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Zhu L, Qiao L, Dou X, Song X, Chang J, Zeng X, Xu C. Lactobacillus casei ATCC 393 combined with vasoactive intestinal peptide alleviates dextran sodium sulfate-induced ulcerative colitis in C57BL/6 mice via NF-κB and Nrf2 signaling pathways. Biomed Pharmacother 2023; 165:115033. [PMID: 37379640 DOI: 10.1016/j.biopha.2023.115033] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 06/08/2023] [Accepted: 06/19/2023] [Indexed: 06/30/2023] Open
Abstract
Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) which is related to an immunological imbalance of the intestinal mucosa. Many clinical evidences indicate probiotics supplementation appears to be effective and safe in patients with UC. Vasoactive intestinal peptide (VIP) is an endogenous neuropeptide with multiple physiological and pathological effects. In this study, we investigated the protective effect of the combination of Lactobacillus casei ATCC 393 (L. casei ATCC 393) with VIP on dextran sodium sulfate (DSS)-induced UC in mice and the potential mechanism. The results showed that, compared with the control group, DSS treatment significantly shortened the colon length, caused inflammation and oxidative stress, and further resulted in the intestinal barrier dysfunction and gut microbiota dysbiosis. In addition, intervention with L. casei ATCC 393, VIP or L. casei ATCC 393 combined with VIP significantly reduced UC disease activity index. However, compared with L. casei ATCC 393 or VIP, L. casei ATCC 393 combined with VIP effectively relieved symptoms of UC by regulating immune response, enhancing antioxidant capacity, and regulating nuclear factor kappa-B (NF-κB) and nuclear factor erythroid-derived-2-like 2 (Nrf2) signaling pathways. In conclusion, this study suggests that L. casei ATCC 393 combined with VIP can effectively relieve DSS-induced UC, which is a promising treatment strategy for UC.
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Affiliation(s)
- Lixu Zhu
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Lei Qiao
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Xina Dou
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Xiaofan Song
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Jiajing Chang
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Xiaonan Zeng
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Chunlan Xu
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China.
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Simon RA, Barazanji N, Jones MP, Bednarska O, Icenhour A, Engström M, Hamilton JP, Keita ÅV, Walter S. Vasoactive intestinal polypeptide plasma levels associated with affective symptoms and brain structure and function in healthy females. Sci Rep 2021; 11:1406. [PMID: 33446759 PMCID: PMC7809454 DOI: 10.1038/s41598-020-80873-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 12/21/2020] [Indexed: 12/16/2022] Open
Abstract
Vasoactive intestinal polypeptide (VIP) is a neuroendocrine peptide distributed throughout the human body, including the CNS, where it is particularly abundant in brain regions associated with anxiety and depression. Based on earlier studies indicating that peripheral VIP may cross through the blood-brain barrier, we hypothesized plasma VIP levels to be associated with symptoms of anxiety and depression, as well as brain volume and resting-state functional connectivity in the amygdala, hippocampus, parahippocampus, and orbitofrontal cortex. Plasma VIP concentrations and anxiety/depression symptoms were measured in 37 healthy females. Functional and structural magnetic resonance imaging were used to evaluate functional connectivity and brain volume respectively, and their associations with VIP concentrations within brain regions associated with anxiety and depression. Negative correlations were found between VIP levels and symptoms of anxiety (r = - 0.44, p = 0.002) and depression (r = - 0.50, p = 0.001). Functional connectivity demonstrated significant VIP-dependent positive associations between the amygdala seed region with both the right parahippocampus (t(33) = 3.1, pFDR = 0.02) and right lateral orbitofrontal cortex (OFC; t(33) = 2.9, pFDR = 0.02). Moreover, VIP concentrations were significantly, positively correlated with brain volume in the left amygdala (r = 0.28, p = 0.007) and left lateral OFC (r = 0.29, p = 0.004). The present findings highlight a potential role for VIP in the neurobiology of affective symptoms.
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Affiliation(s)
- Rozalyn A Simon
- Center for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden
- Division of Diagnostics and Specialist Medicine, Department of Health, Medicine, and Caring Sciences, Linköping University, Linköping, Sweden
| | - Nawroz Barazanji
- Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Michael P Jones
- Department of Psychology, Macquarie University, Sydney, Australia
| | - Olga Bednarska
- Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Adriane Icenhour
- Center for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Maria Engström
- Center for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden
- Division of Diagnostics and Specialist Medicine, Department of Health, Medicine, and Caring Sciences, Linköping University, Linköping, Sweden
| | - J Paul Hamilton
- Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience, Linköping University, Linköping, Sweden
| | - Åsa V Keita
- Division of Surgery, Orthopedics and Oncology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Susanna Walter
- Center for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden.
- Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
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Spoorthi BC, More SS, Gautham SA, Ghosh S, Saha I, Maiti AK. Role of free radical scavenging activity of vasoactive intestinal peptide in the attenuation of mitochondrial dysfunction to ameliorate dextran sulphate sodium-induced colitis in mice: Implications in ulcerative colitis. J Dig Dis 2020; 21:711-723. [PMID: 33405317 DOI: 10.1111/1751-2980.12932] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 06/12/2020] [Accepted: 08/14/2020] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To evaluate the efficacy of vasoactive intestinal peptide (VIP) in treating ulcerative colitis (UC), targeting colonic mitochondrial dysfunction by virtue of its free radical scavenging properties for maintenance of colon mucosal integrity. METHODS A murine model was administered with dextran sodium sulfate (DSS) to induce colitis in C57BL/6J mice at 3.5%/g bodyweight for 3 cycles of 5 days each, followed by an intraperitoneal dose of VIP at 0.5 nmol/L per mouse per day for 10 days. The post-treatment mice were sacrificed and their colon samples were utilized for further analysis. To substantiate the in vivo findings and identify the reactive species involved in progression of UC, Caco-2 cells were subjected to DSS (5%) for 24 hours at 37 °C with or without VIP (10 nmol/L) in the presence or absence of specific free radical scavengers and antioxidants. RESULTS Treatment with VIP reduced histopathological severity of colitis and cell death markers in murine model, leading to partial recovery of inhibited mitochondrial respiratory complexes, altered mitochondrial membrane potential and lowered adenosine triphosphate generation. Interestingly, in vitro treatment with VIP restored mitochondrial functions and its efficacy was equal to super oxide dismutase and dimethyl sulfoxide, indicating involvement of superoxide free radical (O2 •-) and hydroxyl radical (•OH) in progression of UC. However, catalase, Nω-nitro-l-arginine methyl ester and mercaptoethylguanidine were ineffective, indicating non-involvement of hydrogen peroxide, nitric oxide and ONOO- in UC. CONCLUSION By virtue of its free radical scavenging properties VIP can act as a potent anti-colitogenic agent, reversing colonic mitochondrial dysfunction for treating UC.
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Affiliation(s)
| | - Sunil S More
- School of Basic and Applied Sciences, Dayananda Sagar University, Bengaluru, Karnataka, India
| | | | - Shashwati Ghosh
- Department of Zoology, Mitochondrial Biology and Experimental Therapeutics Laboratory, University of North Bengal, Darjeeling, West Bengal, India
| | - Ishita Saha
- Department of Physiology, Medical College Kolkata, Kolkata, West Bengal, India
| | - Arpan Kumar Maiti
- School of Basic and Applied Sciences, Dayananda Sagar University, Bengaluru, Karnataka, India.,Department of Zoology, Mitochondrial Biology and Experimental Therapeutics Laboratory, University of North Bengal, Darjeeling, West Bengal, India
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Alessio A, Pergolizzi S, Gervasi T, Aragona M, Lo Cascio P, Cicero N, Lauriano ER. Biological effect of astaxanthin on alcohol-induced gut damage in Carassius auratus used as experimental model. Nat Prod Res 2020; 35:5737-5743. [DOI: 10.1080/14786419.2020.1830396] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Alesci Alessio
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
| | - S. Pergolizzi
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
| | - T. Gervasi
- Department of Biomedical and Dental Science and Morphofunctional Imaging, University of Messina, Messina, Italy
| | - M. Aragona
- Department of Veterinary Sciences, University of Messina, Messina, Italy
| | - P. Lo Cascio
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
| | - N. Cicero
- Department of Biomedical and Dental Science and Morphofunctional Imaging, University of Messina, Messina, Italy
| | - E. R. Lauriano
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
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Rychlik A, Gonkowski S, Całka J, Makowska K. Vasoactive Intestinal Polypeptide (VIP) in the Intestinal Mucosal Nerve Fibers in Dogs with Inflammatory Bowel Disease. Animals (Basel) 2020; 10:ani10101759. [PMID: 32998326 PMCID: PMC7599766 DOI: 10.3390/ani10101759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 09/25/2020] [Indexed: 11/24/2022] Open
Abstract
Simple Summary Canine inflammatory bowel disease (IBD)—a group of gastrointestinal disorders—is a serious problem in veterinary medicine. The etiology of IBD remains unknown, and its diagnosis and effective treatment are difficult. One of the less-known aspects of IBD pathology is the influence of this disease on the enteric nervous system, which is located in the intestinal wall and regulates most of the gastrointestinal functions. Therefore, the aim of the present study was to evaluate the influence of IBD on the intramucosal nerve fibers containing vasoactive intestinal polypeptide (VIP). VIP is one of the most important substances produced by the enteric nervous structures that is involved in many regulatory processes in the gastrointestinal tract. The obtained results show that IBD induces changes in the density of intramucosal VIP-positive nerve fibers in the canine gastrointestinal tract. It suggests that VIP is involved in the pathological processes occurring during this disease. Observed changes may be a result of neuroprotective and/or adaptive processes regulated by VIP, aimed at the homeostasis maintenance in the inflamed gastrointestinal (GI) tract and induced by proinflammatory factors. Abstract Canine inflammatory bowel disease (IBD) is a group of enteropathies with nonspecific chronic symptoms and poorly understood etiology. Many aspects connected with IBD are not understood. One of them is the participation of the intestinal nervous system in the development of pathological processes. Thus, this study aimed to demonstrate changes in the density of intramucosal nerve fibers containing vasoactive intestinal polypeptide (VIP)—one of the most important intestinal nervous factors caused by the various stages of IBD development. Mucosal biopsy specimens collected from the duodenum, jejunum and descending colon of healthy dogs and dogs with varied severity of IBD were included in the experiment. The density of VIP-like immunoreactive (VIP-LI) nerves was determined by a single immunofluorescence technique and a semi-quantitative method consisting in VIP-LI fiber counts in the field of view (0.1 mm2). The obtained results indicate that IBD induces changes in the density of mucosal VIP-LI nerve fibers in the canine gastrointestinal tract. The initial decrease is followed by an increase in VIP-like immunoreactivity in successive stages of the disease. These observations show that VIP is a neuronal factor that participates in the pathological processes connected with canine IBD. The observed changes probably result from the neuroprotective and/or adaptive properties of VIP. Protective and adaptive reactions induced by inflammation aim to protect the GI tract against damage by proinflammatory factors and ensure the homeostasis in the enteric nervous system (ENS) under the conditions changed by the disease process.
