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Zheng Z, Su Z, Zhang W. Melatonin's Role in Hair Follicle Growth and Development: A Cashmere Goat Perspective. Int J Mol Sci 2025; 26:2844. [PMID: 40243438 PMCID: PMC11988770 DOI: 10.3390/ijms26072844] [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: 02/03/2025] [Revised: 03/15/2025] [Accepted: 03/19/2025] [Indexed: 04/18/2025] Open
Abstract
Hair follicles, unique skin appendages, undergo cyclic phases (anagen, catagen, telogen) governed by melatonin and associated molecular pathways. Melatonin, synthesized in the pineal gland, skin, and gut, orchestrates these cycles through antioxidant activity and signaling cascades (e.g., Wnt, BMP). This review examines melatonin's biosynthesis across tissues, its regulation of cashmere growth patterns, and its interplay with non-coding RNAs and the gut-skin axis. Recent advances highlight melatonin's dual role in enhancing antioxidant capacity (via Keap1-Nrf2) and modulating gene expression (e.g., Wnt10b, CTNNB1) to promote hair follicle proliferation. By integrating multi-omics insights, we construct a molecular network of melatonin's regulatory mechanisms, offering strategies to improve cashmere yield and quality while advancing therapies for human alopecia.
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Affiliation(s)
| | | | - Wei Zhang
- State Key Laboratory of Animal Nutrition and Feeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China; (Z.Z.); (Z.S.)
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Niu T, Ding Z, Zeng J, Yan Z, Duan H, Lv J, Zhang Y, Zhang L, Hu J. Melatonin Sources in Sheep Rumen and Its Role in Reproductive Physiology. Animals (Basel) 2024; 14:3451. [PMID: 39682413 DOI: 10.3390/ani14233451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 08/30/2024] [Accepted: 09/04/2024] [Indexed: 12/18/2024] Open
Abstract
In mammals, the melatonin (Mel) concentration in the gastrointestinal tract is 400 times greater than in the pineal gland. However, the origin of Mel in the gastrointestinal tract and its role in reproductive regulation remains unclear. Therefore, we analyzed three potential Mel sources (feed, microorganisms, and the rumen wall) for their contribution to high Mel levels in the rumen and their biological effects. The feed contained high Mel concentrations, and Mel in rumen fluid and blood peaked two hours after feeding. Rumen microbial analysis showed a strong positive correlation between Mel and specific microbes, including Megasphaera, Butyrivibrio, Acetobacter, and Olsenella. In vitro experiments indicated that rumen microorganisms synthesized Mel from tryptophan. The rumen wall also contains key enzymes, AANAT and HIOMT, which catalyze Mel synthesis and membrane receptors MT1 and MT2 that mediate the function of Mel, suggesting that the rumen wall synthesizes Mel. Mel peaked in both rumen fluid and blood two hours after feeding. Feeding also altered blood levels of Mel, Gonadotropin-releasing hormone (GnRH), Luteinizing hormone (LH), Follicle-stimulating hormone (FSH), progesterone (P4), and Estradiol (E2), with a correlation between Mel and fluctuations in GnRH, LH, P4, and E2 levels. Our findings suggest that feed is the primary source of high Mel levels in the rumen and impacts reproductive hormone fluctuations. This study elucidates the origin of high rumen Mel concentrations and reveals that food intake affects the natural secretion of various hormones, offering a new perspective on food sources for regulating reproductive physiology.
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Affiliation(s)
- Tian Niu
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou 730070, China
| | - Ziqiang Ding
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China
| | - Jianlin Zeng
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou 730070, China
| | - Zhenxing Yan
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou 730070, China
| | - Hongwei Duan
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou 730070, China
| | - Jianshu Lv
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou 730070, China
| | - Yong Zhang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou 730070, China
| | - Lihong Zhang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou 730070, China
| | - Junjie Hu
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou 730070, China
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3
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Zimmermann P, Kurth S, Pugin B, Bokulich NA. Microbial melatonin metabolism in the human intestine as a therapeutic target for dysbiosis and rhythm disorders. NPJ Biofilms Microbiomes 2024; 10:139. [PMID: 39604427 PMCID: PMC11603051 DOI: 10.1038/s41522-024-00605-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 11/10/2024] [Indexed: 11/29/2024] Open
Abstract
Melatonin (MT) (N-acetyl-5-methoxytryptamine) is an indoleamine recognized primarily for its crucial role in regulating sleep through circadian rhythm modulation in humans and animals. Beyond its association with the pineal gland, it is synthesized in various tissues, functioning as a hormone, tissue factor, autocoid, paracoid, and antioxidant, impacting multiple organ systems, including the gut-brain axis. However, the mechanisms of extra-pineal MT production and its role in microbiota-host interactions remain less understood. This review provides a comprehensive overview of MT, including its production, actions sites, metabolic pathways, and implications for human health. The gastrointestinal tract is highlighted as an additional source of MT, with an examination of its effects on the intestinal microbiota. This review explores whether the microbiota contributes to MT in the intestine, its relationship to food intake, and the implications for human health. Due to its impacts on the intestinal microbiota, MT may be a valuable therapeutic agent for various dysbiosis-associated conditions. Moreover, due to its influence on intestinal MT levels, the microbiota may be a possible therapeutic target for treating health disorders related to circadian rhythm dysregulation.
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Affiliation(s)
- Petra Zimmermann
- Department of Community Health, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
- Department of Paediatrics, Fribourg Hospital, Fribourg, Switzerland.
- Infectious Diseases Research Group, Murdoch Children's Research Institute, Parkville, VIC, Australia.
- Department of Paediatrics, The University of Melbourne, Parkville, VIC, Australia.
| | - Salome Kurth
- Department of Psychology, University of Fribourg, Fribourg, Switzerland
| | - Benoit Pugin
- Laboratory of Food Systems Biotechnology, Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
| | - Nicholas A Bokulich
- Laboratory of Food Systems Biotechnology, Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
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4
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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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Pan J, Yao WL, Liu LP, Wang BS, Chai WZ, Huang Z, Fan XP, He WH, Wang WH, Zhang WD. Moniezia benedeni infection increases IgE + cells in sheep (Ovis aries) small intestine. Vet Parasitol 2024; 328:110169. [PMID: 38520755 DOI: 10.1016/j.vetpar.2024.110169] [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: 10/17/2023] [Revised: 03/07/2024] [Accepted: 03/10/2024] [Indexed: 03/25/2024]
Abstract
The concentration of immunoglobulin (Ig) E is the lowest among serum Igs, but it can induces type I hypersensitivity and plays an important role in anti-parasitic infection. The present study aimed to explore the residence characteristics of IgE+ cells in the sheep small intestine and the impact of Moniezia benedeni infection on them. The recombinant plasmids pET-28a-IgE were constructed and induced and expressed in Escherichia coli. BL21 (DE3). The rabbit anti-sheep IgE polyclonal antibody was prepared using the obtained recombinant protein as antigen. Finally, the levels of IgE+ cells in the small intestine of healthy (Control group) and naturally M. benedeni-infected (Infected group) sheep were detected analyzed. The results showed that the rabbit anti-sheep IgE polyclonal antibody with good immunogenicity (titer = 1: 128000) could specifically bind to the heavy chain of natural sheep IgE. In the Control group, the IgE+ cells were mainly distributed in lamina propria of the small intestine, and the densities were significantly decreased from duodenum to ileum (P<0.05), with respective values of (4.28 cells / 104 μm2, 1.80 cells / 104 μm2, and 1.44 cells / 104 μm2 in duodenum, jejunum, and ileum. In the Infected group, IgE+ cells density were 6.26 cells / 104 μm2, 3.01 cells / 104 μm2, and 2.09 cells / 104 μm2 in duodenum, jejunum and ileum respectively, which were significantly higher in all segments compared to the Control group (P<0.05), increasing by 46.26%, 67.22% and 45.14%, respectively. In addition, compared with the Control group, the IgE protein levels were significantly increased in all intestinal segments of the Infected group (P<0.01), however, there was no significant differences among the different intestinal segments within the same group (P>0.05). The results demonstrated that M. benedeni infection could significantly increase the content of IgE and the distribution density of its secreting cells in sheep small intestine. The intestinal mucosal immune system of sheep presented obvious specificity against M. benedeni infection. This lays a good foundation for further exploring molecular mechanisms of the intestinal mucosal immune system monitoring and responding to M. benedeni infection.
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Affiliation(s)
- Jing Pan
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu 730070, China
| | - Wan-Ling Yao
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu 730070, China
| | - Li-Ping Liu
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu 730070, China
| | - Bao-Shan Wang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu 730070, China
| | - Wen-Zhu Chai
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu 730070, China
| | - Zhen Huang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu 730070, China
| | - Xi-Ping Fan
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu 730070, China
| | - Wan-Hong He
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu 730070, China
| | - Wen-Hui Wang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu 730070, China
| | - Wang-Dong Zhang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu 730070, China.
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Kennaway DJ. The mammalian gastro-intestinal tract is a NOT a major extra-pineal source of melatonin. J Pineal Res 2023; 75:e12906. [PMID: 37649458 DOI: 10.1111/jpi.12906] [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: 07/01/2023] [Revised: 07/31/2023] [Accepted: 08/16/2023] [Indexed: 09/01/2023]
Abstract
In 1992, a paper reported that the melatonin content of the rat duodenum was 24 000 ± 2000 pg/g tissue (range: 4000-100 000 pg/g) while the pineal melatonin content was 580 000 ± 36 000 pg/g. The data has been used for the last 30 years to infer that the gut produces 400 hundred times more melatonin than the pineal gland and that it is the source of plasma melatonin during the daytime. No-one has ever challenged the statement. In this review, evidence is summarised from the literature that pinealectomy eliminates melatonin from the circulation and that studies to the contrary have relied upon poorly validated immunoassays that overstate the levels. Similarly studies that have reported increases in plasma melatonin following tryptophan administration failed to account for cross reactivity of tryptophan and its metabolites in immunoassays. The most extraordinary observation from the literature is that in those studies that have measured melatonin in the gut since 1992, the tissue content is vastly lower than the original report, even when the methodology used could be overestimating the melatonin content due to cross reactivity. Using the more contemporary results we can calculate that rather than a 400:1 ratio of duodenum: pineal melatonin, a ratio of 0.05-0.19: 1 is likely. The gut is not a major extra-pineal source of melatonin; indeed it may well not produce any.
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Affiliation(s)
- David J Kennaway
- Robinson Research Institute and Adelaide School of Medicine, University of Adelaide, Adelaide Health and Medical Science Building, North Terrace, Adelaide, South Australia, Australia
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Sutradhar S, Yasmin F, Roy A, Sarkar R, Mukherjee S. Age-related changes in the gut melatonin levels and its possible role in the regulation of feeding and digestibility, with the development of the gut from fingerling to adult stages of carp, Catla catla. J Comp Physiol B 2023; 193:647-660. [PMID: 37833416 DOI: 10.1007/s00360-023-01519-z] [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: 06/30/2023] [Revised: 09/01/2023] [Accepted: 09/15/2023] [Indexed: 10/15/2023]
Abstract
The present study aims to understand the feeding-related age-bound changes in gut histoarchitecture and its response to gut melatonin (GM) titer regulating major digestive enzymes in carp, Catla catla. Therefore, gut samples were collected from different growth stages of carp, viz. (i) fingerling (FL), body weight (BW) ≥ 3 g to ≤ 20 g; (ii) advanced fingerling (AFL), BW > 20 g to ≤ 40 g; (iii) early juvenile (EJv), BW > 40 g to ≤ 70 g; (iv) juvenile (Jv), BW > 70 g to ≤ 200 g; (v) late juvenile (LJv), BW > 200 g to ≤ 300 g; (vi) preadult (PA), BW > 300 g to ≤ 500 g; (vii) subadult (SA), BW > 500 g to ≤ 1.00 kg; and (viii) adult (AD), BW > 1 kg to ≤ 2.5 kg. Data analysis revealed that the highest titer of GM was noted in FL, moderate in AFL, Jv, and PA, lower in EJv, SA, and AD, and lowest in LJv. Results depicted a negative correlation between the development of the gut and its melatonin content. Moreover, GM was positively associated with feeding intensity and gastro-somatic index (GaSI) and negatively related to ovarian onset and development. Following correlation and principal component analysis, several pieces of evidence were recorded on the role of gut melatonin in regulating digestive physiology. Finally, it indicates that gut melatonin has a progressively influential role in improving digestion, particularly protein and microbial digestion, with the development of an adult gut from the fingerling stage.
