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Xu S, Yang H, Ainiwaer Z, Fan W, Xu T, Yang K, Wang C. Effects of Rumen-Protected 5-Hydroxytryptophan and Melatonin Supplementation on Antioxidant Capacity, Meat Quality, and Shelf Life of Hu Sheep. Animals (Basel) 2025; 15:1582. [PMID: 40509048 PMCID: PMC12153834 DOI: 10.3390/ani15111582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2025] [Revised: 05/22/2025] [Accepted: 05/27/2025] [Indexed: 06/16/2025] Open
Abstract
This study aimed to investigate the impact of dietary supplementation with RPT 5-HTP and MT on the meat quality and shelf life of Hu sheep. Thirty 4-month-old male Hu sheep with similar body weights (30.84 ± 1.16 kg) were randomly allocated into three groups (one sheep per replicate): a control group (fed a basal diet), a RPT 5-HTP group (basal diet + 222 mg/kg BW RPT 5-HTP), and an MT group (basal diet + 4 mg/d MT). The experimental period lasted 37 days, including a 7-day adaptation phase and a 30-day formal trial. The results show that supplementation with RPT 5-HTP and MT significantly increased MT levels in the longissimus dorsi muscle of Hu sheep (p < 0.05). Compared to the control group, the malondialdehyde (MDA) content in the longissimus dorsi muscle was significantly reduced in the MT and RPT 5-HTP groups (p < 0.05), while catalase (CAT) activity was significantly increased in the MT group (p < 0.05). The drip loss of the longissimus dorsi muscle in Hu sheep was significantly reduced after supplementation with RPT 5-HTP and MT (p < 0.05). Essential amino acids, non-essential amino acids, sweet-tasting amino acids, and umami amino acids in the longissimus dorsi muscle of supplemented groups were significantly elevated (p < 0.05). Both 5-HTP and MT extended the shelf life of mutton; compared to the control, the shelf life was prolonged by 22.08 h in the RPT 5-HTP group and by 45.36 h in the MT group. In conclusion, it was found that 5-HTP and MT had a certain effect on improving the antioxidant capacity of Hu sheep, thereby enhancing the meat quality of mutton and extending its shelf life, with the amino acid content in mutton being increased to improve its umami and flavor.
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Affiliation(s)
| | | | | | | | | | | | - Caidie Wang
- Xinjiang Key Laboratory of Herbivore Nutrition for Meat & Milk, Research Center for Biofeed and Animal Gut Healthz, College of Animal Sciences, Xinjiang Agricultural University, Urumqi 830052, China; (S.X.)
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Amrollahi-Sharifabadi M, Oladejo TO, Ibrahim AS, Shakoor B, Mehrpour O, Sadeghi-Hashjin G, Gonçalves S. Melatonin's paradox: From therapeutic benefits to toxicity warnings. Chem Biol Interact 2025; 417:111556. [PMID: 40383469 DOI: 10.1016/j.cbi.2025.111556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2025] [Revised: 05/03/2025] [Accepted: 05/12/2025] [Indexed: 05/20/2025]
Abstract
Melatonin is an endogenous chemical predominantly synthesized in the pineal gland, widely recognized for its hormonal roles, such as regulating sleep and circadian rhythms. Through mechanisms such as anti-oxidative reduction, anti-inflammatory, and immunomodulation, it is suggested that melatonin exhibits biochemical properties in in vitro conditions. Beyond these functions, melatonin has garnered attention for its pharmacological benefits, particularly as a therapeutic agent that is exogenously administered as a supplement in various diseases ranging from insomnia to immunological and gastrointestinal disorders. However, emerging studies highlight potential toxicological concerns associated with exogenous melatonin use, especially in specific populations. This review provided a comprehensive exploration of melatonin's dual role as a therapeutic and potentially toxic agent. It summarized what is currently known about its pharmacological, toxicological, and biochemical characteristics as well as toxicity mechanisms, and safety concerns in susceptible groups. By highlighting new knowledge gaps about melatonin's clinical uses, the study opens the door for further studies to maximize its therapeutic benefits while maintaining its safety.
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Affiliation(s)
| | - Toheeb Olalekan Oladejo
- Department of Pharmacology and Toxicology, Nazarbayev School of Medicine, Astana, Kazakhstan
| | - Adedayo Sheu Ibrahim
- Department of Pharmacology and Toxicology, Nazarbayev School of Medicine, Astana, Kazakhstan
| | - Bushra Shakoor
- Synthetic and Natural Product Drug Discovery Laboratory, Department of Chemistry, Government College Women University Faisalabad, Faisalabad, 38000, Pakistan
| | - Omid Mehrpour
- Michigan Poison & Drug Information Center, School of Medicine, Wayne State University, Detroit, MI, United States of America
| | - Goudarz Sadeghi-Hashjin
- Department of Comparative Biosciences, College of Veterinary Medicine & Biomedical Science, University of Tehran, Tehran, Iran
| | - Sara Gonçalves
- Academic Clinical Center of Trás-os-Montes and Alto Douro (CACTMAD), University of Trás-os-Montes and Alto Douro, 5000-801, Vila Real, Portugal; School of Health, University of Trás-os-Montes and Alto Douro, 5000-801, Vila Real, Portugal
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Ortiz-Placín C, Salido GM, González A. Melatonin Interplay in Physiology and Disease-The Fountain of Eternal Youth Revisited. Biomolecules 2025; 15:682. [PMID: 40427575 PMCID: PMC12109172 DOI: 10.3390/biom15050682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2025] [Revised: 05/04/2025] [Accepted: 05/06/2025] [Indexed: 05/29/2025] Open
Abstract
Melatonin (N-acetyl-5-methoxytryptamine) is a hormone associated with the regulation of biological rhythms. The indoleamine is secreted by the pineal gland during the night, following a circadian rhythm. The highest plasmatic levels are reached during the night, whereas the lowest levels are achieved during the day. In addition to the pineal gland, other organs and tissues also produce melatonin, like, for example, the retina, Harderian glands, gut, ovaries, testes, skin, leukocytes, or bone marrow. The list of organs is extensive, including the cerebellum, airway epithelium, liver, kidney, adrenals, thymus, thyroid, pancreas, carotid body, placenta, and endometrium. At all these locations, the availability of melatonin is intended for local use. Interestingly, a decline of the circadian amplitude of the melatonin secretion occurs in old subjects in comparison to that found in younger subjects. Moreover, genetic and environmental factors are the primary causes of diseases, and oxidative stress is a key contributor to most pathologies. Numerous studies exist that show interesting effects of melatonin in different models of disease. Impairment in its secretion might have deleterious consequences for cellular physiology. In this regard, melatonin is a natural compound that is a carrier of a not yet completely known potential that deserves consideration. Thus, melatonin has emerged as a helpful ally that could be considered as a guard with powerful tools to orchestrate homeostasis in the body, majorly based on its antioxidant effects. In this review, we provide an overview of the widespread actions of melatonin against diseases preferentially affecting the elderly.
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Affiliation(s)
| | | | - Antonio González
- Institute of Molecular Pathology Biomarkers, University of Extremadura, Avenida de las Ciencias s/n, E-10003 Caceres, Spain; (C.O.-P.); (G.M.S.)
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Ji SM, Yoo H, Kim JI, Choi MJ, Cheon HG. Melatonin induces white-to-beige adipocyte transdifferentiation through melatonin receptor 1-mediated direct browning and indirect M2 polarization. Mol Cell Endocrinol 2025; 597:112439. [PMID: 39653309 DOI: 10.1016/j.mce.2024.112439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 11/27/2024] [Accepted: 12/06/2024] [Indexed: 12/21/2024]
Abstract
Previous studies have shown that melatonin induces adipocyte browning in vivo. However, the underlying mechanisms of melatonin action at the cellular level remain elusive. In this study, we investigated the mechanisms underlying melatonin-induced browning in 3T3-L1 adipocytes and RAW 264.7 macrophages. Melatonin caused the transdifferentiation of fully differentiated white adipocytes into beige adipocytes, which involves the activation of melatonin receptor 1, followed by increased phosphorylation of p38 MAPK and Akt. Both luzindole (LZ), a non-selective melatonin receptor antagonist, and selective melatonin receptor 1 knockdown attenuated the browning effects of melatonin. Melatonin also induced M2 polarization in RAW 264.7, involving the melatonin receptor 1-Src-STAT3/STAT6 phosphorylation signaling cascade. Melatonin-treated M2-conditioned medium (CM) contained increased levels of catecholamine (CA) and induced beige adipocytes when treated with differentiated 3T3-L1 white adipocytes. In vivo oral administration of melatonin to high-fat diet (HFD)-induced obese (DIO) mice reduced body weight, accompanied by increased expression of uncoupling protein-1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in subcutaneous adipose tissues. Moreover, arginase-1 (Arg1) and mannose receptor C type-1 (MRC1) levels were markedly higher in the melatonin-treated groups, suggesting that melatonin induces adipose browning and M2 polarization in vivo. Collectively, melatonin-induced adipocyte browning appeared to be reflected by the sum of melatonin receptor 1-activated direct browning effects and indirect M2 polarization-mediated effects.
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MESH Headings
- Animals
- Mice
- Melatonin/pharmacology
- Cell Transdifferentiation/drug effects
- Adipocytes, White/drug effects
- Adipocytes, White/cytology
- Adipocytes, White/metabolism
- Adipocytes, Beige/drug effects
- Adipocytes, Beige/metabolism
- Adipocytes, Beige/cytology
- 3T3-L1 Cells
- RAW 264.7 Cells
- Male
- Signal Transduction/drug effects
- Mice, Inbred C57BL
- Cell Polarity/drug effects
- Receptor, Melatonin, MT1/metabolism
- Diet, High-Fat
- Obesity/pathology
- Obesity/metabolism
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Affiliation(s)
- Seong Mi Ji
- Department of Pharmacology, College of Medicine, Gachon University, Incheon 21999, Republic of Korea
| | - Hana Yoo
- Department of Pharmacology, College of Medicine, Gachon University, Incheon 21999, Republic of Korea
| | - Jea Il Kim
- Department of Health Sciences and Technology, Gachon Advanced Institute for Health Sciences and Technology, Gachon University, Incheon, 21999, Republic of Korea
| | - Mi Jin Choi
- Department of Pharmacology, College of Medicine, Gachon University, Incheon 21999, Republic of Korea
| | - Hyae Gyeong Cheon
- Department of Pharmacology, College of Medicine, Gachon University, Incheon 21999, Republic of Korea; Department of Health Sciences and Technology, Gachon Advanced Institute for Health Sciences and Technology, Gachon University, Incheon, 21999, Republic of Korea.
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Markus RP, Sousa KS, Ulrich H, Ferreira ZS. Partners in health and disease: pineal gland and purinergic signalling. Purinergic Signal 2025; 21:99-112. [PMID: 39031242 PMCID: PMC11958924 DOI: 10.1007/s11302-024-10037-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 07/02/2024] [Indexed: 07/22/2024] Open
Abstract
In mammal's pineal glands, ATP interacts with the high-affinity P2Y1 and the low-affinity P2X7 receptors. ATP released from sympathetic nerve terminals potentiates noradrenaline-induced serotonin N-acetyltransferase (Snat) transcription, N-acetylserotonin (NAS), and melatonin (MLT) synthesis. Circulating melatonin impairs the expression of adhesion molecules in endothelial cells, blocking the migration of leukocytes. Acute defence response induced by pathogen- and danger/damage-associated molecular patterns (PAMPs and DAMPs) triggers the NF-κB pathway in pinealocytes and blocks the transcription of Snat. Therefore, the darkness hormone is not released, and neutrophils and monocytes migrate to the lesion sites. ATP released in high amounts from apoptotic and death cells was considered a DAMP, and the blockage of P2X7 receptors was tested as a new class of drugs for treating brain damage. However, this is not a simple equation. High ATP injected in a lateral ventricle blocked MLT, but not NAS, synthesis as it impairs the transcription of acetyl serotonin N-methyltransferase. NAS is released in the plasma and the cerebral spinal fluid. NAS also blocks the rolling and adhesion of leukocytes to endothelial cells. Otherwise, it is metabolised specifically in each brain area to provide the requested concentration of MLT as a neuroprotector. As observed in physiological conditions, high extracellular ATP, different from the other DAMPs, reports the environmental light/dark cycle rhythm because NAS substitutes MLT as the nocturnal chemical indicator, the darkness hormone. Thus, blocking the P2X7R should not be considered a universal therapy for improving acute strokes, as MLT and ATP are partners in health and disease.
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Affiliation(s)
- Regina P Markus
- Laboratory of Chronopharmacology, Department of Physiology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil.
| | - Kassiano S Sousa
- Laboratory of Chronopharmacology, Department of Physiology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
| | - Henning Ulrich
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
| | - Zulma S Ferreira
- Laboratory of Chronopharmacology, Department of Physiology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil.
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Titon SCM, Neto PGG, Titon B, de Figueiredo AC, Markus RP, Gomes FR, Assis VR. Immune-pineal-ocular Axis in Amphibians: Unveiling A Novel Connection. Integr Comp Biol 2024; 64:1309-1319. [PMID: 38658196 DOI: 10.1093/icb/icae026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 04/17/2024] [Accepted: 04/19/2024] [Indexed: 04/26/2024] Open
Abstract
Melatonin is a hormone known as an endogenous temporal marker signaling the dark phase of the day. Although the eyes seem to be the main site of melatonin production in amphibians, little information is available about the natural variation in ocular melatonin levels and its modulation following immune stimulation. We investigated the daily variation of plasma and ocular melatonin levels in bullfrogs (Lithobates catesbeianus) and their modulation following an immune stimulation with lipopolysaccharide (LPS) in yellow cururu toads (Rhinella icterica). For the daily variation, bullfrogs were bled and then euthanized for eye collection every 3 h over 24 h to determine plasma and ocular melatonin levels. We found a positive correlation between ocular and plasma melatonin levels, with maximum values at night (22 h) for both plasma and the eyes. For immune stimulation, yellow cururu toads received an intraperitoneal injection of LPS or saline solution during the day (10 h) or at night (22 h). Two hours after injection, toads were bled and euthanized for eye collection to obtain plasma and ocular melatonin levels. In addition, the liver and bone marrow were collected to investigate local melatonin modulation. Our results demonstrate that retinal light-controlled rhythmic melatonin production is suppressed while liver and bone marrow melatonin levels increase during the inflammatory assemblage in anurans. Interestingly, the LPS injection decreased only ocular melatonin levels, reinforcing the central role of the eyes (i.e., retina) as an essential organ of melatonin production, and a similar role to the pineal gland during the inflammatory response in amphibians. Together, these results point to a possible immune-pineal-ocular axis in amphibians, yet to be fully described in this group.