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Affiliation(s)
- Andrzej Rychlik
- Department of Clinical Diagnostics, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego 14, 10-957 Olsztyn, Poland;
| | - Sławomir Gonkowski
- Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego 13, 10-957 Olsztyn, Poland; (S.G.); (J.C.)
| | - Jarosław Całka
- Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego 13, 10-957 Olsztyn, Poland; (S.G.); (J.C.)
| | - Krystyna Makowska
- Department of Clinical Diagnostics, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego 14, 10-957 Olsztyn, Poland;
- Correspondence: ; Tel.: +44-895-234-460
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Zhang Y, Zhang H, Zhang K, Li Z, Guo T, Wu T, Hou X, Feng N. Co-hybridized composite nanovesicles for enhanced transdermal eugenol and cinnamaldehyde delivery and their potential efficacy in ulcerative colitis. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2020; 28:102212. [PMID: 32334099 DOI: 10.1016/j.nano.2020.102212] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 02/16/2020] [Accepted: 04/10/2020] [Indexed: 02/06/2023]
Abstract
Percutaneous absorption of drugs can be enhanced by ethosomes, which are nanocarriers with excellent deformability and drug-loading properties. However, the ethanol within ethosomes increases phospholipid membrane fluidity and permeability, leading to drug leakage during storage. Here, we developed and characterized a new phospholipid nanovesicles that is co-hybridized with hyaluronic acid (HA), ethanol and the encapsulated volatile oil medicines (eugenol and cinnamaldehyde [EUG/CAH]) for transdermal administration. In comparison with EUG/CAH-loaded ethosomes (ES), the formulation stability and percutaneous drug absorption of EUG/CAH-loaded HA-immobilized ethosomes (HA-ES) were significantly improved. After transdermal administration of HA-ES, the interstitial cells of Cajal in the colon of rats with trinitrobenzene sulfonate-induced ulcerative colitis (UC) were significantly increased, and the stem cell factor/c-kit signaling pathway was partly repaired. Overall, HA-ES possesses excellent deformability and showed improved efficacy against UC compared with ES, which is demonstrated as a promising transdermal delivery vehicle for volatile oil medicines.
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Affiliation(s)
- Yongtai Zhang
- Department of Pharmaceutical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hongyu Zhang
- Department of Pharmaceutical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Kai Zhang
- Department of Pharmaceutical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhe Li
- Department of Pharmaceutical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Teng Guo
- Department of Pharmaceutical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tong Wu
- Department of Pharmaceutical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xuefeng Hou
- Department of Pharmaceutical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Nianping Feng
- Department of Pharmaceutical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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Seo S, Miyake H, Alganabi M, Janssen Lok M, O'Connell JS, Lee C, Li B, Pierro A. Vasoactive intestinal peptide decreases inflammation and tight junction disruption in experimental necrotizing enterocolitis. J Pediatr Surg 2019; 54:2520-2523. [PMID: 31668399 DOI: 10.1016/j.jpedsurg.2019.08.038] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 08/24/2019] [Indexed: 11/18/2022]
Abstract
BACKGROUND AND PURPOSE Excessive inflammatory cell infiltration and accumulation in the intestinal mucosa are pathological features of necrotizing enterocolitis (NEC) leading to intestinal barrier disruption. Vasoactive intestinal peptide (VIP) is a potent anti-inflammatory agent that regulates intestinal epithelial barrier homeostasis. We previously demonstrated that VIP-ergic neuron expression is decreased in experimental NEC ileum, and this may be associated with inflammation and barrier compromise. We hypothesize that exogenous VIP administration has a beneficial effect in NEC. METHODS NEC was induced in C57BL/6 mice by gavage feeding, hypoxia, and lipopolysaccharide administration between postnatal day (P) 5 and 9. There were four studied groups: Control (n = 6): Breast feeding without stress factors; Control + VIP (n = 5): Breast feeding + intraperitoneal VIP injection once a day from P5 to P9; NEC (n = 9): mice exposed to NEC induction; NEC + VIP (n = 9): NEC induction + intraperitoneal VIP injection. Terminal ileum was harvested on P9. NEC severity, intestinal inflammation, (IL-6 and TNFα), and Tight junctions (Claudin-3) were evaluated. RESULTS NEC severity and intestinal inflammation were significantly decreased in NEC + VIP compared to NEC. Tight junction expression was significantly increased in NEC + VIP compared to NEC. CONCLUSION VIP administration has a beneficial therapeutic effect in NEC by reducing inflammation and tight junction disruption.
