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Fan H, Shen R, Yan J, Bai Y, Fu Q, Shi X, Du G, Wang D. Pyroptosis the Emerging Link Between Gut Microbiota and Multiple Sclerosis. Drug Des Devel Ther 2024; 18:6145-6164. [PMID: 39717200 PMCID: PMC11665440 DOI: 10.2147/dddt.s489454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 12/11/2024] [Indexed: 12/25/2024] Open
Abstract
This review elucidates the pivotal role of pyroptosis, triggered by gut microbiota, in the development of multiple sclerosis (MS), emphasizing its significance within the gut-brain axis. Our comprehensive analysis of recent literature reveals how dysbiosis in the gut microbiota of MS patients-characterized by reduced microbial diversity and shifts in bacterial populations-profoundly impacts immune regulation and the integrity of the central nervous system (CNS). Pyroptosis, an inflammatory form of programmed cell death, significantly exacerbates MS by promoting the release of inflammatory cytokines and causing substantial damage to CNS tissues. The gut microbiota facilitates this detrimental process through metabolites such as short-chain fatty acids and neuroactive compounds, or self-structural products like lipopolysaccharides (LPS), which modulate immune responses and influence neuronal survival. This review highlights the potential of modulating gut microbiota to regulate pyroptosis, thereby suggesting that targeting this pathway could be a promising therapeutic strategy to mitigate inflammatory responses and preserve neuronal integrity in patients with MS.
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Affiliation(s)
- Hua Fan
- The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, 471003, People’s Republic of China
| | - Ruile Shen
- The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, 471003, People’s Republic of China
| | - Junqiang Yan
- The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, 471003, People’s Republic of China
| | - Yongjie Bai
- The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, 471003, People’s Republic of China
| | - Qizhi Fu
- The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, 471003, People’s Republic of China
| | - Xiaofei Shi
- The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, 471003, People’s Republic of China
| | - Ganqin Du
- The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, 471003, People’s Republic of China
| | - Dongmei Wang
- The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, 471003, People’s Republic of China
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Iida T, Ito Y, Murayama S, Yoshimaru Y, Tatsumi A. Relationship Between Psychological Stress Scores and Urinary 5-HT Levels Over Time Under Psychological Stress. Int J Tryptophan Res 2024; 17:11786469241297911. [PMID: 39640272 PMCID: PMC11618928 DOI: 10.1177/11786469241297911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 10/19/2024] [Indexed: 12/07/2024] Open
Abstract
Background Biomarkers for psychological stress have been examined and the "gut-microbiota-brain axis" is currently attracting attention. An intervention study reported improvements in both the intestinal environment and psychological stress. However, the relationship between psychological stress scores and urinary 5-hydroxytryptamine (u-5-HT), produced by enterochromaffin cells in the intestinal tract, has not yet been investigated over time in healthy subjects under psychological stress. Therefore, the present study examined the relationship between subjective psychological stress (depression and anxiety) scores and u-5-HT levels over time in healthy women. Methods The effects of the objective structured clinical examination (OSCE), considered to be a uniform source of psychological stress, on u-5-HT levels were assessed in 16 third-year female medical university students (21.3 ± 2.1 years old) in Japan with a normal menstrual cycle. A self-administered questionnaire consisting of Zung's Self-rating Depression Scale (SDS) and State-Trait Anxiety Inventory (STAI) was used to evaluate subjective stress 1 month, 1 week, and 1 day before and 1 week after the OSCE. Pearson's product-momentum correlation coefficient was used to calculate the correlation coefficient between u-5-HT levels, STAI, and SDS for each examined period. Result On the day before the OSCE, u-5-HT levels correlated with SDS and STAI (SDS: r = .524, P = .037, State-Anxiety: r = -.718, P = .002). Conclusion A correlation was observed between subjective psychological stress scores and u-5-HT levels in healthy women under psychological stress.
