy metabolism. This review will address the role of melatonin in the MetS focusing on its effects in obesity, insulin resistance and leptin resistance. The overall findings suggest that melatonin should be exploited as a therapeutic tool to prevent or reverse the harmful effects of obesity and its related metabolic disorders.
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Affiliation(s)
- F. Nduhirabandi
- Division of Medical Physiology; Department of Biomedical Sciences; Faculty of Health Sciences; Stellenbosch University; Stellenbosch; South Africa
| | - E. F. du Toit
- School of Medical Science; Griffith University; Southport; Australia
| | - A. Lochner
- Division of Medical Physiology; Department of Biomedical Sciences; Faculty of Health Sciences; Stellenbosch University; Stellenbosch; South Africa
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Gürpınar T, Ekerbiçer N, Uysal N, Barut T, Tarakçı F, Tuglu MI. The effects of the melatonin treatment on the oxidative stress and apoptosis in diabetic eye and brain. ScientificWorldJournal 2012; 2012:498489. [PMID: 22654617 PMCID: PMC3361279 DOI: 10.1100/2012/498489] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2011] [Accepted: 12/08/2011] [Indexed: 11/21/2022] Open
Abstract
Oxidative stress plays an important role in the development of complications in diabetes mellitus. Antioxidant therapy has been thought to decrease oxidative stress. The objective of the present study was to explore the effects of melatonin (MLT) on oxidative stress in diabetic rat eye and brain tissue by using immunohistochemical methods. Diabetes was induced by streptozotocin, (STZ, 55 mg/kg/i.p) in adult rats. MLT was given 10 mg/kg/i.p once a day for 2 weeks beginning from the sixth week. Six weeks later, rats were divided into three groups: control (CR), STZ-induced diabetic (STZ), and STZ-induced diabetic group received melatonin (STZ+MLT). Although no significant difference was observed with respect to antioxidant status, NOS activity tended to be higher in the untreated diabetic rats than in the treated rats. It was observed that MLT treatment improved the histopathological changes including apoptosis and oxidative stress in brain and eye in diabetic rat.
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Affiliation(s)
- Tuğba Gürpınar
- Department of Pharmacology, Faculty of Medicine, Celal Bayar University, 45030 Manisa, Turkey.
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37
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Hardeland R, Madrid JA, Tan DX, Reiter RJ. Melatonin, the circadian multioscillator system and health: the need for detailed analyses of peripheral melatonin signaling. J Pineal Res 2012; 52:139-66. [PMID: 22034907 DOI: 10.1111/j.1600-079x.2011.00934.x] [Citation(s) in RCA: 316] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Evidence is accumulating regarding the importance of circadian core oscillators, several associated factors, and melatonin signaling in the maintenance of health. Dysfunction of endogenous clocks, melatonin receptor polymorphisms, age- and disease-associated declines of melatonin likely contribute to numerous diseases including cancer, metabolic syndrome, diabetes type 2, hypertension, and several mood and cognitive disorders. Consequences of gene silencing, overexpression, gene polymorphisms, and deviant expression levels in diseases are summarized. The circadian system is a complex network of central and peripheral oscillators, some of them being relatively independent of the pacemaker, the suprachiasmatic nucleus. Actions of melatonin on peripheral oscillators are poorly understood. Various lines of evidence indicate that these clocks are also influenced or phase-reset by melatonin. This includes phase differences of core oscillator gene expression under impaired melatonin signaling, effects of melatonin and melatonin receptor knockouts on oscillator mRNAs or proteins. Cross-connections between melatonin signaling pathways and oscillator proteins, including associated factors, are discussed in this review. The high complexity of the multioscillator system comprises alternate or parallel oscillators based on orthologs and paralogs of the core components and a high number of associated factors with varying tissue-specific importance, which offers numerous possibilities for interactions with melatonin. It is an aim of this review to stimulate research on melatonin signaling in peripheral tissues. This should not be restricted to primary signal molecules but rather include various secondarily connected pathways and discriminate between direct effects of the pineal indoleamine at the target organ and others mediated by modulation of oscillators.
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Affiliation(s)
- Rüdiger Hardeland
- Johann Friedrich Blumenbach Institute of Zoology and Anthropology, University of Göttingen, Germany.