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Affiliation(s)
- Shogo Seo
- Division of General and Thoracic Surgery, Translational Medicine Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Pediatric General and Urogenital Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Hiromu Miyake
- Division of General and Thoracic Surgery, Translational Medicine Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Pediatric Surgery, Shizuoka Children's Hospital, Shizuoka, Japan
| | - Mashriq Alganabi
- Division of General and Thoracic Surgery, Translational Medicine Program, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Maarten Janssen Lok
- Division of General and Thoracic Surgery, Translational Medicine Program, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Joshua S O'Connell
- Division of General and Thoracic Surgery, Translational Medicine Program, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Carol Lee
- Division of General and Thoracic Surgery, Translational Medicine Program, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Bo Li
- Division of General and Thoracic Surgery, Translational Medicine Program, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Agostino Pierro
- Division of General and Thoracic Surgery, Translational Medicine Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
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Wang T, Chen N, Ren W, Liu F, Gao F, Ye L, Han Y, Zhang Y, Liu Y. Integrated analysis of circRNAs and mRNAs expression profile revealed the involvement of hsa_circ_0007919 in the pathogenesis of ulcerative colitis. J Gastroenterol 2019; 54:804-818. [PMID: 31037450 DOI: 10.1007/s00535-019-01585-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 04/22/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Ulcerative colitis (UC) is characterized by chronic inflammation in the colon and epigenetic factors underlying the occurrence. Circular RNAs (circRNAs) have been under intensive focus due to the circular construct and gene-regulating functions. However, the changes and roles of circRNAs in UC remain unknown. METHODS Microarrays were used to detect the differentially expressed genes, and quantitative real-time PCR was used to identify the changes in UC. In silico analyses were performed to predict the functions of circRNAs and mRNAs. In vitro, epithelial cell lines were stimulated by pro-inflammation effectors to test the alterations in circRNAs. CircRNAs-microRNAs-mRNAs network clarified the potential mechanisms underlying circRNAs in UC. The binding site between hsa_circ_0007919 and miR-138 or let-7a was verified using dual-luciferase assay. RESULTS A total of 264 significantly dysregulated circRNAs and 1869 differentially expressed mRNAs in inflamed mucosa were compared with the non-inflamed mucosa in UC. Hsa_circ_0004662 and hsa_circ_0007919 were altered largely in UC tissues. Hsa_circ_0007919 was reduced persistently after inflammatory treatments, and it was relevant to Mayo endoscopic subscores and the expression of tight junction molecules. Finally, hsa_circ_0007919 could harbor miR-138, and let-7a to regulate the targeted mRNAs EPC1 and VIPR1. CONCLUSIONS Several circRNAs were differentially expressed in UC. Hsa_circ_0007919 is related to clinical characteristics and epithelial integrity by binding to hsa-let-7a, hsa-miR-138 to regulate the target genes. CircRNAs, especially hsa_circ_0007919, are associated with the pathogenesis and development of UC, with potential diagnostic and therapeutic implications.
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Affiliation(s)
- Tingting Wang
- Institute of Clinical Molecular Biology and Central Laboratory, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing, 100044, People's Republic of China.,Department of Gatroenterology, Peking University People's Hospital, No. 11 Xizhimen South Street, Beijing, 100044, People's Republic of China
| | - Ning Chen
- Department of Gatroenterology, Peking University People's Hospital, No. 11 Xizhimen South Street, Beijing, 100044, People's Republic of China
| | - Weixia Ren
- Institute of Clinical Molecular Biology and Central Laboratory, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing, 100044, People's Republic of China
| | - Fangfang Liu
- Department of Pathology, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing, 100044, People's Republic of China
| | - Fangfang Gao
- Institute of Clinical Molecular Biology and Central Laboratory, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing, 100044, People's Republic of China
| | - Lei Ye
- Institute of Clinical Molecular Biology and Central Laboratory, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing, 100044, People's Republic of China
| | - Ying Han
- Institute of Clinical Molecular Biology and Central Laboratory, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing, 100044, People's Republic of China
| | - Yujun Zhang
- Institute of Clinical Molecular Biology and Central Laboratory, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing, 100044, People's Republic of China.
| | - Yulan Liu
- Department of Gatroenterology, Peking University People's Hospital, No. 11 Xizhimen South Street, Beijing, 100044, People's Republic of China.