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Affiliation(s)
- Sona Sutradhar
- Fish Biology and Endocrinology Laboratory, Department of Zoology, University of North Bengal, Siliguri, Darjeeling, 734013, West Bengal, India
| | - Farha Yasmin
- Fish Biology and Endocrinology Laboratory, Department of Zoology, University of North Bengal, Siliguri, Darjeeling, 734013, West Bengal, India
| | - Arun Roy
- Fish Biology and Endocrinology Laboratory, Department of Zoology, University of North Bengal, Siliguri, Darjeeling, 734013, West Bengal, India
| | - Russel Sarkar
- Fish Biology and Endocrinology Laboratory, Department of Zoology, University of North Bengal, Siliguri, Darjeeling, 734013, West Bengal, India
| | - Sourav Mukherjee
- Fish Biology and Endocrinology Laboratory, Department of Zoology, University of North Bengal, Siliguri, Darjeeling, 734013, West Bengal, India.
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Horodincu L, Solcan C. Influence of Different Light Spectra on Melatonin Synthesis by the Pineal Gland and Influence on the Immune System in Chickens. Animals (Basel) 2023; 13:2095. [PMID: 37443893 DOI: 10.3390/ani13132095] [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: 04/25/2023] [Revised: 06/12/2023] [Accepted: 06/21/2023] [Indexed: 07/15/2023] Open
Abstract
It is well known that the pineal gland in birds influences behavioural and physiological functions, including those of the immune system. The purpose of this research is to examine the endocrine-immune correlations between melatonin and immune system activity. Through a description of the immune-pineal axis, we formulated the objective to determine and describe: the development of the pineal gland; how light influences secretory activity; and how melatonin influences the activity of primary and secondary lymphoid organs. The pineal gland has the ability to turn light information into an endocrine signal suitable for the immune system via the membrane receptors Mel1a, Mel1b, and Mel1c, as well as the nuclear receptors RORα, RORβ, and RORγ. We can state the following findings: green monochromatic light (560 nm) increased serum melatonin levels and promoted a stronger humoral and cellular immune response by proliferating B and T lymphocytes; the combination of green and blue monochromatic light (560-480 nm) ameliorated the inflammatory response and protected lymphoid organs from oxidative stress; and red monochromatic light (660 nm) maintained the inflammatory response and promoted the growth of pathogenic bacteria. Melatonin can be considered a potent antioxidant and immunomodulator and is a critical element in the coordination between external light stimulation and the body's internal response.
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Affiliation(s)
- Loredana Horodincu
- Preclinics Department, Faculty of Veterinary Medicine, "Ion Ionescu de la Brad" Iasi University of Life Sciences, Mihail Sadoveanu Alley, 700489 Iasi, Romania
| | - Carmen Solcan
- Preclinics Department, Faculty of Veterinary Medicine, "Ion Ionescu de la Brad" Iasi University of Life Sciences, Mihail Sadoveanu Alley, 700489 Iasi, Romania
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Yang C, Lu Z, Xia Y, Zhang J, Zou Z, Chen C, Wang X, Tian X, Cheng S, Jiang X. Alterations of Gut-Derived Melatonin in Neurobehavioral Impairments Caused by Zinc Oxide Nanoparticles. Int J Nanomedicine 2023; 18:1899-1914. [PMID: 37057188 PMCID: PMC10088905 DOI: 10.2147/ijn.s386240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Accepted: 12/24/2022] [Indexed: 04/15/2023] Open
Abstract
Purpose The widespread use of zinc oxide nanoparticles (ZnONPs) has raised concerns about its potential toxicity. Melatonin is a neurohormone with tremendous anti-toxic effects. The enterochromaffin cells are an essential source of melatonin in vivo. However, studies on the effects of ZnONPs on endogenous melatonin are minimal. In the present study, we aimed to investigate the effects of ZnONPs exposure on gut-derived melatonin. Methods In the present study, 64 adult male mice were randomly and equally divided into four groups, and each group was exposed to ZnONPs (0, 6.5, 13, 26 mg/kg/day) for 30 days. Subsequently, the neurobehavioral changes were observed. The effects of ZnONPs on the expression of melatonin-related genes arylalkylamine N-acetyltransferase (Aanat), melatonin receptor1A (Mt1/Mtnr1a), melatonin receptor1B (Mt2/Mtnr1b), and neuropeptide Y (Npy) on melatonin synthesis and secretion in duodenum, jejunum, ileum and colon during day and night were also assessed. Results The results revealed that oral exposure to ZnONPs induced impairments of locomotor activity and anxiety-like behavior in adult mice during the day. The transcriptional analysis of brain tissues revealed that exposure to ZnONPs caused profound effects on genes and transcriptional signaling pathways associated with melatonin synthesis and metabolic processes during the day and night. We also observed that, in the duodenum, jejunum, ileum and colon sites, ZnONPs resulted in a significant reduction in the expression of the gut-derived melatonin rate-limiting enzyme Aanat, the membrane receptors Mt1 and Mt2 and Npy during the day and night. Conclusion Taken together, this is the first study shows that oral exposure to ZnONPs interferes with melatonin synthesis and secretion in different intestinal segments of adult mice. These findings will provide novelty insights into the neurotoxic mechanisms of ZnONPs and suggest an alternative strategy for the prevention of ZnONP neurotoxicity.
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Affiliation(s)
- Cantao Yang
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Zhaohong Lu
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Yinyin Xia
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Jun Zhang
- Molecular Biology Laboratory of Respiratory Diseases, Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
- Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Zhen Zou
- Molecular Biology Laboratory of Respiratory Diseases, Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
- Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Chengzhi Chen
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
- Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Xiaoliang Wang
- Medical Sciences Research Center, University-Town Hospital of Chongqing Medical University, Chongqing, 401331, People’s Republic of China
| | - Xin Tian
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Shuqun Cheng
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
- Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
- Correspondence: Shuqun Cheng; Xuejun Jiang, Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Number 1, Yixueyuan Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel +86-23-68485008, Fax +86-23-68485207, Email ;
| | - Xuejun Jiang
- Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
- Center of Experimental Teaching for Public Health, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
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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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11
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Ahluwalia A, Patel K, Hoa N, Brzozowska I, Jones MK, Tarnawski AS. Melatonin ameliorates aging-related impaired angiogenesis in gastric endothelial cells via local actions on mitochondria and VEGF-survivin signaling. Am J Physiol Gastrointest Liver Physiol 2021; 321:G682-G689. [PMID: 34668398 DOI: 10.1152/ajpgi.00101.2021] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 10/12/2021] [Indexed: 02/06/2023]
Abstract
Tissue injury healing is impaired in aging, and this impairment is caused in part by reduced angiogenesis. Melatonin, a neuroendocrine hormone that regulates sleep and circadian rhythm, is also produced in the gastrointestinal tract. The expression of melatonin receptors MT1 and MT2 in gastric endothelial cells and their roles in aging-related impairment of gastric angiogenesis have not been examined. We hypothesized that MT1 and MT2 expression is reduced in gastric endothelial cells of aging rats and that melatonin treatment can upregulate their expression and improve angiogenesis. We examined the expression of MT1 and MT2 in gastric endothelial cells (GECs) isolated from young and aging rats. We also examined the effects of melatonin treatment on angiogenesis, GEC mitochondrial function, expression of vascular endothelial growth factor (VEGF), its signaling receptor (VEGFR-2), and the inhibitor of apoptosis protein, survivin. Young and aging GECs expressed MT1 (in the cytoplasm and mitochondria) and MT2 (in nucleus and mitochondria). In aging GECs, MT1 and MT2 levels, in vitro angiogenesis, and mitochondrial membrane potential were significantly reduced (by 1.5-fold, 1.9-fold, 3.1-fold, and 1.63-fold, respectively) compared with young GECs. Melatonin treatment of aging GECs significantly increased MT1 and MT2 expression compared with the controls, induced nuclear translocation of MT1, and significantly ameliorated the aging-related impairment of angiogenesis and mitochondrial function. Aging GECs have significantly reduced MT1 and MT2 expression, angiogenesis, and mitochondrial membrane potential compared with young GECs. Treatment of aging GECs with melatonin increases expression of VEGF receptor and survivin and ameliorates aging-related impaired angiogenesis and mitochondrial function.NEW & NOTEWORTHY This study showed reduced expression of melatonin receptors MT1 and MT2, angiogenesis, and mitochondrial function in gastric endothelial cells (GECs) isolated from aging rats. Treatment of aging GECs with melatonin increases expression of VEGF receptor and survivin and ameliorates aging-related impaired angiogenesis and mitochondrial function. These studies provide new insight into the mechanisms of the aging-related impairment of angiogenesis and delayed tissue injury healing and provide a rationale for melatonin treatment to reverse these abnormalities.
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MESH Headings
- Age Factors
- Angiogenesis Inducing Agents/pharmacology
- Animals
- Cells, Cultured
- Endothelial Cells/drug effects
- Endothelial Cells/metabolism
- Gastric Mucosa/blood supply
- Melatonin/pharmacology
- Mitochondria/drug effects
- Mitochondria/metabolism
- Neovascularization, Physiologic/drug effects
- Rats, Inbred F344
- Receptor, Melatonin, MT1/agonists
- Receptor, Melatonin, MT1/metabolism
- Receptor, Melatonin, MT2/agonists
- Receptor, Melatonin, MT2/metabolism
- Signal Transduction
- Survivin/metabolism
- Vascular Endothelial Growth Factor A/metabolism
- Rats
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Affiliation(s)
- Amrita Ahluwalia
- Research Service, Veterans Affairs Long Beach Healthcare System (VALBHS), Long Beach, California
| | - Khushin Patel
- Research Service, Veterans Affairs Long Beach Healthcare System (VALBHS), Long Beach, California
| | - Neil Hoa
- Research Service, Veterans Affairs Long Beach Healthcare System (VALBHS), Long Beach, California
| | - Iwona Brzozowska
- Department of Anatomy, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
| | - Michael K Jones
- Research Service, Veterans Affairs Long Beach Healthcare System (VALBHS), Long Beach, California
- Department of Medicine, University of California, Irvine, California
| | - Andrzej S Tarnawski
- Research Service, Veterans Affairs Long Beach Healthcare System (VALBHS), Long Beach, California
- Department of Medicine, University of California, Irvine, California
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12
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Melatonin and Pathological Cell Interactions: Mitochondrial Glucose Processing in Cancer Cells. Int J Mol Sci 2021; 22:ijms222212494. [PMID: 34830375 PMCID: PMC8621753 DOI: 10.3390/ijms222212494] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 10/06/2021] [Accepted: 11/17/2021] [Indexed: 12/18/2022] Open
Abstract
Melatonin is synthesized in the pineal gland at night. Since melatonin is produced in the mitochondria of all other cells in a non-circadian manner, the amount synthesized by the pineal gland is less than 5% of the total. Melatonin produced in mitochondria influences glucose metabolism in all cells. Many pathological cells adopt aerobic glycolysis (Warburg effect) in which pyruvate is excluded from the mitochondria and remains in the cytosol where it is metabolized to lactate. The entrance of pyruvate into the mitochondria of healthy cells allows it to be irreversibly decarboxylated by pyruvate dehydrogenase (PDH) to acetyl coenzyme A (acetyl-CoA). The exclusion of pyruvate from the mitochondria in pathological cells prevents the generation of acetyl-CoA from pyruvate. This is relevant to mitochondrial melatonin production, as acetyl-CoA is a required co-substrate/co-factor for melatonin synthesis. When PDH is inhibited during aerobic glycolysis or during intracellular hypoxia, the deficiency of acetyl-CoA likely prevents mitochondrial melatonin synthesis. When cells experiencing aerobic glycolysis or hypoxia with a diminished level of acetyl-CoA are supplemented with melatonin or receive it from another endogenous source (pineal-derived), pathological cells convert to a more normal phenotype and support the transport of pyruvate into the mitochondria, thereby re-establishing a healthier mitochondrial metabolic physiology.