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38
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Borjigin J, Zhang LS, Calinescu AA. Circadian regulation of pineal gland rhythmicity. Mol Cell Endocrinol 2012; 349:13-9. [PMID: 21782887 PMCID: PMC3202635 DOI: 10.1016/j.mce.2011.07.009] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2011] [Revised: 06/30/2011] [Accepted: 07/01/2011] [Indexed: 01/23/2023]
Abstract
The pineal gland is a neuroendocrine organ of the brain. Its main task is to synthesize and secrete melatonin, a nocturnal hormone with diverse physiological functions. This review will focus on the central and pineal mechanisms in generation of mammalian pineal rhythmicity including melatonin production. In particular, this review covers the following topics: (1) local control of serotonin and melatonin rhythms; (2) neurotransmitters involved in central control of melatonin; (3) plasticity of the neural circuit controlling melatonin production; (4) role of clock genes in melatonin formation; (5) phase control of pineal rhythmicity; (6) impact of light at night on pineal rhythms; and (7) physiological function of the pineal rhythmicity.
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Affiliation(s)
- Jimo Borjigin
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
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39
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Peschke E, Hofmann K, Bähr I, Streck S, Albrecht E, Wedekind D, Mühlbauer E. The insulin-melatonin antagonism: studies in the LEW.1AR1-iddm rat (an animal model of human type 1 diabetes mellitus). Diabetologia 2011; 54:1831-40. [PMID: 21491159 DOI: 10.1007/s00125-011-2138-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2010] [Accepted: 03/14/2011] [Indexed: 02/07/2023]
Abstract
AIMS/HYPOTHESIS It is well documented that melatonin influences insulin secretion mediated by G-protein-coupled melatonin receptor isoforms MT1 and MT2, which are present in rat and human pancreatic islets, as well as in rat insulinoma cells. Recent investigations have proven that hyperinsulinaemic Goto-Kakizaki (GK) rats, which are a rat model of type 2 diabetic rats, and humans have decreased melatonin plasma levels, whereas a streptozotocin-induced rat model of diabetes developed reduced insulin levels combined with increased melatonin levels. METHODS Plasma levels of glucose, insulin and melatonin as well as RNA expression of pineal Aanat, Hiomt (also known as Asmt), insulin receptor, adrenoceptor β1 and the clock genes Per1 and Bmal1 (also known as Arntl) were determined in male and female LEW.1AR1-iddm rats as well as in insulin-substituted LEW.1AR1-iddm rats. RESULTS Severe hypoinsulinaemia in diabetic LEW.1AR1-iddm rats was associated with decreased body weight and increased melatonin plasma levels combined with mainly elevated expression of Aanat, Hiomt, pineal insulin receptor and adrenoceptor β1. The changes were normalised by insulin substitution. Diurnal profiles of plasma melatonin and of antagonistic clock genes Per1 and Bmal1 were maintained in diabetic and insulin-substituted rats. CONCLUSIONS/INTERPRETATION The assumed causal relation between elevated melatonin and reduced insulin levels in LEW.1AR1-iddm rats is supported by the observation that insulin substitution normalised these changes. Further support for this interpretation comes from the observation that in GK rats an increase of plasma insulin was combined with a decrease of plasma noradrenaline (norepinephrine), the most important activator of melatonin synthesis. These relationships between the noradrenergic and insulin pathway support the existence of melatonin-insulin antagonism.
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Affiliation(s)
- E Peschke
- Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, 06097 Halle, Germany.
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Espino J, Pariente JA, Rodríguez AB. Role of melatonin on diabetes-related metabolic disorders. World J Diabetes 2011; 2:82-91. [PMID: 21860691 PMCID: PMC3158876 DOI: 10.4239/wjd.v2.i6.82] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2011] [Revised: 05/20/2011] [Accepted: 05/27/2011] [Indexed: 02/05/2023] Open
Abstract
Melatonin is a circulating hormone that is mainly released from the pineal gland. It is best known as a regulator of seasonal and circadian rhythms, its levels being high during the night and low during the day. Interestingly, insulin levels are also adapted to day/night changes through melatonin-dependent synchronization. This regulation may be explained by the inhibiting action of melatonin on insulin release, which is transmitted through both the pertussis-toxin-sensitive membrane receptors MT1 and MT2 and the second messengers 3’,5’-cyclic adenosine monophosphate, 3’,5’-cyclic guanosine monophosphate and inositol 1,4,5-trisphosphate. Melatonin may influence diabetes and associated metabolic disturbances not only by regulating insulin secretion, but also by providing protection against reactive oxygen species, since pancreatic β-cells are very susceptible to oxidative stress because they possess only low-antioxidative capacity. On the other hand, in several genetic association studies, single nucleotide polymorphysms of the human MT2 receptor have been described as being causally linked to an elevated risk of developing type 2 diabetes. This suggests that these individuals may be more sensitive to the actions of melatonin, thereby leading to impaired insulin secretion. Therefore, blocking the melatonin-induced inhibition of insulin secretion may be a novel therapeutic avenue for type 2 diabetes.