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Sun X, Guo C, Zhao F, Zhu J, Xu Y, Liu ZQ, Yang G, Zhang YY, Gu X, Xiao L, Liu Z, Yang PC. Vasoactive intestinal peptide stabilizes intestinal immune homeostasis through maintaining interleukin-10 expression in regulatory B cells. Am J Cancer Res 2019; 9:2800-2811. [PMID: 31244924 PMCID: PMC6568172 DOI: 10.7150/thno.34414] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 03/25/2019] [Indexed: 12/26/2022] Open
Abstract
Rationale: Immune dysfunction is thought to play an important role in the pathogenesis of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD). However, the underlying mechanism requires further investigation. Vasoactive intestinal peptide (VIP) has immune regulatory functions, but its role in immune regulatory activities in the intestinal mucosa is not fully understood. This study aims to elucidate the role of VIP in the regulation of regulatory B cell (Breg) function in the intestine. Methods: Peripheral blood samples were collected from UC patients and healthy control (HC) subjects. Bregs were isolated from these samples and their immune regulatory function was analyzed. A murine colitis model was established to test the role of VIP in inhibiting inflammation in the intestine. Results: Serum IL-10 and VIP levels were lower in IgE+ (≥0.35 IU/mL) UC patients than that in HC subjects. The immune suppressive function of Bregs isolated from IgE+ UC patients was impaired. IL-10 mRNA decayed spontaneously in Bregs, which was reversed by VIP added to the culture. Tristetraprolin (TTP) bound IL-10 mRNA to speed its decay, which was blocked by VIP in the culture. Administration of VIP efficiently inhibited experimental colitis. Conclusions: Insufficient VIP levels in the microenvironment speeds IL-10 mRNA decay to cause Breg dysfunction. Administration of VIP can inhibit experimental colitis, suggesting the translational potential of VIP in the treatment of IgE+ UC.
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Local delivery of macromolecules to treat diseases associated with the colon. Adv Drug Deliv Rev 2018; 136-137:2-27. [PMID: 30359631 DOI: 10.1016/j.addr.2018.10.009] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 10/10/2018] [Accepted: 10/17/2018] [Indexed: 12/15/2022]
Abstract
Current treatments for intestinal diseases including inflammatory bowel diseases, irritable bowel syndrome, and colonic bacterial infections are typically small molecule oral dosage forms designed for systemic delivery. The intestinal permeability hurdle to achieve systemic delivery from oral formulations of macromolecules is challenging, but this drawback can be advantageous if an intestinal region is associated with the disease. There are some promising formulation approaches to release peptides, proteins, antibodies, antisense oligonucleotides, RNA, and probiotics in the colon to enable local delivery and efficacy. We briefly review colonic physiology in relation to the main colon-associated diseases (inflammatory bowel disease, irritable bowel syndrome, infection, and colorectal cancer), along with the impact of colon physiology on dosage form design of macromolecules. We then assess formulation strategies designed to achieve colonic delivery of small molecules and concluded that they can also be applied some extent to macromolecules. We describe examples of formulation strategies in preclinical research aimed at colonic delivery of macromolecules to achieve high local concentration in the lumen, epithelial-, or sub-epithelial tissue, depending on the target, but with the benefit of reduced systemic exposure and toxicity. Finally, the industrial challenges in developing macromolecule formulations for colon-associated diseases are presented, along with a framework for selecting appropriate delivery technologies.
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Immunomodulatory Roles of PACAP and VIP: Lessons from Knockout Mice. J Mol Neurosci 2018; 66:102-113. [PMID: 30105629 DOI: 10.1007/s12031-018-1150-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 07/31/2018] [Indexed: 02/07/2023]
Abstract
A bidirectional cross-talk is established between the nervous and immune systems through common mediators including neuropeptides, neurotransmitters, and cytokines. Among these, PACAP and VIP are two highly related neuropeptides widely distributed in the organism with purported immunomodulatory actions. Due to their well-known anti-inflammatory properties, administration of these peptides has proven to be beneficial in models of acute and chronic inflammatory diseases. Nevertheless, the relevance of the endogenous source of these peptides in the modulation of immune responses remains to be elucidated. The development of transgenic mice with specific deletions in the genes coding for these neuropeptides (Vip and Adcyap1) or for their G-protein-coupled receptors VPAC1, VPAC2, and PAC1 (Vipr1, Vipr2, Adcyap1r1) has allowed to address this question, underscoring the complexity of the immunoregulatory properties of PACAP and VIP. The goal of this review is to integrate the existing information on the immune phenotypes of mice deficient for PACAP, VIP, or their receptors, to provide a global view on the roles of these endogenous neuropeptides during immunological health and disease.
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Xu CL, Guo Y, Qiao L, Ma L, Cheng YY. Recombinant expressed vasoactive intestinal peptide analogue ameliorates TNBS-induced colitis in rats. World J Gastroenterol 2018; 24:706-715. [PMID: 29456409 PMCID: PMC5807673 DOI: 10.3748/wjg.v24.i6.706] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 12/19/2017] [Accepted: 12/26/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the modulatory effect of recombinant-expressed vasoactive intestinal peptide (VIP) analogue (rVIPa) on trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats.
METHODS Forty-eight rats were randomized into six groups: normal control group (Control), model control group (TNBS), ethanol treatment group (ETOH), and VIP treatment groups with different dosage (rVIPa1nmol, rVIPa2nmol, rVIPa4nmol). Diarrhea and bloody stool were observed. Colonic damage was evaluated histologically. The levels of tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), myeloperoxidase (MPO) and endotoxin in colonic tissue and serum were determined by enzyme-linked immunosorbent assay (ELISA). The expression of occludin, ZO-1, Toll-like receptor 4 (TLR4), and nuclear factor-kappa B p65 (NF-κB p65), IκBα, and p-IκBα were detected by Western blot.
