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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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da Silva JL, Barbosa LV, Pinzan CF, Nardini V, Brigo IS, Sebastião CA, Elias-Oliveira J, Brazão V, Júnior JCDP, Carlos D, Cardoso CRDB. The Microbiota-Dependent Worsening Effects of Melatonin on Gut Inflammation. Microorganisms 2023; 11:microorganisms11020460. [PMID: 36838425 PMCID: PMC9962441 DOI: 10.3390/microorganisms11020460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/31/2023] [Accepted: 02/09/2023] [Indexed: 02/15/2023] Open
Abstract
Dysbiosis and disturbances in gut homeostasis may result in dysregulated responses, which are common in inflammatory bowel diseases (IBD). These conditions may be refractory to the usual treatments and novel therapies are still necessary to reach a more successful regulation of intestinal immunity. The hormone melatonin (MLT) has been raised as a therapeutic alternative because of its known interactions with immune responses and gut microbiota. Hence, we evaluated the effects of MLT in experimental colitis that evolves with intestinal dysbiosis, inflammation and bacterial translocation. C57BL/6 mice were exposed to dextran sulfate sodium and treated with MLT. In acute colitis, the hormone led to increased clinical, systemic and intestinal inflammatory parameters. During remission, continued MLT administration delayed recovery, increased TNF, memory effector lymphocytes and diminished spleen regulatory cells. MLT treatment reduced Bacteroidetes and augmented Actinobacteria and Verrucomicrobia phyla in mice feces. Microbiota depletion resulted in a remarkable reversion of the colitis phenotype after MLT administration, including a counter-regulatory immune response, reduction in TNF and colon macrophages. There was a decrease in Actinobacteria, Firmicutes and, most strikingly, Verrucomicrobia phylum in recovering mice. Finally, these results pointed to a gut-microbiota-dependent effect of MLT in the potentiation of intestinal inflammation.
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Affiliation(s)
- Jefferson Luiz da Silva
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, s/n, Ribeirão Preto 14040-903, SP, Brazil
| | - Lia Vezenfard Barbosa
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, s/n, Ribeirão Preto 14040-903, SP, Brazil
| | - Camila Figueiredo Pinzan
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, s/n, Ribeirão Preto 14040-903, SP, Brazil
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14040-903, SP, Brazil
| | - Viviani Nardini
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, s/n, Ribeirão Preto 14040-903, SP, Brazil
| | - Irislene Simões Brigo
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, s/n, Ribeirão Preto 14040-903, SP, Brazil
| | - Cássia Aparecida Sebastião
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, s/n, Ribeirão Preto 14040-903, SP, Brazil
| | - Jefferson Elias-Oliveira
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14040-903, SP, Brazil
| | - Vânia Brazão
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, s/n, Ribeirão Preto 14040-903, SP, Brazil
| | - José Clóvis do Prado Júnior
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, s/n, Ribeirão Preto 14040-903, SP, Brazil
| | - Daniela Carlos
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14040-903, SP, Brazil
| | - Cristina Ribeiro de Barros Cardoso
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, s/n, Ribeirão Preto 14040-903, SP, Brazil
- Correspondence: ; Tel.:+55-(16)-3315-0257; Fax: +55-(16)-3315-4725
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Qin K, Tang H, Ren Y, Yang D, Li Y, Huang W, Wu Y, Yin Z. Melatonin promotes sirtuin 1 expression and inhibits IRE1α–XBP1S–CHOP to reduce endoplasmic reticulum stress–mediated apoptosis in chondrocytes. Front Pharmacol 2022; 13:940629. [PMID: 36034777 PMCID: PMC9404507 DOI: 10.3389/fphar.2022.940629] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/15/2022] [Indexed: 11/13/2022] Open
Abstract
Osteoarthritis (OA) is the most common chronic disease characterized by a loss of chondrocytes and the degeneration of cartilage. Inflammation plays an important role in the pathogenesis and progression of OA via the activation of the endoplasmic reticulum (ER) stress signaling pathway. In this study, we stimulated human primary chondrocytes with lipopolysaccharide (LPS) to reduce cell viability and induce chondrocyte apoptosis. LPS–stimulated human primary chondrocytes induced ER stress and significantly upregulated the ER chaperone glucose–regulated protein 78 (GRP78) and increased the expression level of C/EBP–homologous protein (CHOP), a key mediator of ER stress––induced apoptosis. Interestingly, melatonin treatment attenuated ER stress–mediated chondrocyte apoptosis. Melatonin inhibited the expression of cleaved caspase-3, cleaved caspase-10, Bax, CHOP, GRP78, cleaved caspase-4, phospho–inositol–requiring enzyme 1α (P-IRE1α), and spliced X-box-binding protein 1 (XBP1S). In an anterior cruciate ligament transection mouse model of OA, melatonin (50 and 150 mg/kg) dose–dependently relieved joint cartilage degeneration and inhibitied of chondrocyte apoptosis. Immunohistochemical analysis indicated that melatonin could promote SIRT1 the expression and inhibit CHOP and cleaved caspase-3 expression in OA mice. In conclusion, our findings demonstrate for the first time that melatonin inhibits the IRE1α-XBP1S-CHOP signaling pathway by promoting the expression of SIRT1 in LPS-treated human chondrocytes and delaying OA progression in vivo.
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Affiliation(s)
- Kunpeng Qin
- Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hao Tang
- Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yi Ren
- Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Di Yang
- Department of Orthopaedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yetian Li
- Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wei Huang
- Department of Orthopaedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yunfeng Wu
- Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- *Correspondence: Yunfeng Wu, ; Zongsheng Yin,
| | - Zongsheng Yin
- Department of Orthopaedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- *Correspondence: Yunfeng Wu, ; Zongsheng Yin,
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Ulva pertusa, a Marine Green Alga, Attenuates DNBS-Induced Colitis Damage via NF-κB/Nrf2/SIRT1 Signaling Pathways. J Clin Med 2022; 11:jcm11154301. [PMID: 35893393 PMCID: PMC9331369 DOI: 10.3390/jcm11154301] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/11/2022] [Accepted: 07/22/2022] [Indexed: 12/23/2022] Open
Abstract
Inflammatory bowel diseases (IBD) including Crohn's disease (CD) and ulcerative colitis (UC) represent gastrointestinal (GI) disorders associated with varied responses to microbial and environmental agents. Natural compounds have been suggested as a valid approach to the management of various GI diseases, particularly the green alga Ulva pertusa, belonging to the Ulvaceae family, which showed powerful biological properties. Here, we aimed to evaluate the effect and the mechanism of Ulva pertusa treatments in a murine model of DNBS-induced colitis. Colitis was induced by DNBS intrarectal installation (4 mg in 100 μL of 50% ethanol), while Ulva pertusa treatments (doses of 10, 50 and 100 mg/kg) were administered orally daily. Ulva pertusa, at the higher doses of 50 and 100 mg/kg, significantly reduced tissue damage DNBS-induced and the consequent inflammatory cascade via NF-κB inhibition. Furthermore, we demonstrated, for the first time, Ulva pertusa action on the SIRT1/Nrf2 axis, enhancing antioxidant response and the modulation of the apoptosis pathway colitis-induced, regulating the expression of p53, Bax, Bcl-2, and Caspases. Taken together, Ulva pertusa could be considered a valid approach for counteracting and blocking the progression of IBDs through modulation of the NF-κB/SIRT1/Nrf2 axis.
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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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Won E, Na KS, Kim YK. Associations between Melatonin, Neuroinflammation, and Brain Alterations in Depression. Int J Mol Sci 2021; 23:ijms23010305. [PMID: 35008730 PMCID: PMC8745430 DOI: 10.3390/ijms23010305] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/21/2021] [Accepted: 12/26/2021] [Indexed: 12/14/2022] Open
Abstract
Pro-inflammatory systemic conditions that can cause neuroinflammation and subsequent alterations in brain regions involved in emotional regulation have been suggested as an underlying mechanism for the pathophysiology of major depressive disorder (MDD). A prominent feature of MDD is disruption of circadian rhythms, of which melatonin is considered a key moderator, and alterations in the melatonin system have been implicated in MDD. Melatonin is involved in immune system regulation and has been shown to possess anti-inflammatory properties in inflammatory conditions, through both immunological and non-immunological actions. Melatonin has been suggested as a highly cytoprotective and neuroprotective substance and shown to stimulate all stages of neuroplasticity in animal models. The ability of melatonin to suppress inflammatory responses through immunological and non-immunological actions, thus influencing neuroinflammation and neurotoxicity, along with subsequent alterations in brain regions that are implicated in depression, can be demonstrated by the antidepressant-like effects of melatonin. Further studies that investigate the associations between melatonin, immune markers, and alterations in the brain structure and function in patients with depression could identify potential MDD biomarkers.