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Affiliation(s)
- Stefanny C M Titon
- Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, Rua do Matão, Trav. 14, 101, São Paulo, SP 05508-090, Brasil
| | - Patrício G Garcia Neto
- Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, Rua do Matão, Trav. 14, 101, São Paulo, SP 05508-090, Brasil
| | - Braz Titon
- Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, Rua do Matão, Trav. 14, 101, São Paulo, SP 05508-090, Brasil
| | - Aymam C de Figueiredo
- Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, Rua do Matão, Trav. 14, 101, São Paulo, SP 05508-090, Brasil
| | - Regina P Markus
- Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, Rua do Matão, Trav. 14, 101, São Paulo, SP 05508-090, Brasil
| | - Fernando R Gomes
- Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, Rua do Matão, Trav. 14, 101, São Paulo, SP 05508-090, Brasil
| | - Vania R Assis
- Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, Rua do Matão, Trav. 14, 101, São Paulo, SP 05508-090, Brasil
- College of Public Health, University of South Florida, Tampa, FL 33612, USA
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7
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Yu M, Xu M, Wang G, Feng J, Zhang M. Effects of Different Photoperiods on Peripheral 5-Hydroxytryptamine Metabolism, Breast Muscle Glucose Metabolism, and Myopathies in Broilers. Metabolites 2024; 14:567. [PMID: 39452948 PMCID: PMC11509524 DOI: 10.3390/metabo14100567] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 10/17/2024] [Accepted: 10/20/2024] [Indexed: 10/26/2024] Open
Abstract
Background: There is a close relationship between breast muscle glucose metabolism, peripheral 5-hydroxytryptamine (5-HT), and myopathies in animals. Here, this study aimed to investigate the effects of different photoperiods on peripheral 5-HT metabolism, white striping (WS), and wooden breast (WB) in broilers. Methods: A total of 216 healthy 5-day-old (d) Arbor Acres (AA) male broilers were randomly assigned to 12L:12D, 18L:6D, and 24L:0D photoperiods for 4 weeks. Results: Compared with the 12L:12D photoperiod, we found the WB score in broilers was significantly increased in the 18L:6D and 24L:0D photoperiod at week 4 (p < 0.05). Muscle glycogen was significantly reduced (p < 0.05) and glycolysis was promoted in the breast muscles of broilers under the 18L:6D and 24L:0D photoperiods at week 2 and 4. Peripheral 5-HT concentrations, the mRNA expression of tryptophan hydroxylase 1 (TPH1) and serotonin transporter (SERT) in the cecal mucosa, and 5-hydroxytryptamine receptor 2A (5-HTR2A) mRNA expression in the breast muscle of broilers significantly up-regulated in the 18L:6D and 24L:0D photoperiod at week 2 and 4 (p < 0.05). Conclusions: Our findings revealed that extending the photoperiod improved the breast muscle growth rate, but up-regulated 5-HT synthesis and secretion to higher peripheral 5-HT, induced breast muscle glucose metabolism disorder, and increased WB incidence rates in broilers.
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Affiliation(s)
- Miao Yu
- State Key Laboratory of Animal Nutrition and Feeding, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Haidian, Beijing 100193, China; (M.Y.); (M.X.); (G.W.); (J.F.)
| | - Mengjie Xu
- State Key Laboratory of Animal Nutrition and Feeding, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Haidian, Beijing 100193, China; (M.Y.); (M.X.); (G.W.); (J.F.)
| | - Guangju Wang
- State Key Laboratory of Animal Nutrition and Feeding, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Haidian, Beijing 100193, China; (M.Y.); (M.X.); (G.W.); (J.F.)
- Adaptation Physiology Group, Wageningen University and Research, 6708 PB Wageningen, The Netherlands
| | - Jinghai Feng
- State Key Laboratory of Animal Nutrition and Feeding, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Haidian, Beijing 100193, China; (M.Y.); (M.X.); (G.W.); (J.F.)
| | - Minhong Zhang
- State Key Laboratory of Animal Nutrition and Feeding, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Haidian, Beijing 100193, China; (M.Y.); (M.X.); (G.W.); (J.F.)
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8
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Panigrahi AK, Pal PK, Sarkar Paria D. Melatonin as an Ameliorative Agent Against Cadmium- and Lead-Induced Toxicity in Fish: an Overview. Appl Biochem Biotechnol 2024; 196:5790-5820. [PMID: 38224395 DOI: 10.1007/s12010-023-04723-3] [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] [Accepted: 09/15/2023] [Indexed: 01/16/2024]
Abstract
Diverse anthropogenic activities and lack of knowledge on its consequences have promoted serious heavy metal contaminations in different aquatic systems throughout the globe. The non-biodegradable nature of most of these toxic heavy metals has increased the concern on their possible bioaccumulation in aquatic organisms as well as in other vertebrates. Among these aquatic species, fish are most sensitive to such contaminated water that not only decreases their chance of survivability in the nature but also increases the probability of biomagnifications of these heavy metals in higher order food chain. After entering the fish body, heavy metals induce detrimental changes in different vital organs by impairing multiple physiological and biochemical pathways that are essential for the species. Such alterations may include tissue damage, induction of oxidative stress, immune-suppression, endocrine disorders, uncontrolled cell proliferation, DNA damage, and even apoptosis. Although uncountable reports have explored the toxic effects of different heavy metals in diverse fish species, but surprisingly, only a few attempts have been made to ameliorate such toxic effects. Since, oxidative stress seems to be the underlying common factor in such heavy metal-induced toxicity, therefore, a potent and endogenous antioxidant with no side effect may be an appropriate therapeutic solution. Apart from summarizing the toxic effects of two important toxicants, i.e., cadmium and lead in fish, the novelty of the present treatise lies in its arguments in favor of using melatonin, an endogenous free radical scavenger and indirect antioxidant, in ameliorating the toxic effects of heavy metals in any fish species.
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Affiliation(s)
- Ashis Kumar Panigrahi
- The University of Burdwan, Burdwan, West Bengal, 713104, India
- Eco-toxicology, Fisheries & Aquaculture Extension Laboratory, Department of Zoology, University of Kalyani, Kalyani, West Beng, al-741235, India
| | - Palash Kumar Pal
- Oxidative Stress and Free Radical Biology Laboratory, Department of Physiology, University of Calcutta, 92, A.P.C. Road, Kolkata, 700009, India
| | - Dipanwita Sarkar Paria
- Department of Zoology, Chandernagore College, The University of Burdwan, Chandernagore, West Beng, al-712136, India.
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Semenova N, Garashchenko N, Kolesnikov S, Darenskaya M, Kolesnikova L. Gut Microbiome Interactions with Oxidative Stress: Mechanisms and Consequences for Health. PATHOPHYSIOLOGY 2024; 31:309-330. [PMID: 39051221 PMCID: PMC11270257 DOI: 10.3390/pathophysiology31030023] [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: 04/11/2024] [Revised: 06/17/2024] [Accepted: 06/20/2024] [Indexed: 07/27/2024] Open
Abstract
Understanding how gut flora interacts with oxidative stress has been the subject of significant research in recent years. There is much evidence demonstrating the existence of the microbiome-oxidative stress interaction. However, the biochemical basis of this interaction is still unclear. In this narrative review, possible pathways of the gut microbiota and oxidative stress interaction are presented, among which genetic underpinnings play an important role. Trimethylamine-N-oxide, mitochondria, short-chain fatty acids, and melatonin also appear to play roles. Moreover, the relationship between oxidative stress and the gut microbiome in obesity, metabolic syndrome, chronic ethanol consumption, dietary supplements, and medications is considered. An investigation of the correlation between bacterial community features and OS parameter changes under normal and pathological conditions might provide information for the determination of new research methods. Furthermore, such research could contribute to establishing a foundation for determining the linkers in the microbiome-OS association.
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Affiliation(s)
- Natalya Semenova
- Scientific Centre for Family Health and Human Reproduction Problems, 664003 Irkutsk, Russia; (N.G.); (S.K.); (M.D.); (L.K.)
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10
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Pathak NK, Sahoo P, Tripathy U. Nonlinear study of indolamines: A hidden property that might have possible implications in neurodegeneration. Talanta 2024; 272:125808. [PMID: 38373364 DOI: 10.1016/j.talanta.2024.125808] [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: 10/03/2023] [Revised: 02/13/2024] [Accepted: 02/14/2024] [Indexed: 02/21/2024]
Abstract
Indolamines (e.g., serotonin and melatonin) are tryptophan-derived class of neurotransmitters and neuromodulators that play crucial roles in mood regulation, sleep-wake cycles, and gastrointestinal functions. These biogenic amines exert their effects by binding to specific receptors in the central nervous system, influencing neuronal activity and signalling cascades. Indolamines are vital in maintaining homeostasis, and imbalances in their levels have been implicated in various neurological and psychiatric disorders. Hence, in the present study, we have investigated the nonlinear properties of indolamines under a continuous wave (CW) and pulsed laser excitation using the closed-aperture (CA) Z-scan technique. The CA Z-scan is a cost-effective and sensitive analytical tool for investigating nonlinear properties. It is observed that indolamines show negative refractive and positive absorptive nonlinearity under in vitro physiological conditions. The origin of nonlinearity is ascribed to the thermo-optical effect governed by the saturated atomic absorption and molecular orientation mechanisms under CW and pulsed laser excitation, respectively. The strength of nonlinearity is found to vary linearly with the concentration of indolamines. Overall, serotonin possesses stronger nonlinearity than melatonin. The maximum nonlinearity (refractive index (n2) & absorption coefficient (β)) for melatonin under CW and pulsed laser excitations are (-1.266 × 10-12 m2W-1 and -1.883 × 10-17 m2W-1) & (8.046 × 10-8 mW-1 and 1.516 × 10-13 mW-1), respectively. Meanwhile, the maximum n2 and β under pulsed laser excitation for serotonin are obtained as -3.195 × 10-17 m2W-1 and 6.149 × 10-12 mW-1, respectively. The outcome of the results may be utilized in understanding processes mediated by indolamines and designing therapeutic interventions.
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Affiliation(s)
- Nitesh Kumar Pathak
- Department of Physics, Indian Institute of Technology (Indian School of Mines) Dhanbad, 826004, Jharkhand, India
| | - Priyadarshi Sahoo
- Department of Physics, Indian Institute of Technology (Indian School of Mines) Dhanbad, 826004, Jharkhand, India
| | - Umakanta Tripathy
- Department of Physics, Indian Institute of Technology (Indian School of Mines) Dhanbad, 826004, Jharkhand, India.
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11
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Jurjus A, El Masri J, Ghazi M, El Ayoubi LM, Soueid L, Gerges Geagea A, Jurjus R. Mechanism of Action of Melatonin as a Potential Adjuvant Therapy in Inflammatory Bowel Disease and Colorectal Cancer. Nutrients 2024; 16:1236. [PMID: 38674926 PMCID: PMC11054672 DOI: 10.3390/nu16081236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 04/18/2024] [Accepted: 04/19/2024] [Indexed: 04/28/2024] Open
Abstract
Inflammatory bowel disease (IBD), a continuum of chronic inflammatory diseases, is tightly associated with immune system dysregulation and dysbiosis, leading to inflammation in the gastrointestinal tract (GIT) and multiple extraintestinal manifestations. The pathogenesis of IBD is not completely elucidated. However, it is associated with an increased risk of colorectal cancer (CRC), which is one of the most common gastrointestinal malignancies. In both IBD and CRC, a complex interplay occurs between the immune system and gut microbiota (GM), leading to the alteration in GM composition. Melatonin, a neuroendocrine hormone, was found to be involved with this interplay, especially since it is present in high amounts in the gut, leading to some protective effects. Actually, melatonin enhances the integrity of the intestinal mucosal barrier, regulates the immune response, alleviates inflammation, and attenuates oxidative stress. Thereby, the authors summarize the multifactorial interaction of melatonin with IBD and with CRC, focusing on new findings related to the mechanisms of action of this hormone, in addition to its documented positive outcomes on the treatment of these two pathologies and possible future perspectives to use melatonin as an adjuvant therapy.
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Affiliation(s)
- Abdo Jurjus
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon; (J.E.M.); (M.G.); (L.S.); (A.G.G.); (R.J.)
| | - Jad El Masri
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon; (J.E.M.); (M.G.); (L.S.); (A.G.G.); (R.J.)
- Faculty of Medical Sciences, Lebanese University, Beirut 6573, Lebanon;
| | - Maya Ghazi
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon; (J.E.M.); (M.G.); (L.S.); (A.G.G.); (R.J.)
- Faculty of Medical Sciences, Lebanese University, Beirut 6573, Lebanon;
| | | | - Lara Soueid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon; (J.E.M.); (M.G.); (L.S.); (A.G.G.); (R.J.)
| | - Alice Gerges Geagea
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon; (J.E.M.); (M.G.); (L.S.); (A.G.G.); (R.J.)
| | - Rosalyn Jurjus
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon; (J.E.M.); (M.G.); (L.S.); (A.G.G.); (R.J.)
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Chen Y, Yang C, Deng Z, Xiang T, Ni Q, Xu J, Sun D, Luo F. Gut microbially produced tryptophan metabolite melatonin ameliorates osteoporosis via modulating SCFA and TMAO metabolism. J Pineal Res 2024; 76:e12954. [PMID: 38618998 DOI: 10.1111/jpi.12954] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 03/22/2024] [Accepted: 03/29/2024] [Indexed: 04/16/2024]
Abstract
Osteoporosis (OP) is a severe global health issue that has significant implications for productivity and human lifespan. Gut microbiota dysbiosis has been demonstrated to be closely associated with OP progression. Melatonin (MLT) is an important endogenous hormone that modulates bone metabolism, maintains bone homeostasis, and improves OP progression. Multiple studies indicated that MLT participates in the regulation of intestinal microbiota and gut barrier function. However, the promising effects of gut microbiota-derived MLT in OP remain unclear. Here, we found that OP resulted in intestinal tryptophan disorder and decreased the production of gut microbiota-derived MLT, while administration with MLT could mitigate OP-related clinical symptoms and reverse gut microbiota dysbiosis, including the diversity of intestinal microbiota, the relative abundance of many probiotics such as Allobaculum and Parasutterella, and metabolic function of intestinal flora such as amino acid metabolism, nucleotide metabolism, and energy metabolism. Notably, MLT significantly increased the production of short-chain fatty acids and decreased trimethylamine N-oxide-related metabolites. Importantly, MLT could modulate the dynamic balance of M1/M2 macrophages, reduce the serum levels of pro-inflammatory cytokines, and restore gut-barrier function. Taken together, our results highlighted the important roles of gut microbially derived MLT in OP progression via the "gut-bone" axis associated with SCFA metabolism, which may provide novel insight into the development of MLT as a promising drug for treating OP.