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Affiliation(s)
- Javier Espino
- Javier Espino, José A Pariente, Ana B Rodríguez, Department of Physiology, Neuroimmunophysiology and Chrononutrition Research Group, Faculty of Science, University of Extremadura, Badajoz 06006, Spain
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Swanson GR, Burgess HJ, Keshavarzian A. Sleep disturbances and inflammatory bowel disease: a potential trigger for disease flare? Expert Rev Clin Immunol 2011; 7:29-36. [PMID: 21162647 DOI: 10.1586/eci.10.83] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Inflammatory bowel disease (IBD) is a waxing and waning disease characterized by diarrhea, abdominal pain and weight loss. Recently, there has been an increased interest in the roles that sleep, circadian rhythms and melatonin could have as regulators of inflammation in the Gl tract. Advances in our understanding of the molecular machinery of the circadian clock, and the discovery of clock genes in the GI tract are opening up new avenues of research for a role of sleep in IBD. Altering circadian rhythm significantly worsens the development of colitis in animal models, and preliminary human studies have shown that patients with IBD are at increased risk for altered sleep patterns. Further research is needed to clarify the role of disturbances in IBD.
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Affiliation(s)
- Garth R Swanson
- Department of Digestive Diseases, Rush University Medical Center, 1725 West Harrison Street, Suite 207, Chicago, IL 60612-3824, USA
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Garfinkel D, Zorin M, Wainstein J, Matas Z, Laudon M, Zisapel N. Efficacy and safety of prolonged-release melatonin in insomnia patients with diabetes: a randomized, double-blind, crossover study. Diabetes Metab Syndr Obes 2011; 4:307-13. [PMID: 21887103 PMCID: PMC3160855 DOI: 10.2147/dmso.s23904] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2011] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Diabetes is a major comorbidity in insomnia patients. The efficacy and safety of prolonged-release melatonin 2 mg in the treatment of glucose, lipid metabolism, and sleep was studied in 36 type 2 diabetic patients with insomnia (11 men, 25 women, age 46-77 years). METHODS In a randomized, double-blind, crossover study, the subjects were treated for 3 weeks (period 1) with prolonged-release melatonin or placebo, followed by a one-week washout period, and then crossed over for another 3 weeks (period 2) of treatment with the other preparation. All tablets were taken 2 hours before bedtime for a period of 3 weeks. In an extension period of 5 months, prolonged-release melatonin was given nightly to all patients in an open-label design. Sleep was objectively monitored in a subgroup of 22 patients using wrist actigraphy. Fasting glucose, fructosamine, insulin, C-peptide, triglycerides, total cholesterol, high-density and low-density lipoprotein cholesterol, and some antioxidants, as well as glycosylated hemoglobin (HbA1c) levels were measured at baseline and at the end of the study. All concomitant medications were continued throughout the study. RESULTS No significant changes in serum glucose, fructosamine, insulin, C-peptide, antioxidant levels or blood chemistry were observed after 3 weeks of prolonged-release melatonin treatment. Sleep efficiency, wake time after sleep onset, and number of awakenings improved significantly with prolonged-release melatonin as compared with placebo. Following 5 months of prolonged-release melatonin treatment, mean HbA1c (±standard deviation) was significantly lower than at baseline (9.13% ± 1.55% versus 8.47% ± 1.67%, respectively, P = 0.005). CONCLUSION Short-term use of prolonged-release melatonin improves sleep maintenance in type 2 diabetic patients with insomnia without affecting glucose and lipid metabolism. Long-term prolonged-release melatonin administration has a beneficial effect on HbA1c, suggesting improved glycemic control.