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Affiliation(s)
- Eunsoo Won
- Department of Psychiatry, Chaum, Seoul 06062, Korea;
- Department of Psychiatry, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea
| | - Kyoung-Sae Na
- Department of Psychiatry, Gachon University Gil Medical Center, Incheon 21565, Korea;
| | - Yong-Ku Kim
- Department of Psychiatry, Korea University Ansan Hospital, Korea University College of Medicine, Ansan 15355, Korea
- Correspondence:
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Melatonin Attenuates Dextran Sodium Sulfate Induced Colitis in Obese Mice. Pharmaceuticals (Basel) 2021; 14:ph14080822. [PMID: 34451919 PMCID: PMC8399719 DOI: 10.3390/ph14080822] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/16/2021] [Accepted: 08/18/2021] [Indexed: 01/03/2023] Open
Abstract
Epidemiological studies have indicated that obesity is an independent risk factor for colitis and that a high-fat diet (HFD) increases the deterioration of colitis-related indicators in mice. Melatonin has multiple anti-inflammatory effects, including inhibiting tumor growth and regulating immune defense. However, the mechanism of its activity in ameliorating obesity-promoted colitis is still unclear. This study explored the possibility that melatonin has beneficial functions in HFD-induced dextran sodium sulfate (DSS)-induced colitis in mice. Here, we revealed that HFD-promoted obesity accelerated DSS-induced colitis, while melatonin intervention improved colitis. Melatonin significantly alleviated inflammation by increasing anti-inflammatory cytokine release and reducing the levels of proinflammatory cytokines in HFD- and DSS-treated mice. Furthermore, melatonin expressed antioxidant activities and reversed intestinal barrier integrity, resulting in improved colitis in DSS-treated obese mice. We also found that melatonin could reduce the ability of inflammatory cells to utilize fatty acids and decrease the growth-promoting effect of lipids by inhibiting autophagy. Taken together, our study indicates that the inhibitory effect of melatonin on autophagy weakens the lipid-mediated prosurvival advantage, which suggests that melatonin-targeted autophagy may provide an opportunity to prevent colitis in obese individuals.
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Wu X, Liu Y, Du J, Li X, Lin J, Ni L, Zhu P, Zhou H, Kong F, Yang H, Geng D, Mao H. Melatonin Attenuates Intervertebral Disk Degeneration via Maintaining Cartilaginous Endplate Integrity in Rats. Front Physiol 2021; 12:672572. [PMID: 34220535 PMCID: PMC8248798 DOI: 10.3389/fphys.2021.672572] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 05/10/2021] [Indexed: 01/08/2023] Open
Abstract
Objective The aim of this study is to verify whether melatonin (Mel) could mitigate intervertebral disk degeneration (IVDD) in rats and to investigate the potential mechanism of it. Method A rat acupuncture model of IVDD was established with intraperitoneal injection of Mel. The effect of Mel on IVDD was analyzed via radiologic and histological evaluations. The specific Mel receptors were investigated in both the nucleus pulposus (NP) and cartilaginous endplates (EPs). In vitro, EP cartilaginous cells (EPCs) were treated by different concentrations of Mel under lipopolysaccharide (LPS) and Luzindole conditions. In addition, LPS-induced inflammatory response and matrix degradation following nuclear factor kappa-B (NF-κB) pathway activation were investigated to confirm the potential mechanism of Mel on EPCs. Results The percent disk height index (%DHI) and MRI signal decreased after initial puncture in the degeneration group compared with the control group, while Mel treatment protected disk height from decline and prevented the loss of water during the degeneration process. In the meantime, the histological staining of the Mel groups showed more integrity and well-ordered construction of the NP and EPs in both low and high concentration than that of the degeneration group. In addition, more deep-brown staining of type II collagen (Coll-II) was shown in the Mel groups compared with the degeneration group. Furthermore, in rat samples, immunohistochemical staining showed more positive cells of Mel receptors 1a and 1b in the EPs, instead of in the NP. Moreover, evident osteochondral lacuna formation was observed in rat EPs in the degeneration group; after Mel treatment, the osteochondral destruction alleviated accompanying fewer receptor activator for nuclear factor-κB ligand (RANKL) and tartrate-resistant acid phosphatase (TRAP)-stained positive cells expressed in the EPs. In vitro, Mel could promote the proliferation of EPCs, which protected EPCs from degeneration under LPS treatment. What is more, Mel downregulated the inflammatory response and matrix degradation of EPCs activated by NF-κB pathway through binding to its specific receptors. Conclusion These results indicate that Mel protects the integrity of the EPs and attenuates IVDD by binding to the Mel receptors in the EPs. It may alleviate the inflammatory response and matrix degradation of EPCs activated by NF-κB pathway.
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Affiliation(s)
- Xiexing Wu
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yijie Liu
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jiacheng Du
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiaoping Li
- Department of Clinical Education, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jiayi Lin
- Department of Orthopedics Center, Ningbo No. 2 Hospital, Ningbo, China
| | - Li Ni
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Pengfei Zhu
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Hong Zhou
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Fanchen Kong
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Huilin Yang
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Dechun Geng
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Haiqing Mao
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, China
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Zefferino R, Di Gioia S, Conese M. Molecular links between endocrine, nervous and immune system during chronic stress. Brain Behav 2021; 11:e01960. [PMID: 33295155 PMCID: PMC7882157 DOI: 10.1002/brb3.1960] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 08/17/2020] [Accepted: 10/30/2020] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION The stress response is different in various individuals, however, the mechanisms that could explain these distinct effects are not well known and the molecular correlates have been considered one at the time. Particular harmful conditions occur if the subject, instead to cope the stressful events, succumb to them, in this case, a cascade reaction happens that through different signaling causes a specific reaction named "sickness behaviour." The aim of this article is to review the complex relations among important molecules belonging to Central nervous system (CNS), immune system (IS), and endocrine system (ES) during the chronic stress response. METHODS After having verified the state of art concerning the function of cortisol, norepinephrine (NE), interleukin (IL)-1β and melatonin, we describe as they work together. RESULTS We propose a speculative hypothesis concerning the complex interplay of these signaling molecules during chronic stress, highlighting the role of IL-1β as main biomarker of this effects, indeed, during chronic stress its increment transforms this inflammatory signal into a nervous signal (NE), in turn, this uses the ES (melatonin and cortisol) to counterbalance again IL-1β. During cortisol resistance, a vicious loop occurs that increments all mediators, unbalancing IS, ES, and CNS networks. This IL-1β increase would occur above all when the individual succumbs to stressful events, showing the Sickness Behaviour Symptoms. IL-1β might, through melatonin and vice versa, determine sleep disorders too. CONCLUSION The molecular links here outlined could explain how stress plays a role in etiopathogenesis of several diseases through this complex interplay.