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13
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Ouyang J, Wang M, Bu D, Ma L, Liu F, Xue C, Du C, Aboragah A, Loor JJ. Ruminal Microbes Exhibit a Robust Circadian Rhythm and Are Sensitive to Melatonin. Front Nutr 2021; 8:760578. [PMID: 34760910 PMCID: PMC8573100 DOI: 10.3389/fnut.2021.760578] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 09/28/2021] [Indexed: 12/13/2022] Open
Abstract
Gut hormones are not only able to regulate digestive, absorptive, and immune mechanisms of the intestine through biological rhythms, but impact the host through their interactions with intestinal microorganisms. Whether hormones in ruminal fluid have an association with the ruminal ecology is unknown. Objectives of the study were to examine relationships between the diurnal change in ruminal hormones and microbiota in lactating cows, and their associations in vivo and in vitro. For the in vivo study, six cows of similar weight (566.8 ± 19.6 kg), parity (3.0 ± 0.0), and milk performance (8,398.7 ± 1,392.9 kg/y) were used. They were adapted to natural light for 2 weeks before sampling and fed twice daily at 07:00 a.m. and 14:00 p.m. Serum, saliva, and ruminal fluid samples were collected at 02:00, 10:00, and 18:00 on the first day and 06:00, 14:00, and 22:00 on the second day of the experimental period. The concentrations of melatonin (MLT), growth hormone (GH), and prolactin (PRL) were measured via radioimmunoassay, whereas amplicon sequencing data were used to analyze relative abundance of microbiota in ruminal fluid. JTK_CYCLE analysis was performed to analyze circadian rhythms of hormone concentrations as well as the relative abundance of microbiota. For the in vitro study, exogenous MLT (9 ng) was added into ruminal fluid incubations to investigate the impacts of MLT on ruminal microbiota. The results not only showed that rumen fluid contains MLT, but the diurnal variation of MLT and the relative abundance of 9% of total rumen bacterial operational taxonomic units (OTUs) follow a circadian rhythm. Although GH and PRL were also detected in ruminal fluid, there was no obvious circadian rhythm in their concentrations. Ruminal MLT was closely associated with Muribaculaceae, Succinivibrionaceae, Veillonellaceae, and Prevotellaceae families in vivo. In vitro, these families were significantly influenced by melatonin treatment, as melatonin treatment increased the relative abundance of families Prevotellaceae, Muribaculaceae while it reduced the relative abundance of Succinivibrionaceae, Veillonellaceae. Collectively, ruminal microbes appear to maintain a circadian rhythm that is associated with the profiles of melatonin. As such, data suggest that secretion of melatonin into the rumen could play a role in host-microbe interactions in ruminants.
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Affiliation(s)
- Jialiang Ouyang
- State Key Laboratory of Sheep Genetic Improvement and Healthy Production, Xinjiang Academy of Agricultural and Reclamation Sciences, Shihezi, China
- Institute of Animal Science, State Key Laboratory of Animal Nutrition, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Mengzhi Wang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Dengpan Bu
- Institute of Animal Science, State Key Laboratory of Animal Nutrition, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China
- Chinese Academy of Agricultural Sciences-World Agroforestry Centre (CAAS-ICRAF) Joint Lab on Agroforestry and Sustainable Animal Husbandry, World Agroforestry Center, East and Central Asia, Beijing, China
| | - Lu Ma
- Institute of Animal Science, State Key Laboratory of Animal Nutrition, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China
| | - Fuyuan Liu
- State Key Laboratory of Sheep Genetic Improvement and Healthy Production, Xinjiang Academy of Agricultural and Reclamation Sciences, Shihezi, China
| | - Chun Xue
- College of Animal Science and Technology, Yangzhou University, Yangzhou, China
| | - Chao Du
- Institute of Animal Science, State Key Laboratory of Animal Nutrition, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China
| | - Ahmad Aboragah
- Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana, IL, United States
| | - Juan J. Loor
- Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana, IL, United States
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14
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Ritwiset A, Khajonrit J, Krongsuk S, Maensiri S. Molecular insight on the formation structure and dynamics of melatonin in an aqueous solution and at the Water-Air interface: A molecular dynamics study. J Mol Graph Model 2021; 108:107983. [PMID: 34274727 DOI: 10.1016/j.jmgm.2021.107983] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 06/27/2021] [Accepted: 07/05/2021] [Indexed: 11/18/2022]
Abstract
Melatonin is a natural hormone that has been shown highly antioxidant effects. Consequently, it has been extensively studied for its therapeutic potential in several diseases such as insomnia, cardiovascular, Alzheimer, and certain types of cancers. Recently, it has been used to adjuvant treatment for COVID-19 patients. It is well-known that melatonin is highly hydrophobic, resulting in lower solubility. However, the molecular structure and dynamic behavior of the formation of melatonin in an aqueous solution and at the water-air interface have not yet been clearly explained. This information is necessary for the melatonin formulation in drug delivery systems. The present work focuses on the molecular structure and dynamics of melatonin molecules in the aqueous solution and at the water-air interface based on using a molecular dynamics simulation study. The results showed that most melatonin molecules were aggregated in an aqueous solution while they were formed a self-assembled monolayer with the ordered structure at the water-air interface. The strong interaction of melatonin depends on their functional group which showed a similar trend for both systems and was sequenced as follows: carbonyl O > indole NH > amide NH > methoxy OA, respectively. However, the carbonyl O and the indole NH groups exhibit strong interactions with water molecules at the interface. Consequently, the two preferred orientations of the melatonin head group can be observed at the water-air interface (i.e., one is to turn the head group to the water surface with the tilted angle of ~40°-60° and the second one is to turn the head group away from the water surface with the tilted angle of ~130°). The longer lifetime of hydrogen bonds formed between melatonin themselves in the bulk water reveals that the stability of melatonin aggregation in an aqueous solution is more stable. Therefore, melatonin has less soluble in an aqueous solution.
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Affiliation(s)
- Aksornnarong Ritwiset
- School of Physics, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima, 30000, Thailand
| | - Jessada Khajonrit
- School of Physics, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima, 30000, Thailand
| | - Sriprajak Krongsuk
- Department of Physics, Faculty of Science, Khon Kaen University, Khon Kaen, 40002, Thailand; Institute of Nanomaterials Research and Innovation for Energy (IN-RIE), Khon Kaen University, Khon Kaen, 40002, Thailand; Institute of Nanomaterials Research and Innovation for Energy (IN-RIE), Research Network of NANOTEC-KKU (RNN), Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Santi Maensiri
- School of Physics, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima, 30000, Thailand; SUT Center of Excellence on Advanced Functional Nanomaterials, Suranaree University of Technology, Nakhon Ratchasima, 30000, Thailand.
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15
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Melhuish Beaupre LM, Brown GM, Gonçalves VF, Kennedy JL. Melatonin's neuroprotective role in mitochondria and its potential as a biomarker in aging, cognition and psychiatric disorders. Transl Psychiatry 2021; 11:339. [PMID: 34078880 PMCID: PMC8172874 DOI: 10.1038/s41398-021-01464-x] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 04/16/2021] [Accepted: 05/14/2021] [Indexed: 02/05/2023] Open
Abstract
Melatonin is an ancient molecule that is evident in high concentrations in various tissues throughout the body. It can be separated into two pools; one of which is synthesized by the pineal and can be found in blood, and the second by various tissues and is present in these tissues. Pineal melatonin levels display a circadian rhythm while tissue melatonin does not. For decades now, melatonin has been implicated in promoting and maintaining sleep. More recently, evidence indicates that it also plays an important role in neuroprotection. The beginning of our review will summarize this literature. As an amphiphilic, pleiotropic indoleamine, melatonin has both direct actions and receptor-mediated effects. For example, melatonin has established effects as an antioxidant and free radical scavenger both in vitro and in animal models. This is also evident in melatonin's prominent role in mitochondria, which is reviewed in the next section. Melatonin is synthesized in, taken up by, and concentrated in mitochondria, the powerhouse of the cell. Mitochondria are also the major source of reactive oxygen species as a byproduct of mitochondrial oxidative metabolism. The final section of our review summarizes melatonin's potential role in aging and psychiatric disorders. Pineal and tissue melatonin levels both decline with age. Pineal melatonin declines in individuals suffering from psychiatric disorders. Melatonin's ability to act as a neuroprotectant opens new avenues of exploration for the molecule as it may be a potential treatment for cases with neurodegenerative disease.
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Affiliation(s)
- Lindsay M Melhuish Beaupre
- Molecular Brain Science Research Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
| | - Gregory M Brown
- Molecular Brain Science Research Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Vanessa F Gonçalves
- Molecular Brain Science Research Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - James L Kennedy
- Molecular Brain Science Research Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
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16
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Yasmin F, Sutradhar S, Das P, Mukherjee S. Gut melatonin: A potent candidate in the diversified journey of melatonin research. Gen Comp Endocrinol 2021; 303:113693. [PMID: 33309697 DOI: 10.1016/j.ygcen.2020.113693] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 11/24/2020] [Accepted: 12/04/2020] [Indexed: 02/08/2023]
Abstract
After being discovered from the bovine pineal gland by Aaron Lerner and co-workers in the year 1958, various distinguished researchers have reported melatonin (5-methoxy-N-acetyl-tryptamine) from several extra-pineal sources, including the gastrointestinal tract (GIT). In the year 1974, Raikhlin and Kvetnoy first detected this molecule in the gastrointestinal tissue. Later, within the last 45 years, many renowned investigators found that the GIT is a rich source of melatonin, in addition to the pineal gland. In the carp gut, the estimation of Arylalkylamine-N-acetyltransferase (AANAT) mRNA/protein levels, which is the rate-determining enzyme for melatonin biosynthesis in the pineal gland, confirmed the endogenous synthesis of melatonin. The remarkable feature of the pineal gland melatonin is its rhythmic synthesis with a peak at dark-phase and lowest at light-phase in synchronization with seasonal environmental light-dark (LD) cycle. Recent studies on carp demonstrated that the melatonin concentrations and the AANAT protein intensities in different gut segments underwent significant daily fluctuations. However, compared to the melatonin rhythm in the pineal gland, the melatonin profiles in gut tissue displayed daily rhythm in parallel with the feeding cycle of the carp, irrespective of LD conditions of the environment. Notably, in carp, the temporal pattern of the gut melatoninergic system found to vary with the environmental non-photic signal(s), such as food entrainment factors (viz. availability of food, timing of food supply, number(s) of feed per day, quality of food) those act as the most dependable synchronizer(s) in daily rhythm characteristics of gut melatonin and AANAT. Thereby in this review, it appears meaningful to highlight the existing data on the mode of synthesis of melatonin in cells of the digestive tract, and most importantly, the regulation of its synthesis. Finally, in comparison with the dynamic actions of melatonin derived from the pineal gland, this review will lead to underline the role of gut-derived melatonin in a variety of physiological functions.