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Affiliation(s)
- Yueqi Chen
- Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing, China
- Department of Orthopedics, Chinese PLA 76th Army Corps Hospital, Beijing, Xining, China
| | - Chuan Yang
- Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing, China
- Department of Biomedical Materials Science, Third Military Medical University, Chongqing, China
| | - Zihan Deng
- Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Tingwen Xiang
- Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Qingrong Ni
- Department of Dermatology, Air Force Medical Center, Fourth Military Medical University, Beijing, China
| | - Jianzhong Xu
- Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Dong Sun
- Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Fei Luo
- Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing, China
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Hartley S, Daville R, Jonathan L, Raverot V, Di Maria J, Bossard I, Bensmail D, Quera-Salva MA, Leotard A. Melatonin secretion and sleep disorders in patients with spinal cord injuries. Spinal Cord 2024; 62:143-148. [PMID: 38347109 DOI: 10.1038/s41393-024-00959-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/15/2024] [Accepted: 01/22/2024] [Indexed: 04/11/2024]
Abstract
STUDY DESIGN Prospective observational study. OBJECTIVES To evaluate melatonin secretion, daytime sleepiness and sleep disorders in patients with spinal cord injuries (SCI), and their association with lesion level. SETTING Specialized neuro rehabilitation hospital in France METHODS: Prospective observational study of patients aged over 18 hospitalized in for spinal cord injury. Sleep quality was measured with the Pittsburgh Sleep Quality Index (PQSI), daytime sleepiness with the Epworth Sleepiness scale (ESS), and melatonin secretion by 24 h urinary dosage of 6-sulphatoxy-melatonin. RESULTS 213 patients were screened, 21 patients were included: 17 complete (AIS A) and 4 lesions (AIS B), 76% of traumatic origin with 12 tetraplegic and 9 paraplegic, mean 10 (range 0.5-40) years after injury. Mean age was 46.8 ± 14.7 years, mean BMI 23.56 ± 4.1 and men outnumbered women (15 vs 6). Melatonin secretion was analyzed by 24 h secretion and by secretion profile. Comparing retained vs abolished secretion, only 23% (4/17) of patients with a lesion above T8 retained melatonin secretion, compared to 80% (4/5) with a lesion below T8 (p = 0.022). Non significant differences were found in secretion profile in patients who retained secretion: no patient with a lesion above T8 had a normal secretion profile compared to 50% with a lesion below T8 and in the impact of partial vs total lesions above T8 in whom 17% (2/12) of complete ASIA-A lesions and 50% (2/4) of incomplete lesions retained secretion. CONCLUSION Lesions of the spinal cord above T8 are strongly associated with abolition of melatonin secretion.
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Affiliation(s)
- Sarah Hartley
- Département de physiologie, explorations fonctionnelles, unité des pathologies du sommeil, AP-HP, Hôpital Raymond Poincaré, GHU Paris Saclay, Garches, France.
| | - Raphaëlla Daville
- Département de physiologie, explorations fonctionnelles, unité des pathologies du sommeil, AP-HP, Hôpital Raymond Poincaré, GHU Paris Saclay, Garches, France
| | - Levy Jonathan
- Service de médecine physique et de réadaptation, Hôpital Raymond Poincaré, GHU Paris Saclay, AP-HP, 104, boulevard Raymond-Poincaré, 92380, Garches, France
- Sleep Lab Initiative In PMR group (SLIIP), Garches, France
| | - Véronique Raverot
- Centre de Biologie et de Pathologie, Groupement Hospitalier Est, 69677, Bron, France
| | - Julie Di Maria
- Département de physiologie, explorations fonctionnelles, unité des pathologies du sommeil, AP-HP, Hôpital Raymond Poincaré, GHU Paris Saclay, Garches, France
- Université Paris-Saclay, UVSQ, « End:icap » U1179 Inserm, 78000, Versailles, France
| | - Isabelle Bossard
- CIC 1429 Inserm Hôpital Raymond Poincaré Garches, 92380, Garches, France
| | - Djamel Bensmail
- Service de médecine physique et de réadaptation, Hôpital Raymond Poincaré, GHU Paris Saclay, AP-HP, 104, boulevard Raymond-Poincaré, 92380, Garches, France
- Université Paris-Saclay, UVSQ, « End:icap » U1179 Inserm, 78000, Versailles, France
| | - M A Quera-Salva
- Département de physiologie, explorations fonctionnelles, unité des pathologies du sommeil, AP-HP, Hôpital Raymond Poincaré, GHU Paris Saclay, Garches, France
| | - Antoine Leotard
- Département de physiologie, explorations fonctionnelles, unité des pathologies du sommeil, AP-HP, Hôpital Raymond Poincaré, GHU Paris Saclay, Garches, France
- Sleep Lab Initiative In PMR group (SLIIP), Garches, France
- Université Paris-Saclay, UVSQ, « End:icap » U1179 Inserm, 78000, Versailles, France
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Shao R, Wang Y, He C, Chen L. Melatonin and its Emerging Physiological Role in Reproduction: A Review and Update. Curr Mol Med 2024; 24:449-456. [PMID: 37070447 DOI: 10.2174/1566524023666230417103201] [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: 10/25/2022] [Revised: 02/24/2023] [Accepted: 02/28/2023] [Indexed: 04/19/2023]
Abstract
Melatonin is a neuroendocrine hormone secreted by the pineal gland. The secretion of melatonin follows a circadian rhythm controlled by the suprachiasmatic nucleus, and its secretion is synchronized with the changes in light and dark periods in nature, with the highest secretion level at night. Melatonin is a critical hormone that coordinates external light stimulation and cellular responses of the body. It transmits information about the environmental light cycle, including the circadian and seasonal rhythms, to the relevant tissues and organs in the body, which, along with changes in its secretion level, ensures that its regulated functional activities are adapted in response to changes in the outside environment. Melatonin takes beneficial actions mainly through the interaction with specific membrane-bound receptors, termed MT1 and MT2. Melatonin also acts as a scavenger of free radicals via non-receptor-mediated mechanism. For more than half of acentury melatonin has been associated with vertebrate reproduction, especially in the context of seasonal breeding. Though modern humans show little remaining reproductive seasonality, the relationships between melatonin and human reproduction continue to attract extensive attention. Melatonin plays important roles in improving mitochondrial function, reducing the damage of free radicals, inducing oocyte maturation, increasing fertilization rate and promoting embryonic development, which improves the outcomes of in vitro fertilization and embryo transfer. The present article reviews the progress that has been made in our evolving understanding of the physiological role of melatonin in reproduction and its potential clinical applications in reproductive medicine.
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Affiliation(s)
- Ruifeng Shao
- Reproductive Medicine Center, Jingzhou Hospital affiliated to Yangtze University, No.60 Jingzhong Road, Jingzhou 434020, Hubei, China
| | - Ying Wang
- Reproductive Medicine Center, Jingzhou Hospital affiliated to Yangtze University, No.60 Jingzhong Road, Jingzhou 434020, Hubei, China
| | - Chihua He
- Reproductive Medicine Center, Jingzhou Hospital affiliated to Yangtze University, No.60 Jingzhong Road, Jingzhou 434020, Hubei, China
| | - Ligang Chen
- Department of Respiratory and Critical Care Medicine, The First People's Hospital of Jingzhou, No.55 Jianghan North Road, Jingzhou 434021, Hubei, China
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Jacobs S, Payne C, Shaboodien S, Kgatla T, Pretorius A, Jumaar C, Sanni O, Butrous G, Maarman G. Gut microbiota crosstalk mechanisms are key in pulmonary hypertension: The involvement of melatonin is instrumental too. Pulm Circ 2023; 13:e12277. [PMID: 37583483 PMCID: PMC10423855 DOI: 10.1002/pul2.12277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 08/02/2023] [Accepted: 08/02/2023] [Indexed: 08/17/2023] Open
Abstract
The microbiota refers to a plethora of microorganisms with a gene pool of approximately three million, which inhabits the human gastrointestinal tract or gut. The latter, not only promotes the transport of nutrients, ions, and fluids from the lumen to the internal environment but is linked with the development of diseases including coronary artery disease, heart failure, and lung diseases. The exact mechanism of how the microbiota achieves crosstalk between itself and distant organs/tissues is not clear, but factors released to other organs may play a role, like inflammatory and genetic factors, and now we highlight melatonin as a novel mediator of the gut-lung crosstalk. Melatonin is present in high concentrations in the gut and the lung and has recently been linked to the pathogenesis of pulmonary hypertension (PH). In this comprehensive review of the literature, we suggest that melatonin is an important link between the gut microbiota and the development of PH (where suppressed melatonin-crosstalk between the gut and lungs could promote the development of PH). More studies are needed to investigate the link between the gut microbiota, melatonin and PH. Studies could also investigate whether microbiota genes play a role in the epigenetic aspects of PH. This is relevant because, for example, dysbiosis (caused by epigenetic factors) could reduce melatonin signaling between the gut and lungs, reduce subcellular melatonin concentrations in the gut/lungs, or reduce melatonin serum levels secondary to epigenetic factors. This area of research is largely unexplored and further studies are warranted.
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Affiliation(s)
- Steve Jacobs
- CARMA: Centre for Cardio‐Metabolic Research in Africa, Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine & Health SciencesStellenbosch UniversityCape TownSouth Africa
| | - Carmen Payne
- CARMA: Centre for Cardio‐Metabolic Research in Africa, Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine & Health SciencesStellenbosch UniversityCape TownSouth Africa
| | - Sara Shaboodien
- CARMA: Centre for Cardio‐Metabolic Research in Africa, Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine & Health SciencesStellenbosch UniversityCape TownSouth Africa
| | - Thato Kgatla
- CARMA: Centre for Cardio‐Metabolic Research in Africa, Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine & Health SciencesStellenbosch UniversityCape TownSouth Africa
| | - Amy Pretorius
- CARMA: Centre for Cardio‐Metabolic Research in Africa, Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine & Health SciencesStellenbosch UniversityCape TownSouth Africa
| | - Chrisstoffel Jumaar
- CARMA: Centre for Cardio‐Metabolic Research in Africa, Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine & Health SciencesStellenbosch UniversityCape TownSouth Africa
| | - Olakunle Sanni
- CARMA: Centre for Cardio‐Metabolic Research in Africa, Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine & Health SciencesStellenbosch UniversityCape TownSouth Africa
| | - Ghazwan Butrous
- School of Pharmacy, Imperial College of LondonUniversity of KentCanterburyUK
| | - Gerald Maarman
- CARMA: Centre for Cardio‐Metabolic Research in Africa, Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine & Health SciencesStellenbosch UniversityCape TownSouth Africa
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Rubinstein MR, Burgueño AL, Quiroga S, Wald MR, Genaro AM. Current Understanding of the Roles of Gut-Brain Axis in the Cognitive Deficits Caused by Perinatal Stress Exposure. Cells 2023; 12:1735. [PMID: 37443769 PMCID: PMC10340286 DOI: 10.3390/cells12131735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 06/15/2023] [Accepted: 06/19/2023] [Indexed: 07/15/2023] Open
Abstract
The term 'perinatal environment' refers to the period surrounding birth, which plays a crucial role in brain development. It has been suggested that dynamic communication between the neuro-immune system and gut microbiota is essential in maintaining adequate brain function. This interaction depends on the mother's status during pregnancy and/or the newborn environment. Here, we show experimental and clinical evidence that indicates that the perinatal period is a critical window in which stress-induced immune activation and altered microbiota compositions produce lasting behavioral consequences, although a clear causative relationship has not yet been established. In addition, we discuss potential early treatments for preventing the deleterious effect of perinatal stress exposure. In this sense, early environmental enrichment exposure (including exercise) and melatonin use in the perinatal period could be valuable in improving the negative consequences of early adversities. The evidence presented in this review encourages the realization of studies investigating the beneficial role of melatonin administration and environmental enrichment exposure in mitigating cognitive alteration in offspring under perinatal stress exposure. On the other hand, direct evidence of microbiota restoration as the main mechanism behind the beneficial effects of this treatment has not been fully demonstrated and should be explored in future studies.
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Affiliation(s)
- Mara Roxana Rubinstein
- Laboratorio de Psiconeuroendocrinoinmunologia, Instituto de Investigaciones Biomédicas, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)—Pontificia Universidad Católica Argentina, Buenos Aires C1107AFF, Argentina; (A.L.B.); (S.Q.); (M.R.W.)
| | | | | | | | - Ana María Genaro
- Laboratorio de Psiconeuroendocrinoinmunologia, Instituto de Investigaciones Biomédicas, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)—Pontificia Universidad Católica Argentina, Buenos Aires C1107AFF, Argentina; (A.L.B.); (S.Q.); (M.R.W.)
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17
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Markowska M, Niemczyk S, Romejko K. Melatonin Treatment in Kidney Diseases. Cells 2023; 12:cells12060838. [PMID: 36980179 PMCID: PMC10047594 DOI: 10.3390/cells12060838] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 03/01/2023] [Accepted: 03/07/2023] [Indexed: 03/11/2023] Open
Abstract
Melatonin is a neurohormone that is mainly secreted by the pineal gland. It coordinates the work of the superior biological clock and consequently affects many processes in the human body. Disorders of the waking and sleeping period result in nervous system imbalance and generate metabolic and endocrine derangements. The purpose of this review is to provide information regarding the potential benefits of melatonin use, particularly in kidney diseases. The impact on the cardiovascular system, diabetes, and homeostasis causes melatonin to be indirectly connected to kidney function and quality of life in people with chronic kidney disease. Moreover, there are numerous reports showing that melatonin plays a role as an antioxidant, free radical scavenger, and cytoprotective agent. This means that the supplementation of melatonin can be helpful in almost every type of kidney injury because inflammation, apoptosis, and oxidative stress occur, regardless of the mechanism. The administration of melatonin has a renoprotective effect and inhibits the progression of complications connected to renal failure. It is very important that exogenous melatonin supplementation is well tolerated and that the number of side effects caused by this type of treatment is low.
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18
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Chen KH, Zeng BY, Zeng BS, Sun CK, Cheng YS, Su KP, Wu YC, Chen TY, Lin PY, Liang CS, Hsu CW, Chu CS, Chen YW, Yeh PY, Wu MK, Tseng PT, Hsu CY. The efficacy of exogenous melatonin supplement in ameliorating irritable bowel syndrome severity: A meta-analysis of randomized controlled trials. J Formos Med Assoc 2023; 122:276-285. [PMID: 36257872 DOI: 10.1016/j.jfma.2022.10.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 09/27/2022] [Accepted: 10/02/2022] [Indexed: 02/22/2023] Open
Abstract
BACKGROUND Irritable bowel syndrome (IBS) was found in 11% of the general population worldwide. The current pharmacologic management of IBS was unsatisfactory, and it was accompanied by a number of adverse events. Melatonin was found to play an important role in gastrointestinal smooth muscle motility. Dysregulation of endogenous melatonin secretion has been found in IBS patients. Exogenous melatonin supplement has become one alternative treatment for IBS, but the evidence is inconclusive. The current meta-analysis sought to determine the efficacy of exogenous melatonin supplement in improving IBS severity in IBS patients. METHODS We included randomized controlled trials (RCTs) that investigated the efficacy of exogenous melatonin supplement in ameliorating IBS severity in IBS patients. This meta-analysis was conducted using a random effects model. The primary target outcomes were changes in IBS severity associated with melatonin or placebo. RESULTS This meta-analysis of 4 RCTs and 115 participants revealed that exogenous melatonin supplement was associated with significantly better improvement in overall IBS severity than placebo (k = 4, Hedges' g = 0.746, 95% confidence intervals = 0.401-1.091, p < 0.001). The subgroup without concurrent medication had the same result (p < 0.001). In addition, exogenous melatonin supplement was also associated with significantly better improvement in IBS pain severity (p < 0.001) and quality of life (p = 0.007) than placebo, but not in abdominal distension (p = 0.111) or sleep quality (p = 0.142). Finally, melatonin was associated with similar safety profiles with placebo. CONCLUSION This meta-analysis provides evidence for the use of exogenous melatonin in IBS patients to ameliorate overall IBS severity, IBS pain severity, and quality of life. TRIAL REGISTRATION PROSPERO CRD42021269451.
