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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: 0] [Impact Index Per Article: 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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Rivera Antonio A, Padilla Martínez I, Márquez-Flores Y, Juárez Solano A, Torres Ramos M, Rosales Hernández M. Protective effect of (E)-(2,4-dihydroxy)-α-aminocinnamic acid, a hydroxy cinnamic acid derivative, in an ulcerative colitis model induced by TNBS. Biosci Rep 2024; 44:BSR20240797. [PMID: 39268608 PMCID: PMC11461179 DOI: 10.1042/bsr20240797] [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: 06/29/2024] [Revised: 09/02/2024] [Accepted: 09/10/2024] [Indexed: 09/17/2024] Open
Abstract
Ulcerative colitis (UC) is a multifactorial disease that causes long-lasting inflammation and ulcers in the digestive tract. UC is the most common form of inflammatory bowel disease (IBD). The current treatment for mild-to-moderate UC involves the use of 5-aminosalicylates (5-ASA), but much of this compound is unabsorbed and metabolized by N-acetylation. Several efforts have since been made to evaluate new molecules from synthetic or natural sources. Recently, it was reported that (E)-(5-chloro-2-hydroxy)-α-aminocinnamic acid (2c) and (E)-(2,4-dihydroxy)-α-aminocinnamic acid (2f) are as good or better myeloperoxidase (MPO) inhibitors and antioxidants than 5-ASA. Then, the present study aimed to evaluate the protective effects of 2c and 2f on a rat model of UC induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). The results showed that TNBS caused the induction of colonic ulcers, as well as a significant increase in MPO activity and malondialdehyde (MDA) and a decrease in glutathione (GSH) content. The administration of 2f, 2c and 5-ASA, decreased the ulcers presence, inhibited MPO peroxidation activity and MPO presence (as determined by immunofluorescence), and increased GSH and reduced MDA content. However, 2f was better than 2c and 5-ASA, then, the principal mechanism by which 2f presented a protective effect in a UC model induced by TNBS in rats is by inhibiting MPO activity and due to its antioxidant activity.
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Affiliation(s)
- Astrid Mayleth Rivera Antonio
- Laboratorio de Biofísica y Biocatálisis, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Salvador Díaz Mirón s/n, Casco de Santo Tomas, Ciudad de México 11340, México
| | - Itzia Irene Padilla Martínez
- Laboratorio de Química Supramolecular y Nanociencias, Unidad Profesional Interdisciplinaria de Biotecnología, Instituto Politécnico Nacional, Avenida Acueducto s/n, Barrio la Laguna Ticomán, Ciudad de México 07340, México
| | - Yazmín Karina Márquez-Flores
- Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Campus Zacatenco, Instituto Politécnico Nacional, Av. Wilfrido Massieu s/n Col. Zacatenco, C.P. 07738, Ciudad de México, México
| | - Alan Hipólito Juárez Solano
- Dirección de investigación del Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez. Av. Insurgentes sur #3877, col. La Fama. Tlalpan, Ciudad de México. C.P. 14269. México
| | - Mónica A. Torres Ramos
- Dirección de investigación del Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez. Av. Insurgentes sur #3877, col. La Fama. Tlalpan, Ciudad de México. C.P. 14269. México
| | - Martha Cecilia Rosales Hernández
- Laboratorio de Biofísica y Biocatálisis, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Salvador Díaz Mirón s/n, Casco de Santo Tomas, Ciudad de México 11340, México
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Ariturk LA, Cilingir S, Kolgazi M, Elmas M, Arbak S, Yapislar H. Docosahexaenoic acid (DHA) alleviates inflammation and damage induced by experimental colitis. Eur J Nutr 2024; 63:2801-2813. [PMID: 39105785 PMCID: PMC11490523 DOI: 10.1007/s00394-024-03468-x] [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: 10/04/2023] [Accepted: 07/05/2024] [Indexed: 08/07/2024]
Abstract
PURPOSE Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic gastrointestinal disorders associated with significant morbidity and complications. This study investigates the therapeutic potential of docosahexaenoic acid (DHA) in a trinitrobenzene sulfonic acid (TNBS) induced colitis model, focusing on inflammation, oxidative stress, and intestinal membrane permeability. METHODS Wistar albino rats were divided into Control, Colitis, and Colitis + DHA groups (n = 8-10/group). The Colitis and Colitis + DHA groups received TNBS intrarectally, while the Control group received saline. DHA (600 mg/kg/day) or saline was administered via gavage for six weeks. Macroscopic and microscopic evaluations of colon tissues were conducted. Parameters including occludin and ZO-1 expressions, myeloperoxidase (MPO) activity, malondialdehyde (MDA), glutathione (GSH), total antioxidant status (TAS), total oxidant status (TOS), Interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) levels were measured in colon tissues. RESULTS Colitis induction led to significantly higher macroscopic and microscopic damage scores, elevated TOS levels, reduced occludin and ZO-1 intensity, decreased mucosal thickness, and TAS levels compared to the Control group (p < 0.001). DHA administration significantly ameliorated these parameters (p < 0.001). MPO, MDA, TNF-α, and IL-6 levels were elevated in the Colitis group but significantly reduced in the DHA-treated group (p < 0.001 for MPO, MDA; p < 0.05 for TNF-α and IL-6). CONCLUSION DHA demonstrated antioxidant and anti-inflammatory effects by reducing reactive oxygen species production, enhancing TAS capacity, preserving GSH content, decreasing proinflammatory cytokine levels, preventing neutrophil infiltration, reducing shedding in colon epithelium, and improving gland structure and mucosal membrane integrity. DHA also upregulated the expressions of occludin and ZO-1, critical for barrier function. Thus, DHA administration may offer a therapeutic strategy or supplement to mitigate colitis-induced adverse effects.
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Affiliation(s)
- Leman Arslan Ariturk
- Faculty of Medicine, Department of Physiology, Marmara University, Istanbul, Turkey
| | - Sumeyye Cilingir
- Faculty of Medicine, Department of Physiology, Acibadem Mehmet Ali Adinlar University, Istanbul, Turkey
| | - Meltem Kolgazi
- Faculty of Medicine, Department of Physiology, Acibadem Mehmet Ali Adinlar University, Istanbul, Turkey
| | - Merve Elmas
- Faculty of Medicine, Department of Histology&Embriology, Acibadem Mehmet Ali Adinlar University, Istanbul, Turkey
| | - Serap Arbak
- Faculty of Medicine, Department of Histology&Embriology, Acibadem Mehmet Ali Adinlar University, Istanbul, Turkey
| | - Hande Yapislar
- Faculty of Medicine, Department of Physiology, Acibadem Mehmet Ali Adinlar University, Istanbul, Turkey.
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Tao Q, Zhang J, Liang Q, Song S, Wang S, Yao X, Gao Q, Wang L. Puerarin alleviates sleep disorders in aged mice related to repairing intestinal mucosal barrier. NATURAL PRODUCTS AND BIOPROSPECTING 2023; 13:29. [PMID: 37698689 PMCID: PMC10497485 DOI: 10.1007/s13659-023-00390-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 08/18/2023] [Indexed: 09/13/2023]
Abstract
More and more evidence suggests that puerarin, a potential remedy for gut inflammation, may have an ameliorative effect on sleep disturbances. However, the relationship between puerarin and sleep disruption has not been extensively researched. This study aims to explore the role and mechanisms of puerarin in improving sleep disorders. We established a light-induced sleep disorder model in mice and assessed the effects of puerarin on cognitive behavior using open field and water maze tests. Pathological detection demonstrated that sleep disturbances resulted in observable damage to the liver, lung, and kidney. Puerarin reversed multi-organ damage and inflammation. Further, puerarin activated paneth cells, resulting in increased lysozyme and TGF-β production, and stimulating intestinal stem cell proliferation. Puerarin also effectively inhibited the expression of F4/80, iNOS, TNF-α, and IL-1β in the small intestine, while it increased Chil3, CD206, and Arg-1 levels. Moreover, puerarin treatment significantly decreased P-P65, TLR4, Bcl-xl, and cleaved caspase-3 protein levels while increasing barrier protein levels, including ZO-1, Occludin, Claudin 1 and E-cadherin suggesting a reduction in inflammation and apoptosis in the gut. Overall, puerarin diminished systemic inflammation, particularly intestinal inflammation, and enhanced intestinal barrier integrity in mice with sleep disorders. Our findings suggest a potential new therapeutic pathway for sleep disorders.
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Affiliation(s)
- Qing Tao
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, Jiangsu, China
| | - Jinhua Zhang
- Department of Clinical Laboratory, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China
| | - Qiao Liang
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, Jiangsu, China
| | - Shiyu Song
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, Jiangsu, China
| | - Shuxia Wang
- Department of Clinical Laboratory, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China
| | - Xiaoming Yao
- Department of Clinical Laboratory, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China
| | - Qian Gao
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, Jiangsu, China.
| | - Lei Wang
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, Jiangsu, China.
- Department of Clinical Laboratory, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China.
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Fang D, Xu T, Sun J, Shi J, Li F, Yin Y, Wang Z, Liu Y. Nicotinamide Mononucleotide Ameliorates Sleep Deprivation-Induced Gut Microbiota Dysbiosis and Restores Colonization Resistance against Intestinal Infections. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2207170. [PMID: 36698264 PMCID: PMC10037695 DOI: 10.1002/advs.202207170] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Indexed: 06/12/2023]
Abstract
Gut microbiota-mediated colonization resistance (CR) is crucial in protecting the host from intestinal infections. Sleep deprivation (SD) is an important contributor in the disturbances of intestinal homeostasis. However, whether and how SD affects host CR remains largely unknown. Here, it is shown that SD impairs intestinal CR in mice, whereas nicotinamide mononucleotide (NMN) supplementation restores it. Microbial diversity and metabolomic analyses suggest that gut microbiota and metabolite profiles in SD-treated mice are highly shaped, whereas NMN reprograms these differences. Specifically, the altered gut microbiota in SD mice further incurs the disorder of secondary bile acids pool accompanied by a decrease in deoxycholic acid (DCA). Conversely, NMN supplementation retakes the potential benefits of DCA, which is associated with specific gut microbiota involved in primary bile acids metabolic flux. In animal models of infection, DCA is effective in preventing and treating bacterial infections when used alone or in combination with antibiotics. Mechanistically, DCA alone disrupts membrane permeability and aggravates oxidative damage, thereby reducing intestinal pathogen burden. Meanwhile, exogenous DCA promotes antibiotic accumulation and destroys oxidant-antioxidant system, thus potentiating antibiotic efficacy. Overall, this work highlights the important roles of gut microbiota and bile acid metabolism in the maintenance of intestinal CR.