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Affiliation(s)
- Doron Garfinkel
- Geriatric Palliative Department, Shoham Geriatric Medical Center, Pardes Hana, Israel
| | | | | | - Zipora Matas
- Biochemistry Laboratory, The E Wolfson Medical Center, Holon, Israel
| | | | - Nava Zisapel
- Neurim Pharmaceuticals Ltd
- Department of Neurobiology, Tel Aviv University, Tel Aviv, Israel
- Correspondence: Nava Zisapel, Department of Neurobiology, The George S Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel, Tel +972 3640 9611, Fax +972 3640 7643, Email
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Peschke E, Schucht H, Mühlbauer E. Long-term enteral administration of melatonin reduces plasma insulin and increases expression of pineal insulin receptors in both Wistar and type 2-diabetic Goto-Kakizaki rats. J Pineal Res 2010; 49:373-81. [PMID: 20840603 DOI: 10.1111/j.1600-079x.2010.00804.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
This paper represents an essential aspect of recent investigations into the functional and clinical implications of insulin-melatonin interrelationships. The aim of the study was to analyze whether melatonin reduces insulin secretion in an animal in a manner comparable to the pattern observed in previous in vitro experiments; to this end, we used two models: Wistar and type 2-diabetic Goto-Kakizaki (GK) rats. Thirty-two Wistar and 32 GK rats were divided into two subgroups of 16 rats each; each subgroup was treated either with or without melatonin. The daily administration of melatonin, starting in 8-wk-old rats, was adjusted to 2.5 mg/kg body weight. Melatonin was given daily during the dark period for 12 hr. After 9 wk of treatment, the rats were sacrificed in the middle of the dark period. Melatonin administration strongly enhanced the plasma melatonin level and diminished the expression of pancreatic melatonin receptor-mRNA, whereas the expression of pineal AA-NAT and HIOMT was unchanged. Furthermore, the experiments showed in agreement with recent in vitro results of pancreatic islets that plasma insulin levels were diminished after melatonin treatment. However, the pineal insulin receptor expression was increased after melatonin administration. The pancreatic expression of glucagon, GLUT2, and glucokinase was decreased in GK rats, whereas the glucose levels, as well as the parameters of glucose sensing, GLUT2-mRNA, and glucokinase-mRNA, were unchanged after melatonin administration in both Wistar and GK rats. In summary, the results show that melatonin administration decreases plasma insulin levels in vivo and, furthermore, that an insulin-melatonin antagonism exists.
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MESH Headings
- Administration, Oral
- Analysis of Variance
- Animals
- Blood Glucose/metabolism
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/genetics
- Diabetes Mellitus, Type 2/metabolism
- Glucagon/biosynthesis
- Glucagon/genetics
- Glucose Transporter Type 2/biosynthesis
- Glucose Transporter Type 2/genetics
- Insulin/blood
- Insulin/genetics
- Male
- Melatonin/pharmacology
- Pineal Gland/drug effects
- Pineal Gland/metabolism
- Rats
- Rats, Transgenic
- Rats, Wistar
- Receptor, Insulin/biosynthesis
- Receptor, Insulin/genetics
- Receptor, Melatonin, MT1/biosynthesis
- Receptor, Melatonin, MT1/genetics
- Receptor, Melatonin, MT2/genetics
- Receptor, Melatonin, MT2/metabolism
- Somatostatin/biosynthesis
- Somatostatin/genetics
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Affiliation(s)
- Elmar Peschke
- Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
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Müssig K, Staiger H, Machicao F, Häring HU, Fritsche A. Genetic variants in MTNR1B affecting insulin secretion. Ann Med 2010; 42:387-93. [PMID: 20597807 DOI: 10.3109/07853890.2010.502125] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The incidence of type 2 diabetes mellitus has markedly increased worldwide over the past decades. Pancreatic beta-cell dysfunction as well as central and peripheral insulin resistance appears to be elementary features in the pathophysiology of type 2 diabetes mellitus. Major environmental conditions predisposing to the development of type 2 diabetes are excessive food intake and sedentary life-style on the background of a genetic predisposition. Recent genome-wide association studies identified several novel type 2 diabetes risk genes, with impaired pancreatic beta-cell function as the underlying mechanism of increased diabetes risk in the majority of genes. Many of the novel type 2 diabetes risk genes, including MTNR1B which encodes one of the two known human melatonin receptors, were unexpected at first glance. However, previous animal as well as human studies already pointed to a significant impact of the melatonin system on the regulation of glucose homeostasis, in addition to its well known role in modulation of sleep and circadian rhythms. This brief review aims to give an overview of how alterations in the melatonin system could contribute to an increased diabetes risk, paying special attention to the role of melatonin receptors in pancreatic beta-cell function.