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Affiliation(s)
- Roberto Zefferino
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Sante Di Gioia
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Massimo Conese
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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Cai L, Chen Q, Yao Z, Sun Q, Wu L, Ni Y. Glucocorticoid receptors involved in melatonin inhibiting cell apoptosis and NLRP3 inflammasome activation caused by bacterial toxin pyocyanin in colon. Free Radic Biol Med 2021; 162:478-489. [PMID: 33189867 DOI: 10.1016/j.freeradbiomed.2020.11.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 10/30/2020] [Accepted: 11/04/2020] [Indexed: 02/07/2023]
Abstract
The immunoinhibitory effect of glucocorticoid and immunoenhancing attributes of melatonin (MEL) are well known, however, the involvement of glucocorticoid receptor (GR) in melatonin modulation of bacterial toxins caused-inflammation has not been studied in colon. Pyocyanin (PCN), a toxin released by Pseudomonas aeruginosa, can destroy cells through generating superoxide products and inflammatory response. Here we report that PCN treatment elevated the generation of reactive oxygen species (ROS), which further lead to mitochondrial swelling and caspase cascades activation both in vivo and in vitro. However, MEL treatment alleviated the oxidative stress caused by PCN on cells through scavenging ROS and restoring the expression of antioxidant enzyme so that to effectively alleviate the apoptosis. Large amounts of ROS can activate the NLRP3 signaling pathway, so MEL inhibited PCN induced NLRP3 inflammasome activation and inflammatory cytokines (IL-1β, IL-8, and TNF-α) secretion. In order to further investigate the molecular mechanism, goblet cells were exposed to MEL and PCN in the presence of luzindole and RU486, inhibitors of MEL receptors and GR respectively. It was found that PCN significantly inhibited the expression level of GR, and MEL effectively alleviated the inhibition phenomenon. Moreover, we found that MEL mainly upregulated the expression of GR to achieve its anti-inflammatory and anti-apoptotic functions rather than through its own receptor (MT2) in colon goblet cells. Therefore, MEL can reverse the inhibitory effects of PCN on GR/p-GR expression to present its anti-oxidative and anti-apoptotic function.
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Affiliation(s)
- Liuping Cai
- Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing, 210095, PR China.
| | - Qu Chen
- Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing, 210095, PR China.
| | - Zhihao Yao
- Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing, 210095, PR China.
| | - Qinwei Sun
- Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing, 210095, PR China.
| | - Lei Wu
- Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing, 210095, PR China.
| | - Yingdong Ni
- Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing, 210095, PR China.
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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: 23] [Impact Index Per Article: 4.6] [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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Mannino G, Caradonna F, Cruciata I, Lauria A, Perrone A, Gentile C. Melatonin reduces inflammatory response in human intestinal epithelial cells stimulated by interleukin-1β. J Pineal Res 2019; 67:e12598. [PMID: 31349378 DOI: 10.1111/jpi.12598] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Revised: 06/24/2019] [Accepted: 07/16/2019] [Indexed: 12/21/2022]
Abstract
Melatonin is the main secretory product of the pineal gland, and it is involved in the regulation of periodic events. A melatonin production independent of the photoperiod is typical of the gut. However, the local physiological role of melatonin at the intestinal tract is poorly characterized. In this study, we evaluated the anti-inflammatory activities of melatonin in an in vitro model of inflamed intestinal epithelium. To this purpose, we assessed different parameters usually associated with intestinal inflammation using IL-1β-stimulated Caco-2 cells. Differentiated monolayers of Caco-2 cells were preincubated with melatonin (1 nmol/L-50 μmol/L) and then exposed to IL-1β. After each treatment, different inflammatory mediators, DNA-breakage, and global DNA methylation status were assayed. To evaluate the involvement of melatonin membrane receptors, we also exposed differentiated monolayers to melatonin in the presence of luzindole, a MT1 and MT2 antagonist. Our results showed that melatonin, at concentrations similar to those obtained in the lumen gut after ingestion of dietary supplements for the treatment of sleep disorders, was able to attenuate the inflammatory response induced by IL-1β. Anti-inflammatory effects were expressed as both a decrease of the levels of inflammatory mediators, including IL-6, IL-8, COX-2, and NO, and a reduced increase in paracellular permeability. Moreover, the protection was associated with a reduced NF-κB activation and a prevention of DNA demethylation. Conversely, luzindole did not reverse the melatonin inhibition of stimulated-IL-6 release. In conclusion, our findings suggest that melatonin, through a local action, can modulate inflammatory processes at the intestinal level, offering new opportunities for a multimodal management of IBD.
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Affiliation(s)
- Giuseppe Mannino
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| | - Fabio Caradonna
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| | - Ilenia Cruciata
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| | - Antonino Lauria
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| | - Anna Perrone
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| | - Carla Gentile
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
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13
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Liu XW, Wang CD. Melatonin alleviates circadian rhythm disruption exacerbating DSS-induced colitis by inhibiting the distribution of HMGB1 in intestinal tissues. Int Immunopharmacol 2019; 73:108-117. [DOI: 10.1016/j.intimp.2019.05.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 05/03/2019] [Accepted: 05/05/2019] [Indexed: 02/07/2023]
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14
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Zhao CN, Wang P, Mao YM, Dan YL, Wu Q, Li XM, Wang DG, Davis C, Hu W, Pan HF. Potential role of melatonin in autoimmune diseases. Cytokine Growth Factor Rev 2019; 48:1-10. [DOI: 10.1016/j.cytogfr.2019.07.002] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 07/11/2019] [Accepted: 07/11/2019] [Indexed: 12/28/2022]
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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: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 03/04/2019] [Accepted: 03/16/2019] [Indexed: 12/17/2022]
Abstract
Within the last few decades, melatonin has increasingly emerged in clinical oncology as a naturally occurring bioactive molecule with substantial anticancer properties and a pharmacological profile optimal for joining the currently available pharmacopeia. In addition, extensive experimental data shows that this chronobiotic agent exerts oncostatic effects throughout all stages of tumor growth, from initial cell transformation to mitigation of malignant progression and metastasis; additionally, melatonin alleviates the side effects and improves the welfare of radio/chemotherapy-treated patients. Thus, the support of clinicians and oncologists for the use of melatonin in both the treatment and proactive prevention of cancer is gaining strength. Because of its epidemiological importance and symptomatic debut in advanced stages of difficult clinical management, colorectal cancer (CRC) is a preferential target for testing new therapies. In this regard, the development of effective forms of clinical intervention for the improvement of CRC outcome, specifically metastatic CRC, is urgent. At the same time, the need to reduce the costs of conventional anti-CRC therapy results is also imperative. In light of this status quo, the therapeutic potential of melatonin, and the direct and indirect critical processes of CRC malignancy it modulates, have aroused much interest. To illuminate the imminent future on CRC research, we focused our attention on the molecular mechanisms underlying the multiple oncostatic actions displayed by melatonin in the onset and evolution of CRC and summarized epidemiological evidence, as well as in vitro, in vivo and clinical findings that support the broadly protective potential demonstrated by melatonin.
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Affiliation(s)
- Emilio Gil-Martín
- Department of Biochemistry, Genetics and Immunology, Biomedical Research Center (CINBIO, 'Centro Singular de Investigación de Galicia'), University of Vigo, Vigo, Spain
| | - Javier Egea
- Molecular Neuroinflammation and Neuronal Plasticity Laboratory, Research Unit, Hospital Universitario Santa Cristina, Madrid, Spain.,Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Madrid, Spain.,Departamento de Farmacología y Terapéutica, Instituto-Fundación Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain
| | - Russel J Reiter
- Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, Texas, USA
| | - Alejandro Romero
- Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Complutense University of Madrid, Madrid, Spain
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16
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Li RX, Li J, Zhang SY, Mi YL, Zhang CQ. Attenuating effect of melatonin on lipopolysaccharide-induced chicken small intestine inflammation. Poult Sci 2018; 97:2295-2302. [PMID: 29596657 DOI: 10.3382/ps/pey084] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2017] [Indexed: 12/12/2022] Open
Abstract
Enriched melatonin (MEL) has been found in the mammalian intestine and has been recently demonstrated to alleviate rodent colitis. In this study, the effect of MEL on lipopolysaccharide (LPS)-induced intestinal inflammations was investigated in new chicken hatchlings. The chicks were fed with a diet supplemented with MEL (12.5 mg/day) from D1 to D10. Meanwhile, the chicks in the LPS or MEL + LPS groups were injected with LPS (10 mg/kg BW, i.p.) at D10. LPS treatment for 6 h increased the expression of IL-6, IL-4, caspase-3 mRNAs and TUNEL-positive cell populations, but decreased populations of the goblet and PCNA+ cells, IgA production and the expression of MUC2 mRNA in the duodenum. Compared with the LPS group, MEL pre-feeding alleviated duodenal inflammation and decreased the expression of TNF-α mRNAs by 23.6% (P = 0.004), IL-6 mRNAs by 69.4% (P = 0.001), IL-4 mRNAs by 4.1% (P = 0.824) and caspase-3 mRNAs by 45.8% (P < 0.001). Conversely, MEL pre-feeding attenuated the LPS-induced changes of IgA production by 161.6% (P = 0.013) and PCNA+ cell populations by 172.1% (P < 0.001) in the duodenum. TLR4 mRNA was also up-regulated by LPS treatment but down-regulated by MEL pre-feeding. In conclusion, dietary MEL could attenuate LPS-induced chick duodenal inflammation by down-regulating the expression of inflammatory cytokines, promoting epithelial cell proliferation, improving the immunological barrier and inhibiting epithelial apoptosis via the mediation of TLR4.