RESULTS Administration with 2 nmol rVIPa prevented TNBS-induced necrosis, hyperemia, swelling, inflammation, etc., pathologic changes observed in the inner surface of colon in experimental rats. Moreover, rVIPa significantly decreased colonic TNF-α level (P < 0.001), MPO activity (P < 0.001) and serum endotoxin level (P < 0.01), and remarkably increased colonic IL-10 content (P < 0.001) in rats with TNBS-induced colitis. Furthermore, compared to the TNBS-induced colitis group, 2 nmol rVIPa treatment up-regulated the levels of occludin (P < 0.05) and ZO-1 (P < 0.05), NF-κB p65 (P < 0.01) and IκBα (P < 0.001), and down-regulated the levels of TLR4.
CONCLUSION rVIPa ameliorates TNBS-induced colonic injury and inflammation and effectively protected the intestinal mucosal barrier function in rats. The mechanism may be related to TLR4/NF-κB-mediated signaling pathway. rVIPa could be used as a new alternative therapy for intestinal inflammatory disorders.
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Affiliation(s)
- Chun-Lan Xu
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, Shaanxi Province, China
| | - Yu Guo
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, Shaanxi Province, China
| | - Lei Qiao
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, Shaanxi Province, China
| | - Li Ma
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, Shaanxi Province, China
| | - Yi-Yi Cheng
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, Shaanxi Province, China
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13
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Soufflet F, Biraud M, Rolli-Derkinderen M, Lardeux B, Trang C, Coron E, Bruley des Varannes S, Bourreille A, Neunlist M. Modulation of VIPergic phenotype of enteric neurons by colonic biopsy supernatants from patients with inflammatory bowel diseases: Involvement of IL-6 in Crohn's disease. Neurogastroenterol Motil 2018; 30. [PMID: 28857361 DOI: 10.1111/nmo.13198] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 08/07/2017] [Indexed: 12/22/2022]
Abstract
BACKGROUND Neuroplastic changes in the enteric nervous system (ENS) observed during IBD might participate in physiopathological processes. Vasoactive intestinal polypeptide has been shown to be involved in intestinal inflammation and barrier functions. We aimed to investigate the modulation of VIP expression in colonic biopsies of IBD patient, the ability of soluble factors from biopsies to reproduce in vitro these modulations and identify soluble factors responsible. METHODS VIP and cytokines mRNA expressions were assessed in colonic biopsies of healthy subjects (HS) and IBD patients from inflamed (I) and non-inflamed areas (NI). Supernatants (SUP) of biopsies were applied to primary culture of ENS and VIP and cytokines mRNA expressions were assessed. The role of cytokines in SUP induced changes in VIP expression was evaluated. KEY RESULTS VIP mRNA expression was lower in biopsies of patients with Crohn's disease (CD) than Ulcerative Colitis (UC) but unchanged as compared to HS. VIP mRNA and protein expression were lower in primary culture of ENS incubated with SUP-CD than with SUP-UC. Furthermore, in CD but not UC, SUP-I reduced VIP expression in the ENS as compared to SUP-NI. Next, IL-6 but not IL-5, IL-10, IL-17, IFN-γ or TNF-α reduced VIP expression in the ENS. Finally, in CD, SUP-I incubated with anti-IL-6 antibody increased VIP expression as compared to SUP-I alone. CONCLUSIONS & INFERENCES Mucosal soluble factors from IBD induce VIP neuroplastic changes in the ENS. IL-6 was identified as a putative soluble factor responsible in part for changes in VIP expression in CD.
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Affiliation(s)
- F Soufflet
- INSERM, UMR1235, Nantes, France.,Université Nantes, Nantes, France.,Institut des Maladies de l'Appareil Digestif, CHU Nantes, Hôpital Hôtel-Dieu, Nantes, France
| | - M Biraud
- INSERM, UMR1235, Nantes, France.,Université Nantes, Nantes, France.,Institut des Maladies de l'Appareil Digestif, CHU Nantes, Hôpital Hôtel-Dieu, Nantes, France
| | - M Rolli-Derkinderen
- INSERM, UMR1235, Nantes, France.,Université Nantes, Nantes, France.,Institut des Maladies de l'Appareil Digestif, CHU Nantes, Hôpital Hôtel-Dieu, Nantes, France
| | - B Lardeux
- INSERM, UMR1235, Nantes, France.,Université Nantes, Nantes, France.,Institut des Maladies de l'Appareil Digestif, CHU Nantes, Hôpital Hôtel-Dieu, Nantes, France
| | - C Trang
- INSERM, UMR1235, Nantes, France.,Institut des Maladies de l'Appareil Digestif, CHU Nantes, Hôpital Hôtel-Dieu, Nantes, France.,CIC Inserm 1413, CHU Nantes, Hôpital Hôtel-Dieu, Nantes, France
| | - E Coron
- INSERM, UMR1235, Nantes, France.,Université Nantes, Nantes, France.,Institut des Maladies de l'Appareil Digestif, CHU Nantes, Hôpital Hôtel-Dieu, Nantes, France.,CIC Inserm 1413, CHU Nantes, Hôpital Hôtel-Dieu, Nantes, France
| | - S Bruley des Varannes
- INSERM, UMR1235, Nantes, France.,Université Nantes, Nantes, France.,Institut des Maladies de l'Appareil Digestif, CHU Nantes, Hôpital Hôtel-Dieu, Nantes, France.,CIC Inserm 1413, CHU Nantes, Hôpital Hôtel-Dieu, Nantes, France