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Affiliation(s)
- Tadayuki Iida
- Department of Physical Therapy, Faculty of Health and Welfare, Prefectural University of Hiroshima, Japan
| | - Yasuhiro Ito
- Department of Medical Technology, Yokkaichi Nursing and Medical Care University, Mie, Japan
| | - Susumu Murayama
- Department of Physical Therapy, Hospital of Shiromachi, Mihara, Hiroshima, Japan
| | | | - Asami Tatsumi
- Department of Public Health, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
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Halder N, Yadav S, Lal G. Neuroimmune communication of the cholinergic system in gut inflammation and autoimmunity. Autoimmun Rev 2024; 23:103678. [PMID: 39500481 DOI: 10.1016/j.autrev.2024.103678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 11/01/2024] [Accepted: 11/01/2024] [Indexed: 11/08/2024]
Abstract
Neuroimmune communication in the body forms a bridge between two central regulatory systems of the body, i.e., nervous and immune systems. The cholinergic system is a crucial modulatory neurotransmitter in the central and peripheral nervous system. It includes the neurotransmitter acetylcholine (ACh), the enzyme required for the synthesis of ACh (choline acetyltransferase, ChAT), the enzyme required for its degradation (acetylcholinesterase, AChE), and cholinergic receptors (Nicotinic acetylcholine receptors and muscarinic acetylcholine receptors). The cholinergic system in neurons is well known for its role in cognitive function, sensory perception, motor control, learning, and memory processes. It has been shown that the non-neuronal cholinergic system (NNCS) is present in various tissues and immune cells and forms a neuroimmune communications system. In the present review, we discussed the NNCS on immune cells, its role in homeostasis and inflammatory reactions in the gut, and how it can be exploited in treating inflammatory responses.
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Affiliation(s)
- Namrita Halder
- Biotechnology Research and Innovation Council-National Centre for Cell Science (BRIC-NCCS), SPPU campus, Ganeshkhind, Pune, MH-411007, India
| | - Sourabh Yadav
- Biotechnology Research and Innovation Council-National Centre for Cell Science (BRIC-NCCS), SPPU campus, Ganeshkhind, Pune, MH-411007, India
| | - Girdhari Lal
- Biotechnology Research and Innovation Council-National Centre for Cell Science (BRIC-NCCS), SPPU campus, Ganeshkhind, Pune, MH-411007, India.
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El-Abasy HM, Elsaid MEA, Abdelkader EM, Shehatou GSG. Metformin's cardioprotective role in isoprenaline-induced myocardial infarction: Unveiling insights into the AMPK, NF-κB, JAK2/STAT3 pathways, and cholinergic regulation. Life Sci 2024; 357:123115. [PMID: 39369846 DOI: 10.1016/j.lfs.2024.123115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 10/02/2024] [Accepted: 10/03/2024] [Indexed: 10/08/2024]
Abstract
AIM Despite advancements in treatment modalities, myocardial infarction (MI) remains a significant global cause of mortality and morbidity. Metformin (MET), a commonly used antidiabetic medication, has demonstrated potential in various cardioprotective mechanisms. This study investigated whether MET could alleviate the histopathological, electrocardiographic, and molecular consequences of MI in rats. MATERIALS AND METHODS The study hypothesis was tested using an isoprenaline (ISOP)-induced MI model, where male Wistar rats were injected with ISOP (85 mg/kg/day, s.c., for 2 days) and treated with MET at the doses of 500 and 1000 mg/kg/day for 18 days or left untreated. KEY FINDINGS ISOP-treated rats exhibited several indicators of MI, including significant ST-segment depression and prolonged QT-intervals on ECGs, worsened left ventricular histopathology with increased inflammatory cell infiltration, reduced expression of cardiac CHRM2, a cardioprotective cholinergic receptor, adaptive increases in AMPK and α7nAchR levels, and elevated levels of iNOS, NO, STAT3, JAK2, IL-6, TNF-α, and NF-κB. These effects were attenuated in rats treated with either low or high doses of MET. MET administration restored normal ECG recordings, diminished oxidative stress and inflammatory mediators, and downregulated NF-κB expression. Moreover, MET improved CHRM2 expression and normalized α7nAchR levels. Additionally, MET influenced the expression of key signaling molecules such as Akt, STAT3, and JAK2. SIGNIFICANCE These findings might suggest that MET exerts cardioprotective effects in ISOP-induced MI in rats by mitigating critical inflammatory signaling pathways and regulating protective cholinergic mechanisms in the heart.