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Affiliation(s)
- Karsten Müssig
- Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University, Member of the German Centre for Diabetes Research (DZD), 72076 Tübingen, Germany
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45
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Metabolic syndrome: Aggression control mechanisms gone out of control. Med Hypotheses 2010; 74:578-89. [DOI: 10.1016/j.mehy.2009.09.014] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2009] [Accepted: 09/07/2009] [Indexed: 01/13/2023]
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46
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Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev 2009; 41:89-295. [PMID: 19514967 DOI: 10.1080/03602530902843483] [Citation(s) in RCA: 536] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Pharmacogenetics is the study of how interindividual variations in the DNA sequence of specific genes affect drug response. This article highlights current pharmacogenetic knowledge on important human drug-metabolizing cytochrome P450s (CYPs) to understand the large interindividual variability in drug clearance and responses in clinical practice. The human CYP superfamily contains 57 functional genes and 58 pseudogenes, with members of the 1, 2, and 3 families playing an important role in the metabolism of therapeutic drugs, other xenobiotics, and some endogenous compounds. Polymorphisms in the CYP family may have had the most impact on the fate of therapeutic drugs. CYP2D6, 2C19, and 2C9 polymorphisms account for the most frequent variations in phase I metabolism of drugs, since almost 80% of drugs in use today are metabolized by these enzymes. Approximately 5-14% of Caucasians, 0-5% Africans, and 0-1% of Asians lack CYP2D6 activity, and these individuals are known as poor metabolizers. CYP2C9 is another clinically significant enzyme that demonstrates multiple genetic variants with a potentially functional impact on the efficacy and adverse effects of drugs that are mainly eliminated by this enzyme. Studies into the CYP2C9 polymorphism have highlighted the importance of the CYP2C9*2 and *3 alleles. Extensive polymorphism also occurs in other CYP genes, such as CYP1A1, 2A6, 2A13, 2C8, 3A4, and 3A5. Since several of these CYPs (e.g., CYP1A1 and 1A2) play a role in the bioactivation of many procarcinogens, polymorphisms of these enzymes may contribute to the variable susceptibility to carcinogenesis. The distribution of the common variant alleles of CYP genes varies among different ethnic populations. Pharmacogenetics has the potential to achieve optimal quality use of medicines, and to improve the efficacy and safety of both prospective and currently available drugs. Further studies are warranted to explore the gene-dose, gene-concentration, and gene-response relationships for these important drug-metabolizing CYPs.
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Affiliation(s)
- Shu-Feng Zhou
- School of Health Sciences, RMIT University, Bundoora, Victoria, Australia.
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47
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Bojková B, Orendás P, Friedmanová L, Kassayová M, Datelinka I, Ahlersová E, Ahlers I. Prolonged melatonin administration in 6-month-old Sprague-Dawley rats: metabolic alterations. ACTA ACUST UNITED AC 2008; 95:65-76. [PMID: 18389999 DOI: 10.1556/aphysiol.95.2008.4] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The aim of this work was to evaluate the effect of prolonged melatonin administration on chosen metabolic and hormonal variables in male and female Sprague-Dawley rats. Melatonin was administered in tap water (4 microg/ml) daily from the 6th month of age. Rats were fed a standard type of diet ad libitum and were kept in a light regimen L:D--12:12h. The experiment was terminated after 12 weeks of melatonin administration. Melatonin decreased body mass during the whole experiment in females and from the 42nd day of the experiment in males. Relative heart muscle weight in females and absolute/relative thymus weight in males were increased after melatonin administration. Melatonin decreased glycaemia, heart muscle glycogen concentration in females and liver glycogen concentration in both sexes. Serum insulin concentration in males was decreased; serum corticosterone concentration was increased in both males and females. Serum triacylglycerol and heart muscle cholesterol concentration in females were decreased, however in males serum and heart muscle cholesterol concentration was increased. Liver phospholipid concentration in females was decreased and heart muscle phospholipid concentration in males was increased. Melatonin increased malondialdehyde concentration in heart muscle in males and in liver in both sexes. Melatonin induced prominent sex-dependent changes in both carbohydrate and lipid metabolism.
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Affiliation(s)
- B Bojková
- Department of Animal Physiology, Institute of Biology and Ecology, Faculty of Science, P. J. Safárik University, Moyzesova 11, 041 67 Kosice, Slovak Republic.