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Affiliation(s)
- R X Li
- Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - J Li
- Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - S Y Zhang
- Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Y L Mi
- Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - C Q Zhang
- Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
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17
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Khairy H, Saleh H, Badr AM, Marie MAS. Therapeutic efficacy of osthole against dinitrobenzene sulphonic acid induced-colitis in rats. Biomed Pharmacother 2018; 100:42-51. [DOI: 10.1016/j.biopha.2018.01.104] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 01/16/2018] [Accepted: 01/24/2018] [Indexed: 02/07/2023] Open
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18
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Fadda LM, Mohamed AM, Ali HM, Hagar H, Aldossari M. Prophylactic administration of carnosine and melatonin abates the incidence of renal toxicity induced by an over dose of titanium dioxide nanoparticles. J Biochem Mol Toxicol 2018; 32:e22040. [PMID: 29469982 DOI: 10.1002/jbt.22040] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Revised: 01/22/2018] [Accepted: 01/25/2018] [Indexed: 11/08/2022]
Abstract
The alleviative effects of two antioxidants, carnosine (Car) and melatonin (Mel), against titanium dioxide nanoparticles (TiO2 -NPs) toxicity-induced oxidative and inflammatory renal damage were examined in rats. Administration of these antioxidants along with TiO2 -NPs effectively reduced serum urea, uric acid, creatinine, glucose, tumor necrosis factor-α, interleukin-6, C-reactive protein, immunoglobulin G, vascular endothelial growth factor, and nitric oxide, as well as a significant amelioration of the decrease in glutathione levels in renal tissue was observed, compared to those in rats treated with TiO2 -NPs alone. The renoprotective properties of the antioxidants were confirmed by reduced intensity of renal damage as demonstrated by histological findings. In conclusion, Car and Mel play protective roles against TiO2 -NPs-induced renal inflammation and oxidative injury, likely due to their antioxidant and anti-inflammatory properties.
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Affiliation(s)
- Laila Mohamed Fadda
- Pharmacology Department, Faculty of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Azza M Mohamed
- Biochemistry Department, Faculty of Science-Al Faisaliah, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.,Therapeutic Chemistry Department, National Research Center, Dokki, Egypt
| | - Hanaa Mahmoud Ali
- Genetic and Cytology Department, National Research Center, Dokki, Egypt.,Common First Year Deanship, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Hanan Hagar
- Pharmacology Unit (31), Medical College and King Khalid University Hospital, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Manal Aldossari
- Master degree student at Pharmacology Department; Faculty of Pharmacy, King Saud University, Riyadh, KSA
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19
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Effects of Melatonin on Intestinal Microbiota and Oxidative Stress in Colitis Mice. BIOMED RESEARCH INTERNATIONAL 2018; 2018:2607679. [PMID: 29546052 PMCID: PMC5818891 DOI: 10.1155/2018/2607679] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Revised: 12/29/2017] [Accepted: 01/04/2018] [Indexed: 12/15/2022]
Abstract
This study investigated the antioxidant capacity and intestinal bacteria community in a mouse model of DSS-induced colitis. Twenty mice were randomly assigned to two treatments: mice with colitis induced by 5% DSS (DSS group) and mice with colitis induced by 5% DSS that also received melatonin treatment (MEL group). The DSS group showed significantly less antioxidant capability than the MEL group, but the two groups did not differ significantly in terms of diversity index (Shannon and Simpson), bacterial culture abundance (Chao1 and ACE), and coverage (Good's coverage estimator). Bacteroidetes were the most abundant phylum in the DSS group (58.93%), followed by Firmicutes with 31.46% and Proteobacteria with 7.97%. In contrast, Firmicutes were the most abundant in the MEL group (49.48%), followed by Bacteroidetes with 41.63% and Proteobacteria with 7.50%. The results support the use of melatonin for prevention of intestinal bowel disease due to its modulatory effect on antioxidant capability and microbiota in mice with colitis. Melatonin was demonstrated to improve the oxidative stress resistance of mice with colitis and regulate the intestinal microbial flora, thus improving intestinal health.
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20
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21
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Li J, Li R, Liu G, Lv C, Mi Y, Zhang C. Effect of melatonin on renewal of chicken small intestinal mucosa. Poult Sci 2017; 96:2942-2949. [DOI: 10.3382/ps/pex085] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 03/20/2017] [Indexed: 12/27/2022] Open
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22
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Guo JY, Li F, Wen YB, Cui HX, Guo ML, Zhang L, Zhang YF, Guo YJ, Guo YX. Melatonin inhibits Sirt1-dependent NAMPT and NFAT5 signaling in chondrocytes to attenuate osteoarthritis. Oncotarget 2017; 8:55967-55983. [PMID: 28915567 PMCID: PMC5593538 DOI: 10.18632/oncotarget.18356] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 05/12/2017] [Indexed: 12/24/2022] Open
Abstract
Osteoarthritis (OA) is a degenerative joint disease mainly characterized by cartilage degradation. Interleukin-1β (IL-1β) contributes to OA pathogenesis by enhancing oxidative stress and inflammation. Melatonin reportedly elicits potent protection against OA. However, the role of melatonin and underlying mechanism in IL-1β-stimulated chondrocytes remain largely unclear. In this study, we found that melatonin inhibited IL-1β-induced toxicity and sirtuin 1 (Sirt1) enhancement in human chondrocytes. Melatonin reduced the IL-1β-increased nicotinamide phosphoribosyltransferase (NAMPT) expression and the NAD+ level in chondrocytes in a Sirt1-dependent manner. In turn, the inhibitory effect of melatonin on Sirt1 was mediated by NAMPT. Moreover, melatonin suppressed IL-1β-induced Sirt1-mediated matrix metalloproteinase (MMP)-3 and MMP-13 production. Melatonin also decreased the Sirt1-steered nuclear factor of activated T cells 5 (NFAT5) expression in IL-1β-challenged chondrocytes. NFAT5 depletion mimicked the suppressive effects of melatonin on IL-1β-elevated production of inflammatory mediators, including tumor necrosis factor-α (TNF-α), IL-1β, prostaglandin E2 (PGE2), and nitric oxide (NO) in chondrocytes. TNF-α, IL-1β, PGE2, or NO decrease caused the similar reduction of MMP-3 and MMP-13 by melatonin in IL-1β-insulted chondrocytes. Highly consistent with in vitro findings, in vivo results demonstrated that melatonin repressed the expression of relevant genes in rat OA pathogenesis in anterior cruciate ligament transection model. Overall, these results indicate that melatonin effectively reduced IL-1β-induced MMP production by inhibiting Sirt1-dependent NAMPT and NFAT5 signaling in chondrocytes, suggesting melatonin as a potential therapeutic alternative for chondroprotection of OA patients.