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Affiliation(s)
- Dan Fang
- College of Veterinary MedicineYangzhou UniversityYangzhou225009P. R. China
| | - Tianqi Xu
- College of Veterinary MedicineYangzhou UniversityYangzhou225009P. R. China
| | - Jingyi Sun
- College of Veterinary MedicineYangzhou UniversityYangzhou225009P. R. China
| | - Jingru Shi
- College of Veterinary MedicineYangzhou UniversityYangzhou225009P. R. China
| | - Fulei Li
- College of Veterinary MedicineYangzhou UniversityYangzhou225009P. R. China
| | - Yanqing Yin
- College of Veterinary MedicineYangzhou UniversityYangzhou225009P. R. China
| | - Zhiqiang Wang
- College of Veterinary MedicineYangzhou UniversityYangzhou225009P. R. China
- Jiangsu Co‐innovation Center for Prevention and Control of Important Animal Infectious Diseases and ZoonosesJoint International Research Laboratory of Agriculture and Agri‐Product Safety the Ministry of Education of ChinaYangzhou UniversityYangzhou225009P. R. China
- Institute of Comparative MedicineYangzhou UniversityYangzhou225009P. R. China
| | - Yuan Liu
- College of Veterinary MedicineYangzhou UniversityYangzhou225009P. R. China
- Jiangsu Co‐innovation Center for Prevention and Control of Important Animal Infectious Diseases and ZoonosesJoint International Research Laboratory of Agriculture and Agri‐Product Safety the Ministry of Education of ChinaYangzhou UniversityYangzhou225009P. R. China
- Institute of Comparative MedicineYangzhou UniversityYangzhou225009P. R. China
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Şirinyıldız F, Cesur G. Investigation of the Effects of Apelin 13 on Experimental Ulcerative Colitis. MEANDROS MEDICAL AND DENTAL JOURNAL 2022. [DOI: 10.4274/meandros.galenos.2022.86729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Ahmed O, Farid A, Elamir A. Dual role of melatonin as an anti-colitis and anti-extra intestinal alterations against acetic acid-induced colitis model in rats. Sci Rep 2022; 12:6344. [PMID: 35428860 PMCID: PMC9012815 DOI: 10.1038/s41598-022-10400-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 04/06/2022] [Indexed: 12/14/2022] Open
Abstract
The available ulcerative colitis drugs exhibit limited outcomes and adverse side effects. Therefore, our study aimed to investigate the therapeutic efficacy of melatonin in acetic acid (AA)-induced colitis to establish a possible treatment for colitis and its impacts on vital organs. Following colitis induction (2 ml 5% AA, rectally), rats were orally received melatonin (5 mg/kg) once per day for 6 days after colitis induction. Then, histopathological examination of colon, kidney, liver, and spleen was conducted, interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), myeloperoxidase (MPO), malondialdehyde (MDA), glutathione (GSH), and total antioxidant capacity (TAC) levels were assessed in colon tissue. Colitis induction in untreated rats caused necrotic effects in colon tissues, a significant increase in colonic IL-1β, TNF-α, MPO, and MDA levels, and a remarkable decrease in GSH and TAC levels in colon tissue in comparison to the control group. Meanwhile, melatonin treatment reversed these parameters by improving the microscopic and macroscopic colitis features and extra-intestinal (kidney, liver, and spleen) changes in all treated rats compared to the colitis control group. These results denote a reduction in colitis severity due to the anti-inflammatory and anti-oxidative effects of melatonin and its positive impact on the vital organs.
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Affiliation(s)
- Osama Ahmed
- Zoology Department, Faculty of Science, Cairo University, Giza, 12613, Egypt.
| | - Alyaa Farid
- Zoology Department, Faculty of Science, Cairo University, Giza, 12613, Egypt
| | - Azza Elamir
- Zoology Department, Faculty of Science, Cairo University, Giza, 12613, Egypt
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Yener S, Akbulut KG, Karakuş R, Erdoğan D, Acartürk F. Development of melatonin loaded pectin nanoparticles for the treatment of inflammatory bowel disease: In vitro and in vivo studies. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2021.102861] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Dunford J, Lee AT, Morgan MM. Tetrahydrocannabinol (THC) Exacerbates Inflammatory Bowel Disease in Adolescent and Adult Female Rats. THE JOURNAL OF PAIN 2021; 22:1040-1047. [PMID: 33727159 DOI: 10.1016/j.jpain.2021.02.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 12/19/2020] [Accepted: 02/22/2021] [Indexed: 01/15/2023]
Abstract
Inflammatory Bowel Disease (IBD) is a life-long disorder that often begins between the ages of 15 and 30. Anecdotal reports suggest cannabinoids may be an effective treatment. This study sought to determine whether home cage wheel running is an effective method to assess IBD, and whether Tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, can restore wheel running depressed by IBD. Adolescent and adult female Sprague-Dawley rats were individually housed in a cage with a running wheel. Rats were injected with trinitrobenzene sulphonic acid (TNBS) into the rectum to induce IBD-like symptoms. One day later, both vehicle and TNBS treated rats were injected with a low dose of THC (0.32 mg/kg, s.c.) or vehicle. Administration of TNBS depressed wheel running in adolescent and adult rats. No antinociceptive effect of THC was evident when administered 1 day after TNBS. In fact, administration of THC prolonged TNBS-induced depression of wheel running for over 5 days in adolescent and adult rats. These results show that home cage wheel running is depressed by TNBS-induced IBD, making it a useful tool to evaluate the behavioral consequences of IBD, and that administration of THC, instead of producing antinociception, exacerbates TNBS-induced IBD. PERSPECTIVE: This article advances research on inflammatory bowel disease in two important ways: 1) Home cage wheel running is a new and sensitive tool to assess the behavioral consequences of IBD in adolescent and adult rats; and 2) Administration of the cannabinoid THC exacerbates the negative behavioral effects of IBD.
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Affiliation(s)
- Jeremy Dunford
- Department of Psychology, Washington State University Vancouver, Vancouver, WA
| | - Andrea T Lee
- Department of Psychology, Washington State University Vancouver, Vancouver, WA
| | - Michael M Morgan
- Department of Psychology, Washington State University Vancouver, Vancouver, WA.
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Gao T, Wang Z, Cao J, Dong Y, Chen Y. Melatonin attenuates microbiota dysbiosis of jejunum in short-term sleep deprived mice. J Microbiol 2020; 58:588-597. [PMID: 32424577 DOI: 10.1007/s12275-020-0094-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 03/24/2020] [Accepted: 03/24/2020] [Indexed: 12/22/2022]
Abstract
Our study demonstrated that sleep deprivation resulted in homeostasis disorder of colon. Our study goes deeper into the positive effects of melatonin on small intestinal microbiota disorder caused by sleep deprivation. We successfully established a multiplatform 72 h sleep deprivation mouse model with or without melatonin supplementation, and analyzed the change of small intestinal microbiota using high-throughput sequencing of the 16S rRNA. We found melatonin supplementation suppressed the decrease of plasma melatonin level in sleep deprivation mice. Meanwhile, melatonin supplementation improved significantly the reduction in OTU numbers and the diversity and richness of jejunal microbiota and the abundance of Bacteroidaeae and Prevotellaceae, as well as an increase in the Firmicutes-to-Bacteroidetes ratio and the content of Moraxellaceae and Aeromonadaceae in the jejunum of sleep deprived-mice. Moreover, melatonin supplementation reversed the change of metabolic pathway in sleep deprived-mice, including metabolism, signal transduction mechanisms and transcription etc, which were related to intestinal health. Furthermore, melatonin supplementation inverted the sleep deprivation-induced a decline of anti-inflammatory cytokines (IL-22) and an increase of the ROS and proinflammatory cytokines (IL-17) in jejunum. These findings suggested that melatonin, similar to a probiotics agent, can reverse sleep deprivation-induced small intestinal microbiota disorder by suppressing oxidative stress and inflammation response.
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Affiliation(s)
- Ting Gao
- College of Veterinary Medicine, China Agricultural University, Beijing, 100193, P. R. China
| | - Zixu Wang
- College of Veterinary Medicine, China Agricultural University, Beijing, 100193, P. R. China
| | - Jing Cao
- College of Veterinary Medicine, China Agricultural University, Beijing, 100193, P. R. China
| | - Yulan Dong
- College of Veterinary Medicine, China Agricultural University, Beijing, 100193, P. R. China
| | - Yaoxing Chen
- College of Veterinary Medicine, China Agricultural University, Beijing, 100193, P. R. China.