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Affiliation(s)
- Hamsa M El-Abasy
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, International Coastal Road, Gamasa, Dakahliya, Egypt
| | - Mahmoud E A Elsaid
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, International Coastal Road, Gamasa, Dakahliya, Egypt.
| | - Eman M Abdelkader
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, International Coastal Road, Gamasa, Dakahliya, Egypt
| | - George S G Shehatou
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, International Coastal Road, Gamasa, Dakahliya, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Dakahliya, Egypt
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Sun Z, Liu C, Huang L, Bo L, Li X, Lv C, Li J, Yang J, Zhao Y. The efficacy of preemptive multimodal analgesia in elderly patients undergoing laparoscopic colorectal surgery: a randomized controlled trial. Sci Rep 2024; 14:25438. [PMID: 39455612 PMCID: PMC11511970 DOI: 10.1038/s41598-024-75720-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 10/08/2024] [Indexed: 10/28/2024] Open
Abstract
Objective To evaluate the effectiveness of preemptive multimodal analgesiain elderly patients undergoing laparoscopic colorectal surgery. Methods A prospective randomized controlled study was conducted in the Department of Gastrointestinal Surgery of the Second Hospital of Hebei Medical University from January 2022 to December 2022. A total of 133 patients were included according to the criteria and randomly divided into preemptive analgesia (PRA) group (test group, 67patients) and postoperative analgesia (POA) group (control group, 66patients). Results The Visual Analog Scale (VAS)scores of PRA group 24 h, 48 h, and 72 h after operation were lower than those of POA group, and the difference was statistically significant, P < 0.001.The incidences of postoperative gastrointestinal dysfunction (POGD) and postoperative delirium (POD)in PRA group were 13.43% and 8.98%, respectively, which were significantly lower than those in POA group (31.82% and 24.24%), P < 0.05. The levels of IL-6 and IL-10 in PRA group after the operation were 17.54 ± 2.13 ng/L and 15.57 ± 1.71 ng/L respectively, which were lower than those in POA group (25.45 ± 2.95 ng/L and 23.45 ± 1.88 ng/L), P < 0.05. The level of acetylcholinesterase(AchE) was 56.34 ± 5.62 nmol/L in the POA group, which was significantly higher than that in the POA group (49.59 ± 5.52 nmol/L), P < 0.001. Conclusion Preemptive multimodal analgesia can reduce the incidence of POGD and POD in elderly patients undergoing laparoscopic gastrocolic surgery, improve the recovery process of postoperative gastrointestinal function, increase the concentrations of propionic acid and butyric acid in short chain fatty acids (SCFAs) and the number of beneficial intestinal bacteria.
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Affiliation(s)
- Zhangnan Sun
- Department of Anesthesiology, the Second Hospital of Hebei Medical University, NO 215Heping West Road, Shijiazhuang, Hebei, 050000, China
| | - Chaolei Liu
- Department of Anesthesiology, the Second Hospital of Hebei Medical University, NO 215Heping West Road, Shijiazhuang, Hebei, 050000, China.