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Affiliation(s)
- Jia Yi Guo
- Luoyang Orthopedic Hospital of Henan Province, Luoyang, Henan, China
| | - Feng Li
- Luoyang Orthopedic Hospital of Henan Province, Luoyang, Henan, China
| | - Yong Bing Wen
- Luoyang Orthopedic Hospital of Henan Province, Luoyang, Henan, China
| | - Hong Xun Cui
- Luoyang Orthopedic Hospital of Henan Province, Luoyang, Henan, China
| | - Ma Long Guo
- Luoyang Orthopedic Hospital of Henan Province, Luoyang, Henan, China
| | - Lin Zhang
- Department of Surgery, Advanced Clinical Skills Centre, University of Auckland, Auckland, New Zealand
| | - Yun Fei Zhang
- Luoyang Orthopedic Hospital of Henan Province, Luoyang, Henan, China
| | - Yan Jin Guo
- Luoyang Orthopedic Hospital of Henan Province, Luoyang, Henan, China
| | - Yan Xing Guo
- Luoyang Orthopedic Hospital of Henan Province, Luoyang, Henan, China
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23
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Burke KE, Boumitri C, Ananthakrishnan AN. Modifiable Environmental Factors in Inflammatory Bowel Disease. Curr Gastroenterol Rep 2017; 19:21. [PMID: 28397132 PMCID: PMC5651146 DOI: 10.1007/s11894-017-0562-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2023]
Abstract
PURPOSE OF REVIEW Environmental factors may influence predisposition to develop inflammatory bowel diseases (Crohn's disease, ulcerative colitis) or alter its natural history by modification of both the host immune response and intestinal microbial composition. The purpose of this review is to translate such evidence into clinical practice by a focus on interventional studies that have modified such environmental influences to improve disease outcomes. RECENT FINDINGS Several environmental influences have been identified in the recent literature including tobacco use, diet, antibiotics, vitamin D deficiency, stress, appendectomy, and oral contraceptive use. Some risk factors have similar influences on both Crohn's disease and ulcerative colitis while others are disease-specific or have divergent effects. Emerging epidemiologic evidence has confirmed the association of many of these factors with incident disease using prospective data. In addition, laboratory data has supported their mechanistic plausibility and relevance to intestinal inflammation.
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Affiliation(s)
- Kristin E Burke
- Division of Gastroenterology, Massachusetts General Hospital, Boston, USA
| | - Christine Boumitri
- Division of Gastroenterology, University of Missouri-Columbia, Columbia, USA
| | - Ashwin N Ananthakrishnan
- Division of Gastroenterology, Massachusetts General Hospital, Boston, USA.
- Massachusetts General Hospital Crohn's and Colitis Center, 165 Cambridge Street, 9th Floor, Boston, MA, 02114, USA.
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24
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Esteban-Zubero E, López-Pingarrón L, Alatorre-Jiménez MA, Ochoa-Moneo P, Buisac-Ramón C, Rivas-Jiménez M, Castán-Ruiz S, Antoñanzas-Lombarte Á, Tan DX, García JJ, Reiter RJ. Melatonin's role as a co-adjuvant treatment in colonic diseases: A review. Life Sci 2017; 170:72-81. [PMID: 27919824 DOI: 10.1016/j.lfs.2016.11.031] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Revised: 11/17/2016] [Accepted: 11/30/2016] [Indexed: 02/07/2023]
Abstract
Melatonin is produced in the pineal gland as well as many other organs, including the enterochromaffin cells of the digestive mucosa. Melatonin is a powerful antioxidant that resists oxidative stress due to its capacity to directly scavenge reactive species, to modulate the antioxidant defense system by increasing the activities of antioxidant enzymes, and to stimulate the innate immune response through its direct and indirect actions. In addition, the dysregulation of the circadian system is observed to be related with alterations in colonic motility and cell disruptions due to the modifications of clock genes expression. In the gastrointestinal tract, the activities of melatonin are mediated by melatonin receptors (MT2), serotonin (5-HT), and cholecystokinin B (CCK2) receptors and via receptor-independent processes. The levels of melatonin in the gastrointestinal tract exceed by 10-100 times the blood concentrations. Also, there is an estimated 400 times more melatonin in the gut than in the pineal gland. Gut melatonin secretion is suggested to be influenced by the food intake. Low dose melatonin treatment accelerates intestinal transit time whereas high doses may decrease gut motility. Melatonin has been studied as a co-adjuvant treatment in several gastrointestinal diseases including irritable bowel syndrome (IBS), constipation-predominant IBS (IBS-C), diarrhea-predominant IBS (IBS-D), Crohn's disease, ulcerative colitis, and necrotizing enterocolitis. The purpose of this review is to provide information regarding the potential benefits of melatonin as a co-adjuvant treatment in gastrointestinal diseases, especially IBS, Crohn's disease, ulcerative colitis, and necrotizing enterocolitis.
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Affiliation(s)
- Eduardo Esteban-Zubero
- Department of Pharmacology and Physiology, University of Zaragoza. Calle Domingo Miral s/n, 50009 Zaragoza, Spain.
| | - Laura López-Pingarrón
- Department of Medicine, Psychiatry and Dermatology, University of Zaragoza. Calle Domingo Miral s/n, 50009 Zaragoza, Spain
| | - Moisés Alejandro Alatorre-Jiménez
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
| | - Purificación Ochoa-Moneo
- Department of Medicine, Psychiatry and Dermatology, University of Zaragoza. Calle Domingo Miral s/n, 50009 Zaragoza, Spain
| | - Celia Buisac-Ramón
- Primary Care Unit, Sector Zaragoza III, Avenida San Juan Bosco 5, 50009 Zaragoza, Spain
| | - Miguel Rivas-Jiménez
- Department of Medicine, Psychiatry and Dermatology, University of Zaragoza. Calle Domingo Miral s/n, 50009 Zaragoza, Spain
| | - Silvia Castán-Ruiz
- Primary Care Unit, Sector Zaragoza III, Avenida San Juan Bosco 5, 50009 Zaragoza, Spain
| | - Ángel Antoñanzas-Lombarte
- Department of Medicine, Psychiatry and Dermatology, University of Zaragoza. Calle Domingo Miral s/n, 50009 Zaragoza, Spain
| | - Dun-Xian Tan
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
| | - José Joaquín García
- Department of Pharmacology and Physiology, University of Zaragoza. Calle Domingo Miral s/n, 50009 Zaragoza, Spain
| | - Russel J Reiter
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
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25
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Gultekin FA, Emre AU, Celik SK, Barut F, Tali U, Sumer D, Turkcu UO. Effects of humanin on experimental colitis induced by 2,4,6-trinitrobenzene sulphonic acid in rats. Saudi J Gastroenterol 2017; 23:105-111. [PMID: 28361841 PMCID: PMC5385712 DOI: 10.4103/sjg.sjg_318_16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND/AIM The excessive apoptosis of intestinal epithelial cells (IECs) partly accounts for the development of colonic inflammation and eventually results in ulcerative colitis (UC). Humanin, an endogenous anti-apoptotic peptide, has previously been shown to protect against Alzheimer's disease and a variety of cellular insults. The present study aimed to investigate the effects of glysin variant of humanin (HNG) on 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats. MATERIALS AND METHODS Rats were divided into four groups as follows: Group 1 (n = 8): control; isotonic saline solution 0.1 ml/rat rectally, Group 2 (n = 8): TNBS colitis; 0.1 ml of a 2.5% (w/v) TNBS solution in 50% ethanol rectally, Group 3 (n = 8): 10 μM HNG, and Group 4 (n = 8): 20 μM HNG intraperitoneal (ip) on day 2 and 6 after rectal TNBS administration. Rats were sacrificed 7 days after the induction of colitis. Blood and tissue samples were harvested for biochemical and histopathological analysis. RESULTS HNG treatment significantly ameliorated weight loss and macroscopic and microscopic scores. TNBS-induced colitis significantly increased the colonic mRNA expression of tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and caspase-3 activities in group II in comparison to the group I. HNG treatment was associated with an inhibition of mRNA expression of TNF-α and IL-1β, and a decrease in caspase-3 activities in colon tissues in group III and IV when compared to group II. CONCLUSION The results of this study indicate that HNG treatment may exert beneficial effects in UC by decreasing inflammatory reactions and apoptosis.