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Park YS, Kim SH, Park JW, Kho Y, Seok PR, Shin JH, Choi YJ, Jun JH, Jung HC, Kim EK. Melatonin in the colon modulates intestinal microbiota in response to stress and sleep deprivation. Intest Res 2020; 18:325-336. [PMID: 32564539 PMCID: PMC7385569 DOI: 10.5217/ir.2019.00093] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 02/26/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND/AIMS Stress is closely related to the deterioration of digestive disease. Melatonin has potent anti-inflammatory properties. The objective of this study was to determine the effect of water stress (WS) and sleep deprivation (SD) on intestinal microbiota and roles of melatonin in stressful condition. METHODS We used C57BL/6 mice and specially designed water bath for stress and SD for 10 days. We measured melatonin concentrations in serum, feces, and colon tissues by high-performance liquid chromatography. Genomic DNA was extracted from feces and amplified using primers targeting V3 to V4 regions of bacterial 16S ribosomal RNA genes. RESULTS Compared to the control, melatonin concentration was lower in the WS and SD. Fecal concentration was 0.132 pg/mL in control, 0.062 pg/mL in WS, and 0.068 pg/mL in SD. In colon tissue, it was 0.45 pg/mL in control, 0.007 pg/mL in WS, and 0.03 pg/mL in SD. After melatonin treatment, melatonin concentrations in feces and colon tissue were recovered to the level of control. Metagenomic analysis of microbiota showed abundance in colitogenic microbiota in WS and SD. Melatonin injection attenuated this harmful effect. WS and SD showed decreased Lactobacillales and increased Erysipelotrichales and Enterobacteriales. Melatonin treatment increased Akkermansia muciniphila and Lactobacillus and decreased Bacteroides massiliensis and Erysipelotrichaceae. CONCLUSIONS This study showed that stress and SD could affect intestinal dysbiosis and increase colitogenic microbiota, which could contribute to the aggravating digestive disease. Melatonin concentrations in feces and colon tissue decreased under WS and SD. Melatonin treatment brought recovery of melatonin concentration in colon tissue and modulating dysbiosis of intestinal microbiota.
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Affiliation(s)
- Young Sook Park
- Division of Gastroenterology, Department of Internal Medicine, Nowon Eulji Medical Center, Eulji University School of Medicine, Seoul, Korea
| | - Soo Hyung Kim
- Division of Gastroenterology, Department of Internal Medicine, Nowon Eulji Medical Center, Eulji University School of Medicine, Seoul, Korea
| | - Jong Won Park
- Division of Gastroenterology, Department of Internal Medicine, Nowon Eulji Medical Center, Eulji University School of Medicine, Seoul, Korea
| | - Younglim Kho
- Department of Health, Environment and Safety, Graduate School of Health Science, Eulji University, Seongnam, Korea
| | - Pu Rum Seok
- Departemnt of Biomedical Laboratory Science, Graduate School of Health Science, Eulji University, Seongnam, Korea
| | - Jae-Ho Shin
- Department of Biomedical Laboratory Science, Eulji University, Seongnam, Korea
| | - Yoon Ji Choi
- Departemnt of Biomedical Laboratory Science, Graduate School of Health Science, Eulji University, Seongnam, Korea
| | - Jin-Hyun Jun
- Departemnt of Biomedical Laboratory Science, Graduate School of Health Science, Eulji University, Seongnam, Korea
| | - Hee Chan Jung
- Division of Gastroenterology, Department of Internal Medicine, Nowon Eulji Medical Center, Eulji University School of Medicine, Seoul, Korea
| | - Eun Kyung Kim
- Department of Pathology, Eulji University School of Medicine, Seoul, Korea
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12
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Kim SW, Kim S, Son M, Cheon JH, Park YS. Melatonin controls microbiota in colitis by goblet cell differentiation and antimicrobial peptide production through Toll-like receptor 4 signalling. Sci Rep 2020; 10:2232. [PMID: 32042047 PMCID: PMC7010660 DOI: 10.1038/s41598-020-59314-7] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 01/14/2020] [Indexed: 12/12/2022] Open
Abstract
Microbial dysbiosis has long been postulated to be associated with the pathogenesis of inflammatory bowel disease (IBD). Although evidence supporting the anti-colitic effects of melatonin have been accumulating, it is not clear how melatonin affects the microbiota. Herein, we investigated the effects of melatonin on the microbiome in colitis and identified involvement of Toll-like receptor (TLR) 4 signalling in the effects. Melatonin improved dextran sulfate sodium (DSS)-induced colitis and reverted microbial dysbiosis in wild-type (WT) mice but not in TLR4 knockout (KO) mice. Induction of goblet cells was observed with melatonin administration, which was accompanied by suppression of Il1b and Il17a and induction of melatonin receptor and Reg3β, an antimicrobial peptide (AMP) against Gram-negative bacteria. In vitro, melatonin treatment of HT-29 intestinal epithelial cells promotes mucin and wound healing and inhibits growth of Escherichia coli. Herein, we showed that melatonin significantly increases goblet cells, Reg3β, and the ratio of Firmicutes to Bacteriodetes by suppressing Gram-negative bacteria through TLR4 signalling. Our study suggests that sensing of bacteria through TLR4 and regulation of bacteria through altered goblet cells and AMPs is involved in the anti-colitic effects of melatonin. Melatonin may have use in therapeutics for IBD.
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Affiliation(s)
- Seung Won Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.,Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Soochan Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Mijeong Son
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.,Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.,Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Young Sook Park
- Department of Internal Medicine, Eulji Hospital, Eulji University School of Medicine, Seoul, Korea.
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13
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Melatonin alleviates oxidative stress in sleep deprived mice: Involvement of small intestinal mucosa injury. Int Immunopharmacol 2019; 78:106041. [PMID: 31835081 DOI: 10.1016/j.intimp.2019.106041] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 10/23/2019] [Accepted: 11/08/2019] [Indexed: 01/20/2023]
Abstract
BACKGROUND Previous research demonstrated that sleep deprivation (SD) resulted in intestinal homeostasis disorder in colon. The present study was further performed to clarify the role of melatonin in SD-induced small intestinal (SI) mucosal injury. METHODS We successfully established a multiplatform 72 h SD mouse model with or without melatonin supplementation to explore the improvement of melatonin in the destruction of SI induced by SD. RESULTS Melatonin supplementation suppressed an increase of corticosterone level and a decrease of melatonin level caused by SD. Meanwhile, we observed that melatonin supplementation in sleep deprived mice markedly reversed a decrease of the villi length/crypt depth (V/C) ratio and the number of goblet cells, PCNA positive cells, the expressions of MUC2 and tight junction proteins, as well as an upregulation of the expressions of autophagic proteins in the duodenum, jejunum and ileum. Furthermore, melatonin supplementation inverted the SD-induced the decline of antioxidant enzyme activities (T-AOC and CAT etc) and anti-inflammatory cytokines (IL-10 and IFN-γ) and the increase of oxidative product MDA, pro-inflammatory cytokines (IL-6 and TNF-α), p-P65 and p-IκB proteins in the SI. CONCLUSIONS These findings suggested that melatonin may be used as a probiotic agent to reverse SD-induced SI mucosa injury by suppressing oxidative stress and NF-κB pathway activation.
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14
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Gao T, Wang Z, Dong Y, Cao J, Lin R, Wang X, Yu Z, Chen Y. Role of melatonin in sleep deprivation-induced intestinal barrier dysfunction in mice. J Pineal Res 2019; 67:e12574. [PMID: 30929267 DOI: 10.1111/jpi.12574] [Citation(s) in RCA: 158] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 03/20/2019] [Accepted: 03/21/2019] [Indexed: 12/18/2022]
Abstract
Intestinal diseases caused by sleep deprivation (SD) are severe public health threats worldwide. This study focuses on the effect of melatonin on intestinal mucosal injury and microbiota dysbiosis in sleep-deprived mice. Mice subjected to SD had significantly elevated norepinephrine levels and decreased melatonin content in plasma. Consistent with the decrease in melatonin levels, we observed a decrease of antioxidant ability, down-regulation of anti-inflammatory cytokines and up-regulation of pro-inflammatory cytokines in sleep-deprived mice, which resulted in colonic mucosal injury, including a reduced number of goblet cells, proliferating cell nuclear antigen-positive cells, expression of MUC2 and tight junction proteins and elevated expression of ATG5, Beclin1, p-P65 and p-IκB. High-throughput pyrosequencing of 16S rRNA demonstrated that the diversity and richness of the colonic microbiota were decreased in sleep-deprived mice, especially in probiotics, including Akkermansia, Bacteroides and Faecalibacterium. However, the pathogen Aeromonas was markedly increased. By contrast, supplementation with 20 and 40 mg/kg melatonin reversed these SD-induced changes and improved the mucosal injury and dysbiosis of the microbiota in the colon. Our results suggest that the effect of SD on intestinal barrier dysfunction might be an outcome of melatonin suppression rather than a loss of sleep per se. SD-induced intestinal barrier dysfunction involved the suppression of melatonin production and activation of the NF-κB pathway by oxidative stress.
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Affiliation(s)
- Ting Gao
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Animal Medicine, China Agricultural University, Beijing, China
| | - Zixu Wang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Animal Medicine, China Agricultural University, Beijing, China
| | - Yulan Dong
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Animal Medicine, China Agricultural University, Beijing, China
| | - Jing Cao
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Animal Medicine, China Agricultural University, Beijing, China
| | - Rutao Lin
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Animal Medicine, China Agricultural University, Beijing, China
| | - Xintong Wang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Animal Medicine, China Agricultural University, Beijing, China
| | - Zhengquan Yu
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing, China
| | - Yaoxing Chen
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Animal Medicine, China Agricultural University, Beijing, China
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15
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Gil-Martín E, Egea J, Reiter RJ, Romero A. The emergence of melatonin in oncology: Focus on colorectal cancer. Med Res Rev 2019; 39:2239-2285. [PMID: 30950095 DOI: 10.1002/med.21582] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 03/04/2019] [Accepted: 03/16/2019] [Indexed: 12/17/2022]
Abstract
Within the last few decades, melatonin has increasingly emerged in clinical oncology as a naturally occurring bioactive molecule with substantial anticancer properties and a pharmacological profile optimal for joining the currently available pharmacopeia. In addition, extensive experimental data shows that this chronobiotic agent exerts oncostatic effects throughout all stages of tumor growth, from initial cell transformation to mitigation of malignant progression and metastasis; additionally, melatonin alleviates the side effects and improves the welfare of radio/chemotherapy-treated patients. Thus, the support of clinicians and oncologists for the use of melatonin in both the treatment and proactive prevention of cancer is gaining strength. Because of its epidemiological importance and symptomatic debut in advanced stages of difficult clinical management, colorectal cancer (CRC) is a preferential target for testing new therapies. In this regard, the development of effective forms of clinical intervention for the improvement of CRC outcome, specifically metastatic CRC, is urgent. At the same time, the need to reduce the costs of conventional anti-CRC therapy results is also imperative. In light of this status quo, the therapeutic potential of melatonin, and the direct and indirect critical processes of CRC malignancy it modulates, have aroused much interest. To illuminate the imminent future on CRC research, we focused our attention on the molecular mechanisms underlying the multiple oncostatic actions displayed by melatonin in the onset and evolution of CRC and summarized epidemiological evidence, as well as in vitro, in vivo and clinical findings that support the broadly protective potential demonstrated by melatonin.