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Affiliation(s)
- Farha Yasmin
- Fish Biology and Endocrinology Laboratory, Department of Zoology, University of North Bengal, Darjeeling-734013, India
| | - Sona Sutradhar
- Fish Biology and Endocrinology Laboratory, Department of Zoology, University of North Bengal, Darjeeling-734013, India
| | - Poulami Das
- Fish Biology and Endocrinology Laboratory, Department of Zoology, University of North Bengal, Darjeeling-734013, India
| | - Sourav Mukherjee
- Fish Biology and Endocrinology Laboratory, Department of Zoology, University of North Bengal, Darjeeling-734013, India.
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17
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Trotta RJ, Lemley CO, Vonnahme KA, Swanson KC. Effects of nutrient restriction and melatonin supplementation from mid-to-late gestation on maternal and fetal small intestinal carbohydrase activities in sheep. Domest Anim Endocrinol 2021; 74:106555. [PMID: 32947201 DOI: 10.1016/j.domaniend.2020.106555] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 07/27/2020] [Accepted: 08/17/2020] [Indexed: 02/06/2023]
Abstract
The objective of this experiment was to evaluate the effects of nutrient restriction and melatonin supplementation during mid-to-late gestation on maternal and fetal small intestinal carbohydrase activities in sheep. Ewes were randomly assigned to one of 4 dietary treatments arranged in a 2 × 2 factorial design. Ewes were fed to provide 100% (adequate; ADQ) or 60% (restricted; RES) of nutrient recommendations, and diets were supplemented with either no melatonin (control; CON) or 5 mg melatonin/d (melatonin; MEL). This resulted in 4 treatment groups: CON-ADQ (n = 7), CON-RES (n = 8), MEL-ADQ (n = 8), MEL-RES (n = 8). Treatments began on day 50 of gestation, and ewes were euthanized on day 130 for tissue collection. The maternal and fetal small intestine were collected and assayed for small intestinal carbohydrase activities. Data were analyzed using the GLM procedure of SAS with fetal sex, melatonin, nutrition, and the melatonin by nutrition interaction included in the model statement. There were no melatonin by nutrition interactions for maternal or fetal small intestinal protein concentration or carbohydrase activities (P ≥ 0.11). Dietary melatonin supplementation decreased (P = 0.03) maternal small intestinal protein concentration by 22.7% and increased (P = 0.03) maternal small intestinal glucoamylase, isomaltase, and maltase activity per gram protein by 45.5%, 41.3%, and 40.6%, respectively. Nutrient restriction from mid-to-late gestation did not influence (P ≥ 0.46) maternal small intestinal protein concentration, or maltase, isomaltase, and lactase activity. Maternal glucoamylase activity per gram intestine increased (P = 0.05) with nutrient restriction by 49.1%. Melatonin supplementation and maternal nutrient restriction did not influence (P ≥ 0.15) fetal small intestinal protein concentration, or glucoamylase, isomaltase, and lactase activity. Maternal nutrient restriction from mid-to-late gestation decreased (P = 0.05) fetal maltase activity per gram intestine by 20.5% but did not influence fetal maltase activity per gram protein. These data indicate that some maternal and fetal carbohydrases are influenced by nutrient restriction and melatonin supplementation in sheep. More information is needed to understand how nutritional and hormonal factors regulate digestive enzyme activity in ruminants to design improved maternal nutrition programs to optimize fetal growth and development while maintaining maternal productivity.
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Affiliation(s)
- R J Trotta
- Department of Animal Sciences, North Dakota State University, Fargo, ND 58108, USA
| | - C O Lemley
- Department of Animal Sciences, North Dakota State University, Fargo, ND 58108, USA
| | - K A Vonnahme
- Department of Animal Sciences, North Dakota State University, Fargo, ND 58108, USA
| | - K C Swanson
- Department of Animal Sciences, North Dakota State University, Fargo, ND 58108, USA.
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18
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Shor EK, Brown SP, Freeman DA. A novel role for the pineal gland: Regulating seasonal shifts in the gut microbiota of Siberian hamsters. J Pineal Res 2020; 69:e12696. [PMID: 32969515 DOI: 10.1111/jpi.12696] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 09/04/2020] [Accepted: 09/11/2020] [Indexed: 12/25/2022]
Abstract
The gut microbiota plays a significant role in a variety of host behavioral and physiological processes. The mechanisms by which the gut microbiota and the host communicate are not fully resolved but include both humoral and direct neural signals. The composition of the microbiota is affected by internal (host) factors and external (environmental) factors. One such signal is photoperiod, which is represented endogenously by nocturnal pineal melatonin (MEL) secretion. Removal of the MEL signal via pinealectomy abolishes many seasonal responses to photoperiod. In Siberian hamsters (Phodopus sungorus), MEL drives robust seasonal shifts in physiology and behavior, such as immunity, stress, body mass, and aggression. While the profile of the gut microbiota also changes by season, it is unclear whether these changes are driven by pineal signals. We hypothesized that the pineal gland mediates seasonal alterations in the composition of the gut microbiota. To test this, we placed pinealectomized and intact hamsters into long or short photoperiods for 8 weeks, collected weekly fecal samples, and measured weekly food intake, testis volume, and body mass. We determined microbiota composition using 16S rRNA sequencing (Illumina MiSeq). We found significant effects of treatment and time on the abundances of numerous bacterial genera. We also found significant associations between individual OTU abundances and body mass, testis mass, and food intake, respectively. Finally, results indicate a relationship between overall community structure, and body and testis masses. These results firmly establish a role for the pineal gland in mediating seasonal alterations in the gut microbiota. Further, these results identify a novel neuroendocrine pathway by which a host regulates seasonal shifts in gut community composition, and indicates a relationship between seasonal changes in the gut microbiota and seasonal physiological adjustments.
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Affiliation(s)
- Elyan K Shor
- Department of Biological Sciences, Center for Biodiversity Research, University of Memphis, Memphis, TN, USA
| | - Shawn P Brown
- Department of Biological Sciences, Center for Biodiversity Research, University of Memphis, Memphis, TN, USA
| | - David A Freeman
- Department of Biological Sciences, Center for Biodiversity Research, University of Memphis, Memphis, TN, USA
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19
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Majka J, Wierdak M, Brzozowska I, Magierowski M, Szlachcic A, Wojcik D, Kwiecien S, Magierowska K, Zagajewski J, Brzozowski T. Melatonin in Prevention of the Sequence from Reflux Esophagitis to Barrett's Esophagus and Esophageal Adenocarcinoma: Experimental and Clinical Perspectives. Int J Mol Sci 2018; 19:2033. [PMID: 30011784 PMCID: PMC6073539 DOI: 10.3390/ijms19072033] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 07/08/2018] [Accepted: 07/10/2018] [Indexed: 12/14/2022] Open
Abstract
Melatonin is a tryptophan-derived molecule with pleiotropic activities which is produced in all living organisms. This "sleep" hormone is a free radical scavenger, which activates several anti-oxidative enzymes and mechanisms. Melatonin, a highly lipophilic hormone, can reach body target cells rapidly, acting as the circadian signal to alter numerous physiological functions in the body. This indoleamine can protect the organs against a variety of damaging agents via multiple signaling. This review focused on the role played by melatonin in the mechanism of esophagoprotection, starting with its short-term protection against acute reflux esophagitis and then investigating the long-term prevention of chronic inflammation that leads to gastroesophageal reflux disease (GERD) and Barrett's esophagus. Since both of these condition are also identified as major risk factors for esophageal carcinoma, we provide some experimental and clinical evidence that supplementation therapy with melatonin could be useful in esophageal injury by protecting various animal models and patients with GERD from erosions, Barrett's esophagus and neoplasia. The physiological aspects of the synthesis and release of this indoleamine in the gut, including its release into portal circulation and liver uptake is examined. The beneficial influence of melatonin in preventing esophageal injury from acid-pepsin and acid-pepsin-bile exposure in animals as well as the usefulness of melatonin and its precursor, L-tryptophan in prophylactic and supplementary therapy against esophageal disorders in humans, are also discussed.
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Affiliation(s)
- Jolanta Majka
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland.
| | - Mateusz Wierdak
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland.
| | - Iwona Brzozowska
- Department of Anatomy, Faculty of Medicine, Jagiellonian University Medical College, 33-332 Cracow, Poland.
| | - Marcin Magierowski
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland.
| | - Aleksandra Szlachcic
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland.
| | - Dagmara Wojcik
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland.
| | - Slawomir Kwiecien
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland.
| | - Katarzyna Magierowska
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland.
| | - Jacek Zagajewski
- Department of Biochemistry, Faculty of Medicine, Jagiellonian University Medical College, 31-034 Cracow, Poland.
| | - Tomasz Brzozowski
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland.
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Vasques ER, Cunha JEM, Kubrusly MS, Coelho AM, Sanpietri SN, Nader HB, Tersariol ILS, Lima MA, Chaib E, D'Albuquerque LAC. THE M-RNA, EXPRESSION OF SERCA2 AND NCX1 IN THE PROCESS OF PHARMACOLOGICAL CELL PROTECTION IN EXPERIMENTAL ACUTE PANCREATITIS INDUCED BY TAUROCHOLATE. ACTA ACUST UNITED AC 2018; 31:e1352. [PMID: 29947686 PMCID: PMC6049993 DOI: 10.1590/0102-672020180001e1352] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 01/30/2018] [Indexed: 12/14/2022]
Abstract
Background: Intracellular calcium overload is known to be a precipitating factor of pancreatic cell injury in acute pancreatitis (AP). Intracellular calcium homeostasis depends of Plasmatic Membrane Calcium ATPase (PMCA), Sarcoplasmic Endothelial Reticulum Calcium ATPase 2 (SERCA 2) and the Sodium Calcium Exchanger (NCX1). The antioxidant melatonin (Mel) and Trisulfate Disaccharide (TD) that accelerates NCX1 action could reduce the cell damage determined by the AP. Aim: To evaluate m-RNA expressions of SERCA2 and NCX1 in acute pancreatitis induced by sodium taurocholate in Wistar rats pre-treated with melatonin and/or TD. Methods: Wistar rats were divided in groups: 1) without AP; 2) AP without pre-treatment; 3) AP and Melatonin; 4) AP and TD; 5) AP and Melatonin associated to TD. Pancreatic tissue samples were collected for detection of SERCA2 and NCX1 m-R NA levels by polymerase chain reaction (PCR). Results: Increased m-RNA expression of SERCA2 in the melatonin treated group, without increase of m-RNA expression of the NCX1. The TD did not affect levels of SERCA2 and NCX1 m-RNA expressions. The combined melatonin and TD treatment reduced the m-RNA expression of SERCA2. Conclusions: The effect of melatonin is restricted to increased m-RNA expression of SERCA2. Although TD does not affect gene expression, its action in accelerating calcium exchanger function can explain the slightest expression of SERCA2 m-RNA when associated with Melatonin, perhaps by a joint action of drugs with different and but possibly complementary mechanisms.