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Affiliation(s)
- Fatma A. Gultekin
- Department of General Surgery, School of Medicine, Bulent Ecevit University, Zonguldak, Turkey,Address for correspondence: Dr. Fatma A. Gultekin, Department of General Surgery, School of Medicine, Bulent Ecevit University, Zonguldak - 67600, Turkey. E-mail:
| | - Ali U. Emre
- Department of General Surgery, School of Medicine, Bulent Ecevit University, Zonguldak, Turkey
| | - Sevim K. Celik
- Department of Medical Biology, School of Medicine, Bulent Ecevit University, Zonguldak, Turkey
| | - Figen Barut
- Department of Pathology, School of Medicine, Bulent Ecevit University, Zonguldak, Turkey
| | - Ufuk Tali
- Department of General Surgery, Can Goverment Hospital, Çanakkale, Turkey
| | - Demet Sumer
- Department of General Surgery, Nevsehir Goverment Hospital, Nevsehir, Turkey
| | - Ummuhani O. Turkcu
- Department of Medical Biochemistry, Mugla School of Health Sciences, Mugla Sitki Kocman University, Mugla, Turkey
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26
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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: 35] [Impact Index Per Article: 3.9] [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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27
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Calvo J, Maldonado M. The role of melatonin in autoimmune and atopic diseases. AIMS MOLECULAR SCIENCE 2016. [DOI: 10.3934/molsci.2016.2.158] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
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28
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Liu N, Gong B, Jin Z, Wang X, Wei M, Yang F, Li Y, Shi Q. Sodic alkaline stress mitigation by exogenous melatonin in tomato needs nitric oxide as a downstream signal. JOURNAL OF PLANT PHYSIOLOGY 2015; 186-187:68-77. [PMID: 26412100 DOI: 10.1016/j.jplph.2015.07.012] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Revised: 06/30/2015] [Accepted: 07/03/2015] [Indexed: 05/03/2023]
Abstract
The present study was designed to determine the interactive effect of exogenous melatonin and nitric oxide (NO) on sodic alkaline stress mitigation in tomato seedlings. It was observed that exogenous melatonin treatment elevated NO levels in alkaline-stressed tomato roots. However, exogenous NO had little effects on melatonin levels. Importantly, melatonin-induced NO generation was accompanied by increased tolerance to alkaline stress. Chemical scavenging of NO reduced melatonin-induced alkaline stress tolerance and defense genes' expression. However, inhibition of melatonin biosynthesis had a little effect on NO-induced alkaline stress tolerance. These results strongly suggest that NO, acting as a downstream signal, is involved in the melatonin-induced tomato tolerance to alkaline stress. This process creates a new signaling pathway for improving stress tolerance in plant.
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Affiliation(s)
- Na Liu
- State Key Laboratory of Crop Biology, Scientific Observing and Experimental Station of Environment Controlled Agricultural Engineering in Huang-Huai-Hai Region, Ministry of Agriculture, PR China; College of Horticulture Science and Engineering, Shandong Agricultural University, Tai'an 271018, PR China
| | - Biao Gong
- State Key Laboratory of Crop Biology, Scientific Observing and Experimental Station of Environment Controlled Agricultural Engineering in Huang-Huai-Hai Region, Ministry of Agriculture, PR China; College of Horticulture Science and Engineering, Shandong Agricultural University, Tai'an 271018, PR China
| | - Zhiyong Jin
- State Key Laboratory of Crop Biology, Scientific Observing and Experimental Station of Environment Controlled Agricultural Engineering in Huang-Huai-Hai Region, Ministry of Agriculture, PR China; College of Horticulture Science and Engineering, Shandong Agricultural University, Tai'an 271018, PR China
| | - Xiufeng Wang
- State Key Laboratory of Crop Biology, Scientific Observing and Experimental Station of Environment Controlled Agricultural Engineering in Huang-Huai-Hai Region, Ministry of Agriculture, PR China; College of Horticulture Science and Engineering, Shandong Agricultural University, Tai'an 271018, PR China
| | - Min Wei
- State Key Laboratory of Crop Biology, Scientific Observing and Experimental Station of Environment Controlled Agricultural Engineering in Huang-Huai-Hai Region, Ministry of Agriculture, PR China; College of Horticulture Science and Engineering, Shandong Agricultural University, Tai'an 271018, PR China
| | - Fengjuan Yang
- State Key Laboratory of Crop Biology, Scientific Observing and Experimental Station of Environment Controlled Agricultural Engineering in Huang-Huai-Hai Region, Ministry of Agriculture, PR China; College of Horticulture Science and Engineering, Shandong Agricultural University, Tai'an 271018, PR China
| | - Yan Li
- State Key Laboratory of Crop Biology, Scientific Observing and Experimental Station of Environment Controlled Agricultural Engineering in Huang-Huai-Hai Region, Ministry of Agriculture, PR China; College of Horticulture Science and Engineering, Shandong Agricultural University, Tai'an 271018, PR China
| | - Qinghua Shi
- State Key Laboratory of Crop Biology, Scientific Observing and Experimental Station of Environment Controlled Agricultural Engineering in Huang-Huai-Hai Region, Ministry of Agriculture, PR China; College of Horticulture Science and Engineering, Shandong Agricultural University, Tai'an 271018, PR China.
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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: 52] [Impact Index Per Article: 5.2] [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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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: 32] [Impact Index Per Article: 3.2] [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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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: 27] [Impact Index Per Article: 2.5] [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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Sobczak M, Fabisiak A, Murawska N, Wesołowska E, Wierzbicka P, Wlazłowski M, Wójcikowska M, Zatorski H, Zwolińska M, Fichna J. Current overview of extrinsic and intrinsic factors in etiology and progression of inflammatory bowel diseases. Pharmacol Rep 2014; 66:766-75. [PMID: 25149979 DOI: 10.1016/j.pharep.2014.04.005] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Revised: 03/29/2014] [Accepted: 04/09/2014] [Indexed: 12/16/2022]
Abstract
Inflammatory bowel diseases (IBD) are chronic, relapsing disorders affecting gastrointestinal (GI) tract and associated with intestinal mucosa damage and inflammation. The principal therapeutic goals in IBD include control of the intestinal inflammation and treatment of the major symptoms, mainly abdominal pain and diarrhea. Current therapeutic strategies for IBD rely on the use of non-specific anti-inflammatory agents and immunosuppressive drugs (e.g. aminosalicylates, monoclonal antibodies, and antibiotics), which cause severe side effects, and - in a significant number of patients - do not induce long-term benefits. In this review, we summarize the epidemiology and the most important risk factors of IBD, including genetic, immunological and environmental. Our main focus is to discuss pharmacological targets for current and future treatments of IBD.
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Affiliation(s)
- Marta Sobczak
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Adam Fabisiak
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Natalia Murawska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Ewelina Wesołowska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Paulina Wierzbicka
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Marcin Wlazłowski
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Marta Wójcikowska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Hubert Zatorski
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Marta Zwolińska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Łódź, Poland.
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Abstract
: Ulcerative colitis (UC), an inflammatory bowel disease, affects many people across the globe, and its prevalence is increasing steadily. Inflammation and oxidative stress play a vital role in the perpetuation of inflammatory process and the subsequent DNA damage associated with the development of UC. UC induces not only local but also systemic damage, which involves the perturbation of multiple molecular pathways. Furthermore, UC leads to an increased risk of colorectal cancer, the third most common malignancy in humans. Most of the drugs used for the treatment of UC are unsatisfactory because they are generally mono-targeted, relatively ineffective and unaffordable for many people. Thus, agents that can target multiple molecular pathways and are less expensive have enormous potential to treat UC. Melatonin has beneficial effects against UC in experimental and clinical studies because of its ability to modulate several molecular pathways of inflammation, oxidative stress, fibrosis, and cellular injury. However, many novel targets are yet to be explored on which melatonin may act to exert its favorable effects in UC. It is time to explore improved intervention strategies with melatonin in UC on the basis of studies investigating different molecular targets using proteomic and genomic approaches. This review identifies various molecular targets for melatonin with the intent of providing novel strategies for combating UC and the associated extraintestinal manifestations of this debilitating disease.
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Affiliation(s)
- Gopabandhu Jena
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Punjab, India
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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: 52] [Impact Index Per Article: 4.3] [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: 16] [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: 60] [Impact Index Per Article: 5.0] [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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Bizzarri M, Proietti S, Cucina A, Reiter RJ. Molecular mechanisms of the pro-apoptotic actions of melatonin in cancer: a review. Expert Opin Ther Targets 2013; 17:1483-96. [DOI: 10.1517/14728222.2013.834890] [Citation(s) in RCA: 134] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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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: 73] [Impact Index Per Article: 6.1] [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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Melatonin: buffering the immune system. Int J Mol Sci 2013; 14:8638-83. [PMID: 23609496 PMCID: PMC3645767 DOI: 10.3390/ijms14048638] [Citation(s) in RCA: 471] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Revised: 04/06/2013] [Accepted: 04/07/2013] [Indexed: 12/29/2022] Open
Abstract
Melatonin modulates a wide range of physiological functions with pleiotropic effects on the immune system. Despite the large number of reports implicating melatonin as an immunomodulatory compound, it still remains unclear how melatonin regulates immunity. While some authors argue that melatonin is an immunostimulant, many studies have also described anti-inflammatory properties. The data reviewed in this paper support the idea of melatonin as an immune buffer, acting as a stimulant under basal or immunosuppressive conditions or as an anti-inflammatory compound in the presence of exacerbated immune responses, such as acute inflammation. The clinical relevance of the multiple functions of melatonin under different immune conditions, such as infection, autoimmunity, vaccination and immunosenescence, is also reviewed.