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Affiliation(s)
- Keng-Hsu Chen
- Department of Medical Education, E-Da Hospital, E-Da Healthcare Group, Kaohsiung, Taiwan
| | - Bing-Yan Zeng
- Department of Internal Medicine, E-Da Dachang Hospital, Kaohsiung, Taiwan; Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Bing-Syuan Zeng
- Department of Internal Medicine, E-Da Cancer Hospital, Kaohsiung, Taiwan; Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Cheuk-Kwan Sun
- Department of Emergency Medicine, E-Da Hospital, Kaohsiung, Taiwan; School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan
| | - Yu-Shian Cheng
- Department of Psychiatry, Tsyr-Huey Mental Hospital, Kaohsiung Jen-Ai's Home, Taiwan; Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Kuan-Pin Su
- Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan; College of Medicine, China Medical University, Taichung, Taiwan; An-Nan Hospital, China Medical University, Tainan, Taiwan
| | - Yi-Cheng Wu
- Department of Sports Medicine, Landseed International Hospital, Taoyuan, Taiwan
| | - Tien-Yu Chen
- Department of Psychiatry, Tri-Service General Hospital; School of Medicine, National Defense Medical Center, Taipei, Taiwan; Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Pao-Yen Lin
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chih-Sung Liang
- Department of Psychiatry, Beitou Branch, Tri-Service General Hospital; School of Medicine, National Defense Medical Center, Taipei, Taiwan; Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Chih-Wei Hsu
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Che-Sheng Chu
- Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Center for Geriatric and Gerontology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Yen-Wen Chen
- Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung City, Taiwan
| | - Pin-Yang Yeh
- Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan
| | - Ming-Kung Wu
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
| | - Ping-Tao Tseng
- Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung City, Taiwan; Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan; Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan; Institute of Precision Medicine, National Sun Yat-sen University, Kaohsiung City, Taiwan.
| | - Chung-Yao Hsu
- Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Neurology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
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Serotonin and Melatonin in Human Lower Gastrointestinal Tract. Diagnostics (Basel) 2023; 13:diagnostics13020204. [PMID: 36673013 PMCID: PMC9857959 DOI: 10.3390/diagnostics13020204] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 12/21/2022] [Accepted: 12/28/2022] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND AND AIMS Melatonin is a ubiquitous hormone produced not only by the pineal gland but also by other organs and tissues. It is involved in the regulation of several gastrointestinal functions. The main cells responsible for the production and release of extrapineal melatonin are the enterochromaffin (EC) cells that produce serotonin. They are involved in the pathogenesis of neuromotor disorders that characterize functional gastrointestinal disorders and in the pathophysiology of inflammatory intestinal diseases. Our aim was the immunohistochemical highlighting on biopsy samples of normal gastrointestinal mucosa and in ulcerative colitis (UC) of immunoreactive cells for melatonin and serotonin in order to identify any differences in their distribution. MATERIALS AND METHODS Our prospective case-control study involves the highlighting on human mucosal biopsies of immunoreactive cells for melatonin and serotonin. All patients undergoing colonoscopy + ileoscopy were considered eligible for the study, divided into two groups: 1. patients with active ulcerative colitis (UC); 2. control group consisting of patients undergoing endoscopic examination for colorectal cancer screening. RESULTS Twenty-one patients were enrolled. The controls had a higher concentration of EC cells containing 5HT particularly in the rectum (p value ≤ 0.05). In patients with active colitis the expression of 5-HT-iR was greater in all tracts of the colon. The correlation analysis in UC patients shows that a higher expression of 5-HT-iR+ cells corresponds to a lower extension of the disease and a greater severity of the same. CONCLUSIONS 5HT+ cells decreased in the case of UC compared to healthy controls. In the severe disease, there was an increase in the expression of melatonin-secreting cells, probably as a compensatory response to the inflammation and oxidative stress. This increase is negatively correlated with the extent of the disease and positively with the severity of the same.
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Cyrino JC, de Figueiredo AC, Córdoba-Moreno MO, Gomes FR, Titon SCM. Day Versus Night Melatonin and Corticosterone Modulation by LPS in Distinct Tissues of Toads (Rhinella Icterica). Integr Comp Biol 2022; 62:1606-1617. [PMID: 35568500 DOI: 10.1093/icb/icac028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 04/30/2022] [Indexed: 01/05/2023] Open
Abstract
Pathogen-associated molecular patterns modulate melatonin (MEL) production in the pineal and extra-pineal sites and corticosterone (CORT) synthesis in the adrenal/interrenal and other tissues. Both MEL and CORT play essential and complex immunomodulatory roles, controlling the inflammatory response. Given that most of what we know about these interactions is derived from mammalian studies, discovering how MEL and CORT are modulated following an immune challenge in anurans would increase understanding of how conserved these immune-endocrine interactions are in vertebrates. Herein, we investigated the modulation of MEL and CORT in plasma vs. local tissues of toads (Rhinella icterica) in response to an immune challenge with lipopolysaccharide (LPS; 2 mg/kg) at day and night. Blood samples were taken 2 hours after injection (noon and midnight), and individuals were killed for tissue collection (bone marrow, lungs, liver, and intestine). MEL and CORT were determined in plasma and tissue homogenates. LPS treatment increased MEL concentration in bone marrow during the day. Intestine MEL levels were higher at night than during the day, particularly in LPS-injected toads. Bone marrow and lungs showed the highest MEL levels among tissues. Plasma MEL levels were not affected by either the treatment or the phase. Plasma CORT levels increased in LPS-treated individuals, with an accentuated increase at night. Otherwise, CORT concentration in the tissues was not affected by LPS exposure. Modulation of MEL levels in bone marrow suggests this tissue may participate in the toad's inflammatory response assembly. Moreover, MEL and CORT levels were different in tissues, pointing to an independent modulation of hormonal concentration. Our results suggest an important role of immune challenge in modulating MEL and CORT, bringing essential insights into the hormone-immune interactions during anuran's inflammatory response.
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Affiliation(s)
- João Cunha Cyrino
- Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, São Paulo CEP 05508-090, São Paulo, Brasil
| | - Aymam Cobo de Figueiredo
- Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, São Paulo CEP 05508-090, São Paulo, Brasil
| | - Marlina Olyissa Córdoba-Moreno
- Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, São Paulo CEP 05508-090, São Paulo, Brasil
| | - Fernando Ribeiro Gomes
- Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, São Paulo CEP 05508-090, São Paulo, Brasil
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Iesanu MI, Zahiu CDM, Dogaru IA, Chitimus DM, Pircalabioru GG, Voiculescu SE, Isac S, Galos F, Pavel B, O’Mahony SM, Zagrean AM. Melatonin-Microbiome Two-Sided Interaction in Dysbiosis-Associated Conditions. Antioxidants (Basel) 2022; 11:2244. [PMID: 36421432 PMCID: PMC9686962 DOI: 10.3390/antiox11112244] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 11/07/2022] [Accepted: 11/09/2022] [Indexed: 08/27/2023] Open
Abstract
Melatonin is a pineal indolamine, allegedly known as a circadian rhythm regulator, and an antioxidative and immunomodulatory molecule. In both experimental and clinical trials, melatonin has been shown to have positive effects in various pathologies, as a modulator of important biochemical pathways including inflammation, oxidative stress, cell injury, apoptosis, and energy metabolism. The gut represents one of melatonin's most abundant extra pineal sources, with a 400-times-higher concentration than the pineal gland. The importance of the gut microbial community-namely, the gut microbiota, in multiple critical functions of the organism- has been extensively studied throughout time, and its imbalance has been associated with a variety of human pathologies. Recent studies highlight a possible gut microbiota-modulating role of melatonin, with possible implications for the treatment of these pathologies. Consequently, melatonin might prove to be a valuable and versatile therapeutic agent, as it is well known to elicit positive functions on the microbiota in many dysbiosis-associated conditions, such as inflammatory bowel disease, chronodisruption-induced dysbiosis, obesity, and neuropsychiatric disorders. This review intends to lay the basis for a deeper comprehension of melatonin, gut microbiota, and host-health subtle interactions.
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Affiliation(s)
- Mara Ioana Iesanu
- Department of Functional Sciences, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Pediatrics, Marie Curie Emergency Children’s Hospital, 041451 Bucharest, Romania
| | - Carmen Denise Mihaela Zahiu
- Department of Functional Sciences, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Ioana-Alexandra Dogaru
- Department of Functional Sciences, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Diana Maria Chitimus
- Department of Functional Sciences, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Gratiela Gradisteanu Pircalabioru
- Section Earth, Environmental and Life Sciences, Research Institute of the University of Bucharest, 050663 Bucharest, Romania
- Academy of Romanian Scientists, 54 Splaiul Independentei Street, District 5, 050094 Bucharest, Romania
| | - Suzana Elena Voiculescu
- Department of Functional Sciences, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Sebastian Isac
- Department of Functional Sciences, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Anesthesiology and Intensive Care I, ‘Fundeni’ Clinical Institute, 022328 Bucharest, Romania
| | - Felicia Galos
- Department of Pediatrics, Marie Curie Emergency Children’s Hospital, 041451 Bucharest, Romania
- Department of Pediatrics, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Bogdan Pavel
- Department of Functional Sciences, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Siobhain M. O’Mahony
- Department of Anatomy and Neuroscience, University College Cork, T12 XF62 Cork, Ireland
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland
| | - Ana-Maria Zagrean
- Department of Functional Sciences, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
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22
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Zhang B, Chen T, Cao M, Yuan C, Reiter RJ, Zhao Z, Zhao Y, Chen L, Fan W, Wang X, Zhou X, Li C. Gut Microbiota Dysbiosis Induced by Decreasing Endogenous Melatonin Mediates the Pathogenesis of Alzheimer's Disease and Obesity. Front Immunol 2022; 13:900132. [PMID: 35619714 PMCID: PMC9127079 DOI: 10.3389/fimmu.2022.900132] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 04/13/2022] [Indexed: 01/15/2023] Open
Abstract
Lifestyle choices, external environment, aging, and other factors influence the synthesis of melatonin. Although the physiological functions of melatonin have been widely studied in relation to specific organs, the systemic effects of endogenous melatonin reduction has not been reported. This study evaluates the systemic changes and possible pathogenic risks in an endogenous melatonin reduction (EMR) mouse model deficient in the rate limiting enzyme in melatonin production, arylalkylamine N-acetyltransferase (Aanat) gene. Using this model, we identified a new relationship between melatonin, Alzheimer’s disease (AD), and gut microbiota. Systematic changes were evaluated using multi-omics analysis. Fecal microbiota transplantation (FMT) was performed to examine the role of gut microbiota in the pathogenic risks of EMR. EMR mice exhibited a pan-metabolic disorder, with significant transcriptome changes in 11 organs, serum metabolome alterations as well as microbiota dysbiosis. Microbiota dysbiosis was accompanied by increased gut permeability along with gut and systemic inflammation. Correlation analysis revealed that systemic inflammation may be related to the increase of Ruminiclostridium_5 relative abundance. 8-month-old EMR mice had AD-like phenotypes, including Iba-1 activation, A β protein deposition and decreased spatial memory ability. Moreover, EMR mice showed decreased anti stress ability, under high-fat diet, EMR mice had greater body weight and more obvious hepatic steatosis compared with WT group. FMT improved gut permeability, systemic inflammation, and AD-related phenotypes, while reducing obesity in EMR mice. Our findings suggest EMR causes systemic changes mediated by gut microbiota dysbiosis, which may be a pathogenic factor for AD and obesity, we further proved the gut microbiota is a potential target for the prevention and treatment of AD and obesity.
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Affiliation(s)
- Boqi Zhang
- College of Animal Sciences, Jilin University, Changchun, China
| | - Tong Chen
- College of Animal Sciences, Jilin University, Changchun, China
| | - Maosheng Cao
- College of Animal Sciences, Jilin University, Changchun, China
| | - Chenfeng Yuan
- College of Animal Sciences, Jilin University, Changchun, China
| | - Russel J Reiter
- Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, United States
| | - Zijiao Zhao
- College of Animal Sciences, Jilin University, Changchun, China
| | - Yun Zhao
- College of Animal Sciences, Jilin University, Changchun, China
| | - Lu Chen
- College of Animal Sciences, Jilin University, Changchun, China
| | - Wenjing Fan
- College of Animal Sciences, Jilin University, Changchun, China
| | - Xin Wang
- College of Animal Sciences, Jilin University, Changchun, China
| | - Xu Zhou
- College of Animal Sciences, Jilin University, Changchun, China
| | - Chunjin Li
- College of Animal Sciences, Jilin University, Changchun, China
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23
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Tripathi AM, Khan S, Chaudhury NK. Radiomitigation by Melatonin in C57BL/6 Mice: Possible Implications as Adjuvant in Radiotherapy and Chemotherapy. In Vivo 2022; 36:1203-1221. [PMID: 35478105 DOI: 10.21873/invivo.12820] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/28/2022] [Accepted: 03/03/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIM Melatonin (N-acetyl-5-methoxytryptamine), a chief secretory molecule of the pineal gland, has multiple properties, and numerous clinical investigations regarding its actions are in progress. This study investigated the radiomitigative role of melatonin in C57BL/6 mice. MATERIALS AND METHODS Melatonin (100 mg/kg) was orally administered once daily starting at 1 h on day 1 and subsequently every 24 h until day 7 after whole-body irradiation (WBI) and survival was monitored for 30 days. The bone marrow, spleen, and intestine were studied to evaluate the mitigative potential of melatonin after radiation-induced damage. RESULTS Melatonin significantly improved the survival upto 60% and 90% after 9 Gy (lethal) and 7.5 Gy (sub-lethal) WBI, respectively. Melatonin alleviated WBI-induced myelosuppression and pancytopenia, and increased white blood cell, red blood cell, platelet, and lymphocyte (CD4+ and CD8+) counts in peripheral blood. Bone marrow and spleen cellularity were restored through enhanced haematopoiesis. Melatonin ameliorated the damage in the small intestine, and promoted recovery of villi length, crypts number, and goblet cell count. CONCLUSION Melatonin mitigates the radiation-induced injury in the gastrointestinal and haematopoietic systems. The observed radiomitigative properties of melatonin can also be useful in the context of adjuvant therapy for cancer and radiotherapy.