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Affiliation(s)
| | | | | | - Ana Maria Coelho
- Gastroenterology Department LIM 37, University of São Paulo Medical School
| | - Sandra N Sanpietri
- Gastroenterology Department LIM 37, University of São Paulo Medical School
| | - Helena B Nader
- Pharmacology Department of Federal University of São Paulo, São Paulo, SP, Brazil
| | - Ivarne L S Tersariol
- Pharmacology Department of Federal University of São Paulo, São Paulo, SP, Brazil
| | - Marcelo A Lima
- Pharmacology Department of Federal University of São Paulo, São Paulo, SP, Brazil
| | - Eleazar Chaib
- Gastroenterology Department LIM 37, University of São Paulo Medical School
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Abstract
AbstractPeripheral concentrations of melatonin in the neonatal mammal are low and the diurnal rhythm is not apparent during the first days or weeks of life. Maternal milk provides a rhythmic although low source of melatonin to the newborn. Diurnal rhythm of serum melatonin was monitored in Friesian calves from birth to 4 weeks of age. Some of the calves under 1 week of age had no clear nocturnal elevation of serum concentrations of melatonin. Thereafter the nocturnal melatonin elevation was apparent in all calves and of the same amplitude as in adult cattle. The effect of oral intake of night-time milk or milk supplemented with low doses of synthetic melatonin was studied during day-time in a group of Ayrshire calves aged 1 to 5 weeks. Two and a half or 3 litres of night-time milk with a mean melatonin concentration of 40 pg/ml, providing 01 to 012 μg melatonin, did not cause any change in the day-time serum concentrations of melatonin, neither did addition of melatonin in doses up to 10 μg per animal. Only the highest dose of melatonin 200 μg in 2 l of milk (01 μg/ml) caused an elevation of day-time serum concentrations of melatonin. These studies show that the pineal gland of a very youg calf is functional and that the concentration of melatonin in blood does not reflect the concentration in milk at the time of feeding. The presence of melatonin in milk suggests, however, its potential significance for the neonate.
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Areco V, Rodriguez V, Marchionatti A, Carpentieri A, Tolosa de Talamoni N. Melatonin not only restores but also prevents the inhibition of the intestinal Ca(2+) absorption caused by glutathione depleting drugs. Comp Biochem Physiol A Mol Integr Physiol 2016; 197:16-22. [PMID: 26970583 DOI: 10.1016/j.cbpa.2016.03.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 02/26/2016] [Accepted: 03/03/2016] [Indexed: 02/07/2023]
Abstract
We have previously demonstrated that melatonin (MEL) blocks the inhibition of the intestinal Ca(2+) absorption caused by menadione (MEN). The purpose of this study were to determine whether MEL not only restores but also prevents the intestinal Ca(2+) absorption inhibited either by MEN or BSO, two drugs that deplete glutathione (GSH) in different ways, and to analyze the mechanisms by which MEN and MEL alter the movement of Ca(2+) across the duodenum. To know this, chicks were divided into four groups: 1) controls, 2) MEN treated, 3) MEL treated, and 4) treated sequentially with MEN and MEL or with MEN and MEL at the same time. In a set of experiments, chicks treated with BSO or sequentially with BSO and MEL or with BSO and MEL at the same time were used. MEL not only restored but also prevented the inhibition of the chick intestinal Ca(2+) absorption produced by either MEN or BSO. MEN altered the protein expression of molecules involved in the transcellular as well as in the paracellular pathway of the intestinal Ca(2+) absorption. MEL restored partially both pathways through normalization of the O2(-) levels. The nitrergic system was not altered by any treatment. In conclusion, MEL prevents or restores the inhibition of the intestinal Ca(2+) absorption caused by different GSH depleting drugs. It might become one drug for the treatment of intestinal Ca(2+) absorption under oxidant conditions having the advantage of low or null side effects.
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Affiliation(s)
- Vanessa Areco
- Laboratorio "Dr. Fernando Cañas", Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Pabellón Argentina, 2do. Piso, Ciudad Universitaria, 5000 Córdoba, Argentina
| | - Valeria Rodriguez
- Laboratorio "Dr. Fernando Cañas", Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Pabellón Argentina, 2do. Piso, Ciudad Universitaria, 5000 Córdoba, Argentina
| | - Ana Marchionatti
- Laboratorio "Dr. Fernando Cañas", Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Pabellón Argentina, 2do. Piso, Ciudad Universitaria, 5000 Córdoba, Argentina
| | - Agata Carpentieri
- Laboratorio "Dr. Fernando Cañas", Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Pabellón Argentina, 2do. Piso, Ciudad Universitaria, 5000 Córdoba, Argentina; Química Biológica, Facultad de Odontología, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Nori Tolosa de Talamoni
- Laboratorio "Dr. Fernando Cañas", Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-Universidad Nacional de Córdoba), Pabellón Argentina, 2do. Piso, Ciudad Universitaria, 5000 Córdoba, Argentina.
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Muñoz-Pérez JL, López-Patiño MA, Álvarez-Otero R, Gesto M, Soengas JL, Míguez JM. Characterization of melatonin synthesis in the gastrointestinal tract of rainbow trout (Oncorhynchus mykiss): distribution, relation with serotonin, daily rhythms and photoperiod regulation. J Comp Physiol B 2016; 186:471-84. [DOI: 10.1007/s00360-016-0966-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Revised: 01/22/2016] [Accepted: 01/25/2016] [Indexed: 10/22/2022]
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Shang B, Shi H, Wang X, Guo X, Wang N, Wang Y, Dong L. Protective effect of melatonin on myenteric neuron damage in experimental colitis in rats. Fundam Clin Pharmacol 2016; 30:117-27. [PMID: 26787455 DOI: 10.1111/fcp.12181] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2015] [Revised: 12/28/2015] [Accepted: 01/13/2016] [Indexed: 12/22/2022]
Affiliation(s)
- Boxin Shang
- Department of Gastroenterology; Second Affiliated Hospital of Xi'an Jiaotong University; Xi'an 710004 Shaanxi Province China
| | - Haitao Shi
- Department of Gastroenterology; Second Affiliated Hospital of Xi'an Jiaotong University; Xi'an 710004 Shaanxi Province China
| | - Xiaoyan Wang
- Department of Gastroenterology; Second Affiliated Hospital of Xi'an Jiaotong University; Xi'an 710004 Shaanxi Province China
| | - Xiaoyan Guo
- Department of Gastroenterology; Second Affiliated Hospital of Xi'an Jiaotong University; Xi'an 710004 Shaanxi Province China
| | - Nan Wang
- Department of Gastroenterology; Second Affiliated Hospital of Xi'an Jiaotong University; Xi'an 710004 Shaanxi Province China
| | - Yan Wang
- Department of Gastroenterology; Second Affiliated Hospital of Xi'an Jiaotong University; Xi'an 710004 Shaanxi Province China
| | - Lei Dong
- Department of Gastroenterology; Second Affiliated Hospital of Xi'an Jiaotong University; Xi'an 710004 Shaanxi Province China
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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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Acuña-Castroviejo D, Escames G, Venegas C, Díaz-Casado ME, Lima-Cabello E, López LC, Rosales-Corral S, Tan DX, Reiter RJ. Extrapineal melatonin: sources, regulation, and potential functions. Cell Mol Life Sci 2014; 71:2997-3025. [PMID: 24554058 PMCID: PMC11113552 DOI: 10.1007/s00018-014-1579-2] [Citation(s) in RCA: 757] [Impact Index Per Article: 68.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Revised: 01/26/2014] [Accepted: 01/27/2014] [Indexed: 12/15/2022]
Abstract
Endogenous melatonin is synthesized from tryptophan via 5-hydroxytryptamine. It is considered an indoleamine from a biochemical point of view because the melatonin molecule contains a substituted indolic ring with an amino group. The circadian production of melatonin by the pineal gland explains its chronobiotic influence on organismal activity, including the endocrine and non-endocrine rhythms. Other functions of melatonin, including its antioxidant and anti-inflammatory properties, its genomic effects, and its capacity to modulate mitochondrial homeostasis, are linked to the redox status of cells and tissues. With the aid of specific melatonin antibodies, the presence of melatonin has been detected in multiple extrapineal tissues including the brain, retina, lens, cochlea, Harderian gland, airway epithelium, skin, gastrointestinal tract, liver, kidney, thyroid, pancreas, thymus, spleen, immune system cells, carotid body, reproductive tract, and endothelial cells. In most of these tissues, the melatonin-synthesizing enzymes have been identified. Melatonin is present in essentially all biological fluids including cerebrospinal fluid, saliva, bile, synovial fluid, amniotic fluid, and breast milk. In several of these fluids, melatonin concentrations exceed those in the blood. The importance of the continual availability of melatonin at the cellular level is important for its physiological regulation of cell homeostasis, and may be relevant to its therapeutic applications. Because of this, it is essential to compile information related to its peripheral production and regulation of this ubiquitously acting indoleamine. Thus, this review emphasizes the presence of melatonin in extrapineal organs, tissues, and fluids of mammals including humans.
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Affiliation(s)
- Darío Acuña-Castroviejo
- Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Avda. del Conocimiento s/n, Armilla, 18100, Granada, Spain,
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27
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LIANG ZHIHAI, QIN MENGBIN, TANG GUODU, YANG HUIYING, SU JUAN, HUANG JIEAN. Melatonin reduces inflammation and recovers endogenous ghrelin in acute necrotizing pancreatitis in rats. Mol Med Rep 2014; 9:2599-605. [DOI: 10.3892/mmr.2014.2132] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2013] [Accepted: 03/12/2014] [Indexed: 11/06/2022] Open
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Carpentieri A, Marchionatti A, Areco V, Perez A, Centeno V, Tolosa de Talamoni N. Antioxidant and antiapoptotic properties of melatonin restore intestinal calcium absorption altered by menadione. Mol Cell Biochem 2013; 387:197-205. [PMID: 24234419 DOI: 10.1007/s11010-013-1885-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2013] [Accepted: 11/05/2013] [Indexed: 12/11/2022]
Abstract
The intestinal Ca²⁺ absorption is inhibited by menadione (MEN) through oxidative stress and apoptosis. The aim of this study was to elucidate whether the antioxidant and antiapoptotic properties of melatonin (MEL) could protect the gut against the oxidant MEN. For this purpose, 4-week-old chicks were divided into four groups: (1) controls, (2) treated i.p. with MEN (2.5 μmol/kg of b.w.), (3) treated i.p. with MEL (10 mg/kg of b.w.), and (4) treated with 10 mg MEL/kg of b.w after 2.5 μmol MEN/kg of b.w. Oxidative stress was assessed by determination of glutathione (GSH) and protein carbonyl contents as well as antioxidant enzyme activities. Apoptosis was assayed by the TUNEL technique, protein expression, and activity of caspase 3. The data show that MEL restores the intestinal Ca²⁺ absorption altered by MEN. In addition, MEL reversed the effects caused by MEN such as decrease in GSH levels, increase in the carbonyl content, alteration in mitochondrial membrane permeability, and enhancement of superoxide dismutase and catalase activities. Apoptosis triggered by MEN in the intestinal cells was arrested by MEL, as indicated by normalization of the mitochondrial membrane permeability, caspase 3 activity, and DNA fragmentation. In conclusion, MEL reverses the inhibition of intestinal Ca²⁺ absorption produced by MEN counteracting oxidative stress and apoptosis. These findings suggest that MEL could be a potential drug of choice for the reversal of impaired intestinal Ca²⁺ absorption in certain gut disorders that occur with oxidative stress and apoptosis.