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Crespo I, San-Miguel B, Prause C, Marroni N, Cuevas MJ, González-Gallego J, Tuñón MJ. Glutamine treatment attenuates endoplasmic reticulum stress and apoptosis in TNBS-induced colitis. PLoS One 2012; 7:e50407. [PMID: 23209735 PMCID: PMC3508929 DOI: 10.1371/journal.pone.0050407] [Citation(s) in RCA: 104] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2012] [Accepted: 10/18/2012] [Indexed: 12/23/2022] Open
Abstract
Endoplasmic reticulum (ER) stress and apoptotic cell death play an important role in the pathogenesis and perpetuation of inflammatory bowel disease (IBD). We aimed to explore the potential of glutamine to reduce ER stress and apoptosis in a rat model of experimental IBD. Colitis was induced in male Wistar rats by intracolonic administration of 30 mg of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Glutamine (25 mg/dL) was given by rectal route daily for 2 d or 7 d. Both oxidative stress (TBARS concentration and oxidised/reduced glutathione ratio) and ER stress markers (CHOP, BiP, calpain-1 and caspase-12 expression) increased significantly within 48 h of TNBS instillation, and glutamine attenuated the extent of the changes. Glutamine also inhibited the significant increases of ATF6, ATF4 and spliced XBP-1 mRNA levels induced by TNBS instillation. TNBS-colitis resulted in a significant increase in p53 and cytochrome c expression, and a reduced Bcl-xL expression and Bax/Bcl-2 ratio. These effects were significantly inhibited by glutamine. Treatment with the amino acid also resulted in significant decreases of caspase-9, caspase-8 and caspase-3 activities. Double immunofluorescence staining showed co-localization of CHOP and cleaved caspase-3 in colon sections. Phospho-JNK and PARP-1 expression was also significantly higher in TNBS-treated rats, and treatment with glutamine significantly decreased JNK phosphorylation and PARP-1 proteolysis. To directly address the effect of glutamine on ER stress and apoptosis in epithelial cells, the ER stress inducers brefeldin A and tunicamycin were added to Caco-2 cells that were treated with glutamine (5 mM and 10 mM). The significant enhancement in PERK, ATF6 phosphorylated IRE1, BiP and cleaved caspase-3 expression induced by brefeldin A and tunicamycin was partly prevented by glutamine. Data obtained indicated that modulation of ER stress signalling and anti-apoptotic effects contribute to protection by glutamine against damage in TNBS-induced colitis.
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Affiliation(s)
- Irene Crespo
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
| | | | - Carolina Prause
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
| | - Norma Marroni
- Porto Alegre Clinical Hospital, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - María J. Cuevas
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
| | - Javier González-Gallego
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
| | - María J. Tuñón
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
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42
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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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43
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Nair SM, Rahman RMA, Clarkson AN, Sutherland BA, Taurin S, Sammut IA, Appleton I. Melatonin treatment following stroke induction modulates L-arginine metabolism. J Pineal Res 2011; 51:313-23. [PMID: 21605165 DOI: 10.1111/j.1600-079x.2011.00891.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The efficacy of melatonin treatment in experimental stroke has been established. Some of the neuroprotective properties have been attributed to its anti-oxidant and anti-inflammatory effects. Nitric oxide synthases (NOS) and cyclooxygenases (COX) are considered to have a significant role in the inflammatory milieu occurring in acute stroke. While previous reports have shown that pretreatment with melatonin in a stroke model can modulate NOS isoforms, the effect of post-treatment with melatonin on l-arginine metabolism has not been investigated. This study initially examined the effect of melatonin (1 nm-1 mm) on l-arginine metabolism pathways in human fibrosarcoma fibroblasts (HT-1080) fibroblasts. Evidence of neuroprotection with melatonin was evaluated in rats subjected to middle cerebral artery occlusion (MCAO). Animals were treated with three daily doses of 5 mg/kg i.p., starting 1 hr after the onset of ischemia. Constitutive NOS activity but not expression was significantly increased by in vitro exposure (72 hr) to melatonin. In addition, melatonin treatment increased arginase activity by increasing arginase II expression. In vivo studies showed that melatonin treatment after MCAO significantly inhibited inducible NOS activity and attenuated expression of the inducible isoform, resulting in decreased total NOS activity and tissue nitrite levels. COX activity was significantly reduced with melatonin treatment. The neuroprotective anti-inflammatory effects of melatonin were consistent with the substantial reduction in infarct volume throughout the cortex and striatum and recovery of mitochondrial enzyme activities. The evidence presented here suggests that modulation of l-arginine metabolism by melatonin make it a valuable neuroprotective therapy for stroke.
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Affiliation(s)
- Shiva M Nair
- Department of Pharmacology and Toxicology, School of Medical Sciences, University of Otago, Dunedin, New Zealand
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Chen CQ, Fichna J, Bashashati M, Li YY, Storr M. Distribution, function and physiological role of melatonin in the lower gut. World J Gastroenterol 2011; 17:3888-98. [PMID: 22025877 PMCID: PMC3198018 DOI: 10.3748/wjg.v17.i34.3888] [Citation(s) in RCA: 158] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2011] [Revised: 03/18/2011] [Accepted: 03/25/2011] [Indexed: 02/06/2023] Open
Abstract
Melatonin is a hormone with endocrine, paracrine and autocrine actions. It is involved in the regulation of multiple functions, including the control of the gastrointestinal (GI) system under physiological and pathophysiological conditions. Since the gut contains at least 400 times more melatonin than the pineal gland, a review of the functional importance of melatonin in the gut seems useful, especially in the context of recent clinical trials. Melatonin exerts its physiological effects through specific membrane receptors, named melatonin-1 receptor (MT1), MT2 and MT3. These receptors can be found in the gut and their involvement in the regulation of GI motility, inflammation and pain has been reported in numerous basic and clinical studies. Stable levels of melatonin in the lower gut that are unchanged following a pinealectomy suggest local synthesis and, furthermore, implicate physiological importance of endogenous melatonin in the GI tract. Presently, only a small number of human studies report possible beneficial and also possible harmful effects of melatonin in case reports and clinical trials. These human studies include patients with lower GI diseases, especially patients with irritable bowel syndrome, inflammatory bowel disease and colorectal cancer. In this review, we summarize the presently available information on melatonin effects in the lower gut and discuss available in vitro and in vivo data. We furthermore aim to evaluate whether melatonin may be useful in future treatment of symptoms or diseases involving the lower gut.
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45
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Liu X, Wang JM. Iridoid glycosides fraction of Folium syringae leaves modulates NF-κB signal pathway and intestinal epithelial cells apoptosis in experimental colitis. PLoS One 2011; 6:e24740. [PMID: 21931839 PMCID: PMC3172289 DOI: 10.1371/journal.pone.0024740] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2011] [Accepted: 08/16/2011] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND AND AIMS Iridoid glycosides (IG), the major active fraction of F. syringae leaves has been demonstrated to have strong anti-inflammatory properties to ulcerative colitis (UC) in our previous study. The aim of this study was to investigate whether IG modulates the inflammatory response in experimental colitis at the level of NF-κB signal pathway and epithelial cell apoptosis. METHODS UC in rats was induced by administration with dextran sulfate sodium (DSS) in drinking water. The inflammatory damage was assessed by disease activity index (DAI), macroscopic findings, histology and myeloperoxidase (MPO) activity. The effect of IG on pro-inflammatory cytokines TNF-α, IL-8, COX-2 and regulatory peptide TGF-β1 was measured. Epithelial cell apoptosis and the protein and mRNA expressions of Fas/FasL, Bcl-2/Bax, caspase-3, NF-κB p65, IκBα, p-IκBα and IKKβ were detected by TUNEL method, immunohistochemistry, Western blotting and real-time quantitative PCR, respectively. RESULTS IG significantly ameliorated macroscopic damage and histological changes, reduced the activity of MPO, and strongly inhibited epithelial cell apoptosis. Moreover, IG markedly depressed TNF-α, IL-8, COX-2 and TGF-β1 levels in the colon tissues in a dose-dependent manner. Furthermore, IG significantly blocked of NF-κB signaling by inhibiting IκBα phosphorylation/degradation and IKKβ activity, down-regulated the protein and mRNA expressions of Fas/FasL, Bax and caspase-3, and activated Bcl-2 in intestinal epithelial cells. CONCLUSIONS These results demonstrated for the first time that IG possessed marked protective effects on experimental colitis through inhibition of epithelial cell apoptosis and blockade of NF-κB signal pathway.