| | - Lining Huang
- Department of Anesthesiology, the Second Hospital of Hebei Medical University, NO 215Heping West Road, Shijiazhuang, Hebei, 050000, China
| | - Lijun Bo
- Department of Anesthesiology, the Second Hospital of Hebei Medical University, NO 215Heping West Road, Shijiazhuang, Hebei, 050000, China
| | - Xuze Li
- Department of Anesthesiology, the Second Hospital of Hebei Medical University, NO 215Heping West Road, Shijiazhuang, Hebei, 050000, China
| | - Chang Lv
- Department of Anesthesiology, the Second Hospital of Hebei Medical University, NO 215Heping West Road, Shijiazhuang, Hebei, 050000, China
| | - Jin Li
- Department of Anesthesiology, the Second Hospital of Hebei Medical University, NO 215Heping West Road, Shijiazhuang, Hebei, 050000, China
| | - Jiaojiao Yang
- Department of Anesthesiology, the Second Hospital of Hebei Medical University, NO 215Heping West Road, Shijiazhuang, Hebei, 050000, China
| | - Yue Zhao
- Department of Anesthesiology, the Second Hospital of Hebei Medical University, NO 215Heping West Road, Shijiazhuang, Hebei, 050000, China
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Zhou Y, Yin ZH, Sun MS, Wang YY, Yang C, Li SH, Liang FR, Liu F. Global research trends in postoperative ileus from 2011 to 2023: A scientometric study. World J Gastrointest Surg 2024; 16:3020-3031. [PMID: 39351552 PMCID: PMC11438810 DOI: 10.4240/wjgs.v16.i9.3020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 08/13/2024] [Accepted: 08/22/2024] [Indexed: 09/18/2024] Open
Abstract
BACKGROUND Postoperative ileus (POI) is a common complication after abdominal surgery with high morbidity, which hinders patient recovery, prolongs hospitalization, and increases healthcare costs. Therefore, POI has become a global public health challenge. POI triggering is multifactorial. Autonomic and hormonal mechanisms are generally involved in POI pathogenesis. Recent studies have shown that beta adrenergic signaling of enteric glia is a POI trigger. Currently, the status quo, trends, and frontiers of global research on POI remain unclear. AIM To explore the current status, trends, and frontiers of POI research from 2011 to the present based on bibliometric analysis. METHODS Publications published on POI research from 2011 to 2023 were retrieved on June 1, 2023, from the Web of Science Core Collection. CiteSpace 6.2.R2 and VOSviewer were used to conduct bibliometric visualization. RESULTS In total, 778 POI records published from 2011 to 2023 were retrieved. Over the past few decades, the annual cumulative number of related articles has linearly increased, with China and the United States of America contributing prominently. All publications were from 59 countries and territories. China and the University of Bonn were the top contributing country and institution, respectively. Neurogastroenterology & Motility was the most prolific journal. The Journal of Gastrointestinal Surgery had the highest number of citations. Wehner Sven was the most productive author. Burst keywords (e.g., colon, prolonged ileus, acupuncture, paralytic ileus, pathophysiology, rectal cancer, gastrointestinal function, risk) and a series of reference citation bursts provided evidence for the research frontiers in recent years. CONCLUSION This study demonstrates trends in the published literature on POI and provides new insights for researchers. It emphasizes the importance of multidisciplinary cooperation in the development of this field.
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Affiliation(s)
- Yan Zhou
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Zi-Han Yin
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Ming-Sheng Sun
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Yang-Yang Wang
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Chen Yang
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Shu-Hao Li
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Fan-Rong Liang
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Fang Liu
- Department of Integrated Chinese and Western Medicine, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610041, Sichuan Province, China
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Bor S, Kalkan İH, Savarino E, Rao S, Tack J, Pasricha J, Cangemi D, Schol J, Karunaratne T, Ghisa M, Ahuja NK, Lacy B. Prokinetics-safety and efficacy: The European Society of Neurogastroenterology and Motility/The American Neurogastroenterology and Motility Society expert review. Neurogastroenterol Motil 2024; 36:e14774. [PMID: 38462678 DOI: 10.1111/nmo.14774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 02/02/2024] [Accepted: 02/13/2024] [Indexed: 03/12/2024]
Abstract
BACKGROUND Prokinetics are a class of pharmacological drugs designed to improve gastrointestinal (GI) motility, either regionally or across the whole gut. Each drug has its merits and drawbacks, and based on current evidence as high-quality studies are limited, we have no clear recommendation on one class or other. However, there remains a large unmet need for both regionally selective and/or globally acting prokinetic drugs that work primarily intraluminally and are safe and without systemic side effects. PURPOSE Here, we describe the strengths and weaknesses of six classes of prokinetic drugs, including their pharmacokinetic properties, efficacy, safety and tolerability and potential indications.