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Affiliation(s)
- Emilio Gil-Martín
- Department of Biochemistry, Genetics and Immunology, Biomedical Research Center (CINBIO, 'Centro Singular de Investigación de Galicia'), University of Vigo, Vigo, Spain
| | - Javier Egea
- Molecular Neuroinflammation and Neuronal Plasticity Laboratory, Research Unit, Hospital Universitario Santa Cristina, Madrid, Spain.,Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Madrid, Spain.,Departamento de Farmacología y Terapéutica, Instituto-Fundación Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain
| | - Russel J Reiter
- Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, Texas, USA
| | - Alejandro Romero
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Complutense University of Madrid, Madrid, Spain
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16
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Nabavi SM, Nabavi SF, Sureda A, Xiao J, Dehpour AR, Shirooie S, Silva AS, Baldi A, Khan H, Daglia M. Anti-inflammatory effects of Melatonin: A mechanistic review. Crit Rev Food Sci Nutr 2019; 59:S4-S16. [DOI: 10.1080/10408398.2018.1487927] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Affiliation(s)
- Seyed Mohammad Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Seyed Fazel Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Antoni Sureda
- Grup de Nutrici_o Comunit_aria i Estr_es Oxidatiu and CIBEROBN (Physiopathology of Obesity and Nutrition), Universitat de les Illes Balears, Palma de E-07122 Mallorca, Spain
| | - Janbo Xiao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Control in Chinese Medicine, University of Macau, Macau SAR, China
| | - Ahmad Reza Dehpour
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Samira Shirooie
- School of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ana Sanches Silva
- National Institute for Agricultural and Veterinary Research (INIAV), I.P., Vairão, Vila do Conde, Portugal; Center for Study in Animal Science (CECA), ICETA, University of Oporto, Oporto, Portugal
| | - Alessandra Baldi
- Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Pavia, Italy
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan, Pakistan
| | - Maria Daglia
- Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Pavia, Italy
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17
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Kim TK, Park YS, Baik HW, Jun JH, Kim EK, Sull JW, Sung HJ, Choi JW, Chung SH, Gye MC, Lim JY, Kim JB, Kim SH. Melatonin modulates adiponectin expression on murine colitis with sleep deprivation. World J Gastroenterol 2016; 22:7559-7568. [PMID: 27672276 PMCID: PMC5011669 DOI: 10.3748/wjg.v22.i33.7559] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Revised: 07/11/2016] [Accepted: 08/01/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To determine adiponectin expression in colonic tissue of murine colitis and systemic cytokine expression after melatonin treatments and sleep deprivation.
METHODS The following five groups of C57BL/6 mice were used in this study: (1) group I, control; (2) group II, 2% DSS induced colitis for 7 d; (3) group III, 2% DSS induced colitis and melatonin treatment; (4) group IV, 2% DSS induced colitis with sleep deprivation (SD) using specially designed and modified multiple platform water baths; and (5) group V, 2% DSS induced colitis with SD and melatonin treatment. Melatonin (10 mg/kg) or saline was intraperitoneally injected daily to mice for 4 d. The body weight was monitored daily. The degree of colitis was evaluated histologically after sacrificing the mice. Immunohistochemical staining and Western blot analysis was performed using anti-adiponectin antibody. After sampling by intracardiac punctures, levels of serum cytokines were measured by ELISA.
RESULTS Sleep deprivation in water bath exacerbated DSS induced colitis and worsened weight loss. Melatonin injection not only alleviated the severity of mucosal injury, but also helped survival during stressful condition. The expression level of adiponectin in mucosa was decreased in colitis, with the lowest level observed in colitis combined with sleep deprivation. Melatonin injection significantly (P < 0.05) recovered the expression of adiponectin. The expression levels of IL-6 and IL-17 were increased in the serum of mice with DSS colitis but decreased after melatonin injection.
CONCLUSION This study suggested that melatonin modulated adiponectin expression in colonic tissue and melatonin and adiponectin synergistically potentiated anti-inflammatory effects on colitis with sleep deprivation.
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18
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Farez MF, Calandri IL, Correale J, Quintana FJ. Anti-inflammatory effects of melatonin in multiple sclerosis. Bioessays 2016; 38:1016-26. [DOI: 10.1002/bies.201600018] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Affiliation(s)
- Mauricio F. Farez
- Center for Research on Neuroimmunological Diseases (CIEN); Raúl Carrea Institute for Neurological Research (FLENI); Buenos Aires Argentina
- Department of Neurology; Raúl Carrea Institute for Neurological Research (FLENI); Buenos Aires Argentina
| | - Ismael L. Calandri
- Department of Neurology; Raúl Carrea Institute for Neurological Research (FLENI); Buenos Aires Argentina
| | - Jorge Correale
- Center for Research on Neuroimmunological Diseases (CIEN); Raúl Carrea Institute for Neurological Research (FLENI); Buenos Aires Argentina
- Department of Neurology; Raúl Carrea Institute for Neurological Research (FLENI); Buenos Aires Argentina
| | - Francisco J. Quintana
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital; Harvard Medical School; Boston MA USA
- The Broad Institute; Cambridge MA USA
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19
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Swanson GR, Gorenz A, Shaikh M, Desai V, Forsyth C, Fogg L, Burgess HJ, Keshavarzian A. Decreased melatonin secretion is associated with increased intestinal permeability and marker of endotoxemia in alcoholics. Am J Physiol Gastrointest Liver Physiol 2015; 308:G1004-11. [PMID: 25907689 PMCID: PMC4469868 DOI: 10.1152/ajpgi.00002.2015] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Accepted: 04/15/2015] [Indexed: 01/31/2023]
Abstract
Chronic heavy alcohol use is known to cause gut leakiness and alcoholic liver disease (ALD), but only 30% of heavy drinkers develop increased intestinal permeability and ALD. The hypothesis of this study was that disruption of circadian rhythms is a potential risk factor in actively drinking alcoholics for gut leakiness and endotoxemia. We studied 20 subjects with alcohol use disorder (AD) and 17 healthy controls (HC, 6 day workers, 11 night workers). Subjects wore a wrist actiwatch for 7 days and underwent a 24-h dim light phase assessment and urine collection for intestinal permeability. The AD group had significantly less total sleep time and increased fragmentation of sleep (P < 0.05). AD also had significantly lower plasma melatonin levels compared with the HC [mean area under the curve (AUC) 322.78 ± 228.21 vs. 568.75 ± 304.26 pg/ml, P = 0.03]. In the AD group, AUC of melatonin was inversely correlated with small bowel and colonic intestinal permeability (lactulose-to-mannitol ratio, r = -0.39, P = 0.03; urinary sucralose, r = -0.47, P = 0.01). Cosinor analysis of lipopolysaccharide-binding protein (marker of endotoxemia) and lipopolysaccharide every 4 h for 24 h in HC and AD subjects had a midline estimating statistic of rhythm of 5,026.15 ± 409.56 vs. 6,818.02 ± 628.78 ng/ml (P < 0.01) and 0.09 ± 0.03 vs. 0.15 ± 0.19 EU/ml (P < 0.05), respectively. We found plasma melatonin was significantly lower in the AD group, and lower melatonin levels correlated with increased intestinal permeability and a marker of endotoxemia. Our study suggests the suppression of melatonin in AD may promote gut leakiness and endotoxemia.
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Affiliation(s)
- Garth R. Swanson
- 1Department of Digestive Diseases, Rush University Medical Center, Chicago, Illinois;
| | - Annika Gorenz
- 1Department of Digestive Diseases, Rush University Medical Center, Chicago, Illinois;
| | - Maliha Shaikh
- 1Department of Digestive Diseases, Rush University Medical Center, Chicago, Illinois;
| | - Vishal Desai
- 1Department of Digestive Diseases, Rush University Medical Center, Chicago, Illinois;
| | - Christopher Forsyth
- 1Department of Digestive Diseases, Rush University Medical Center, Chicago, Illinois;
| | - Louis Fogg
- 4Community, Systems and Mental Health Nursing, Rush University, Chicago, Illinois
| | - Helen J. Burgess
- 2Departments of Behavioral Sciences and Internal Medicine, Rush University Medical Center, Chicago, Illinois;
| | - Ali Keshavarzian
- 1Department of Digestive Diseases, Rush University Medical Center, Chicago, Illinois; ,3Departments of Pharmacology, Molecular Biophysics & Physiology, Rush University Medical Center, Chicago, Illinois; and
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20
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Parekh PJ, Oldfield Iv EC, Challapallisri V, Ware JC, Johnson DA. Sleep disorders and inflammatory disease activity: chicken or the egg? Am J Gastroenterol 2015; 110:484-488. [PMID: 25155226 DOI: 10.1038/ajg.2014.247] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Accepted: 06/30/2014] [Indexed: 02/07/2023]
Abstract
Sleep dysfunction is a highly prevalent condition that has long been implicated in accelerating disease states characterized by having an inflammatory component such as systemic lupus erythematosus, HIV, and multiple sclerosis. Inflammatory bowel disease (IBD) is a chronic, debilitating disease that is characterized by waxing and waning symptoms, which are a direct result of increased circulating inflammatory cytokines. Recent studies have demonstrated sleep dysfunction and the disruption of the circadian rhythm to result in an upregulation of inflammatory cytokines. Not only does this pose a potential trigger for disease flares but also an increased risk of malignancy in this subset of patients. This begs to question whether or not there is a therapeutic role of sleep cycle and circadian rhythm optimization in the prevention of IBD flares. Further research is needed to clarify the role of sleep dysfunction and alterations of the circadian rhythm in modifying disease activity and also in reducing the risk of malignancy in patients suffering from IBD.