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Affiliation(s)
- Xin Liu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
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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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47
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Rahimian R, Fakhfouri G, Daneshmand A, Mohammadi H, Bahremand A, Rasouli MR, Mousavizadeh K, Dehpour AR. Adenosine A2A receptors and uric acid mediate protective effects of inosine against TNBS-induced colitis in rats. Eur J Pharmacol 2010; 649:376-81. [PMID: 20868668 DOI: 10.1016/j.ejphar.2010.09.044] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2010] [Revised: 08/28/2010] [Accepted: 09/07/2010] [Indexed: 12/17/2022]
Abstract
Inflammatory bowel disease comprises chronic recurrent inflammation of gastrointestinal tract. This study was conducted to investigate inosine, a potent immunomodulator, in 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced chronic model of experimental colitis, and contribution of adenosine A(2A) receptors and the metabolite uric acid as possible underlying mechanisms. Experimental colitis was rendered in rats by a single colonic administration of 10 mg of TNBS. Inosine, potassium oxonate (a hepatic uricase inhibitor), SCH-442416 (a selective adenosine A(2A) receptor antagonist), inosine+potassium oxonate, or inosine+SCH-442416 were given twice daily for 7 successive days. At the end of experiment, macroscopic and histopathologic scores, colonic malondialdehyde (MDA), Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-1beta (IL-1β) levels, and myeloperoxidase (MPO) activity were assessed. Plasma uric acid level was measured throughout the experiment. Both macroscopic and histological features of colonic injury were markedly ameliorated by either inosine, oxonate or inosine+oxonate. Likewise, the elevated amounts of MPO and MDA abated as well as those of TNF-α and IL-1β (P<0.05). SCH-442416 partially reversed the effect of inosine on theses markers, while inosine+oxonate showed a higher degree of protection than each treatment alone (P<.0.05). No significant difference was observed between TNBS and SCH-442416 groups. Uric acid levels were significantly higher in inosine or oxonate groups compared to control. Inosine+oxonate resulted in an even more elvelated uric acid level than each treatment alone (P<0.05). Inosine elicits notable anti-inflammatory effects on TNBS-induced colitis in rats. Uric acid and adenosine A(2A) receptors contribute to these salutary properties.
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Affiliation(s)
- Reza Rahimian
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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48
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Bertrand PP, Bertrand RL, Camello PJ, Pozo MJ. Simultaneous measurement of serotonin and melatonin from the intestine of old mice: the effects of daily melatonin supplementation. J Pineal Res 2010; 49:23-34. [PMID: 20374441 DOI: 10.1111/j.1600-079x.2010.00760.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Ageing is associated with important changes in gastrointestinal function and in the levels of intestinal hormones secreted. Enterochromaffin (EC) cells containing serotonin (5-HT) and melatonin may play a major role in maintaining gut function during ageing. Our aim was to characterise the mucosal availability of 5-HT and melatonin in the ileum and colon of a mouse model of ageing. Female young mice (2-5 month; n = 6), aged mice (22-24 months; n = 6) and aged mice treated with melatonin (n = 6; 10 mg/kg/day) were examined. Electrochemical methods were used to measure 5-HT and melatonin concentrations near the mucosal surface of ileum and distal colon. Amperometry studies showed that steady state levels of 5-HT from ileum and colon were decreased in aged mice treated with melatonin when compared to aged mice, while compression-evoked 5-HT release was unchanged. Differential pulse voltammetry studies showed that young mice had concentrations of 5-HT of 4.8 +/- 0.8 mum in the ileum and 4.9 +/- 1.0 mum in the colon. Concentrations of melatonin were 5.7 +/- 1.4 mum in the ileum and 5.6 +/- 1.9 mum in the colon. Compared to young mice, the levels of 5-HT and melatonin were increased in aged mice (combined ileum and colon: 5-HT = 130% and melatonin = 126% of young mice) and decreased in melatonin-treated mice (5-HT = 94% and melatonin = 82%). In conclusion, our data show that the availability of gut 5-HT and melatonin is increased in aged mice and melatonin treatment suppresses natural gastrointestinal production of 5-HT and melatonin in the aged mouse intestine.
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Affiliation(s)
- P P Bertrand
- Department of Physiology, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
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49
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Matheus N, Mendoza C, Iceta R, Mesonero JE, Alcalde AI. Melatonin inhibits serotonin transporter activity in intestinal epithelial cells. J Pineal Res 2010; 48:332-9. [PMID: 20210852 DOI: 10.1111/j.1600-079x.2010.00757.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Gastrointestinal serotonin (5-HT) and melatonin are two closely related neuromodulators which are synthesised in the enterochromaffin cells of the intestinal epithelium and which have been shown to be involved in the physiopathology of the gastrointestinal tract. The effects of 5-HT depend on 5-HT availability which is, in part, modulated by the serotonin transporter (SERT). This transporter provides an efficient 5-HT uptake after release and is expressed in the membrane of the enterocytes. Although the origin and effects of 5-HT and melatonin are similar, the interrelationship between them in the gastrointestinal tract is unknown. The main aim of this study was to determine whether melatonin affects SERT activity and expression, and, if so, to elucidate the mechanisms involved. Caco-2 cell line was used to carry out the study as these cells have been shown to endogenously express SERT. The results showed that melatonin inhibits SERT activity by affecting both V(max) and kt kinetic constants although SERT synthesis or intracellular trafficking did not appear to be affected. The melatonin effect seemed to be independent of melatonin receptors MT(1) and MT(2) and protein kinase C and cAMP intracellular pathways. Our results suggest that the inhibition of SERT might be due to a catalytic effect of melatonin on the allosteric citalopram-sensitive site in SERT. This study shows, for the first time, that melatonin modulates SERT activity, thus demonstrating the feedback system between melatonin and the serotoninergic system in the gastrointestinal tract.
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Affiliation(s)
- Nyurky Matheus
- Departamento de Farmacología y Fisiología, Universidad de Zaragoza, Spain
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50
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Protective effect of melatonin against mitomycin C-induced genotoxic damage in peripheral blood of rats. J Biomed Biotechnol 2009; 2009:791432. [PMID: 19859567 PMCID: PMC2764378 DOI: 10.1155/2009/791432] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2009] [Accepted: 08/05/2009] [Indexed: 11/17/2022] Open
Abstract
Mitomycin C (MMC) generates free radicals when metabolized. We investigated the effect of melatonin against MMC-induced genotoxicity in polychromatic erythrocytes and MMC-induced lipid peroxidation in brain and liver homogenates. Rats (N = 36) were classified into 4 groups: control, melatonin, MMC, and MMC + melatonin. Melatonin and MMC doses of
10 mg/kg and 2 mg/kg, respectively, were injected intraperitoneally. Peripheral blood samples were collected at 0, 24, 48, 72, and 96 hours posttreatment and homogenates were obtained at 96 hours posttreatment. The number of micronucleated polychromatic erythrocytes (MN-PCE) per 1000 PCE was used as a genotoxic marker. Malondialdehyde (MDA) plus 4-hydroxyalkenal (4-HDA) levels were used as an index of lipid peroxidation. The MMC group showed a significant increase in MN-PCE at 24, 48, 72, and 96 hours that was significantly reduced with melatonin begin coadministrated. No significant differences were found in lipid peroxidation. Our results indicate that MMC-induced genotoxicity can be reduced by melatonin.
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