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Polo García J, Serrano Garcés S, Pérez de la Cruz M, Gil Chamorro S, Rodilla Rodilla E, Maestre Fernández J. Antidepresivos y glándula pineal. Semergen 2008. [DOI: 10.1016/s1138-3593(08)71877-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Abstract
Melatonin influences insulin secretion both in vivo and in vitro. (i) The effects are MT(1)-and MT(2)-receptor-mediated. (ii) They are specific, high-affinity, pertussis-toxin-sensitive, G(i)-protein-coupled, leading to inhibition of the cAMP-pathway and decrease of insulin release. [Correction added after online publication 4 December 2007: in the preceding sentence, 'increase of insulin release' was changed to 'decrease of insulin release'.] Furthermore, melatonin inhibits the cGMP-pathway, possibly mediated by MT(2) receptors. In this way, melatonin likely inhibits insulin release. A third system, the IP(3)-pathway, is mediated by G(q)-proteins, phospholipase C and IP(3), which mobilize Ca(2+) from intracellular stores, with a resultant increase in insulin. (iii) Insulin secretion in vivo, as well as from isolated islets, exhibits a circadian rhythm. This rhythm, which is apparently generated within the islets, is influenced by melatonin, which induces a phase shift in insulin secretion. (iv) Observation of the circadian expression of clock genes in the pancreas could possibly be an indication of the generation of circadian rhythms in the pancreatic islets themselves. (v) Melatonin influences diabetes and associated metabolic disturbances. The diabetogens, alloxan and streptozotocin, lead to selective destruction of beta-cells through their accumulation in these cells, where they induce the generation of ROS. Beta-cells are very susceptible to oxidative stress because they possess only low-antioxidative capacity. Results suggest that melatonin in pharmacological doses provides protection against ROS. (vi) Finally, melatonin levels in plasma, as well as the arylalkylamine-N-acetyltransferase (AANAT) activity, are lower in diabetic than in nondiabetic rats and humans. In contrast, in the pineal gland, the AANAT mRNA is increased and the insulin receptor mRNA is decreased, which indicates a close interrelationship between insulin and melatonin.
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Affiliation(s)
- Elmar Peschke
- Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Germany.
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Arreola-Espino R, Urquiza-Marín H, Ambriz-Tututi M, Araiza-Saldaña CI, Caram-Salas NL, Rocha-González HI, Mixcoatl-Zecuatl T, Granados-Soto V. Melatonin reduces formalin-induced nociception and tactile allodynia in diabetic rats. Eur J Pharmacol 2007; 577:203-10. [PMID: 17920585 DOI: 10.1016/j.ejphar.2007.09.006] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2007] [Revised: 09/17/2007] [Accepted: 09/18/2007] [Indexed: 12/27/2022]
Abstract
The purpose of this study was to assess the antinociceptive and antiallodynic effect of melatonin as well as its possible mechanism of action in diabetic rats. Streptozotocin (50 mg/kg) injection caused hyperglycemia within 1 week. Formalin-evoked flinching was increased in diabetic rats as compared to non-diabetic rats. Oral administration of melatonin (10-300 mg/kg) dose-dependently reduced flinching behavior in diabetic rats. In addition, K-185 (a melatonin MT(2) receptor antagonist, 0.2-2 mg/kg, s.c.) completely blocked the melatonin-induced antinociception in diabetic rats, whereas that naltrexone (a non-selective opioid receptor antagonist, 1 mg/kg, s.c.) and naltrindole (a selective delta opioid receptor antagonist, 0.5 mg/kg, s.c.), but not 5'-guanidinonaltrindole (a selective kappa opioid receptor antagonist, 1 mg/kg, s.c.), partially reduced the antinociceptive effect of melatonin. Given alone K-185, naltrexone, naltrindole or 5'-guanidinonaltrindole did not modify formalin-induced nociception in diabetic rats. Four to 8 weeks after diabetes induction, tactile allodynia was observed in the streptozotocin-injected rats. On this condition, oral administration of melatonin (75-300 mg/kg) dose-dependently reduced tactile allodynia in diabetic rats. Both antinociceptive and antiallodynic effects were not related to motor changes as melatonin did not modify number of falls in the rotarod test. Results indicate that melatonin is able to reduce formalin-induced nociception and tactile allodynia in streptozotocin-injected rats. In addition, data suggest that melatonin MT(2) and delta opioid receptors may play an important role in these effects.
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Affiliation(s)
- Rosaura Arreola-Espino
- Instituto de Investigaciones Químico-Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, Michoacán, Mexico
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