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Affiliation(s)
- Parth J Parekh
- Department ofInternal Medicine, Eastern Virginia Medical School, Norfolk, Virginia, USA
| | | | | | - J Catsby Ware
- Department of Sleep Medicine, Eastern Virginia Medical School, Norfolk, Virginia, USA
| | - David A Johnson
- Gastroenterology Division, Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, Virginia, USA
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21
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Park YS, Chung SH, Lee SK, Kim JH, Kim JB, Kim TK, Kim DS, Baik HW. Melatonin improves experimental colitis with sleep deprivation. Int J Mol Med 2015; 35:979-86. [PMID: 25625560 PMCID: PMC4735700 DOI: 10.3892/ijmm.2015.2080] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Accepted: 12/22/2014] [Indexed: 12/28/2022] Open
Abstract
Sleep deprivation (SD) is an epidemic phenomenon in modern countries, and its harmful effects are well known. SD acts as an aggravating factor in inflammatory bowel disease. Melatonin is a sleep-related neurohormone, also known to have antioxidant and anti-inflammatory effects in the gastrointestinal tract; however, the effects of melatonin on colitis have been poorly characterized. Thus, in this study, we assessed the measurable effects of SD on experimental colitis and the protective effects of melatonin. For this purpose, male imprinting control region (ICR) mice (n=24) were used; the mice were divided into 4 experimental groups as follows: the control, colitis, colitis with SD and colitis with SD and melatonin groups. Colitis was induced by the administration of 5% dextran sulfate sodium (DSS) in the drinking water for 6 days. The mice were sleep-deprived for 3 days. Changes in body weight, histological analyses of colon tissues and the expression levels of pro-inflammatory cytokines and genes were evaluated. SD aggravated inflammation and these effects were reversed by melatonin in the mice with colitis. In addition, weight loss in the mice with colitis with SD was significantly reduced by the injection of melatonin. Treatment with melatonin led to high survival rates in the mice, in spite of colitis with SD. The levels of pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-17, interferon-γ and tumor necrosis factor-α, in the serum of mice were significantly increased by SD and reduced by melatonin treatment. The melatonin-treated group showed a histological improvement of inflammation. Upon gene analysis, the expression of the inflammatory genes, protein kinase Cζ (PKCζ) and calmodulin 3 (CALM3), was increased by SD, and the levels decreased following treatment with melatonin. The expression levels of the apoptosis-related inducible nitric oxide synthase (iNOS) and wingless-type MMTV integration site family, member 5A (Wnt5a) genes was decreased by SD, but increased following treatment with melatonin. Treatment with melatonin reduced weight loss and prolonged survival in mice with colitis with SD. Melatonin exerted systemic anti-inflammatory effects. Gene analysis revealed a possible mechanism of action of melatonin in inflammation and sleep disturbance. Thus, melatonin may be clinically applicable for patients with inflammatory bowel disease, particulary those suffering from sleep disturbances.
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Affiliation(s)
- Young-Sook Park
- Department of Gastroenterology, School of Medicine, Eulji University, Daejeon 301-746, Republic of Korea
| | - Sook-Hee Chung
- Department of Gastroenterology, Ajou University School of Medicine, Suwon 443-721, Republic of Korea
| | - Seong-Kyu Lee
- Department of Biochemistry and Molecular Biology, School of Medicine, Eulji University, Daejeon 301-746, Republic of Korea
| | - Ja-Hyun Kim
- Department of Biochemistry and Molecular Biology, School of Medicine, Eulji University, Daejeon 301-746, Republic of Korea
| | - Jun-Bong Kim
- Department of Gastroenterology, School of Medicine, Eulji University, Daejeon 301-746, Republic of Korea
| | - Tae-Kyun Kim
- Department of Gastroenterology, School of Medicine, Eulji University, Daejeon 301-746, Republic of Korea
| | - Dong-Shin Kim
- Department of Gastroenterology, School of Medicine, Eulji University, Daejeon 301-746, Republic of Korea
| | - Haing-Woon Baik
- Department of Biochemistry and Molecular Biology, School of Medicine, Eulji University, Daejeon 301-746, Republic of Korea
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22
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Wang K, Dong K, Yan Y, Xu W, Zhang L, Zhao G, Xing J. In vitro and in vivo study of a colon-targeting pH-sensitive hydrocortisone sodium succinate hydrogel. RSC Adv 2015. [DOI: 10.1039/c5ra06884c] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The aim of this study was to prepare and characterize a novel pH-sensitive hydrocortisone sodium succinate loaded hydrogel (HSS-GEL) for specifically delivering HSS to the colon, and evaluate its targeting properties.
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Affiliation(s)
- Ke Wang
- School of Pharmacy
- Xi'an Jiaotong University
- Xi'an
- China
| | - Kai Dong
- School of Pharmacy
- Xi'an Jiaotong University
- Xi'an
- China
| | - Yan Yan
- School of Pharmacy
- Xi'an Jiaotong University
- Xi'an
- China
| | - Wei Xu
- School of Pharmacy
- Xi'an Jiaotong University
- Xi'an
- China
| | - Lu Zhang
- School of Pharmacy
- Xi'an Jiaotong University
- Xi'an
- China
| | - Guilan Zhao
- School of Pharmacy
- Xi'an Jiaotong University
- Xi'an
- China
| | - Jianfeng Xing
- School of Pharmacy
- Xi'an Jiaotong University
- Xi'an
- China
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23
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Esiringü F, Tuğcu-Demiröz F, Acartürk F, Coşkun Cevher Ş, Bircan F, Sarı Kılıçaslan SM. Investigation of the effect of intracolonic melatonin gel formulation on acetic acid-induced colitis. Drug Deliv 2014; 23:2318-2326. [PMID: 25547269 DOI: 10.3109/10717544.2014.982773] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The aims of the present study were to develop a colon-specific gel formulation of melatonin with sodium alginate and to evaluate its in vitro characteristics and intracolonic performance on oxidative stress parameters, such as nitric oxide (NOx), malondialdehyde (MDA) and glutathione (GSH) levels in rats with acetic acid-induced colitis. The melatonin-alginate gel formulations were prepared and their physico-pharmaceutical properties were determined. Formulation M5, which contained 3% of sodium alginate and 20% polyethylene glycol, was used for in vivo studies. The in vivo studies were conducted in rats with acetic acid-induced colitis. NOx, MDA and GSH levels were determined and histological investigations were performed. It was found that formulation M5 was the most suitable formulation for the colon-specific melatonin gel, in terms of pH, viscosity, drug release and mucoadhesion properties. The MDA levels in the tissues of Group 2 (treated with an intracolonic gel formulation without melatonin) were found to be significantly higher than in Group 1 (the untreated group). NOx levels decreased with the intracolonic and systemic melatonin treatment in the colitis-induced rats. Neither intracolonic nor intra-peritoneal (IP) melatonin treatment affected GSH levels. The epitelization of the colon tissues in groups administered with intracolonic melatonin, IP melatonin, and the intracolonic gel formulation without melatonin was much better than that found in the untreated group. It was concluded that melatonin participated in various defense mechanisms against the colonic inflammatory process, and that the dose, route and formulation type were the most important parameters in the effectiveness of melatonin.
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Affiliation(s)
- Figen Esiringü
- a Department of Pharmaceutical Technology, Faculty of Pharmacy , Gazi University , Ankara , Turkey
| | - Fatmanur Tuğcu-Demiröz
- a Department of Pharmaceutical Technology, Faculty of Pharmacy , Gazi University , Ankara , Turkey
| | - Füsun Acartürk
- a Department of Pharmaceutical Technology, Faculty of Pharmacy , Gazi University , Ankara , Turkey
| | - Şule Coşkun Cevher
- b Department of Biology, Faculty of Science , Gazi University , Ankara , Turkey , and
| | - Filiz Bircan
- b Department of Biology, Faculty of Science , Gazi University , Ankara , Turkey , and
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Tanideh N, Nematollahi SL, Hosseini SV, Hosseinzadeh M, Mehrabani D, Safarpour A, Sepehrimanesh M, Koohi-Hosseinabadi O, Najibi A. The Healing Effect of Hypericum perforatum Extract on Acetic Acid-Induced Ulcerative Colitis in Rat. ACTA ACUST UNITED AC 2014. [DOI: 10.17795/acr-25188] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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25
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Melatonin attenuates dextran sodium sulfate induced colitis with sleep deprivation: possible mechanism by microarray analysis. Dig Dis Sci 2014; 59:1134-41. [PMID: 24429513 DOI: 10.1007/s10620-013-3013-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Accepted: 12/20/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND Inflammatory bowel disease is a chronic inflammatory condition of the gastrointestinal tract. It can be aggravated by stress, like sleep deprivation, and improved by anti-inflammatory agents, like melatonin. We aimed to investigate the effects of sleep deprivation and melatonin on inflammation. We also investigated genes regulated by sleep deprivation and melatonin. METHODS In the 2% DSS induced colitis mice model, sleep deprivation was induced using modified multiple platform water bath. Melatonin was injected after induction of colitis and colitis with sleep deprivation. Also mRNA was isolated from the colon of mice and analyzed via microarray and real-time PCR. RESULTS Sleep deprivation induced reduction of body weight, and it was difficult for half of the mice to survive. Sleep deprivation aggravated, and melatonin attenuated the severity of colitis. In microarrays and real-time PCR of mice colon tissues, mRNA of adiponectin and aquaporin 8 were downregulated by sleep deprivation and upregulated by melatonin. However, mRNA of E2F transcription factor (E2F2) and histocompatibility class II antigen A, beta 1 (H2-Ab1) were upregulated by sleep deprivation and downregulated by melatonin. CONCLUSION Melatonin improves and sleep deprivation aggravates inflammation of colitis in mice. Adiponectin, aquaporin 8, E2F2 and H2-Ab1 may be involved in the inflammatory change aggravated by sleep deprivation and attenuated by melatonin.