| | - A Bourreille
- INSERM, UMR1235, Nantes, France.,Université Nantes, Nantes, France.,Institut des Maladies de l'Appareil Digestif, CHU Nantes, Hôpital Hôtel-Dieu, Nantes, France.,CIC Inserm 1413, CHU Nantes, Hôpital Hôtel-Dieu, Nantes, France
| | - M Neunlist
- INSERM, UMR1235, Nantes, France.,Université Nantes, Nantes, France.,Institut des Maladies de l'Appareil Digestif, CHU Nantes, Hôpital Hôtel-Dieu, Nantes, France
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14
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Barrenschee M, Zorenkov D, Böttner M, Lange C, Cossais F, Scharf AB, Deuschl G, Schneider SA, Ellrichmann M, Fritscher-Ravens A, Wedel T. Distinct pattern of enteric phospho-alpha-synuclein aggregates and gene expression profiles in patients with Parkinson's disease. Acta Neuropathol Commun 2017; 5:1. [PMID: 28057070 PMCID: PMC5217296 DOI: 10.1186/s40478-016-0408-2] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 12/18/2016] [Indexed: 01/16/2023] Open
Abstract
Phosphorylated alpha-synuclein (p-α-syn) containing Lewy bodies (LBs) and Lewy neurites (LNs) are neuropathological hallmarks of Parkinson’s disease (PD) in the central nervous system (CNS). Since they have been also demonstrated in the enteric nervous system (ENS) of PD patients, the aim of the study was to analyze enteric p-α-syn positive aggregates and intestinal gene expression. Submucosal rectal biopsies were obtained from patients with PD and controls and processed for dual-label-immunohistochemistry for p-α-syn and PGP 9.5. p-α-syn positive aggregates in nerve fibers and neuronal somata were subjected to a morphometric analysis. mRNA expression of α-syn and dopaminergic, serotonergic, VIP (vaso intestinal peptide) ergic, cholinergic, muscarinergic neurotransmitter systems were investigated using qPCR. Frequency of p-α-syn positive nerve fibers was comparable between PD and controls. Although neuronal p-α-syn positive aggregates were detectable in both groups, total number and area of p-α-syn positive aggregates were increased in PD patients as was the number of small and large sized aggregates. Increased expression of dopamine receptor D1, VIP and serotonin receptor 3A was observed in PD patients, while serotonin receptor 4 and muscarinic receptor 3 (M3R) were downregulated. M3R expression correlated negative with the number of small sized p-α-syn positive aggregates. The findings strengthen the hypothesis that the CNS pathology of increased p-α-syn in PD also applies to the ENS, if elaborated morphometry is applied and give further insights in altered intestinal gene expression in PD. Although the mere presence of p-α-syn positive aggregates in the ENS should not be regarded as a criterion for PD diagnosis, elaborated morphometric analysis of p-α-syn positive aggregates in gastrointestinal biopsies could serve as a suitable tool for in-vivo diagnosis of PD.
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15
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Wu X, Conlin VS, Morampudi V, Ryz NR, Nasser Y, Bhinder G, Bergstrom KS, Yu HB, Waterhouse CCM, Buchan AMJ, Popescu OE, Gibson WT, Waschek JA, Vallance BA, Jacobson K. Vasoactive intestinal polypeptide promotes intestinal barrier homeostasis and protection against colitis in mice. PLoS One 2015; 10:e0125225. [PMID: 25932952 PMCID: PMC4416880 DOI: 10.1371/journal.pone.0125225] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Accepted: 03/22/2015] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease is a chronic gastrointestinal inflammatory disorder associated with changes in neuropeptide expression and function, including vasoactive intestinal peptide (VIP). VIP regulates intestinal vasomotor and secretomotor function and motility; however, VIP's role in development and maintenance of colonic epithelial barrier homeostasis is unclear. Using VIP deficient (VIPKO) mice, we investigated VIP's role in epithelial barrier homeostasis, and susceptibility to colitis. Colonic crypt morphology and epithelial barrier homeostasis were assessed in wildtype (WT) and VIPKO mice, at baseline. Colitic responses were evaluated following dinitrobenzene sulfonic acid (DNBS) or dextran-sodium sulfate (DSS) exposure. Mice were also treated with exogenous VIP. At baseline, VIPKO mice exhibited distorted colonic crypts, defects in epithelial cell proliferation and migration, increased apoptosis, and altered permeability. VIPKO mice also displayed reduced goblet cell numbers, and reduced expression of secreted goblet cell factors mucin 2 and trefoil factor 3. These changes were associated with reduced expression of caudal type homeobox 2 (Cdx2), a master regulator of intestinal function and homeostasis. DNBS and DSS-induced colitis were more severe in VIPKO than WT mice. VIP treatment rescued the phenotype, protecting VIPKO mice against DSS colitis, with results comparable to WT mice. In conclusion, VIP plays a crucial role in the development and maintenance of colonic epithelial barrier integrity under physiological conditions and promotes epithelial repair and homeostasis during colitis.