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Affiliation(s)
- Serhat Bor
- Division of Gastroenterology, School of Medicine & Ege Reflux Study Group, Ege University, Izmir, Turkey
| | - İsmail H Kalkan
- Department of Gastroenterology, School of Medicine, TOBB University of Economics and Technology, Ankara, Turkey
| | - Edoardo Savarino
- Gastroenterology Unit, Azienda Ospedale Università di Padova (AOUP), Padua, Italy
| | - Satish Rao
- Division of Gastroenterology and Hepatology, Digestive Health Center, Augusta University, Augusta, Georgia, USA
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium
| | - Jay Pasricha
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland, USA
| | - David Cangemi
- Division of Gastroenterology & Hepatology, Mayo Clinic, Jacksonville, Florida, USA
| | - Jolien Schol
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - Tennekon Karunaratne
- Division of Gastroenterology/Hepatology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Matteo Ghisa
- Digestive Endoscopy Unit, Division of Gastroenterology, Padua University Hospital, Padua, Italy
| | - Nitin K Ahuja
- Division of Gastroenterology, Penn Medicine, Philadelphia, Pennsylvania, USA
| | - Brian Lacy
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
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Liu S, Fu W, Fu J, Chen G, He Y, Zheng T, Ma T. Electroacupuncture alleviates intestinal inflammation via a distinct neuro-immune signal pathway in the treatment of postoperative ileus. Biomed Pharmacother 2024; 173:116387. [PMID: 38471276 DOI: 10.1016/j.biopha.2024.116387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 02/29/2024] [Accepted: 03/06/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND The induction of intestinal inflammation as a result of abdominal surgery is an essential factor in postoperative ileus (POI) development. Electroacupuncture (EA) at ST36 has been demonstrated to relieve intestinal inflammation and restore gastrointestinal dysmotility in POI. This study aims to elucidate the neuroimmune pathway involved in the anti-inflammatory properties of EA in POI. METHODS After intestinal manipulation (IM) was performed to induce POI, intestinal inflammation and motility were assessed 24 h post-IM, by evaluating gastrointestinal transit (GIT), cytokines expression, and leukocyte infiltration. Experimental surgery, pharmacological intervention, and genetic knockout mice were used to elucidate the neuroimmune mechanisms of EA. RESULTS EA at ST36 significantly improved GIT and reduced the expression of pro-inflammatory cytokines and leukocyte infiltration in the intestinal muscularis following IM in mice. The anti-inflammatory effectiveness of EA treatment was abolished by sub-diaphragmatic vagotomy, whereas splenectomy did not hinder the anti-inflammatory benefits of EA treatment. The hexamethonium chloride (HEX) administration contributes to a notable reduction in the EA capacity to suppress inflammation and enhance motility dysfunction, and EA is ineffective in α7 nicotinic acetylcholine receptor (α7nAChR) knockout mice. CONCLUSIONS EA at ST36 prevents intestinal inflammation and dysmotility through a neural circuit that requires vagal innervation but is independent of the spleen. Further findings revealed that the process involves enteric neurons mediating the vagal signal and requires the presence of α7nAChR. These findings suggest that utilizing EA at ST36 may represent a possible therapeutic approach for POI and other immune-related gastrointestinal diseases.
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Affiliation(s)
- Shuchang Liu
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin 300052, China
| | - Wei Fu
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin 300052, China
| | - Jingnan Fu
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin 300052, China; Department of Minimally Invasive Surgery, Characteristics Medical Center of Chinese People Armed Police Force, Tianjin 300162, China
| | - Guibing Chen
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin 300052, China; Department of Gastrointestinal Surgery, Clinical Medical College and The First Affilliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610500, China
| | - Yuxin He
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin 300052, China
| | - Ting Zheng
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin 300052, China
| | - Tao Ma
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin 300052, China.