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Trivedi PP, Jena GB. Melatonin reduces ulcerative colitis-associated local and systemic damage in mice: investigation on possible mechanisms. Dig Dis Sci 2013; 58:3460-74. [PMID: 23975342 DOI: 10.1007/s10620-013-2831-6] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2013] [Accepted: 07/27/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Ulcerative colitis (UC) is a chronic gastrointestinal disorder. Substantial research reveals that melatonin has beneficial effects in ulcerative colitis both experimentally and clinically. We have previously reported that ulcerative colitis was associated with local and systemic damage in mice. The purpose of this study was to reveal the novel targets of melatonin in its protective mechanism against ulcerative colitis in mice. We also wished to determine whether or not melatonin protected against ulcerative colitis-induced systemic damage in mice. METHODS Ulcerative colitis was induced in mice by use of 3% (w/v) dextran sulfate sodium for two cycles. One cycle comprised 7 days of DSS-treated water followed by 14 days of normal drinking water. Melatonin was administered at doses of 2, 4, or 8 mg/kg bw/day, po throughout. The effect of melatonin in mice with UC was evaluated by use of biochemical data, histological evaluation, comet and micronucleus assays, immunohistochemistry, and western blot analysis. RESULTS The results indicated that melatonin treatment ameliorated the severity of ulcerative colitis by modulating a variety of molecular targets, for example nuclear factor kappa B, cyclooxygenase-2, interleukin 17, signal transducer and activator of transcription 3, nuclear erythroid 2-related factor 2, matrix metalloproteinase-9, and connective tissue growth factor. Further, ulcerative colitis increased gut permeability, plasma lipopolysaccharide level, systemic inflammation, and genotoxicity. Melatonin treatment led to mucosal healing and reduced ulcerative colitis-induced elevated gut permeability and reduced the plasma LPS level, systemic inflammation, and genotoxicity. CONCLUSION Melatonin ameliorated ulcerative colitis-associated local and systemic damage in mice.
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Affiliation(s)
- P P Trivedi
- Department of Pharmacology and Toxicology, Facility for Risk Assessment and Intervention Studies, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab, 160062, India,
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The effect of melatonin on plasma markers of inflammation and on expression of nuclear factor-kappa beta in acetic acid-induced colitis in the rat. Dig Dis Sci 2013; 58:3156-64. [PMID: 23925818 DOI: 10.1007/s10620-013-2811-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2013] [Accepted: 07/15/2013] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIMS Melatonin may be involved in gastrointestinal tract physiology and could affect inflammation-related gastrointestinal disorders. Rat models of ulcerative colitis imply melatonin is beneficial. To determine potential pathophysiological mechanisms, we assessed colonic nuclear factor-kappa beta expression and measured serum levels of pentraxin-3, lipid peroxides, and total thiols in an acetic acid model of this disease. MATERIALS AND METHODS Thirty rats were divided into five groups: a control group, an acetic acid-induced colitis group, a group treated with melatonin before colitis induction, a group treated short-term after colitis induction, and a group treated long-term after colitis induction. After four weeks, blood samples were taken for measurement of pentraxin-3, lipid peroxide, and total thiols. Sections of the colon were taken for histopathological examination and immunohistochemical detection of nuclear factor-kappa beta expression. RESULTS Melatonin administration reduced nuclear factor-kappa beta immunohistochemical expression, reduced serum levels of lipid peroxide and pentraxin-3, and maintained serum levels of total thiols. However, in long-term treatment the protective effect of melatonin was not as marked. CONCLUSION Melatonin is effective in prevention and short-term treatment of the inflammatory process in acetic-acid induced colitis whereas the benefit of long-term treatment is unclear. Benefit may be linked to protection mechanisms against inflammatory processes by inhibiting the nuclear factor-kappa beta and conserving endogenous antioxidant reserves of total thiols, thus reducing the level of colonic damage possibly caused by lipid peroxides.
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Topcu-Tarladacalisir Y, Akpolat M, Uz YH, Kizilay G, Sapmaz-Metin M, Cerkezkayabekir A, Omurlu IK. Effects of curcumin on apoptosis and oxidoinflammatory regulation in a rat model of acetic acid-induced colitis: the roles of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase. J Med Food 2013; 16:296-305. [PMID: 23566056 DOI: 10.1089/jmf.2012.2550] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
The present study evaluated the effects of curcumin on epithelial cell apoptosis, the immunoreactivity of the phospho-c-Jun N-terminal kinase (JNK) and phospho-p38 mitogen-activated protein kinases (MAPKs) in inflamed colon mucosa, and oxidative stress in a rat model of ulcerative colitis induced by acetic acid. Rats were randomly divided into three groups: control, acetic acid, and acetic acid+curcumin. Curcumin (100 mg/kg per day, intragastrically) was administered 10 days before the induction of colitis and was continued for two additional days. Acetic acid-induced colitis caused a significant increase in the macroscopic and microscopic tissue ranking scores as well as an elevation in colonic myeloperoxidase (MPO) activity, malondialdehyde (MDA) levels, and the number of apoptotic epithelial cells in colon tissue compared to controls. In the rat colon, immunoreactivity of phospho-p38 MAPK was increased, whereas the phospho-JNK activity was decreased following the induction of colitis. Curcumin treatment was associated with amelioration of macroscopic and microscopic colitis sores, decreased MPO activity, and decreased MDA levels in acetic acid-induced colitis. Furthermore, oral curcumin supplementation clearly prevented programmed cell death and restored immunreactivity of MAPKs in the colons of colitic rats. The results of this study suggest that oral curcumin treatment decreases colon injury and is associated with decreased inflammatory reactions, lipid peroxidation, apoptotic cell death, and modulating p38- and JNK-MAPK pathways.
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Chojnacki C, Wiśniewska-Jarosińska M, Kulig G, Majsterek I, Reiter RJ, Chojnacki J. Evaluation of enterochromaffin cells and melatonin secretion exponents in ulcerative colitis. World J Gastroenterol 2013; 19:3602-3607. [PMID: 23801861 PMCID: PMC3691046 DOI: 10.3748/wjg.v19.i23.3602] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2012] [Revised: 01/11/2013] [Accepted: 04/19/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To study an assessment of the number of enterochromaffin cells and expression of hydroxyindole-O-methyltransferase in colonic mucosa and urine excretion of 6-sulfatoxymelatonin in patients with ulcerative colitis.
METHODS: The study included 30 healthy subjects (group I-C), 30 patients with ulcerative proctitis [group II-ulcerative proctitis (UP)] and 30 patients with ulcerative colitis [group III-ulcerative colitis (UC)] in acute phases of these diseases. The number of enterochromaffin cells (EC) was estimated in rectal and colonic mucosa. Bioptates were assembled from many different parts of the large intestine. Immunorective cells collected from various parts of the colon were counted according to the Eurovision DAKO (Dako A/S, Copenhagen, Denmark) System in the range of 10 fields in each bioptate at × 200 magnification. The level of mRNA expression of hydroxyindole-O-methyltransferase (HIOMT) in colonic mucosa was estimated with RT-PCR. Urine 6-sulfatoxymelatonin (6-HMS) excretion was determined immunoenzymatically using an IBL (IBL International GmbH, Hamburg, Germany) kit (RE 54031).
RESULTS: The number of EC cells in healthy subjects (C) was 132.40 ± 31.26. In patients of group II (UP) and group III (UC) the number of these cells was higher - 225.40 ± 37.35 (P < 0.001) and - 225.24 ± 40.50 (P < 0.001) respectively. Similar differences were related to HIOMT expression, which was 1.04 ± 0.36 in group C, 1.56 ± 0.56 (P < 0.01) in group UP and 2.00 ± 0.35 (P < 0.001) in group UC. Twenty-four hour 6-HMS urinary excretion was as follows: C - 16.32 ± 4.95 μg/24 h, UP - 26.30 ± 7.29 μg/24 h (P < 0.01), UC - 42.30 ± 12.56 μg/24h (P < 0.001). A correlation between number of EC cells and 6-HMS excretion was noted in all groups: r = 0.766 in patients with UP, r = 0.703 with UC and r = 0.8551 in the control group; the correlation between the results is statistically significant.
CONCLUSION: In the acute phases of both UP and UC, proliferation of EC cells and high expression of HIOMT and urine excretion of 6-HMS is noted. These changes may represent a beneficial response in the anti-inflammatory and defense mechanism.
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Lin GJ, Huang SH, Chen SJ, Wang CH, Chang DM, Sytwu HK. Modulation by melatonin of the pathogenesis of inflammatory autoimmune diseases. Int J Mol Sci 2013; 14:11742-66. [PMID: 23727938 PMCID: PMC3709754 DOI: 10.3390/ijms140611742] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Revised: 05/15/2013] [Accepted: 05/16/2013] [Indexed: 12/14/2022] Open
Abstract
Melatonin is the major secretory product of the pineal gland during the night and has multiple activities including the regulation of circadian and seasonal rhythms, and antioxidant and anti-inflammatory effects. It also possesses the ability to modulate immune responses by regulation of the T helper 1/2 balance and cytokine production. Autoimmune diseases, which result from the activation of immune cells by autoantigens released from normal tissues, affect around 5% of the population. Activation of autoantigen-specific immune cells leads to subsequent damage of target tissues by these activated cells. Melatonin therapy has been investigated in several animal models of autoimmune disease, where it has a beneficial effect in a number of models excepting rheumatoid arthritis, and has been evaluated in clinical autoimmune diseases including rheumatoid arthritis and ulcerative colitis. This review summarizes and highlights the role and the modulatory effects of melatonin in several inflammatory autoimmune diseases including multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes mellitus, and inflammatory bowel disease.