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Affiliation(s)
- Xiujuan Wu
- Department of Pediatrics, Division of Gastroenterology, BC Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
- Child and Family Research Institute, BC Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
| | - Victoria S. Conlin
- Department of Pediatrics, Division of Gastroenterology, BC Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
- Child and Family Research Institute, BC Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
| | - Vijay Morampudi
- Department of Pediatrics, Division of Gastroenterology, BC Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
- Child and Family Research Institute, BC Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
| | - Natasha R. Ryz
- Department of Pediatrics, Division of Gastroenterology, BC Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
- Child and Family Research Institute, BC Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
| | - Yasmin Nasser
- Department of Pediatrics, Division of Gastroenterology, BC Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
- Child and Family Research Institute, BC Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
| | - Ganive Bhinder
- Department of Pediatrics, Division of Gastroenterology, BC Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
- Child and Family Research Institute, BC Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
| | - Kirk S. Bergstrom
- Department of Pediatrics, Division of Gastroenterology, BC Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
- Child and Family Research Institute, BC Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
- Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, United States of America
| | - Hong B. Yu
- Department of Pediatrics, Division of Gastroenterology, BC Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
- Child and Family Research Institute, BC Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
| | | | | | - Oana E. Popescu
- Department of Pathology, BC Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
| | - William T. Gibson
- Child and Family Research Institute, BC Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
| | - James A. Waschek
- Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, United States of America
| | - Bruce A. Vallance
- Department of Pediatrics, Division of Gastroenterology, BC Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
- Child and Family Research Institute, BC Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
| | - Kevan Jacobson
- Department of Pediatrics, Division of Gastroenterology, BC Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
- Child and Family Research Institute, BC Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada
- * E-mail:
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Chandrasekharan B, Nezami BG, Srinivasan S. Emerging neuropeptide targets in inflammation: NPY and VIP. Am J Physiol Gastrointest Liver Physiol 2013; 304:G949-57. [PMID: 23538492 PMCID: PMC3680683 DOI: 10.1152/ajpgi.00493.2012] [Citation(s) in RCA: 103] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The enteric nervous system (ENS), referred to as the "second brain," comprises a vast number of neurons that form an elegant network throughout the gastrointestinal tract. Neuropeptides produced by the ENS play a crucial role in the regulation of inflammatory processes via cross talk with the enteric immune system. In addition, neuropeptides have paracrine effects on epithelial secretion, thus regulating epithelial barrier functions and thereby susceptibility to inflammation. Ultimately the inflammatory response damages the enteric neurons themselves, resulting in deregulations in circuitry and gut motility. In this review, we have emphasized the concept of neurogenic inflammation and the interaction between the enteric immune system and enteric nervous system, focusing on neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP). The alterations in the expression of NPY and VIP in inflammation and their significant roles in immunomodulation are discussed. We highlight the mechanism of action of these neuropeptides on immune cells, focusing on the key receptors as well as the intracellular signaling pathways that are activated to regulate the release of cytokines. In addition, we also examine the direct and indirect mechanisms of neuropeptide regulation of epithelial tight junctions and permeability, which are a crucial determinant of susceptibility to inflammation. Finally, we also discuss the potential of emerging neuropeptide-based therapies that utilize peptide agonists, antagonists, siRNA, oligonucleotides, and lentiviral vectors.
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Affiliation(s)
- Bindu Chandrasekharan
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
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17
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Zacharko-Siembida A, Valverde Piedra JL, Szymańczyk S, Arciszewski MB. Immunolocalization of NOS, VIP, galanin and SP in the small intestine of suckling pigs treated with red kidney bean (Phaseolus vulgaris) lectin. Acta Histochem 2013; 115:219-25. [PMID: 22819292 DOI: 10.1016/j.acthis.2012.06.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2012] [Revised: 06/25/2012] [Accepted: 06/26/2012] [Indexed: 01/29/2023]
Abstract
Lectins belong to a family of glycoproteins that can act both beneficially and detrimentally on the morphology of the small intestine. The aim of the study was to determine whether experimental treatment with red kidney bean (Phaseolus vulgaris) lectin influences the chemical code of the small intestine nervous system of suckling pigs. The immunolocalization sites of vasoactive intestinal polypeptide (VIP), nitric oxide synthase (NOS), substance P (SP) and galanin were determined in control and lectin-treated animals. In all segments of the small intestine (duodenum, jejunum, ileum), the subpopulations of VIP-, NOS-, SP- and galanin-immunoreactive (IR) myenteric neurons were unchanged. After lectin stimulation, increased proportions of NOS-IR and decreased numbers of VIP-IR submucous neurons/mucosa innervating nerve fibers were observed in the duodenum, jejunum and ileum. In lectin-treated animals down-regulation of submucous neurons expressing SP and up-regulation of galanin-IR submucous neurons were seen in the duodenum and jejunum (but not in the ileum). The distribution patterns of NOS-IR, galanin-IR and SP-IR nerve fibers supplying the duodenum, jejunum and ileum of the lectin-treated animals showed no substantial differences in relation to control piglets. We conclude that exposure to red kidney bean (P. vulgaris) lectin substantially changes the chemical content of VIP, NOS, SP and galanin in submucous neurons of the small intestine. These results are in line with previous findings outlining the key role(s) of these substances in enteric neuroplasticity processes and may constitute the basis for further functional studies on maturation of the gut.
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Affiliation(s)
- Anna Zacharko-Siembida
- Department of Animal Anatomy and Histology, Faculty of Veterinary Medicine, University of Life Sciences, Akademicka 12, 20-033, Lublin, Poland
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