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9
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Jun S, Oh S, Jung JE, Kwon IG, Noh SH. A randomized controlled study to assess the effect of mosapride citrate on intestinal recovery following gastrectomy. Sci Rep 2024; 14:7030. [PMID: 38528113 PMCID: PMC10963721 DOI: 10.1038/s41598-024-57870-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Accepted: 03/22/2024] [Indexed: 03/27/2024] Open
Abstract
The enhanced recovery after surgery (ERAS) protocol, including prokinetic medications, is commonly used to prevent postoperative ileus. Prospective studies evaluating the effectiveness of mosapride citrate, a prokinetic 5-hydroxytryptamine 4 receptor agonist, in patients undergoing gastrectomy within the ERAS framework are lacking. This double-blind randomized trial included patients who were scheduled for laparoscopic or robotic gastrectomy for gastric cancer. Participants were randomly assigned to either a control (placebo) or experimental (mosapride citrate) group, with drugs administered on postoperative days 1-5. Bowel motility was evaluated based on bowel transit time measured using radiopaque markers, first-flatus time, and amount of food intake. No significant differences were observed in baseline characteristics between the two groups. On postoperative day 3, no significant difference was observed in the number of radiopaque markers visible in the colon between the groups. All factors associated with bowel recovery, including the time of first flatus, length of hospital stay, amount of food intake, and severity of abdominal discomfort, were similar between the two groups. Mosapride citrate does not benefit the recovery of intestinal motility after minimally invasive gastrectomy in patients with gastric cancer. Therefore, routine postoperative use of mosapride citrate is not recommended in such patients.
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Affiliation(s)
- Shiyeol Jun
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Seyeol Oh
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Ji Eun Jung
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - In Gyu Kwon
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
| | - Sung Hoon Noh
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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Stavely R, Robinson AM, Fraser S, Filippone RT, Stojanovska V, Eri R, Apostolopoulos V, Sakkal S, Nurgali K. Bone marrow-derived mesenchymal stem cells mitigate chronic colitis and enteric neuropathy via anti-inflammatory and anti-oxidative mechanisms. Sci Rep 2024; 14:6649. [PMID: 38503815 PMCID: PMC10951223 DOI: 10.1038/s41598-024-57070-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 03/14/2024] [Indexed: 03/21/2024] Open
Abstract
Current treatments for inflammatory bowel disease (IBD) are often inadequate due to limited efficacy and toxicity, leading to surgical resection in refractory cases. IBD's broad and complex pathogenesis involving the immune system, enteric nervous system, microbiome, and oxidative stress requires more effective therapeutic strategies. In this study, we investigated the therapeutic potential of bone marrow-derived mesenchymal stem cell (BM-MSC) treatments in spontaneous chronic colitis using the Winnie mouse model which closely replicates the presentation and inflammatory profile of ulcerative colitis. The 14-day BM-MSC treatment regimen reduced the severity of colitis, leading to the attenuation of diarrheal symptoms and recovery in body mass. Morphological and histological abnormalities in the colon were also alleviated. Transcriptomic analysis demonstrated that BM-MSC treatment led to alterations in gene expression profiles primarily downregulating genes related to inflammation, including pro-inflammatory cytokines, chemokines and other biomarkers of inflammation. Further evaluation of immune cell populations using immunohistochemistry revealed a reduction in leukocyte infiltration upon BM-MSC treatment. Notably, enteric neuronal gene signatures were the most impacted by BM-MSC treatment, which correlated with the restoration of neuronal density in the myenteric ganglia. Moreover, BM-MSCs exhibited neuroprotective effects against oxidative stress-induced neuronal loss through antioxidant mechanisms, including the reduction of mitochondrial-derived superoxide and attenuation of oxidative stress-induced HMGB1 translocation, potentially relying on MSC-derived SOD1. These findings suggest that BM-MSCs hold promise as a therapeutic intervention to mitigate chronic colitis by exerting anti-inflammatory effects and protecting the enteric nervous system from oxidative stress-induced damage.