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Affiliation(s)
- Gu-Jiun Lin
- Department of Biology and Anatomy, National Defense Medical Center, No. 161, Section 6, MinChuan East Road, Neihu, Taipei City 114, Taiwan; E-Mail:
| | - Shing-Hwa Huang
- Department of General Surgery, Tri-Service General Hospital, No.325, Section 2, Chenggong Rd., Neihu District, Taipei City 114, Taiwan; E-Mail:
| | - Shyi-Jou Chen
- Graduate Institute of Medical Sciences, National Defense Medical Center, No. 161, Section 6, MinChuan East Road, Neihu, Taipei City 114, Taiwan; E-Mails: (S.-J.C.); (C.-H.W.)
- Department of Pediatrics, Tri-Service General Hospital, No.325, Section 2, Chenggong Rd., Neihu District, Taipei City 114, Taiwan
| | - Chih-Hung Wang
- Graduate Institute of Medical Sciences, National Defense Medical Center, No. 161, Section 6, MinChuan East Road, Neihu, Taipei City 114, Taiwan; E-Mails: (S.-J.C.); (C.-H.W.)
- Department of Otolaryngology—Head and Neck Surgery, Tri-Service General Hospital, No.325, Section 2, Chenggong Rd., Neihu District, Taipei City 114, Taiwan
- Institute of Undersea and Hyperbaric Medicine, National Defense Medical Center, No. 161, Section 6, MinChuan East Road, Neihu, Taipei City 114, Taiwan
- Department of Microbiology and Immunology, National Defense Medical Center, No. 161, Section 6, MinChuan East Road, Neihu, Taipei City 114, Taiwan
| | - Deh-Ming Chang
- Rheumatology/Immunology/Allergy, Tri-Service General Hospital, No.325, Section 2, Chenggong Rd., Neihu District, Taipei City 114, Taiwan; E-Mail:
| | - Huey-Kang Sytwu
- Department of Microbiology and Immunology, National Defense Medical Center, No. 161, Section 6, MinChuan East Road, Neihu, Taipei City 114, Taiwan
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +886-2-8792-3100 (ext. 18540); Fax: +886-2-8792-1774
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Xing JF, Sun JN, Sun JY, You CY, Dong K, Lv J, Dong YL. Protective effects of 3,4-oxo-isopropylidene-shikimic acid on experimental colitis induced by trinitrobenzenesulfonic acid in rats. Dig Dis Sci 2012; 57:2045-54. [PMID: 22476587 DOI: 10.1007/s10620-012-2155-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2012] [Accepted: 03/16/2012] [Indexed: 02/26/2023]
Abstract
BACKGROUND 3,4-Oxo-isopropylidene-shikimic acid (ISA) is a derivative of shikimic acid (SA). SA is extracted from Illicium verum Hook.fil., which has been used in traditional Chinese medicine and used for treating vomiting, stomach aches, insomnia, skin inflammation, and rheumatic pain. AIMS To investigate the effects and the protective mechanism of 3,4-oxo-isopropylidene-shikimic acid on experimental colitis model induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) in rats. METHODS Colitis in rats was induced by colonic administration with TNBS. ISA (50, 100, and 200 mg/kg) was administered for 12 days to experimental colitis rats. The inflammatory degree was assessed by macroscopic damage score, colon weight/length ratios (mg/cm), and myeloperoxidase (MPO) activity. Malondialdehyde (MDA), glutathione (GSH), and nitric oxide (NO) levels, and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), inducible nitric oxide synthase (iNOS) activities were measured with biochemical methods. RESULTS ISA significantly ameliorated macroscopic damage, reduced colon weight/length ratios and the activity of MPO, depressed MDA and NO levels and iNOS activity, and enhanced GSH level, and GSH-Px and SOD activities in the colon tissues of experimental colitis in a dose-dependent manner. Moreover, the effect of ISA (200 mg/kg) was as effective as sulfasalazine (500 mg/kg). CONCLUSIONS The findings of this study demonstrate the protective effect of ISA on experimental colitis, probably due to an antioxidant action.
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Affiliation(s)
- Jian-Feng Xing
- Department of Pharmacy, College of Medicine, Xi'an Jiaotong University, Xi'an 710061, China.
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Tasdemir S, Parlakpinar H, Vardi N, Kaya E, Acet A. Effect of endogen-exogenous melatonin and erythropoietin on dinitrobenzene sulfonic acid-induced colitis. Fundam Clin Pharmacol 2011; 27:299-307. [PMID: 22151426 DOI: 10.1111/j.1472-8206.2011.01016.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Inflammatory bowel disease has been linked to elevated T cells. Excessive production of reactive oxygen species and apoptosis are known to be accompanied by intestinal inflammation. This study was designed to investigate the effects of melatonin (MEL) and erythropoietin (EPO), which is a known anti-inflammatory and antiapoptotic agent, in dinitrobenzene sulfonic acid (DNBS)-induced colitis in pinealectomized (Px) rats. In microscopically results, epithelial and goblet cell loss, absence of crypts, and increased colonic caspase-3 activity were observed in the DNBS group. Also, in flow cytometric analysis, the percentage of CD4+ T cells was highest in the DNBS group. Treatment with MEL or EPO had a curative effect on DNBS-induced colitis. The MEL + EPO groups showed significantly greater improvement when compared with the other treatment groups. Our results indicate that the combination of EPO and MEL may exert more beneficial effects than either agent used alone.
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Affiliation(s)
- Seda Tasdemir
- Department of Pharmacology, Inonu University, Medical Faculty, Malatya, Turkey.
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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: 155] [Impact Index Per Article: 11.1] [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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Motilva V, García-Mauriño S, Talero E, Illanes M. New paradigms in chronic intestinal inflammation and colon cancer: role of melatonin. J Pineal Res 2011; 51:44-60. [PMID: 21752096 DOI: 10.1111/j.1600-079x.2011.00915.x] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
In intestinal bowel disease (IBD), immune-mediated conditions exert their effects through various cells and proinflammatory mediators. Recent data support a participation of the endoplasmic reticulum stress and mitochondrial dysfunctions in IBD. Moreover, it is evident that chronic degenerative pathologies, including IBD, share comparable disease mechanisms with alteration in the autophagy mechanisms. Chronic inflammation in IBD exposes these patients to a number of signals known to have tumorigenic effects. This circuitry of inflammation and cancer modifies apoptosis and autophagy, and promotes cellular cycle progression, invasion, and angiogenesis. Melatonin has been shown as a specific antioxidant reducing oxidative damage in both lipid and aqueous cell environments. However, several studies provide further insight into the molecular mechanisms of melatonin action in the colon. In this line, recent data suggest that melatonin modulates autophagy and sirtuin activity. An anti-autophagic property of melatonin has been demonstrated, and it could contribute to its anti-oncogenic activity. Nevertheless, there is no information about whether antitumoral effects of melatonin on colon cancer are dependent on autophagy. Sirtuins have pleiotropic effects on cancer development, being reported both as facilitator and as suppressor of colon cancer development. Sirtuins and melatonin are connected through the circadian clock machinery, and melatonin seems able to correct the alterations in sirtuin activity associated with several pathological conditions. Autophagy and sirtuin activities are linked through 5'AMP-activated protein kinase (AMPK) activation, which switches on autophagy and increases sirtuin. The effect of melatonin on AMPK and the impact of this effect on IBD and colon cancer remain an open question.
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Affiliation(s)
- Virginia Motilva
- Department of Pharmacology, University of Seville, Seville, Spain.
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Lee JS, Park SY, Thapa D, Choi MK, Chung IM, Park YJ, Yong CS, Choi HG, Kim JA. Grifola frondosa water extract alleviates intestinal inflammation by suppressing TNF-alpha production and its signaling. Exp Mol Med 2010; 42:143-54. [PMID: 20054232 DOI: 10.3858/emm.2010.42.2.016] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
TNF-alpha is a major cytokine involved in inflammatory bowel disease (IBD). In this study, water extract of Grifola frondosa (GFW) was evaluated for its protective effects against colon inflammation through the modulation of TNF-alpha action. In coculture of HT-29 human colon cancer cells with U937 human monocytic cells, TNF-alpha-induced monocyte adhesion to HT-29 cells was significantly suppressed by GFW (10, 50, 100 micg/ml). The reduced adhesion by GFW correlated with the suppressed expression of MCP-1 and IL-8, the major IBD-associated chemokines. In addition, treatment with GFW significantly suppressed TNF-alpha-induced reactive oxygen species production and NF-kappaB transcriptional activity in HT-29 cells. In differentiated U937 monocytic cells, LPS-induced TNF-alpha production, which is known to be mediated through NF-kappaB activation, was significantly suppressed by GFW. In an in vivo rat model of IBD, oral administration of GFW for 5 days (1 g/kg per day) significantly inhibited the trinitrobenzene sulfonic acid (TNBS)-induced weight loss, colon ulceration, myeloperoxidase activity, and TNF-alpha expression in the colon tissue. Moreover, the effect of GFW was similar to that of intra-peritoneal injection of 5-aminosalicylic acid (5-ASA), an active metabolite of sulfasalazine, commonly used drug for the treatment of IBD. The results suggest that GFW ameliorates colon inflammation by suppressing production of TNF-alpha as well as its signaling through NF-kappaB leading to the expression of inflammatory chemokines, MCP-1 and IL-8. Taken together, the results strongly suggest GFW is a valuable medicinal food for IBD treatment, and thus may be used as an alternative medicine for IBD.