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Affiliation(s)
- Akanchha Mani Tripathi
- Division of Radiation Biodosimetry, Institute of Nuclear Medicine and Allied Science, Defence Research & Development Organization, Delhi, India
| | - Shahanshah Khan
- Division of Radiation Biodosimetry, Institute of Nuclear Medicine and Allied Science, Defence Research & Development Organization, Delhi, India
| | - Nabo Kumar Chaudhury
- Division of Radiation Biodosimetry, Institute of Nuclear Medicine and Allied Science, Defence Research & Development Organization, Delhi, India
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24
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Li W, Li T, Liu L, Han Q, Zhang H, Sun Y, Hao R, Ma S. Seasonal photoperiodic influence of pineal melatonin on hypothalamic-pituitary-adrenal axis-hippocampal-receptor in male rats. JOURNAL OF TRADITIONAL CHINESE MEDICAL SCIENCES 2022. [DOI: 10.1016/j.jtcms.2022.03.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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25
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Zhao ZX, Yuan X, Cui YY, Liu J, Shen J, Jin BY, Feng BC, Zhai YJ, Zheng MQ, Kou GJ, Zhou RC, Li LX, Zuo XL, Li SY, Li YQ. Melatonin Mitigates Oxazolone-Induced Colitis in Microbiota-Dependent Manner. Front Immunol 2022; 12:783806. [PMID: 35116024 PMCID: PMC8805729 DOI: 10.3389/fimmu.2021.783806] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 12/23/2021] [Indexed: 12/18/2022] Open
Abstract
Levels of type 2 cytokines are elevated in the blood and intestinal tissues of ulcerative colitis (UC) patients in the active phase; this phenomenon indicates the participation of type 2 immune response in UC progression. The beneficial effects of melatonin in dextran sodium sulfate (DSS) and 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis models have been illustrated, but its role in the oxazolone (Oxa)-induced colitis model (driven by type 2 immune response) remains relatively unknown. We investigated the relationship between melatonin concentration and the severity of UC, revealing a significantly negative correlation. Subsequently, we investigated the effects of melatonin in Oxa-induced colitis mice and the potential underlying mechanisms. Administration of melatonin significantly counteracted body weight loss, colon shortening, and neutrophil infiltration in Oxa-induced colitis mice. Melatonin treatment mitigated Oxa-induced colitis by suppressing type 2 immune response. In addition, melatonin attenuated intestinal permeability by enhancing the expression of ZO-1 and occludin in colitis mice. Interestingly, the protective effect of melatonin was abolished when the mice were co-housed, indicating that the regulation of gut microbiota by melatonin was critical in alleviating Oxa-induced colitis. Subsequently, 16S rRNA sequencing was performed to explore the microbiota composition. Decreased richness and diversity of intestinal microbiota at the operational taxonomic unit (OTU) level resulted from melatonin treatment. Melatonin also elevated the abundance of Bifidobacterium, a well-known probiotic, and reduced proportions of several harmful bacterial genera, such as Desulfovibrio, Peptococcaceae, and Lachnospiraceae. Fecal microbiota transplantation (FMT) was used to explore the role of microbiota in the function of melatonin in Oxa-induced colitis. Microbiota transplantation from melatonin-treated mice alleviated Oxa-induced colitis, suggesting that the microbiome participates in the relief of Oxa-induced colitis by melatonin. Our findings demonstrate that melatonin ameliorates Oxa-induced colitis in a microbiota-dependent manner, suggesting the therapeutic potential of melatonin in treating type 2 immunity-associated UC.
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Affiliation(s)
- Zi-xiao Zhao
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xi Yuan
- Advanced Medical Research Institute, Shandong University, Jinan, China
| | - Yan-yan Cui
- Advanced Medical Research Institute, Shandong University, Jinan, China
| | - Jun Liu
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Robot Engineering Laboratory for Precise Diagnosis and Therapy of GI Tumor, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jing Shen
- Advanced Medical Research Institute, Shandong University, Jinan, China
| | - Bi-ying Jin
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Bing-cheng Feng
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yun-jiao Zhai
- Advanced Medical Research Institute, Shandong University, Jinan, China
| | - Meng-qi Zheng
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Guan-jun Kou
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ru-chen Zhou
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Li-xiang Li
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Robot Engineering Laboratory for Precise Diagnosis and Therapy of GI Tumor, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiu-li Zuo
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Robot Engineering Laboratory for Precise Diagnosis and Therapy of GI Tumor, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shi-yang Li
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Advanced Medical Research Institute, Shandong University, Jinan, China
- Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan, China
| | - Yan-qing Li
- Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Laboratory of Translational Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Robot Engineering Laboratory for Precise Diagnosis and Therapy of GI Tumor, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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Yener S, Akbulut KG, Karakuş R, Erdoğan D, Acartürk F. Development of melatonin loaded pectin nanoparticles for the treatment of inflammatory bowel disease: In vitro and in vivo studies. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2021.102861] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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27
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Bendarska-Czerwińska A, Zmarzły N, Morawiec E, Panfil A, Bryś K, Czarniecka J, Ostenda A, Dziobek K, Sagan D, Boroń D, Michalski P, Pallazo-Michalska V, Grabarek BO. Endocrine disorders and fertility and pregnancy: An update. Front Endocrinol (Lausanne) 2022; 13:970439. [PMID: 36733805 PMCID: PMC9887196 DOI: 10.3389/fendo.2022.970439] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 12/28/2022] [Indexed: 01/18/2023] Open
Abstract
It is estimated that more and more couples suffer from fertility and pregnancy maintenance disorders. It is associated with impaired androgen secretion, which is influenced by many factors, ranging from genetic to environmental. It is also important to remember that fertility disorders can also result from abnormal anatomy of the reproductive male and female organ (congenital uterine anomalies - septate, unicornuate, bicornuate uterus; acquired defects of the uterus structure - fibroids, polyps, hypertrophy), disturbed hormonal cycle and obstruction of the fallopian tubes resulting from the presence of adhesions due to inflammation, endometriosis, and surgery, abnormal rhythm of menstrual bleeding, the abnormal concentration of hormones. There are many relationships between the endocrine organs, leading to a chain reaction when one of them fails to function properly. Conditions in which the immune system is involved, including infections and autoimmune diseases, also affect fertility. The form of treatment depends on infertility duration and the patient's age. It includes ovulation stimulation with clomiphene citrate or gonadotropins, metformin use, and weight loss interventions. Since so many different factors affect fertility, it is important to correctly diagnose what is causing the problem and to modify the treatment regimen if necessary. This review describes disturbances in the hormone secretion of individual endocrine organs in the context of fertility and the maintenance of pregnancy.
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Affiliation(s)
- Anna Bendarska-Czerwińska
- Department of Molecular, Biology Gyncentrum Fertility Clinic, Katowice, Poland
- Faculty of Medicine, Academy of Silesia, Zabrze, Poland
- American Medical Clinic, Katowice, Poland
- *Correspondence: Anna Bendarska-Czerwińska, ; Nikola Zmarzły, ; Beniamin Oskar Grabarek,
| | - Nikola Zmarzły
- Department of Histology, Cytophysiology and Embryology, Faculty of Medicine, University of Technology, Academy of Silesia in Katowice, Zabrze, Poland
- *Correspondence: Anna Bendarska-Czerwińska, ; Nikola Zmarzły, ; Beniamin Oskar Grabarek,
| | - Emilia Morawiec
- Department of Molecular, Biology Gyncentrum Fertility Clinic, Katowice, Poland
- Department of Histology, Cytophysiology and Embryology, Faculty of Medicine, University of Technology, Academy of Silesia in Katowice, Zabrze, Poland
- Department of Microbiology, Faculty of Medicine, University of Technology, Academy of Silesia in Katowice, Zabrze, Poland
| | - Agata Panfil
- Department of Histology, Cytophysiology and Embryology, Faculty of Medicine, University of Technology, Academy of Silesia in Katowice, Zabrze, Poland
| | - Kamil Bryś
- Department of Histology, Cytophysiology and Embryology, Faculty of Medicine, University of Technology, Academy of Silesia in Katowice, Zabrze, Poland
| | - Justyna Czarniecka
- Department of Histology, Cytophysiology and Embryology, Faculty of Medicine, University of Technology, Academy of Silesia in Katowice, Zabrze, Poland
| | | | | | - Dorota Sagan
- Medical Center Dormed Medical SPA, Busko-Zdroj, Poland
| | - Dariusz Boroń
- Department of Histology, Cytophysiology and Embryology, Faculty of Medicine, University of Technology, Academy of Silesia in Katowice, Zabrze, Poland
- Department of Gynaecology and Obstetrics, Faculty of Medicine, Academy of Silesia, Zabrze, Poland
- Department of Gynecology and Obstetrics with Gynecologic Oncology, Ludwik Rydygier Memorial Specialized Hospital, Kraków, Poland
- Department of Gynecology and Obstetrics, TOMMED Specjalisci od Zdrowia, Katowice, Poland
| | | | | | - Beniamin Oskar Grabarek
- Department of Molecular, Biology Gyncentrum Fertility Clinic, Katowice, Poland
- Department of Histology, Cytophysiology and Embryology, Faculty of Medicine, University of Technology, Academy of Silesia in Katowice, Zabrze, Poland
- Department of Gynaecology and Obstetrics, Faculty of Medicine, Academy of Silesia, Zabrze, Poland
- Department of Gynecology and Obstetrics with Gynecologic Oncology, Ludwik Rydygier Memorial Specialized Hospital, Kraków, Poland
- Department of Gynecology and Obstetrics, TOMMED Specjalisci od Zdrowia, Katowice, Poland
- *Correspondence: Anna Bendarska-Czerwińska, ; Nikola Zmarzły, ; Beniamin Oskar Grabarek,
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Therapeutic potential of melatonin in colorectal cancer: Focus on lipid metabolism and gut microbiota. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166281. [PMID: 34610472 DOI: 10.1016/j.bbadis.2021.166281] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 08/24/2021] [Accepted: 09/26/2021] [Indexed: 12/24/2022]
Abstract
Colorectal cancer (CRC) is one of the most common gastrointestinal malignancies. The occurrence and development of CRC are complicated processes. Obesity and dysbacteriosis have been increasingly regarded as the main risk factors for CRC. Understanding the etiology of CRC from multiple perspectives is conducive to screening for some potential drugs or new treatment strategies to limit the serious side effects of conventional treatment and prolong the survival of CRC patients. Melatonin, a natural indoleamine, is mainly produced by the pineal gland, but it is also abundant in other tissues, including the gastrointestinal tract, retina, testes, lymphocytes, and Harder's glands. Melatonin could participate in lipid metabolism by regulating adipogenesis and lipolysis. Additionally, many studies have focused on the potential beneficial effects of melatonin in CRC, such as promotion of apoptosis; inhibition of cell proliferation, migration, and invasion; antioxidant activity; and immune regulation. Meaningfully, gut microbiota is the main determinant of all aspects of health and disease (including obesity and tumorigenesis). The gut microbiota is of great significance for understanding the relationship between obesity and increased risk of CRC. Although the current understanding of how the melatonin-mediated gut microbiota coordinates a variety of physiological and pathological activities is fairly comprehensive, there are still many unknown topics to be explored in the face of a complex nutritional status and a changeable microbiota. This review summarizes the potential links among melatonin, lipid metabolism, gut microbiota, and CRC to promote the development of melatonin as a preventive and therapeutic agent for CRC.
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C de Figueiredo A, A K Nogueira L, C M Titon S, R Gomes F, E de Carvalho J. Immune and hormonal regulation of the Boa constrictor (Serpentes; Boidae) in response to feeding. Comp Biochem Physiol A Mol Integr Physiol 2021; 264:111119. [PMID: 34793953 DOI: 10.1016/j.cbpa.2021.111119] [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: 08/31/2021] [Revised: 11/09/2021] [Accepted: 11/11/2021] [Indexed: 11/17/2022]
Abstract
Feeding upregulates immune function and the systemic and local (gastrointestinal tract) concentrations of some immunoregulatory hormones, as corticosterone (CORT) and melatonin (MEL), in mammals and anurans. However, little is known about the immune and hormonal regulation in response to feeding in other ectothermic vertebrates, especially snakes, in which the postprandial metabolic changes are pronounced. Here, we investigated the effects feeding have on hormonal and innate immune responses in the snake, Boa constrictor. We divided juvenile males into two groups: fasting and fed with mice (30% of body mass). We measured the rates of oxygen consumption, plasma CORT levels, heterophil/lymphocyte ratio (HL ratio), plasma bacterial killing ability (BKA), and stomach and intestine MEL in fasting snakes and 48 h after meal intake. We observed increased rates of oxygen consumption, plasma CORT levels, and HL ratio, along with a tendency of decreased stomach and intestine MEL in fed snakes compared to fasting ones. BKA was not affected by feeding. Overall, we found that feeding modulates metabolic rates, CORT levels, and immune cell distribution in boas. Increased baseline CORT may be important to mobilize energy to support the metabolic increment during the postprandial period. Increased HL ratio might be an immunoregulatory effect of increased CORT, which has been shown in different physiological situations such as in response to immune challenge. Our results suggest that feeding activates the hypothalamic-pituitary-adrenal axis and modulates immune cell redistribution, possibly contributing to fighting potential injuries and infections derived from predation and from pathogens present in ingested food.
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Affiliation(s)
- Aymam C de Figueiredo
- Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, Rua do Matão - Travessa 14 - N 101, Cidade Universitária, CEP 05508-900, São Paulo, SP, Brazil.
| | - Letícia A K Nogueira
- Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Campus Diadema, CEP 09972-270, Diadema, SP, Brazil
| | - Stefanny C M Titon
- Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, Rua do Matão - Travessa 14 - N 101, Cidade Universitária, CEP 05508-900, São Paulo, SP, Brazil
| | - Fernando R Gomes
- Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, Rua do Matão - Travessa 14 - N 101, Cidade Universitária, CEP 05508-900, São Paulo, SP, Brazil
| | - José E de Carvalho
- Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Campus Diadema, CEP 09972-270, Diadema, SP, Brazil
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30
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de Figueiredo AC, Titon SCM, Cyrino JC, Nogueira LAK, Gomes FR. Immune and hormonal modulation in the postprandial period of bullfrogs (Lithobates catesbeianus). J Exp Biol 2021; 224:272629. [PMID: 34704595 DOI: 10.1242/jeb.243153] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 10/25/2021] [Indexed: 11/20/2022]
Abstract
Mammals show immune up-regulation and increased plasma and local (gastrointestinal tract) concentrations of some immunoregulatory hormones, such as corticosterone and melatonin, after feeding. However, little is known about the endocrine and immune modulation in the postprandial period of ectothermic animals. This study investigated the effects of feeding on endocrine and immune responses in the bullfrog (Lithobates catesbeianus). Frogs were fasted for 10 days and divided into two groups: fasted and fed with fish feed (5% of body mass). Blood and gastrointestinal tract tissues (stomach and intestine) were collected at 6, 24, 48, 96 and 168 h to measure neutrophil/lymphocyte ratio, plasma bacterial killing ability, phagocytosis of blood leukocytes, plasma corticosterone and melatonin, and stomach and intestine melatonin. Feeding increased plasma corticosterone at 24 h and decreased it at 168 h, and increased neutrophil/lymphocyte ratio at 6, 24 and 96 h. We also observed decreased bacterial killing ability 48 h after feeding. Stomach melatonin increased after 17 days of fasting. We show that feeding activates the hypothalamic-pituitary-interrenal axis and promotes transient immunosuppression, without stimulating an inflammatory response. Increased corticosterone may mobilize energy to support digestive processes and melatonin may protect the stomach during fasting. We conclude that feeding modulates secretion of immunoregulatory hormones, initially increasing plasma corticosterone levels, followed by a decrease at the end of meal digestion, and causes systemic immune cell redistribution, increasing neutrophil/lymphocyte ratio for almost the entire period of meal digestion in bullfrogs. Also, fasting modulates secretion of melatonin in the stomach.