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Affiliation(s)
- Rhian Stavely
- Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Ainsley M Robinson
- Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia
| | - Sarah Fraser
- Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia
| | | | - Vanesa Stojanovska
- Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Rajaraman Eri
- School of Science, STEM College, RMIT University, Melbourne, VIC, Australia
| | - Vasso Apostolopoulos
- Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia
- Immunology Program, Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC, Australia
| | - Samy Sakkal
- Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia
| | - Kulmira Nurgali
- Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia.
- Department of Medicine Western Health, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia.
- Regenerative Medicine and Stem Cells Program, Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC, Australia.
- Enteric Neuropathy Lab, Western Centre for Health, Research and Education, St Albans, VIC, 3021, Australia.
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11
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Raouf Z, Steinway SN, Scheese D, Lopez CM, Duess JW, Tsuboi K, Sampah M, Klerk D, El Baassiri M, Moore H, Tragesser C, Prindle T, Wang S, Wang M, Jang HS, Fulton WB, Sodhi CP, Hackam DJ. Colitis-Induced Small Intestinal Hypomotility Is Dependent on Enteroendocrine Cell Loss in Mice. Cell Mol Gastroenterol Hepatol 2024; 18:53-70. [PMID: 38438014 PMCID: PMC11127033 DOI: 10.1016/j.jcmgh.2024.02.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 02/23/2024] [Accepted: 02/26/2024] [Indexed: 03/06/2024]
Abstract
BACKGROUND & AIMS The abdominal discomfort experienced by patients with colitis may be attributable in part to the presence of small intestinal dysmotility, yet mechanisms linking colonic inflammation with small-bowel motility remain largely unexplored. We hypothesize that colitis results in small intestinal hypomotility owing to a loss of enteroendocrine cells (EECs) within the small intestine that can be rescued using serotonergic-modulating agents. METHODS Male C57BL/6J mice, as well as mice that overexpress (EECOVER) or lack (EECDEL) NeuroD1+ enteroendocrine cells, were exposed to dextran sulfate sodium (DSS) colitis (2.5% or 5% for 7 days) and small intestinal motility was assessed by 70-kilodalton fluorescein isothiocyanate-dextran fluorescence transit. EEC number and differentiation were evaluated by immunohistochemistry, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining, and quantitative reverse-transcriptase polymerase chain reaction. Mice were treated with the 5-hydroxytryptamine receptor 4 agonist prucalopride (5 mg/kg orally, daily) to restore serotonin signaling. RESULTS DSS-induced colitis was associated with a significant small-bowel hypomotility that developed in the absence of significant inflammation in the small intestine and was associated with a significant reduction in EEC density. EEC loss occurred in conjunction with alterations in the expression of key serotonin synthesis and transporter genes, including Tph1, Ddc, and Slc6a4. Importantly, mice overexpressing EECs revealed improved small intestinal motility, whereas mice lacking EECs had worse intestinal motility when exposed to DSS. Finally, treatment of DSS-exposed mice with the 5-hydroxytryptamine receptor 4 agonist prucalopride restored small intestinal motility and attenuated colitis. CONCLUSIONS Experimental DSS colitis induces significant small-bowel dysmotility in mice owing to enteroendocrine loss that can be reversed by genetic modulation of EEC or administering serotonin analogs, suggesting novel therapeutic approaches for patients with symptomatic colitis.