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Sun X, Shao Y, Jin Y, Huai J, Zhou Q, Huang Z, Wu J. Melatonin reduces bacterial translocation by preventing damage to the intestinal mucosa in an experimental severe acute pancreatitis rat model. Exp Ther Med 2013; 6:1343-1349. [PMID: 24255660 PMCID: PMC3829749 DOI: 10.3892/etm.2013.1338] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Accepted: 09/27/2013] [Indexed: 01/26/2023] Open
Abstract
Recent studies have demonstrated that melatonin significantly decreased all studied acute pancreatitis-associated inflammatory parameters, in addition to reducing apoptosis and necrosis associated with pancreatic injury. However, the effect of melatonin on gut barrier dysfunction and bacterial translocation has not been fully elucidated. This study aimed to investigate the protective effects of melatonin on intestinal integrity in a rat model of severe acute pancreatitis (SAP) to evaluate whether melatonin prevented intestine barrier dysfunction and reduced bacterial translocation. Forty male Sprague Dawley (SD) rats were randomly divided into three groups, with 8 rats in the sham operation (SO) group, 18 rats in the SAP group and 14 SAP rats in the melatonin treatment (MT) group. SAP was induced by retrograde injection of 4% taurocholate into the biliopancreatic duct. Melatonin was administered 30 min prior to taurocholate injection in the melatonin-treated rats. All rats were sacrificed 24 h subsequent to pancreatitis induction. Real-time fluorescence quantitative polymerase chain reaction was used to detect and quantify Escherichia coli (E. coli) O157 in postcava blood. The microvilli structure was also analyzed with transmission electron microscopy. The level of E. coli DNA in the MT group was significantly lower than in rats in the SAP group. No E. coli DNA was detected in the control group. Villus height and crypt depth in the ileum were significantly higher in the MT and control groups compared to the SAP group, and were significantly higher in the MT group than in the SAP group. These results suggested that melatonin prevented gut barrier dysfunction and reduced bacterial translocation, resulting in reduced pancreatic-associated infections and decreased early mortality rates.
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Affiliation(s)
- Xuecheng Sun
- Department of Gastroenterology and Hepatology, First Affiliated Hospital of Wenzhou Medical College, Wenzhou, Zhejiang 325000, P.R. China
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Does melatonin homeostasis play a role in continuous epigastric pain syndrome? Int J Mol Sci 2013; 14:12550-62. [PMID: 23771022 PMCID: PMC3709799 DOI: 10.3390/ijms140612550] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Revised: 04/22/2013] [Accepted: 05/16/2013] [Indexed: 02/07/2023] Open
Abstract
Two clinical forms of functional dyspepsia (FD) are listed in the Rome III criteria: postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS), differing in the recurrence of ailments depending on the diet. Continuous EPS (CEPS) is observed in some EPS patients, also at night, but its cause is still unknown. We showed previously that melatonin (MEL) homeostasis may be associated with FD. In the present work we evaluated selected components of melatonin homeostasis in patients with CEPS. The study included 30 patients with CEPS, 21 women and nine men, aged 21-49 years and 30 control subjects (EPS excluded); organic and mental diseases, as well as Helicobacter pylori infection, were excluded in both groups. The average severity of abdominal pain in the last three months was estimated in a 10-point scale (Visual Analog Scale). The levels of mRNA expression of arylalkylamine-N-acetyltransferase (AANAT) and hydroxyindole-O-methyltransferase (HIOMT), the main components of MEL homeostasis, were determined in gastric mucosa with real time PCR. The fasting serum level of MEL (at 09:00 a.m.) and circadian urine excretion of 6-sulfatoxymelatonin (6-HMS) were determined with ELISA. AANAT expression in antral mucosa of control subjects was 1.76 ± 0.41, in the gastric body 1.35 ± 0.38, and in the dyspeptic group 1.42 ± 0.38 (p < 0.05) and 0.92 ± 0.55 (p < 0.05), respectively. HIOMT expression in the control was 2.05 ± 0.70 in the antrum and 1.57 ± 0.69 in the body and in the CEPS group, it was: 1.51 ± 0.57 (p < 0.05) and 0.74 ± 0.31 (p < 0.001), respectively. MEL concentration (pg/mL) was 9.41 ± 3.09 in the control group and 5.62 ± 1.34 (p < 0.01) in the CEPS group. Urinary 6-HMS excretion (μg/24 h) was 11.40 ± 4.46 in the controls and 7.68 ± 2.88 (p < 0.05) in the CEPS. Moreover, a negative correlation was found between the tested parameters and severity of epigastric pain. These results indicate that patients with CEPS may display low level of AANAT and HIOMT expression in gastric mucosa, resulting in decreased MEL synthesis.
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Sommansson A, Nylander O, Sjöblom M. Melatonin decreases duodenal epithelial paracellular permeability via a nicotinic receptor-dependent pathway in rats in vivo. J Pineal Res 2013; 54:282-91. [PMID: 23009576 DOI: 10.1111/jpi.12013] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2012] [Accepted: 08/14/2012] [Indexed: 12/21/2022]
Abstract
Intestinal epithelial intercellular tight junctions (TJs) provide a rate-limiting barrier restricting passive transepithelial movement of solutes. TJs are highly dynamic areas, and their permeability is changed in response to various stimuli. Defects in the intestinal epithelial TJ barrier may contribute to intestinal inflammation or leaky gut. The gastrointestinal tract may be the largest extrapineal source of endogenous melatonin. Melatonin released from the duodenal mucosa is a potent stimulant of duodenal mucosal bicarbonate secretion (DBS). The aim of this study was to elucidate the role of melatonin in regulating duodenal mucosal barrier functions, including mucosal permeability, DBS, net fluid flux, and duodenal motor activity, in the living animal. Rats were anesthetized with thiobarbiturate, and a ~30-mm segment of the proximal duodenum with an intact blood supply was perfused in situ. Melatonin and the selective melatonin receptor antagonist luzindole were perfused luminally or given intravenously. Effects on permeability (blood-to-lumen clearance of (51)Cr-EDTA), DBS, mucosal net fluid flux, and duodenal motility were monitored. Luminal melatonin caused a rapid decrease in paracellular permeability and an increase in DBS, but had no effect on duodenal motor activity or net fluid flux. Luzindole did not influence any of the basal parameters studied, but significantly inhibited the effects of melatonin. The nonselective and noncompetitive nicotinic acetylcholine receptor antagonist mecamylamine abolished the effect of melatonin on duodenal permeability and reduced that on DBS. In conclusion, these findings provide evidence that melatonin significantly decreases duodenal mucosal paracellular permeability and increases DBS. The data support the important role of melatonin in the neurohumoral regulation of duodenal mucosal barrier.
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Affiliation(s)
- Anna Sommansson
- Division of Physiology, Department of Neuroscience, Uppsala University, Uppsala, Sweden
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Fischer TW, Kleszczyński K, Hardkop LH, Kruse N, Zillikens D. Melatonin enhances antioxidative enzyme gene expression (CAT, GPx, SOD), prevents their UVR-induced depletion, and protects against the formation of DNA damage (8-hydroxy-2'-deoxyguanosine) in ex vivo human skin. J Pineal Res 2013; 54:303-12. [PMID: 23110400 DOI: 10.1111/jpi.12018] [Citation(s) in RCA: 243] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Accepted: 09/21/2012] [Indexed: 12/16/2022]
Abstract
UV radiation (UVR) induces serious structural and functional alterations in human skin leading to skin aging and carcinogenesis. Reactive oxygen species are key players in UVR-mediated photodamage and induce the DNA-base-oxidized, intermediate 8-hydroxy-2'-deoxyguanosine (8-OHdG). Herein, we report the protective action of melatonin against UVR-induced 8-OHdG formation and depletion of antioxidative enzymes using ex vivo human full-thickness skin exposed to UVR in a dose (0, 100, 300 mJ/cm(2))- and time-dependent manner (0, 24, 48 hr post-UVR). Dynamics of depletion of antioxidative enzymes including catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD), or 8-OHdG formation were studied by real-time PCR and immunofluorescence/immunohistochemical staining. UVR-treated skin revealed significant and immediate (0 hr 300 mJ/cm(2)) reduction of gene expression, and this effect intensified within 24 hr post-UVR. Simultaneous increase in 8-OHdG-positive keratinocytes occurred already after 0 hr post-UVR reaching 71% and 99% up-regulation at 100 and 300 mJ/cm(2), respectively (P < 0.001). Preincubation with melatonin (10(-3) M) led to 32% and 29% significant reductions in 8-OHdG-positive cells and the prevention of antioxidative enzyme gene and protein suppression. Thus, melatonin was shown to play a crucial role as a potent antioxidant and DNA protectant against UVR-induced oxidative damage in human skin.
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Affiliation(s)
- Tobias W Fischer
- Department of Dermatology, Allergology and Venerology, University of Lübeck, Lübeck, Germany.
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Ahmed R, Mahavadi S, Al-Shboul O, Bhattacharya S, Grider JR, Murthy KS. Characterization of signaling pathways coupled to melatonin receptors in gastrointestinal smooth muscle. ACTA ACUST UNITED AC 2013; 184:96-103. [PMID: 23541890 DOI: 10.1016/j.regpep.2013.03.028] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Revised: 03/06/2013] [Accepted: 03/20/2013] [Indexed: 12/15/2022]
Abstract
Melatonin, a close derivative of serotonin, is involved in physiological regulation of circadian rhythms. In the gastrointestinal (GI) system, melatonin exhibits endocrine, paracrine and autocrine actions and is implicated in the regulation of GI motility. However, it is not known whether melatonin can also act directly on GI smooth muscle cells. The aim of the present study was to determine the expression of melatonin receptors in smooth muscle and identify their signaling pathways. MT1, but not MT2 receptors are expressed in freshly dispersed and cultured gastric smooth muscle cells. Melatonin selectively activated Gq and stimulated phosphoinositide (PI) hydrolysis in freshly dispersed and cultured muscle cells. PI hydrolysis was blocked by the expression of Gq, but not Gi minigene in cultured muscle cells. Melatonin also caused rapid increase in cytosolic Ca(2+) as determined by epifluorescence microscopy in fura-2 loaded single smooth muscle cells, and induced rapid contraction. Melatonin-induced PI hydrolysis and contraction were blocked by a non-selective MT1/MT2 antagonist luzindole (1 μM), but not by a selective MT2 antagonist 4P-PDOT (100 nM), and by the PLC inhibitor U73122. MT2 selective agonist IIK7 (100 nM) had no effect on PI hydrolysis and contraction. We conclude that rabbit gastric smooth muscle cells express melatonin MT1 receptors coupled to Gq. Activation of these receptors causes stimulation of PI hydrolysis and increase in cytosolic Ca(2+), and elicits muscle contraction.
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MESH Headings
- Animals
- Gastrointestinal Tract/metabolism
- Isoindoles/pharmacology
- Muscle Contraction
- Muscle, Smooth/metabolism
- Myocytes, Smooth Muscle/metabolism
- Rabbits
- Receptor, Melatonin, MT1/antagonists & inhibitors
- Receptor, Melatonin, MT1/metabolism
- Receptor, Melatonin, MT2/antagonists & inhibitors
- Receptor, Melatonin, MT2/metabolism
- Signal Transduction
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Affiliation(s)
- Rashad Ahmed
- Department of Physiology and VCU Program in Enteric Neuromuscular Sciences (VPENS), Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, United States
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Kleszczyński K, Tukaj S, Kruse N, Zillikens D, Fischer TW. Melatonin prevents ultraviolet radiation-induced alterations in plasma membrane potential and intracellular pH in human keratinocytes. J Pineal Res 2013; 54:89-99. [PMID: 22856627 DOI: 10.1111/j.1600-079x.2012.01028.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2012] [Accepted: 06/22/2012] [Indexed: 12/13/2022]
Abstract
Melatonin exhibits protective effects against ultraviolet radiation (UVR) via modulation of proinflammatory mediators and its free radical scavenging capacity. To date, several reports presented protective mechanisms of this agent against UVR-induced alterations in mitochondria and nuclei. This investigation evaluates the potent preventing action of melatonin regarding early-stage UVR-mediated perturbations in plasma membrane potential (mbΔψ) and intracellular (cytosolic) pH (pH i) analyzed by flow cytometry. Experiments were carried out in a dose- and time-dependent manner using human keratinocytes [HaCaT and normal human epidermal keratinocytes (NHEK)]. First investigations, which used viability/cytotoxicity assays, showed the gradual mortality with increasing UVR doses and cultivation time. Pre-incubation with melatonin (10(-3) m) prior to UVR exposure reduced lactate dehydrogenase release by 30% (HaCaT) and 28% (NHEK) at the dose of 50 mJ/cm(2) after 48 hr (P < 0.001). Furthermore, UVR caused hyperpolarization of mbΔψ immediately (0 hr) after irradiation (25 or 50 mJ/cm(2)). At the dose of 50 mJ/cm(2), cells cultivated for 48 hr manifested a marked increase in mbΔψ by 112% (HaCaT) and 123% (NHEK). The presence of melatonin significantly protected the cells by 12% (HaCaT) and 14% (NHEK) (P < 0.001). Simultaneously, 50 mJ/cm(2) induced dramatic acidification reaching after 24 hr the level of 6.40 (without melatonin), 6.56 (with melatonin) for HaCaT and 6.11 (without melatonin), 6.43 (with melatonin) for NHEK. The results presented provide information about the protective mechanisms of melatonin itself on one hand and, combined with data reported so far, confirm the potent antiapoptotic action of melatonin.