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Affiliation(s)
- Aymam C de Figueiredo
- Department of Physiology, Institute of Biosciences, Universidade de São Paulo, São Paulo, Rua do Matão - Travessa 14 - N 101, Cidade Universitária - CEP 05508-900, São Paulo, SP, Brazil
| | - Stefanny C M Titon
- Department of Physiology, Institute of Biosciences, Universidade de São Paulo, São Paulo, Rua do Matão - Travessa 14 - N 101, Cidade Universitária - CEP 05508-900, São Paulo, SP, Brazil
| | - João C Cyrino
- Department of Physiology, Institute of Biosciences, Universidade de São Paulo, São Paulo, Rua do Matão - Travessa 14 - N 101, Cidade Universitária - CEP 05508-900, São Paulo, SP, Brazil
| | - Letícia A K Nogueira
- Institute of Environmental, Chemical, and Pharmaceutical Sciences, Universidade Federal de São Paulo, Campus Diadema- CEP 09972-270, Diadema, Brazil
| | - Fernando R Gomes
- Department of Physiology, Institute of Biosciences, Universidade de São Paulo, São Paulo, Rua do Matão - Travessa 14 - N 101, Cidade Universitária - CEP 05508-900, São Paulo, SP, Brazil
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31
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Markus RP, Sousa KS, da Silveira Cruz-Machado S, Fernandes PA, Ferreira ZS. Possible Role of Pineal and Extra-Pineal Melatonin in Surveillance, Immunity, and First-Line Defense. Int J Mol Sci 2021; 22:12143. [PMID: 34830026 PMCID: PMC8620487 DOI: 10.3390/ijms222212143] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/23/2021] [Accepted: 10/27/2021] [Indexed: 02/06/2023] Open
Abstract
Melatonin is a highly conserved molecule found in prokaryotes and eukaryotes that acts as the darkness hormone, translating environmental lighting to the whole body, and as a moderator of innate and acquired defense, migration, and cell proliferation processes. This review evaluates the importance of pineal activity in monitoring PAMPs and DAMPs and in mounting an inflammatory response or innate immune response. Activation of the immune-pineal axis, which coordinates the pro-and anti-inflammatory phases of an innate immune response, is described. PAMPs and DAMPs promote the immediate suppression of melatonin production by the pineal gland, which allows leukocyte migration. Monocyte-derived macrophages, important phagocytes of microbes, and cellular debris produce melatonin locally and thereby initiate the anti-inflammatory phase of the acute inflammatory response. The role of locally produced melatonin in organs that directly contact the external environment, such as the skin and the gastrointestinal and respiratory tracts, is also discussed. In this context, as resident macrophages are self-renewing cells, we explore evidence indicating that, besides avoiding overreaction of the immune system, extra-pineal melatonin has a fundamental role in the homeostasis of organs and tissues.
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Affiliation(s)
- Regina P. Markus
- Laboratory Chronopharmacology, Department Physiology, Institute Bioscience, University of São Paulo, São Paulo 05508-090, Brazil; (K.S.S.); (P.A.F.); (Z.S.F.)
| | - Kassiano S. Sousa
- Laboratory Chronopharmacology, Department Physiology, Institute Bioscience, University of São Paulo, São Paulo 05508-090, Brazil; (K.S.S.); (P.A.F.); (Z.S.F.)
| | - Sanseray da Silveira Cruz-Machado
- Laboratory of Molecular, Endocrine and Reproductive Pharmacology, Department of Pharmacology, Escola Paulista de Medicina, UNIFESP, São Paulo 04044-020, Brazil;
| | - Pedro A. Fernandes
- Laboratory Chronopharmacology, Department Physiology, Institute Bioscience, University of São Paulo, São Paulo 05508-090, Brazil; (K.S.S.); (P.A.F.); (Z.S.F.)
| | - Zulma S. Ferreira
- Laboratory Chronopharmacology, Department Physiology, Institute Bioscience, University of São Paulo, São Paulo 05508-090, Brazil; (K.S.S.); (P.A.F.); (Z.S.F.)
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32
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Brown GM, Pandi-Perumal SR, Pupko H, Kennedy JL, Cardinali DP. Melatonin as an Add-On Treatment of COVID-19 Infection: Current Status. Diseases 2021; 9:64. [PMID: 34562971 PMCID: PMC8482145 DOI: 10.3390/diseases9030064] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 09/14/2021] [Accepted: 09/14/2021] [Indexed: 12/14/2022] Open
Abstract
This brief review was written to provide a perspective on the flurry of reports suggesting that melatonin can be an important add-on therapy for COVID-19. Despite the passage of more than 60 years since its discovery and much evidence representing the contrary, there has been great reluctance to conceive melatonin as anything other than a hormone. Many other body chemicals are known to have multiple roles. Melatonin was first shown to be a hormone derived from the pineal gland, to be actively synthesized there only at night, and to act on targets directly or via the G-protein-coupled receptors (GPCRs) superfamily. It is of note that over 40 years ago, it was also established that melatonin is present, synthesized locally, and acts within the gastrointestinal tract. A wider distribution was then found, including the retina and multiple body tissues. In addition, melatonin is now known to have non-hormonal actions, acting as a free radical scavenger, an antioxidant, and as modulating immunity, dampening down innate tissue responses to invaders while boosting the production of antibodies against them. These actions make it a potentially excellent weapon against infection by the SARS-CoV-2 virus. Early published results support that thesis. Recently, a randomized controlled study reported that low doses of melatonin significantly improved symptoms in hospitalized COVID-19 patients, leading to more rapid discharge with no side effects, while significantly decreasing levels of CRP, proinflammatory cytokines, and modulating dysregulated genes governing cellular and humoral immunity. It is now critical that these trials be repeated, with dose-response studies conducted and safety proven. Numerous randomized controlled trials are ongoing, which should complete those objectives while also allowing for a more thorough evaluation of the mechanisms of action and possible applications to other severe diseases.
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Affiliation(s)
- Gregory M. Brown
- Centre for Addiction and Mental Health, Molecular Brain Sciences, Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada;
| | - Seithikurippu R. Pandi-Perumal
- Somnogen Canada Inc., Toronto, ON M6H 1C5, Canada;
- Saveetha Institute of Medical and Technical Sciences, Saveetha Medical College and Hospitals, Saveetha University, Chennai 600077, India
| | - Harold Pupko
- Primary Care Mental Health Physician, Bathurst St., Toronto, ON M3H 3S3, Canada;
| | - James L. Kennedy
- Centre for Addiction and Mental Health, Molecular Brain Sciences, Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada;
| | - Daniel P. Cardinali
- Faculty of Medical Sciences, Pontificia Universidad Católica Argentina, Buenos Aires 1007, Argentina;
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33
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Zhang Z, Peng Q, Huo D, Jiang S, Ma C, Chang H, Chen K, Li C, Pan Y, Zhang J. Melatonin Regulates the Neurotransmitter Secretion Disorder Induced by Caffeine Through the Microbiota-Gut-Brain Axis in Zebrafish ( Danio rerio). Front Cell Dev Biol 2021; 9:678190. [PMID: 34095150 PMCID: PMC8172981 DOI: 10.3389/fcell.2021.678190] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 04/26/2021] [Indexed: 12/12/2022] Open
Abstract
Melatonin has been widely used as a “probiotic agent” capable of producing strong neurotransmitter secretion regulatory effects, and the microbiota-gut-brain axis-related studies have also highlighted the role of the gut microbiota in neuromodulation. In the present study, a zebrafish neural hyperactivity model was established using caffeine induction to explore the regulatory effects of melatonin and probiotic on neurotransmitter secretion disorder in zebrafish. Disorders of brain neurotransmitter secretion (dopamine, γ-aminobutyric acid, and 5-hydroxytryptamine) caused by caffeine were improved after interference treatment with melatonin or probiotic. Shotgun metagenomic sequencing demonstrated that the melatonin-treated zebrafish gradually restored their normal intestinal microbiota and metabolic pathways. Germ-free (GF) zebrafish were used to verify the essential role of intestinal microbes in the regulation of neurotransmitter secretion. The results of the neurotransmitter and short-chain fatty acid determination revealed that the effect on the zebrafish in the GF group could not achieve that on the zebrafish in the melatonin group after adding the same dose of melatonin. The present research revealed the potential mode of action of melatonin through the microbiota-gut-brain axis to regulate the disruption of neurotransmitter secretion, supporting the future development of psychotropic drugs targeting the intestinal microbiota.
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Affiliation(s)
- Zeng Zhang
- Key Laboratory of Food Nutrition and Functional Food of Hainan Province, College of Food Science and Engineering, Hainan University, Haikou, China
| | - Qiannan Peng
- Key Laboratory of Food Nutrition and Functional Food of Hainan Province, College of Food Science and Engineering, Hainan University, Haikou, China.,Institute of Marine Science and Technology, Shandong University, Qingdao, China
| | - Dongxue Huo
- Key Laboratory of Food Nutrition and Functional Food of Hainan Province, College of Food Science and Engineering, Hainan University, Haikou, China
| | - Shuaiming Jiang
- Key Laboratory of Food Nutrition and Functional Food of Hainan Province, College of Food Science and Engineering, Hainan University, Haikou, China
| | - Chenchen Ma
- Key Laboratory of Food Nutrition and Functional Food of Hainan Province, College of Food Science and Engineering, Hainan University, Haikou, China
| | - Haibo Chang
- Key Laboratory of Food Nutrition and Functional Food of Hainan Province, College of Food Science and Engineering, Hainan University, Haikou, China
| | - Kaining Chen
- Hainan Provincial People's Hospital, Haikou, China
| | - Congfa Li
- Key Laboratory of Food Nutrition and Functional Food of Hainan Province, College of Food Science and Engineering, Hainan University, Haikou, China
| | - Yonggui Pan
- Key Laboratory of Food Nutrition and Functional Food of Hainan Province, College of Food Science and Engineering, Hainan University, Haikou, China
| | - Jiachao Zhang
- Key Laboratory of Food Nutrition and Functional Food of Hainan Province, College of Food Science and Engineering, Hainan University, Haikou, China
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34
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Boutin JA, Jockers R. Melatonin controversies, an update. J Pineal Res 2021; 70:e12702. [PMID: 33108677 DOI: 10.1111/jpi.12702] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 10/11/2020] [Accepted: 10/20/2020] [Indexed: 12/13/2022]
Abstract
Melatonin was discovered more than 60 years ago. Since then, several seminal discoveries have allowed us to define its function as a neuroendocrine hormone and its molecular targets in mammals and many other species. However, many fundamental issues have not yet been solved such as the subcellular localization of melatonin synthesis and the full spectrum of its molecular targets. In addition, a considerable number of controversies persist in the field, mainly concerning how many functions melatonin has. Altogether, this illustrates how "immature" the field still is. The intention of this opinion article is to note the controversies and limitations in the field, to initiate a discussion and to make proposals/guidelines to overcome them and move the field forward.
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Affiliation(s)
- Jean A Boutin
- Institut de Recherches Internationales SERVIER, Suresnes Cedex, France
| | - Ralf Jockers
- INSERM, CNRS, Institut Cochin, Université de Paris, Paris, France
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35
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Kopustinskiene DM, Bernatoniene J. Molecular Mechanisms of Melatonin-Mediated Cell Protection and Signaling in Health and Disease. Pharmaceutics 2021; 13:129. [PMID: 33498316 PMCID: PMC7909293 DOI: 10.3390/pharmaceutics13020129] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/14/2021] [Accepted: 01/18/2021] [Indexed: 01/07/2023] Open
Abstract
Melatonin, an endogenously synthesized indolamine, is a powerful antioxidant exerting beneficial action in many pathological conditions. Melatonin protects from oxidative stress in ischemic/reperfusion injury, neurodegenerative diseases, and aging, decreases inflammation, modulates the immune system, inhibits proliferation, counteracts the Warburg effect, and promotes apoptosis in various cancer models. Melatonin stimulates antioxidant enzymes in the cells, protects mitochondrial membrane phospholipids, especially cardiolipin, from oxidation thus preserving integrity of the membranes, affects mitochondrial membrane potential, stimulates activity of respiratory chain enzymes, and decreases the opening of mitochondrial permeability transition pore and cytochrome c release. This review will focus on the molecular mechanisms of melatonin effects in the cells during normal and pathological conditions and possible melatonin clinical applications.
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Affiliation(s)
- Dalia M. Kopustinskiene
- Institute of Pharmaceutical Technologies, Faculty of Pharmacy, Medical Academy, Lithuanian University of Health Sciences, Sukileliu pr. 13, LT-50161 Kaunas, Lithuania;
| | - Jurga Bernatoniene
- Institute of Pharmaceutical Technologies, Faculty of Pharmacy, Medical Academy, Lithuanian University of Health Sciences, Sukileliu pr. 13, LT-50161 Kaunas, Lithuania;
- Department of Drug Technology and Social Pharmacy, Faculty of Pharmacy, Medical Academy, Lithuanian University of Health Sciences, Sukileliu pr. 13, LT-50161 Kaunas, Lithuania
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36
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Nocturnal Gastroesophageal Reflux Disease (GERD) and Sleep: An Important Relationship That Is Commonly Overlooked. J Clin Gastroenterol 2020; 54:663-674. [PMID: 32657961 DOI: 10.1097/mcg.0000000000001382] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Gastroesophageal reflux disease (GERD) is a prevalent, chronic medical condition that affects 13% of the adult population globally at least once a week. Sleep disturbances are frequently encountered in up to 25% of the GERD patients, likely due to nocturnal gastroesophageal reflux (GER). With advance in diagnostic techniques allowing for an improved understanding of involved physiological mechanisms of nocturnal reflux, there is growing evidence of a bidirectional relationship between GERD and sleep disturbances. Furthermore, nocturnal GER is associated with more complicated GERD. Obstructive sleep apnea (OSA) and GERD also have been linked, but to what degree remains controversial. Treatment of nocturnal GER has been shown to improve both subjective and objective sleep measures. The therapeutic approach includes lifestyle modifications and medication individualization and optimization with proton-pump inhibitors serving as the mainstay of treatment. Antireflux surgery and newer endoscopic procedures have been demonstrated to control nocturnal GER.
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37
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Ma N, Zhang J, Reiter RJ, Ma X. Melatonin mediates mucosal immune cells, microbial metabolism, and rhythm crosstalk: A therapeutic target to reduce intestinal inflammation. Med Res Rev 2020; 40:606-632. [PMID: 31420885 DOI: 10.1002/med.21628] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2019] [Revised: 07/22/2019] [Accepted: 07/26/2019] [Indexed: 12/12/2022]
Abstract
Nowadays, melatonin, previously considered only as a pharmaceutical product for rhythm regulation and sleep aiding, has shown its potential as a co-adjuvant treatment in intestinal diseases, however, its mechanism is still not very clear. A firm connection between melatonin at a physiologically relevant concentration and the gut microbiota and inflammation has recently established. Herein, we summarize their crosstalk and focus on four novelties. First, how melatonin is synthesized and degraded in the gut and exerts potentially diverse phenotypic effects through its diverse metabolites. Second, how melatonin mediates the activation and proliferation of intestinal mucosal immune cells with paracrine and autocrine properties. By modulating T/B cells, mast cells, macrophages and dendritic cells, melatonin immunomodulatory involved in regulating T-cell differentiation, intervening T/B cell interaction and attenuating the production of pro-inflammatory factors, achieving its antioxidant action via specific receptors. Third, how melatonin exerts antimicrobial action and modulates microbial components, such as lipopolysaccharide, amyloid-β peptides via nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) or signal transducers and activators of transcription (STAT1) pathway to modulate intestinal immune function in immune-pineal axis. The last, how melatonin mediates the effect of intestinal bacterial activity signals on the body rhythm system through the NF-κB pathway and influences the mucosal epithelium oscillation via clock gene expression. These processes are achieved at mitochondrial and nuclear levels to control the host immune cell development. Considering unclear mechanisms and undiscovered actions of melatonin in gut-microbiome-immune axis, it's time to reveal them and provide new insight for the outlook of melatonin as a potential therapeutic target in the treatment and management of intestinal diseases.