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Affiliation(s)
- Jong Suk Lee
- College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Korea
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Dost T, Ozkayran H, Gokalp F, Yenisey C, Birincioglu M. The effect of Hypericum perforatum (St. John's Wort) on experimental colitis in rat. Dig Dis Sci 2009; 54:1214-21. [PMID: 18754092 DOI: 10.1007/s10620-008-0477-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2008] [Accepted: 07/24/2008] [Indexed: 01/12/2023]
Abstract
The aim of the present study was to investigate the effect of Hypericum perforatum (HP) on the inflammatory and immune response of colonic mucosa in rat with induced inflammatory bowel disease and that on various enzyme activities in blood and bowel tissue. Male Wistar albino rats were divided into three main groups: control, third day, and seventh day of colitis. Third-day and seventh-day groups were divided into four subgroups. Colitis was induced in all groups except the control group by 2,4,6-trinitrobenzene sulfonic acid (TNBS). The colitis group received saline; treatment groups received HP extract (50, 150, and 300 mg/kg/day, respectively). Glutathione (GSH), catalase (CAT), and malondialdehyde (MDA) activities in blood were measured. Catalase, myeloperoxidase (MPO), glutathione peroxidase (GSH-Px), glutathione reductase (GR), malondialdehyde, and nitric oxide (NO) activities were measured from tissue samples. Colonic damage was significantly reduced by HP extract. Macroscopic scoring of colonic damage significantly reduced in groups given HP extract compared with in the colitis group (P < 0.001). Blood catalase levels were reduced in the HP (150 mg/kg/day) compared with the colitis group (P < 0.01). Blood GSH levels significantly increased in groups treated with HP compared with control (P < 0.001) on the third and seventh day. Tissue GR levels reduced in the colitis and HP (50 mg/kg/day) groups compared with control (P < 0.05). Tissue MPO activity increased in the colitis and treatment groups compared with control (P < 0.007). GSH-Px levels increased in the colitis group compared with control at day 3 (P = 0.006). HP has a protective effect on TNBS-induced inflammatory bowel disease (IBD), probably due to an anti-inflammatory and antioxidant mechanism.
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Affiliation(s)
- Turhan Dost
- Department of Pharmacology, Medical Faculty, Adnan Menderes University, Aydin, Turkey.
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The behavior of rat tooth germ cells on poly(vinyl alcohol). Acta Biomater 2009; 5:1064-74. [PMID: 19136319 DOI: 10.1016/j.actbio.2008.11.023] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2008] [Revised: 11/03/2008] [Accepted: 11/19/2008] [Indexed: 11/21/2022]
Abstract
The purpose of this study was to evaluate the behaviors of rat tooth germ (TG) cells cultured on poly(vinyl alcohol) (PVA). It was found that TG cells suspended and aggregated to form three-dimensional spheroids on PVA. Compared with traditional monolayered cells on tissue culture polystyrene, TG cell spheroids on PVA obviously increased the alkaline phosphatase activity, the degree of mineralization, and upregulated both osteopontin and dentin matrix protein 1 genes, regardless of the seeding density. Surprisingly, PVA appears to activate the alkaline phosphatase activity and mineralization effects on TG cell spheroids in the absence of a differentiation medium. Furthermore, the present study indicates that integrins may play an important role in the mineralization on TG cell spheroids by adding Arg-Gly-Asp (RGD) peptides. Therefore, the information presented here should help to clarify the role of PVA in the regulation of the mineralization, differentiation and integrin-mediation of TG cells.
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Terry PD, Villinger F, Bubenik GA, Sitaraman SV. Melatonin and ulcerative colitis: evidence, biological mechanisms, and future research. Inflamm Bowel Dis 2009; 15:134-40. [PMID: 18626968 DOI: 10.1002/ibd.20527] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Ulcerative colitis (UC) is an inflammatory bowel disease that afflicts up to 1 million people in the US. Current treatments for UC are mostly nonspecific, not always effective, and often accompanied by serious side effects. Therefore, there is considerable interest in finding alternative and more tolerable treatments for this disease. Physiologic data suggest that melatonin is an important regulator of both inflammation and motility in the gastrointestinal tract, and data from in vitro studies, animal experiments, and limited studies in humans suggest that supplemental melatonin may have an ameliorative effect on colitis. In this review we summarize the evidence regarding melatonin as a possible therapeutic agent in UC and discuss possible biological mechanisms and directions for future research.
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Affiliation(s)
- Paul D Terry
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, USA.
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Talero E, Sánchez-Fidalgo S, de la Lastra CA, Illanes M, Calvo JR, Motilva V. Acute and chronic responses associated with adrenomedullin administration in experimental colitis. Peptides 2008; 29:2001-12. [PMID: 18708104 DOI: 10.1016/j.peptides.2008.07.013] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2008] [Revised: 07/07/2008] [Accepted: 07/10/2008] [Indexed: 01/03/2023]
Abstract
Adrenomedullin (AM) is a 52 amino acid peptide and member of the calcitonin gene-related peptide (CGRP) super family. Given that AM has emerged as a potential immuno-regulatory and anti-inflammatory agent in various experimental models, this study has deepened into its possible therapeutic effect in intestinal inflammation analyzing the responses in both acute and chronic (14 and 21 days) phases of TNBS-induced colitis in rats. In the acute model, AM treatment reduced the incidence of diarrhea and the severity of colonic damage, and improved the survival rate at the three doses assayed (50, 100, and 200ng/kg animal). AM administration was able to reduce the early production of TNF-alpha and collaborated to maintaining basal levels of IFN-gamma and IL-10. In the chronic studies the peptide attenuated the extent of the damage with lesser incidence of weight loss and diarrhea (50 and 100ng/kg animal). Cellular neutrophil infiltration, with the subsequent increase in myeloperoxidase (MPO) levels caused by TNBS, was reduced after chronic AM administration. The peptide played a role in the evolution of Th1/Th2 cytokines balance and chronic disease recuperation: levels of proinflammatory TNF-alpha and IFN-gamma decreased and anti-inflammatory IL-10 increased significantly. Cyclooxygenase-2 (COX-2) and nitric oxide synthase (iNOS) protein expression were not modified by AM administration, although a reduction of nitric oxide (NO) production could be detected in the chronic model. These results support a role of AM as an anti-inflammatory factor with beneficial effects in intestinal inflammatory colitis.
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Affiliation(s)
- E Talero
- Department of Pharmacology, School of Pharmacy, University of Seville, C. Prof. Garcia Gonzalez n2, 41012 Seville, Spain
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Akcan A, Kucuk C, Sozuer E, Esel D, Akyildiz H, Akgun H, Muhtaroglu S, Aritas Y. Melatonin reduces bacterial translocation and apoptosis in trinitrobenzene sulphonic acid-induced colitis of rats. World J Gastroenterol 2008; 14:918-24. [PMID: 18240350 PMCID: PMC2687060 DOI: 10.3748/wjg.14.918] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of exogenous melatonin on bacterial translocation and apoptosis in a rat ulcerative colitis model.
METHODS: Rats were randomly assigned to three groups: groupI: control, group II: experimental colitis, group III: colitis plus melatonin treatment. On d 11 after colitis, plasma tumor necrosis factor-α, portal blood endotoxin levels, colon tissue myeloperoxidase and caspase-3 activity were measured. Bacterial translocation was quantified by blood, lymph node, liver and spleen culture.
RESULTS: We observed a significantly reduced incidence of bacterial translocation to the liver, spleen, mesenteric lymph nodes, portal and systemic blood in animals treated with melatonin. Treatment with melatonin significantly decreased the caspase-3 activity in colonic tissues compared to that in trinitrobenzene sulphonic acid- treated rats (16.11 ± 2.46 vs 32.97 ± 3.91, P < 0.01).
CONCLUSION: Melatonin has a protective effect on bacterial translocation and apoptosis.
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Fillmann H, Kretzmann NA, San-Miguel B, Llesuy S, Marroni N, González-Gallego J, Tuñón MJ. Glutamine inhibits over-expression of pro-inflammatory genes and down-regulates the nuclear factor kappaB pathway in an experimental model of colitis in the rat. Toxicology 2007; 236:217-26. [PMID: 17543437 DOI: 10.1016/j.tox.2007.04.012] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2007] [Revised: 04/18/2007] [Accepted: 04/19/2007] [Indexed: 12/14/2022]
Abstract
We investigated the effects of glutamine on markers of oxidative stress, nuclear factor kappaB (NF-kappaB) activation, and pro-inflammatory mediators in a rat model of experimental colitis induced by intracolonic administration of 7% acetic acid. Glutamine (25 mg/kg) was given by rectal route 48 and 24h before acetic acid instillation. Glutamine significantly reduced gross damage and histopathological scores, and partially prevented the decrease of anal pressure observed in the animals receiving acetic acid. Increases in the cytosolic concentration of TBARS and hydroperoxide-initiated chemiluminescence were significantly prevented in glutamine-treated animals. Acetic acid instillation induced a marked increase of the NF-kappaB p65 subunit expression in the nucleus and resulted in significant changes in the cytosolic protein level of IkappaB kinases (IKKalpha and IKKbeta) and the non-phosphorylated form of the inhibitor IkappaBalpha. Protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were significantly increased. All these effects were partially prevented by administration of glutamine. It is concluded that the anti-inflammatory activity of glutamine in a rat model of acetic acid-induced colitis may be mediated, at least in part, by inhibition of the expression of certain pro-inflammatory mediators which are regulated by the oxidative stress-sensitive NF-kappaB signalling pathway.
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Affiliation(s)
- Henrique Fillmann
- Universidade Luterana do Brasil, Hospital de Clinicas Porto Alegre, Brazil
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