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Abstract
Biologically, light including ultraviolet (UV) radiation is vital for life. However, UV exposure does not come without risk, as it is a major factor in the development of skin cancer. Natural protections against UV damage may have been affected by lifestyle changes over the past century, including changes in our sun exposure due to working environments, and the use of sunscreens. In addition, extended "day time" through the use of artificial light may contribute to the disruption of our circadian rhythms; the daily cycles of changes in critical bio-factors including gene expression. Circadian disruption has been implicated in many health conditions, including cardiovascular, metabolic and psychiatric diseases, as well as many cancers. Interestingly, the pineal hormone melatonin plays a role in both circadian regulation as well as protection from UV skin damage, and is therefore an important factor to consider when studying the impact of UV light. This review discusses the beneficial and deleterious effects of solar exposure, including UV skin damage, Vitamin D production, circadian rhythm disruption and the impact of melatonin. Understanding these benefits and risks is critical for the development of protective strategies against solar radiation.
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Affiliation(s)
| | | | - Nihal Ahmad
- Department of Dermatology, University of Wisconsin, Madison, WI, USA
- University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
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Huai J, Shao Y, Sun X, Jin Y, Wu J, Huang Z. Melatonin ameliorates acute necrotizing pancreatitis by the regulation of cytosolic Ca2+ homeostasis. Pancreatology 2012; 12:257-63. [PMID: 22687382 DOI: 10.1016/j.pan.2012.02.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2011] [Revised: 02/05/2012] [Accepted: 02/08/2012] [Indexed: 12/11/2022]
Abstract
OBJECTIVES This study aims to investigate the relationship between the protective effects of melatonin in pancreas and the expression of sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) and Na(+)/Ca(2+) exchanger (NCX) in rats with acute necrotizing pancreatitis (ANP), to verify whether melatonin ameliorates ANP by alleviating calcium overload. METHODS Ninety-six male Sprague-Dawley rats were randomly divided into four groups (sham operation group, ANP group, melatonin treatment group, melatonin contrast group). ANP was induced by the retrograde injection of 4% taurocholate (1 ml/kg body weight) into the biliopancreatic duct. Melatonin (50 mg/kg body weight) was administered 30 min before the induction of ANP in the melatonin treatment group. Rats in each group were euthanized at 1, 4, and 8 h after ANP induction. Pancreatic tissues were removed to measure SERCA and NCX levels and cytosolic calcium ion (Ca(2+)) concentration ([Ca(2+)](i)). RESULTS At each time point, SERCA and NCX levels in the melatonin treatment group were significantly higher than that in the ANP group, and lower than that in the sham group and the melatonin contrast group. These levels did not differ between the 4- and 8-h time points in the ANP group. [Ca(2+)](i) in pancreatic acinar cells was higher in the melatonin treatment group than in the sham group and the melatonin contrast group, but lower than in the ANP group, at each time point. CONCLUSION Melatonin can reduce pancreatic damage via the up-regulation of SERCA and NCX expression, which can alleviate calcium overload in pancreatic acinar cells.
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Affiliation(s)
- Jiaping Huai
- Department of Gastroenterology and Hepatology, First Affiliated Hospital of Wenzhou Medical College, Wenzhou, 325000 Zhejiang, China
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Chen CQ, Fichna J, Bashashati M, Li YY, Storr M. Distribution, function and physiological role of melatonin in the lower gut. World J Gastroenterol 2011; 17:3888-98. [PMID: 22025877 PMCID: PMC3198018 DOI: 10.3748/wjg.v17.i34.3888] [Citation(s) in RCA: 158] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2011] [Revised: 03/18/2011] [Accepted: 03/25/2011] [Indexed: 02/06/2023] Open
Abstract
Melatonin is a hormone with endocrine, paracrine and autocrine actions. It is involved in the regulation of multiple functions, including the control of the gastrointestinal (GI) system under physiological and pathophysiological conditions. Since the gut contains at least 400 times more melatonin than the pineal gland, a review of the functional importance of melatonin in the gut seems useful, especially in the context of recent clinical trials. Melatonin exerts its physiological effects through specific membrane receptors, named melatonin-1 receptor (MT1), MT2 and MT3. These receptors can be found in the gut and their involvement in the regulation of GI motility, inflammation and pain has been reported in numerous basic and clinical studies. Stable levels of melatonin in the lower gut that are unchanged following a pinealectomy suggest local synthesis and, furthermore, implicate physiological importance of endogenous melatonin in the GI tract. Presently, only a small number of human studies report possible beneficial and also possible harmful effects of melatonin in case reports and clinical trials. These human studies include patients with lower GI diseases, especially patients with irritable bowel syndrome, inflammatory bowel disease and colorectal cancer. In this review, we summarize the presently available information on melatonin effects in the lower gut and discuss available in vitro and in vivo data. We furthermore aim to evaluate whether melatonin may be useful in future treatment of symptoms or diseases involving the lower gut.
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Bertrand PP, Bertrand RL, Camello PJ, Pozo MJ. Simultaneous measurement of serotonin and melatonin from the intestine of old mice: the effects of daily melatonin supplementation. J Pineal Res 2010; 49:23-34. [PMID: 20374441 DOI: 10.1111/j.1600-079x.2010.00760.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Ageing is associated with important changes in gastrointestinal function and in the levels of intestinal hormones secreted. Enterochromaffin (EC) cells containing serotonin (5-HT) and melatonin may play a major role in maintaining gut function during ageing. Our aim was to characterise the mucosal availability of 5-HT and melatonin in the ileum and colon of a mouse model of ageing. Female young mice (2-5 month; n = 6), aged mice (22-24 months; n = 6) and aged mice treated with melatonin (n = 6; 10 mg/kg/day) were examined. Electrochemical methods were used to measure 5-HT and melatonin concentrations near the mucosal surface of ileum and distal colon. Amperometry studies showed that steady state levels of 5-HT from ileum and colon were decreased in aged mice treated with melatonin when compared to aged mice, while compression-evoked 5-HT release was unchanged. Differential pulse voltammetry studies showed that young mice had concentrations of 5-HT of 4.8 +/- 0.8 mum in the ileum and 4.9 +/- 1.0 mum in the colon. Concentrations of melatonin were 5.7 +/- 1.4 mum in the ileum and 5.6 +/- 1.9 mum in the colon. Compared to young mice, the levels of 5-HT and melatonin were increased in aged mice (combined ileum and colon: 5-HT = 130% and melatonin = 126% of young mice) and decreased in melatonin-treated mice (5-HT = 94% and melatonin = 82%). In conclusion, our data show that the availability of gut 5-HT and melatonin is increased in aged mice and melatonin treatment suppresses natural gastrointestinal production of 5-HT and melatonin in the aged mouse intestine.
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Affiliation(s)
- P P Bertrand
- Department of Physiology, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
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Sharma S, Haldar C, Chaube SK, Laxmi T, Singh SS. Long-term melatonin administration attenuates low-LET gamma-radiation-induced lymphatic tissue injury during the reproductively active and inactive phases of Indian palm squirrels (Funambulus pennanti). Br J Radiol 2010; 83:137-51. [PMID: 20139262 DOI: 10.1259/bjr/73791461] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
A comparative analysis of low linear energy transfer (LET) gamma-radiation-induced damage in the lymphatic tissue of a tropical seasonal breeder, Indian palm squirrel (Funambulus pennanti), during its reproductively active phase (RAP) and inactive phase (RIP) was performed with simultaneous investigation of the effects of long-term melatonin pre-treatment (100 microg/100 g body weight). A total of 120 squirrels (60 during RAP and 60 during RIP) were divided into 12 groups and sacrificed at 4, 24, 48, 72 and 168 h following 5 Gy gamma-radiation exposure; control groups were excluded from exposure. Total leukocyte count and absolute lymphocyte count (ALC) and melatonin only of peripheral blood, stimulation index, thiobarbituric-acid-reactive substances (TBARS) level, superoxide dismutase (SOD) activity, and the apoptotic index of spleen as analysed by terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end labelling (TUNEL) noted at observed time-points were significantly reduced in melatonin pre-treated groups during RAP and RIP. Long-term melatonin pre-treatment mitigated radiation-induced alterations more prominently during RIP, as assessed by ALC, TBARS, SOD, TUNEL and caspase-3 activity, at some time-points. Our results demonstrate an inhibitory role of melatonin on caspase-3 activity in splenocytes during RAP and RIP following gamma-radiation-induced caspase-mediated apoptosis. Hence, we propose that melatonin might preserve the viability of immune cells of a seasonal breeder against background radiation, which is constantly present in the environment.
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Affiliation(s)
- S Sharma
- Pineal Research Laboratory, Department of Zoology, Banaras Hindu University, Varanasi-221005, India
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Reiter RJ, Paredes SD, Manchester LC, Tan DX. Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin. Crit Rev Biochem Mol Biol 2009; 44:175-200. [PMID: 19635037 DOI: 10.1080/10409230903044914] [Citation(s) in RCA: 375] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The discovery of melatonin and its derivatives as antioxidants has stimulated a very large number of studies which have, virtually uniformly, documented the ability of these molecules to detoxify harmful reactants and reduce molecular damage. These observations have clear clinical implications given that numerous age-related diseases in humans have an important free radical component. Moreover, a major theory to explain the processes of aging invokes radicals and their derivatives as causative agents. These conditions, coupled with the loss of melatonin as organisms age, suggest that some diseases and some aspects of aging may be aggravated by the diminished melatonin levels in advanced age. Another corollary of this is that the administration of melatonin, which has an uncommonly low toxicity profile, could theoretically defer the progression of some diseases and possibly forestall signs of aging. Certainly, research in the next decade will help to define the role of melatonin in age-related diseases and in determining successful aging. While increasing life span will not necessarily be a goal of these investigative efforts, improving health and the quality of life in the aged should be an aim of this research.
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Affiliation(s)
- Russel J Reiter
- Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA.