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Affiliation(s)
- Ning Ma
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Jie Zhang
- Animal Husbandry and Veterinary Department, Beijing Vocational College of Agriculture, Beijing, China
| | - Russel J Reiter
- Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas
| | - Xi Ma
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
- Department of Internal Medicine and Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas
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38
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Xu Z, You W, Liu J, Wang Y, Shan T. Elucidating the Regulatory Role of Melatonin in Brown, White, and Beige Adipocytes. Adv Nutr 2020; 11:447-460. [PMID: 31355852 PMCID: PMC7442421 DOI: 10.1093/advances/nmz070] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 03/28/2019] [Accepted: 06/13/2019] [Indexed: 12/15/2022] Open
Abstract
The high prevalence of obesity and its associated metabolic diseases has heightened the importance of understanding control of adipose tissue development and energy metabolism. In mammals, 3 types of adipocytes with different characteristics and origins have been identified: white, brown, and beige. Beige and brown adipocytes contain numerous mitochondria and have the capability to burn energy and counteract obesity, while white adipocytes store energy and are closely associated with metabolic disorders and obesity. Thus, regulation of the development and function of different adipocytes is important for controlling energy balance and combating obesity and related metabolic disorders. Melatonin is a neurohormone, which plays multiple roles in regulating inflammation, blood pressure, insulin actions, and energy metabolism. This article summarizes and discusses the role of melatonin in white, beige, and brown adipocytes, especially in affecting adipogenesis, inducing beige formation or white adipose tissue browning, enhancing brown adipose tissue mass and activities, improving anti-inflammatory and antioxidative effects, regulating adipokine secretion, and preventing body weight gain. Based on the current findings, melatonin is a potential therapeutic agent to control energy metabolism, adipogenesis, fat deposition, adiposity, and related metabolic diseases.
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Affiliation(s)
- Ziye Xu
- College of Animal Sciences, Zhejiang University, Hangzhou, China; The Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou, China; and Zhejiang Provincial Laboratory of Feed and Animal Nutrition, Hangzhou, China
| | - Wenjing You
- College of Animal Sciences, Zhejiang University, Hangzhou, China; The Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou, China; and Zhejiang Provincial Laboratory of Feed and Animal Nutrition, Hangzhou, China
| | - Jiaqi Liu
- College of Animal Sciences, Zhejiang University, Hangzhou, China; The Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou, China; and Zhejiang Provincial Laboratory of Feed and Animal Nutrition, Hangzhou, China
| | - Yizhen Wang
- College of Animal Sciences, Zhejiang University, Hangzhou, China; The Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou, China; and Zhejiang Provincial Laboratory of Feed and Animal Nutrition, Hangzhou, China
| | - Tizhong Shan
- College of Animal Sciences, Zhejiang University, Hangzhou, China; The Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou, China; and Zhejiang Provincial Laboratory of Feed and Animal Nutrition, Hangzhou, China,Address correspondence to TS (E-mail: )
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39
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Gil-Martín E, Egea J, Reiter RJ, Romero A. The emergence of melatonin in oncology: Focus on colorectal cancer. Med Res Rev 2019; 39:2239-2285. [PMID: 30950095 DOI: 10.1002/med.21582] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 03/04/2019] [Accepted: 03/16/2019] [Indexed: 12/17/2022]
Abstract
Within the last few decades, melatonin has increasingly emerged in clinical oncology as a naturally occurring bioactive molecule with substantial anticancer properties and a pharmacological profile optimal for joining the currently available pharmacopeia. In addition, extensive experimental data shows that this chronobiotic agent exerts oncostatic effects throughout all stages of tumor growth, from initial cell transformation to mitigation of malignant progression and metastasis; additionally, melatonin alleviates the side effects and improves the welfare of radio/chemotherapy-treated patients. Thus, the support of clinicians and oncologists for the use of melatonin in both the treatment and proactive prevention of cancer is gaining strength. Because of its epidemiological importance and symptomatic debut in advanced stages of difficult clinical management, colorectal cancer (CRC) is a preferential target for testing new therapies. In this regard, the development of effective forms of clinical intervention for the improvement of CRC outcome, specifically metastatic CRC, is urgent. At the same time, the need to reduce the costs of conventional anti-CRC therapy results is also imperative. In light of this status quo, the therapeutic potential of melatonin, and the direct and indirect critical processes of CRC malignancy it modulates, have aroused much interest. To illuminate the imminent future on CRC research, we focused our attention on the molecular mechanisms underlying the multiple oncostatic actions displayed by melatonin in the onset and evolution of CRC and summarized epidemiological evidence, as well as in vitro, in vivo and clinical findings that support the broadly protective potential demonstrated by melatonin.
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Affiliation(s)
- Emilio Gil-Martín
- Department of Biochemistry, Genetics and Immunology, Biomedical Research Center (CINBIO, 'Centro Singular de Investigación de Galicia'), University of Vigo, Vigo, Spain
| | - Javier Egea
- Molecular Neuroinflammation and Neuronal Plasticity Laboratory, Research Unit, Hospital Universitario Santa Cristina, Madrid, Spain.,Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Madrid, Spain.,Departamento de Farmacología y Terapéutica, Instituto-Fundación Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain
| | - Russel J Reiter
- Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, Texas, USA
| | - Alejandro Romero
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Complutense University of Madrid, Madrid, Spain
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40
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Ovid D, Hayes TB, Bentley GE. Melatonin Administration Methods for Research in Mammals and Birds. J Biol Rhythms 2018; 33:567-588. [PMID: 30246597 DOI: 10.1177/0748730418795802] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Endocrine research in animals often entails exogenous hormone administration. Special issues arise when developing administration protocols for hormones with circadian and seasonal periodicity. This article reviews various methods for the exogenous administration of hormones with such periodicities by focusing on melatonin. We discuss that methodological variations across studies can affect experimental results. Melatonin administration techniques used in vertebrates includes infusion pumps, beeswax pellets, oral administration, injections, SILASTIC capsules, osmotic pumps, transdermal delivery, beads, and sponges.
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Affiliation(s)
- Dax Ovid
- University of California, Berkeley, CA, USA
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41
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Reiter RJ, Tan DX, Rosales-Corral S, Galano A, Jou MJ, Acuna-Castroviejo D. Melatonin Mitigates Mitochondrial Meltdown: Interactions with SIRT3. Int J Mol Sci 2018; 19:E2439. [PMID: 30126181 PMCID: PMC6121285 DOI: 10.3390/ijms19082439] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 08/03/2018] [Accepted: 08/08/2018] [Indexed: 02/07/2023] Open
Abstract
Melatonin exhibits extraordinary diversity in terms of its functions and distribution. When discovered, it was thought to be uniquely of pineal gland origin. Subsequently, melatonin synthesis was identified in a variety of organs and recently it was shown to be produced in the mitochondria. Since mitochondria exist in every cell, with a few exceptions, it means that every vertebrate, invertebrate, and plant cell produces melatonin. The mitochondrial synthesis of melatonin is not photoperiod-dependent, but it may be inducible under conditions of stress. Mitochondria-produced melatonin is not released into the systemic circulation, but rather is used primarily in its cell of origin. Melatonin's functions in the mitochondria are highly diverse, not unlike those of sirtuin 3 (SIRT3). SIRT3 is an NAD+-dependent deacetylase which regulates, among many functions, the redox state of the mitochondria. Recent data proves that melatonin and SIRT3 post-translationally collaborate in regulating free radical generation and removal from mitochondria. Since melatonin and SIRT3 have cohabitated in the mitochondria for many eons, we predict that these molecules interact in many other ways to control mitochondrial physiology. It is predicted that these mutual functions will be intensely investigated in the next decade and importantly, we assume that the findings will have significant applications for preventing/delaying some age-related diseases and aging itself.
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Affiliation(s)
- Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX 78229, USA.
| | - Dun Xian Tan
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX 78229, USA.
| | - Sergio Rosales-Corral
- Centro de Investigacion Biomedica de Occidente, Instituto Mexicano del Seguro Social, Guardalajara, 4436 Jalisco, Mexico.
| | - Annia Galano
- Departamento de Quimica, Universidad Antonoma Metropolitana-Unidad Iztapalapa, San Rafael Atlixco 186, Col. Vicentina, Iztapalapa, C.P. 09340 Mexico D.F., Mexico.
| | - Mei-Jie Jou
- Department of Physiology and Pharmacology, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan 333, Taiwan.
| | - Dario Acuna-Castroviejo
- Departamento de Fisiologia, Instituto de Biotecnologia, Universidad de Granada, Avenida de Conocimiento S/U, 18016 Granada, Spain.
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42
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MacEachern SJ, Keenan CM, Papakonstantinou E, Sharkey KA, Patel BA. Alterations in melatonin and 5-HT signalling in the colonic mucosa of mice with dextran-sodium sulfate-induced colitis. Br J Pharmacol 2018; 175:1535-1547. [PMID: 29447434 DOI: 10.1111/bph.14163] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2017] [Revised: 01/16/2018] [Accepted: 02/03/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND AND PURPOSE Inflammatory bowel disease (IBD) is characterized by pain, bleeding, cramping and altered gastrointestinal (GI) function. Changes in mucosal 5-HT (serotonin) signalling occur in animal models of colitis and in humans suffering from IBD. Melatonin is co-released with 5-HT from the mucosa and has a wide variety of actions in the GI tract. Here, we examined how melatonin signalling is affected by colitis and determined how this relates to 5-HT signalling. EXPERIMENTAL APPROACH Using electroanalytical approaches, we investigated how 5-HT release, reuptake and availability as well as melatonin availability are altered in dextran sodium sulfate (DSS)-induced colitis in mice. Studies were conducted to explore if melatonin treatment during active colitis could reduce the severity of colitis. KEY RESULTS We observed an increase in 5-HT and a decrease in melatonin availability in DSS-induced colitis. A significant reduction in 5-HT reuptake was observed in DSS-induced colitis animals. A reduction in the content of 5-HT was observed, but no difference in tryptophan levels were observed. A reduction in deoxycholic acid-stimulated 5-HT availability and a significant reduction in mechanically-stimulated 5-HT and melatonin availability were observed in DSS-induced colitis. Orally or rectally administered melatonin once colitis was established did not significantly suppress inflammation. CONCLUSION AND IMPLICATIONS Our data suggest that DSS-induced colitis results in a reduction in melatonin availability and an increase in 5-HT availability, due to a reduction/loss of tryptophan hydroxylase 1 enzyme, 5-HT content and 5-HT transporters. Mechanosensory release was more susceptible to inflammation when compared with chemosensory release.
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Affiliation(s)
- Sarah J MacEachern
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada.,Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Catherine M Keenan
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada.,Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
| | | | - Keith A Sharkey
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.,Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada.,Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
| | - Bhavik Anil Patel
- School of Pharmacy and Biomolecular Sciences, University of Brighton, Huxley Building, Brighton, UK.,Centre for Stress and Age-related Diseases, University of Brighton, Huxley Building, Brighton, UK
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Chojnacki C, Błasiak J, Fichna J, Chojnacki J, Popławski T. Evaluation of Melatonin Secretion and Metabolism Exponents in Patients with Ulcerative and Lymphocytic Colitis. Molecules 2018; 23:molecules23020272. [PMID: 29382152 PMCID: PMC6017024 DOI: 10.3390/molecules23020272] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 01/21/2018] [Accepted: 01/26/2018] [Indexed: 12/15/2022] Open
Abstract
Inflammatory bowel diseases, particularly ulcerative colitis (UC) and lymphocytic colitis (LC), affect many people. The role of melatonin in the pathogenesis of UC is precisely determined, whereas in LC it remains unknown. The aim of this study was to compare the expression of the melatonin-synthesizing enzymes tryptophan hydroxylase (TPH1), arylalkylamine-N-acetyltransferase (AANAT), and N-acetylserotonin methyltransferase (ASMT) in the colonic mucosa and urinary excretion of 6-sulfatoxymelatonin in patients with ulcerative and lymphocytic colitis. The study included 30 healthy subjects (group C), 30 patients with severe ulcerative colitis (group UC), and 30 patients with lymphocytic colitis (group LC). The diagnosis was based on endoscopic, histological, and laboratory examinations. Biopsy specimens were collected from right, transverse, and left parts of the colon. The levels of mRNA expression, TPH1, AANAT, and ASMT were estimated in the colonic mucosa with RT-PCR. The urine concentration of aMT6s was determined by the photometric method. The expression of TPH1, AANAT, and ASMT in colonic mucosa in UC and LC patients was significantly higher than in healthy subjects. Significant differences were found in the urinary aMT6s excretion: group C—13.4 ± 4.8 µg/24 h, group UC—7.8 ± 2.6 µg/24 h (p < 0.01), group LC—19.2 ± 6.1 µg/24 h (p < 0.01). Moreover, a negative correlation was found between fecal calprotectin and MT6s—in patients with UC − r = −0.888 and with LC − r = −0.658. These results indicate that patients with UC and those with LC may display high levels of melatonin-synthesizing enzymes in their colonic mucosa, which could possibly be related to increased melatonin synthesis as an adaptive antioxidant activity.
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Affiliation(s)
- Cezary Chojnacki
- Department of Clinical Nutrition and Gastroenterological Diagnostics, Medical University, 90-647 Lodz, Poland.
| | - Janusz Błasiak
- Department of Molecular Genetics, University of Lodz, 90-647 Lodz, Poland.
| | - Jakub Fichna
- Department of Biochemistry, Medical University of Lodz, 90-647 Lodz, Poland.
| | - Jan Chojnacki
- Department of Clinical Nutrition and Gastroenterological Diagnostics, Medical University, 90-647 Lodz, Poland.
| | - Tomasz Popławski
- Department of Molecular Genetics, University of Lodz, 90-647 Lodz, Poland.
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Liu L, Zhang S, Bao J, He X, Tong D, Chen C, Ying Q, Zhang Q, Zhang C, Li J. Melatonin Improves Laying Performance by Enhancing Intestinal Amino Acids Transport in Hens. Front Endocrinol (Lausanne) 2018; 9:426. [PMID: 30105005 PMCID: PMC6077205 DOI: 10.3389/fendo.2018.00426] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 07/09/2018] [Indexed: 01/11/2023] Open
Abstract
The high concentration of melatonin (MEL) in the intestinal mucosa suggests that it has a special physiological function in intestine. In hens, previous studies have shown that MEL treatment promoted egg-laying performance. Considering the importance of amino acids (AA) for egg formation, we hypothesized that MEL may enhance the intestinal absorption of AA from the feed, thus promoting egg laying performance. In this study, we supplemented the hens with MEL for two consecutive weeks. The results showed that, compared with control group, feeding with 0.625 mg MEL/kg diets gave rise to higher egg laying rate (by 4.3%, P = 0.016), increased eggshell thickness (by 16.9%, P < 0.01) and albumen height (by 4.5%, P = 0.042). Meanwhile, feeding with 0.625 and 2.5 mg MEL/kg diets could significantly increase serum levels of aspartic acid, threonine, serine, glutamic acid, glycine, alanine, isoleucine, leucine, tyrosine, phenylalanine, lysine, histidine, arginine, and proline. Furthermore, a 0.625 mg MEL/kg diets could significantly increase the expression of PepT1 (by 3949.9%), B0AT (by 6045.9%), b0, +AT (by 603.5%), and EAAT3 (by 412.7%) in the jejunum. Additionally, in the cultured intestinal crypt "organoids," treatment with 0.5 μM MEL could significantly enhance the expression of PepT1, b0, +AT and EAAT3 mRNAs by 35.4%, 110.0%, and 160.1%, respectively. Detection of MEL concentration in serum and intestinal fluid suggested that lower dosage of MEL feeding was mainly acted on intestine locally, and further increased intestinal antioxidases (GPx-3, SOD-1 or PRDX-3) mRNA expression. Taken together, we demonstrated that MEL feeding in laying hens could locally promote the expression and function of AA transporter in small intestine by up-regulating antioxidases expression, and finally elevate laying performance.