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Muñoz JL, Ceinos RM, Soengas JL, Míguez JM. A simple and sensitive method for determination of melatonin in plasma, bile and intestinal tissues by high performance liquid chromatography with fluorescence detection. J Chromatogr B Analyt Technol Biomed Life Sci 2009; 877:2173-7. [DOI: 10.1016/j.jchromb.2009.06.001] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2009] [Revised: 05/21/2009] [Accepted: 06/01/2009] [Indexed: 10/20/2022]
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Fischer TW, Slominski A, Zmijewski MA, Reiter RJ, Paus R. Melatonin as a major skin protectant: from free radical scavenging to DNA damage repair. Exp Dermatol 2008; 17:713-30. [DOI: 10.1111/j.1600-0625.2008.00767.x] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
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Konturek PC, Konturek SJ, Burnat G, Brzozowski T, Brzozowska I, Reiter RJ. Dynamic physiological and molecular changes in gastric ulcer healing achieved by melatonin and its precursor L-tryptophan in rats. J Pineal Res 2008; 45:180-90. [PMID: 18298459 DOI: 10.1111/j.1600-079x.2008.00574.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Following induction of gastric ulcer in rats by serosal application of acetic acid, local mucosal necrosis ensues accompanied by a reduction in mucosal microcirculation and by almost immediate expression of inducible nitric oxide (NO) synthase (iNOS) and proinflammatory cytokines. Daily application of melatonin (20 mg/kg) or l-tryptophan (100 mg/kg) accelerates ulcer healing by affecting the cyclooxygenase-2 (COX-2)-prostaglandin (PG) system with excessive production of protective PG, especially in later period of ulcer healing. Furthermore, expression of hypoxia inducible factor, vascular-endothelial growth factor, an activation of cNOS-NO system and the stimulation of sensory nerves with the expression and release of calcitonin gene related peptide (CGRP) appear to aid the restoration of mucosal repair and microcirculation in the ulcer bed. The enhanced expression of the melatonin MT(2) receptors (MT(2)-R) combined with overexpression of key enzymes involved in biosynthesis of melatonin such as N-acetyltransferase and hydroxyindole-O-methyltransferase contribute to the acceleration of ulcer healing by this indole. Melatonin-induced acceleration of ulcer healing is also mediated by release of gastrin and ghrelin, the most potent stimulants of gastric mucosal cell proliferation and mucosal repair. These sequential steps in ulcer healing accelerated by melatonin can be interfered with by the blockade of MT(2)R, COX-2/PG and cNOS/NO systems, and by reduction in the inflammatory iNOS/NO system. Thus, melatonin and its precursor l-tryptophan, trigger the cascade of molecular events leading to the functional improvement in ulcer healing.
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Affiliation(s)
- Peter C Konturek
- Department of Internal Medicine, Erlangen-Nuremberg University, Erlangen, Germany.
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44
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Konturek SJ, Brzozowski T, Konturek PC, Zwirska-Korczala K, Reiter RJ. Day/night differences in stress-induced gastric lesions in rats with an intact pineal gland or after pinealectomy. J Pineal Res 2008; 44:408-15. [PMID: 18086146 DOI: 10.1111/j.1600-079x.2007.00543.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The formation of acute gastric lesions depends upon the balance between the aggressive factors promoting mucosal damage and the natural defense mechanisms. Previous studies have shown that melatonin inhibits gastric acid secretion, enhances the release of gastrin, augments gastric blood flow (GBF), increases the cyclooxygenase-2 (COX-2)-prostaglandin (PG) system and scavenges free radicals, resulting in the prevention of stress-induced gastric lesions. Besides the pineal gland, melatonin is also generated in large amounts in the gastrointestinal tract and due to its antioxidant and anti-inflammatory properties; this indole might serve as local protective endogen preventing the development of acute gastric damage. The results of the present study indicate that stress-induced gastric lesions show circadian variations with an increase in the day time and a decline at night. These changes are inversely related to plasma melatonin levels. Following pinealectomy, stress-induced gastric mucosal lesions were more pronounced both during the day and at night, and were accompanied by markedly reduced plasma melatonin levels with a pronounced reduction in mucosal generation of prostaglandin E(2) (PGE(2)), GBF and increased free radical formation and by small rise in plasma melatonin during the dark phase. We conclude that stress-induced gastric ulcerations exhibit a circadian variation with an increase in the day and attenuation at night and that these fluctuations of gastric stress ulcerogenesis occur also after pinealectomy, depending upon the interaction of COX-PG and free radicals, probably mediated by the changes in local gastric melatonin.
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Affiliation(s)
- Stanisław J Konturek
- Department of Clinical Physiology, Jagiellonian University Medical College, Cracow, Poland.
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Abstract
Melatonin, the chief secretory product of the pineal gland, has long been known to modulate hair growth, pigmentation and/or molting in many species, presumably as a key neuroendocrine regulator that couples coat phenotype and function to photoperiod-dependent environmental and reproductive changes. However, the detailed effects and mechanisms of this surprisingly pleiotropic indole on the hair follicle (HF) regarding growth control and pigmentation have not yet been completely understood. While unspecific melatonin binding sites have long been identified (e.g., in goat and mouse HFs), specific melatonin membrane MT2 receptor transcripts and both protein and mRNA expression for a specific nuclear melatonin binding site [retinoid-related orphan receptor alpha (RORalpha)] have only recently been identified in murine HFs. MT1, known to be expressed in human skin cells, is not transcribed in mouse skin. After initial enzymologic data from hamster skin related to potential intracutaneous melatonin synthesis, it has recently been demonstrated that murine and human skin, namely human scalp HFs in anagen, are important sites of extrapineal melatonin synthesis. Moreover, HF melatonin production is enhanced by catecholamines (as it classically occurs in the pineal gland). Melatonin may also functionally play a role in hair-cycle control, as it down-regulates both apoptosis and estrogen receptor-alpha expression, and modulates MT2 and RORalpha expression in murine skin in a hair-cycle-dependent manner. Because of melatonin's additional potency as a free radical scavenger and DNA repair inducer, the metabolically and proliferatively highly active anagen hair bulb may also exploit melatonin synthesis in loco as a self-cytoprotective strategy.
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Affiliation(s)
- Tobias W Fischer
- Department of Dermatology, University Hospital Schleswig-Holstein, University of Lübeck, Lübeck, Germany
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Fernández-Durán B, Ruibal C, Polakof S, Ceinos RM, Soengas JL, Míguez JM. Evidence for arylalkylamine N-acetyltransferase (AANAT2) expression in rainbow trout peripheral tissues with emphasis in the gastrointestinal tract. Gen Comp Endocrinol 2007; 152:289-94. [PMID: 17292900 DOI: 10.1016/j.ygcen.2006.12.008] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2006] [Revised: 11/15/2006] [Accepted: 12/18/2006] [Indexed: 01/16/2023]
Abstract
In fish, melatonin is reported to be produced mainly in the pineal organ, but there is also evidence for the presence of melatonin in a number of extrapineal sites where it could act as an intracellular mediator or paracrine signal. The present study use the reverse transcription-polymerase chain reaction (RT-PCR) to evaluate the expression of the enzyme arylalkylamine-N-acetyltransferase (AANAT2), which catalyzes the limiting step for melatonin synthesis, in different peripheral tissues of rainbow trout, with emphasis in the gastrointestinal tract (GIT). The results show AANAT2 gene expression in almost all peripheral tissues tested, including gills, kidney, muscle, skin, liver, Brockmann bodies, gall bladder, spleen and GIT, but not in adipose tissue. Furthermore, in trout GIT we observed that AANAT2 is expressed only in the muscular layer of all segments tested (esophagus, stomach, pyloric ceca, foregut, midgut and hindgut), but not in the mucosal layer. No significant differences were obtained among the different GIT segments evaluated. These results support an almost ubiquitous synthesis of melatonin in peripheral organs of rainbow trout, which can be related with a local role of the hormone as autocrine or paracrine factor. In addition, our data support the existence of a local synthesis of melatonin in trout GIT, which is discussed and could be involved in some sort of endocrine regulation of feeding and digestive activity, acting as an antioxidant or contributing to maintain melatonin levels in plasma.
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Affiliation(s)
- Begoña Fernández-Durán
- Laboratorio de Fisioloxía Animal, Departmento de Bioloxía Funcional e Ciencias da Saude, Facultade de Bioloxía, Universidade de Vigo, Edificio de Ciencias Experimentais, Campus Universitario, E-36310 Vigo, Spain
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Singh SS, Haldar C. Biological significance of daily variation in immunity ofPerdicula asiatica: role of melatonin and testosterone. BIOL RHYTHM RES 2007. [DOI: 10.1080/09291010600902652] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Alqarawi AA, Elmougy SA. The existence of extrapineal locations for melatonin synthesis in the one-humped camel (Camelus dromedarius). BIOL RHYTHM RES 2007. [DOI: 10.1080/09291010600832289] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Vera LM, De Pedro N, Gómez-Milán E, Delgado MJ, Sánchez-Muros MJ, Madrid JA, Sánchez-Vázquez FJ. Feeding entrainment of locomotor activity rhythms, digestive enzymes and neuroendocrine factors in goldfish. Physiol Behav 2007; 90:518-24. [PMID: 17196229 DOI: 10.1016/j.physbeh.2006.10.017] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2006] [Revised: 10/23/2006] [Accepted: 10/30/2006] [Indexed: 09/30/2022]
Abstract
The existence of food anticipatory activity (FAA) in animals subjected to daily feeding schedules seems to be mediated by a feeding-entrainable oscillator (FEO). Such an FEO may help in anticipating meal time and so optimizing food acquisition and nutrient utilization. In this study we investigated the existence of FAA and whether digestive enzymes, plasma cortisol, hypothalamic NPY and gastrointestinal tract (GIT) and plasma melatonin were entrained by periodic feeding in goldfish. We observed that periodically fed goldfish showed FAA in locomotor activity as well as in amylase and NPY. Alkaline protease and GIT melatonin were higher after feeding, whereas plasma cortisol levels were reduced. Plasma melatonin remained unmodified before and after meal time. These results suggested that scheduled feeding entrained both behavioral and certain physiological patterns in goldfish, FAA being of adaptive value to anticipate a meal and prepare the digestive physiology of fish.
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Affiliation(s)
- L M Vera
- Department of Physiology, Faculty of Biology, University of Murcia, 30100 Murcia, Spain
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Schultz CL, Edrington TS, Callaway TR, Schroeder SB, Hallford DM, Genovese KJ, Anderson RC, Nisbet DJ. The influence of melatonin on growth of E. coli O157:H7 in pure culture and exogenous melatonin on faecal shedding of E. coli O157:H7 in experimentally infected wethers. Lett Appl Microbiol 2006; 43:105-10. [PMID: 16834729 DOI: 10.1111/j.1472-765x.2006.01909.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
AIMS To determine if exogenous melatonin (MEL) influences growth of Escherichia coli O157:H7 in pure culture and if MEL affects faecal shedding patterns of E. coli O157:H7 or total leucocyte counts in sheep. METHODS AND RESULTS Two strains of E. coli O157:H7 were cultured in the presence of varying concentrations of MEL. Maximal specific growth rates of E.coli O157:H7 strains were not affected by MEL addition in pure culture. Wethers (n = 16) received either 0 (CONT) or 25 mg MEL hd(-1) day(-1) for 21 days. Daily shedding patterns of E. coli O157:H7 were not different (P > 0.10) between groups with faecal populations of E. coli O157:H7 decreasing daily (P < 0.01) in both groups. However, shedding tended to differ between the control and treated group by the end of the experiment. Total WBC and differential leucocyte counts were not affected by treatment. CONCLUSIONS Melatonin had no affect on specific growth rates in pure culture nor did the administration of exogenous MEL alter bacterial shedding patterns or immune response indicators in experimentally infected wethers exposed to a long photoperiod. SIGNIFICANCE AND IMPACT OF THE STUDY Although MEL did not affect shedding patterns or gastrointestinal populations of E. coli O157:H7, the tendency for MEL-treated sheep to shed less E. coli O157:H7 towards the end of the experiment warrants further research. Providing MEL for a longer period of time, or at greater concentrations, may elucidate a potential role that MEL plays in the seasonal shedding patterns of E. coli O157:H7 in livestock.
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Affiliation(s)
- C L Schultz
- Land O' Lakes, Purina Feed, LLC, St Louis, MO, USA
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