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Affiliation(s)
- Lijuan Liu
- Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Siyu Zhang
- Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Jiayang Bao
- Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Xiaowen He
- Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Danni Tong
- Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Cong Chen
- Yanping Bureau of Animal Husbandry, Veterinary & Aquatic Products, Nanping, China
| | | | - Qing Zhang
- Yanping Bureau of Animal Husbandry, Veterinary & Aquatic Products, Nanping, China
| | - Caiqiao Zhang
- Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China
- *Correspondence: Jian Li
| | - Jian Li
- Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China
- Caiqiao Zhang
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Jaworek J, Leja-Szpak A, Nawrot-Porąbka K, Szklarczyk J, Kot M, Pierzchalski P, Góralska M, Ceranowicz P, Warzecha Z, Dembinski A, Bonior J. Effects of Melatonin and Its Analogues on Pancreatic Inflammation, Enzyme Secretion, and Tumorigenesis. Int J Mol Sci 2017; 18:ijms18051014. [PMID: 28481310 PMCID: PMC5454927 DOI: 10.3390/ijms18051014] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 04/26/2017] [Accepted: 05/02/2017] [Indexed: 12/14/2022] Open
Abstract
Melatonin is an indoleamine produced from the amino acid l-tryptophan, whereas metabolites of melatonin are known as kynuramines. One of the best-known kynuramines is N1-acetyl-N1-formyl-5-methoxykynuramine (AFMK). Melatonin has attracted scientific attention as a potent antioxidant and protector of tissue against oxidative stress. l-Tryptophan and kynuramines share common beneficial features with melatonin. Melatonin was originally discovered as a pineal product, has been detected in the gastrointestinal tract, and its receptors have been identified in the pancreas. The role of melatonin in the pancreatic gland is not explained, however several arguments support the opinion that melatonin is probably implicated in the physiology and pathophysiology of the pancreas. (1) Melatonin stimulates pancreatic enzyme secretion through the activation of entero-pancreatic reflex and cholecystokinin (CCK) release. l-Tryptophan and AFMK are less effective than melatonin in the stimulation of pancreatic exocrine function; (2) Melatonin is a successful pancreatic protector, which prevents the pancreas from developing of acute pancreatitis and reduces pancreatic damage. This effect is related to its direct and indirect antioxidant action, to the strengthening of immune defense, and to the modulation of apoptosis. Like melatonin, its precursor and AFMK are able to mimic its protective effect, and it is commonly accepted that all these substances create an antioxidant cascade to intensify the pancreatic protection and acinar cells viability; (3) In pancreatic cancer cells, melatonin and AFMK activated a signal transduction pathway for apoptosis and stimulated heat shock proteins. The role of melatonin and AFMK in pancreatic tumorigenesis remains to be elucidated.
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Affiliation(s)
- Jolanta Jaworek
- Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, 31-126 Kraków, Poland.
| | - Anna Leja-Szpak
- Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, 31-126 Kraków, Poland.
| | - Katarzyna Nawrot-Porąbka
- Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, 31-126 Kraków, Poland.
| | - Joanna Szklarczyk
- Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, 31-126 Kraków, Poland.
| | - Michalina Kot
- Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, 31-126 Kraków, Poland.
| | - Piotr Pierzchalski
- Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, 31-126 Kraków, Poland.
| | - Marta Góralska
- Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, 31-126 Kraków, Poland.
| | - Piotr Ceranowicz
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Kraków, Poland.
| | - Zygmunt Warzecha
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Kraków, Poland.
| | - Artur Dembinski
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Kraków, Poland.
| | - Joanna Bonior
- Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, 31-126 Kraków, Poland.
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Abstract
This work is the result of a technical research patent on dendritogenesis and neuronal maturation, in which the existence was determined of patent documents involving the use of melatonin for the treatment of anxiety, obesity and related diseases of the peripheral and CNS. In this study, an analysis of the state of the art in order to collect technical and scientific elements for the drafting of a new patent on the use of the melatonin molecule in stimulating neuronal maturation in dendritogenesis and mammals was conducted in adults. This study is based on an invention related with this novel use of melatonin.
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47
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Rtibi K, Selmi S, Jabri MA, Mamadou G, Limas-Nzouzi N, Sebai H, El-Benna J, Marzouki L, Eto B, Amri M. Effects of aqueous extracts from Ceratonia siliqua L. pods on small intestinal motility in rats and jejunal permeability in mice. RSC Adv 2016. [DOI: 10.1039/c6ra03457h] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The current study was performed to assess the effects of carob pod aqueous extracts (CPAE, pulp, seeds or mixture) on gastrointestinal transit (GIT) and intestinal epithelium permeability.
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Affiliation(s)
- Kaïs Rtibi
- Laboratory of Neurophysiology and Functional Pathology
- Department of Biological Sciences
- Faculty of Sciences of Tunis
- Tunis 2092
- Tunisia
| | - Slimen Selmi
- Laboratory Functional Physiology and Bio-resources Valorisation
- Higher Institute of Biotechnology of Beja
- University of Jendouba
- 9000 Beja
- Tunisia
| | - Mohamed-Amine Jabri
- Laboratory Functional Physiology and Bio-resources Valorisation
- Higher Institute of Biotechnology of Beja
- University of Jendouba
- 9000 Beja
- Tunisia
| | | | | | - Hichem Sebai
- Laboratory Functional Physiology and Bio-resources Valorisation
- Higher Institute of Biotechnology of Beja
- University of Jendouba
- 9000 Beja
- Tunisia
| | - Jamel El-Benna
- INSERM U1149 Biomedical Research Centre
- Faculty of Medicine X. Bichat
- 75018 Paris
- France
| | - Lamjed Marzouki
- Laboratory of Neurophysiology and Functional Pathology
- Department of Biological Sciences
- Faculty of Sciences of Tunis
- Tunis 2092
- Tunisia
| | - Bruno Eto
- TransCell-Lab
- Faculty of Medicine X. Bichat
- 75018 Paris
- France
| | - Mohamed Amri
- Laboratory of Neurophysiology and Functional Pathology
- Department of Biological Sciences
- Faculty of Sciences of Tunis
- Tunis 2092
- Tunisia
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48
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Jeong JK, Park SY. Melatonin regulates the autophagic flux via activation of alpha-7 nicotinic acetylcholine receptors. J Pineal Res 2015; 59:24-37. [PMID: 25808024 DOI: 10.1111/jpi.12235] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 03/17/2015] [Indexed: 02/06/2023]
Abstract
Our previous study suggested that melatonin-mediated neuroprotective effects are related with the activation of autophagy. However, the mechanism of melatonin-mediated autophagic activation in prion-mediated mitochondrial damage is not reported. Alpha-7 nicotinic acetylcholine receptors (α7nAchR) is a member of nicotinic acetylcholine receptors, and α7nAchR activation regulates via melatonin. Thus, we hypothesized that melatonin-mediated neuroprotective effect related with to autophagy pathway as a result of α7nAchR regulation. Inactivation of α7nAchR inhibited melatonin-mediated autophagic activation and protective effect against prion-mediated mitochondrial neurotoxicity. Also, knockdown of ATG5 blocked the melatonin-mediated neuroprotection and did not influence to the activation of α7nAchR caused by melatonin. This report is the first study demonstrating that melatonin-mediated autophagic activation regulates via modulation of α7nAchR signals, and upregulation of α7nAchR signals induced by melatonin plays a pivotal role in neuroprotection of prion-mediated mitochondrial neurotoxicity. Our results suggested that regulator of α7 nAChR signals including melatonin may have used for neuroprotective strategies for the neurodegenerative disorders including prion diseases.
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Affiliation(s)
- Jae-Kyo Jeong
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Jeonju, Korea
- Department of Bioactive Material Sciences and Research Center of Bioactive Materials, Chonbuk National University, Jeonju, Korea
| | - Sang-Youel Park
- Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Jeonju, Korea
- Department of Bioactive Material Sciences and Research Center of Bioactive Materials, Chonbuk National University, Jeonju, Korea
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Zhang L, Gong JT, Zhang HQ, Song QH, Xu GH, Cai L, Tang XD, Zhang HF, Liu FE, Jia ZS, Zhang HW. Melatonin Attenuates Noise Stress-induced Gastrointestinal Motility Disorder and Gastric Stress Ulcer: Role of Gastrointestinal Hormones and Oxidative Stress in Rats. J Neurogastroenterol Motil 2015; 21:189-99. [PMID: 25537679 PMCID: PMC4398253 DOI: 10.5056/jnm14119] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Revised: 11/05/2014] [Accepted: 11/05/2014] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND/AIMS There are increasing evidences for gastrointestinal motility disorder (GIMD) and gastric stress ulcer induced by noise stress. The present study was to investigate the reversed effect of melatonin on GIMD and gastric stress ulcer induced by noise stress and potential mechanism. METHODS Noise stress was induced on rats, and melatonin (15 mg/kg) was administered to rats by intraperitoneal injection. Differences were assessed in gastric residual rate (GRR), small intestine propulsion rate (SPR), Guth injury score, cortisol, gastrointestinal hormones (calcitonin-gene-related peptide and motilin) and oxidative stress markers (superoxide dismutase and malondialde hyde) in blood plasma as well as gastric mucosa homogenate with or without melatonin. The pathological examination of gastric mucosa was also performed. RESULTS The GRR and SPR were improved by noise stress compared with control (P < 0.05). The pathological examination and Guth injury score revealed gastric stress ulcer. Moreover, the levels of cortisol, motilin and malondialdehyde in blood plasma and ma-londialdehyde in gastric mucosa homogenate were increased by noise stress (P < 0.05). CGRP and superoxide dismutase activ-ity in both of blood plasma and gastric mucosa homogenate were significantly decreased (P< 0.05). Furthermore, melatonin reversed changes in GRR, SPR, pathological examination, Guth injury score, cortisol, motilin, CGRP, superoxide dismutase activity and malondialdehyde (P < 0.05). CONCLUSIONS Melatonin is effective in reversing the GIMD and gastric stress ulcer induced by noise stress. The underlying mechanism may be involved in oxidative stress and gastrointestinal hormones.
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Affiliation(s)
- Lei Zhang
- Experiment Teaching Center of Basic Medicine, The Fourth Military Medical University, Xi'an, Shan Xi province, China.,Department of General Surgery, No.406 hospital, Da Lian, Liao Ning Province, China.,State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, Shan Xi Province, China
| | - Ji T Gong
- Department of Otorhinolaryngology, Baoji Hospital of Chinese Medicine, Shan Xi Province, China
| | - Hu Q Zhang
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shan Xi Province, China
| | - Quan H Song
- Department of General Surgery, No.406 hospital, Da Lian, Liao Ning Province, China
| | - Guang H Xu
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, Shan Xi Province, China
| | - Lei Cai
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, Shan Xi Province, China
| | - Xiao D Tang
- Department of General Surgery, No.406 hospital, Da Lian, Liao Ning Province, China
| | - Hai F Zhang
- Experiment Teaching Center of Basic Medicine, The Fourth Military Medical University, Xi'an, Shan Xi province, China
| | - Fang-E Liu
- Experiment Teaching Center of Basic Medicine, The Fourth Military Medical University, Xi'an, Shan Xi province, China
| | - Zhan S Jia
- Department of Infectious Diseases, Tangdu Hospital, the Fourth Military Medical University, Xi'an, China
| | - Hong W Zhang
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, Shan Xi Province, China
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50
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Söderquist F, Hellström PM, Cunningham JL. Human gastroenteropancreatic expression of melatonin and its receptors MT1 and MT2. PLoS One 2015; 10:e0120195. [PMID: 25822611 PMCID: PMC4378860 DOI: 10.1371/journal.pone.0120195] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Accepted: 02/05/2015] [Indexed: 12/29/2022] Open
Abstract
Background and Aim The largest source of melatonin, according to animal studies, is the gastrointestinal (GI) tract but this is not yet thoroughly characterized in humans. This study aims to map the expression of melatonin and its two receptors in human GI tract and pancreas using microarray analysis and immunohistochemistry. Method Gene expression data from normal intestine and pancreas and inflamed colon tissue due to ulcerative colitis were analyzed for expression of enzymes relevant for serotonin and melatonin production and their receptors. Sections from paraffin-embedded normal tissue from 42 individuals, representing the different parts of the GI tract (n=39) and pancreas (n=3) were studied with immunohistochemistry using antibodies with specificity for melatonin, MT1 and MT2 receptors and serotonin. Results Enzymes needed for production of melatonin are expressed in both GI tract and pancreas tissue. Strong melatonin immunoreactivity (IR) was seen in enterochromaffin (EC) cells partially co-localized with serotonin IR. Melatonin IR was also seen in pancreas islets. MT1 and MT2 IR were both found in the intestinal epithelium, in the submucosal and myenteric plexus, and in vessels in the GI tract as well as in pancreatic islets. MT1 and MT2 IR was strongest in the epithelium of the large intestine. In the other cell types, both MT2 gene expression and IR were generally elevated compared to MT1. Strong MT2, IR was noted in EC cells but not MT1 IR. Changes in gene expression that may result in reduced levels of melatonin were seen in relation to inflammation. Conclusion Widespread gastroenteropancreatic expression of melatonin and its receptors in the GI tract and pancreas is in agreement with the multiple roles ascribed to melatonin, which include regulation of gastrointestinal motility, epithelial permeability as well as enteropancreatic cross-talk with plausible impact on metabolic control.
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MESH Headings
- Adult
- Case-Control Studies
- Colitis, Ulcerative/genetics
- Colitis, Ulcerative/metabolism
- Colitis, Ulcerative/pathology
- Enterochromaffin Cells/metabolism
- Gastrointestinal Tract/anatomy & histology
- Gastrointestinal Tract/metabolism
- Gene Expression
- Humans
- Immunohistochemistry
- Melatonin/metabolism
- Pancreas/anatomy & histology
- Pancreas/metabolism
- Receptor, Melatonin, MT1/genetics
- Receptor, Melatonin, MT1/metabolism
- Receptor, Melatonin, MT2/genetics
- Receptor, Melatonin, MT2/metabolism
- Serotonin/metabolism
- Tissue Distribution
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Affiliation(s)
- Fanny Söderquist
- Department of Neuroscience, Psychiatry, Uppsala University, Uppsala, Sweden
| | - Per M. Hellström
- Department of Medical Sciences, Gastroenterology/Hepatology, Uppsala University, Uppsala, Sweden
| | - Janet L. Cunningham
- Department of Neuroscience, Psychiatry, Uppsala University, Uppsala, Sweden
- * E-mail:
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