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Affiliation(s)
- Zachariah Raouf
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Steve N Steinway
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Daniel Scheese
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Carla M Lopez
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Johannes W Duess
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Koichi Tsuboi
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Maame Sampah
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Daphne Klerk
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Mahmoud El Baassiri
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Hannah Moore
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Cody Tragesser
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Thomas Prindle
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Sanxia Wang
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Menghan Wang
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Hee-Seong Jang
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - William B Fulton
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Chhinder P Sodhi
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - David J Hackam
- Division of Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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12
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Duan WQ, Cai MC, Ma QQ, Huang P, Zhang JH, Wei TF, Shang D, Leng AJ, Qu JL. Exploring the chemical components of Kuanchang-Shu granule and its protective effects of postoperative ileus in rats by regulating AKT/HSP90AA1/eNOS pathway. Chin Med 2024; 19:29. [PMID: 38383512 PMCID: PMC10880223 DOI: 10.1186/s13020-024-00892-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 01/21/2024] [Indexed: 02/23/2024] Open
Abstract
BACKGROUND Postoperative ileus (POI) is a common obstruction of intestinal content passage caused by almost all abdominal operations that seriously strokes the quality of life of patients. Kuanchang-Shu granule (KCSG), a classic modified prescription based on "Da-Cheng-Qi Decoction", has obtained satisfactory efficacy in the clinical therapeutics of POI. However, its material basis and holistic molecular mechanism against POI have not been revealed. METHODS The chemical ingredients of KCSG were first characterized by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS). Subsequently, an integration strategy of the network pharmacology and molecular docking based on above identified ingredients was performed to unveil the potential targets involved in the treatment of KCSG on POI. Finally, intestinal manipulation induced rat POI model was constructed to verify the efficacy and predicted mechanism of KCSG against POI. RESULTS In total, 246 ingredients mainly including organic acids, flavonoids, quinones, alkaloids, terpenoids, phenylpropanoids and phenols were identified. 41 essential ingredients, 24 crucial targets as well as 15 relevant signaling pathways were acquired based on network pharmacology analysis. Pharmacodynamic research showed that KCSG treatment could protect intestinal histological damage, promote the recovery of measurement of gastrointestinal transit disorder and inhibit the secretion of myeloperoxidase in the distal ileum tissues. The up-regulated expression of p-AKT and down-regulated expression of p-eNOS and HSP9OAA1 predicted by molecular docking and validated by western blotting showed that AKT/eNOS/HSP90AA1 pathway may be one of the crucial mechanisms that mediates the protective effect of KCSG.
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Affiliation(s)
- Wen-Qian Duan
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, No. 222, Zhongshan Road, Dalian, 116011, China
- Institute (College) of Integrative Medicine, Dalian Medical University, No. 9, South Road of Lvshun, Dalian, 116044, China
| | - Ming-Chen Cai
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Dalian Medical University, No. 222, Zhongshan Road, Dalian, 116011, China
| | - Qi-Qi Ma
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, No. 222, Zhongshan Road, Dalian, 116011, China
| | - Peng Huang
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, No. 222, Zhongshan Road, Dalian, 116011, China
- Institute (College) of Integrative Medicine, Dalian Medical University, No. 9, South Road of Lvshun, Dalian, 116044, China
| | - Jia-Hui Zhang
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, No. 222, Zhongshan Road, Dalian, 116011, China
- Institute (College) of Integrative Medicine, Dalian Medical University, No. 9, South Road of Lvshun, Dalian, 116044, China
| | - Tian-Fu Wei
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, No. 222, Zhongshan Road, Dalian, 116011, China
- Institute (College) of Integrative Medicine, Dalian Medical University, No. 9, South Road of Lvshun, Dalian, 116044, China
| | - Dong Shang
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, No. 222, Zhongshan Road, Dalian, 116011, China
- Institute (College) of Integrative Medicine, Dalian Medical University, No. 9, South Road of Lvshun, Dalian, 116044, China
| | - Ai-Jing Leng
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Dalian Medical University, No. 222, Zhongshan Road, Dalian, 116011, China.
| | - Jia-Lin Qu
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, No. 222, Zhongshan Road, Dalian, 116011, China.
- Institute (College) of Integrative Medicine, Dalian Medical University, No. 9, South Road of Lvshun, Dalian, 116044, China.
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13
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Rahman AA, Stavely R, Pan W, Ott L, Ohishi K, Ohkura T, Han C, Hotta R, Goldstein AM. Optogenetic Activation of Cholinergic Enteric Neurons Reduces Inflammation in Experimental Colitis. Cell Mol Gastroenterol Hepatol 2024; 17:907-921. [PMID: 38272444 PMCID: PMC11026705 DOI: 10.1016/j.jcmgh.2024.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 01/16/2024] [Accepted: 01/17/2024] [Indexed: 01/27/2024]
Abstract
BACKGROUND & AIMS Intestinal inflammation is associated with loss of enteric cholinergic neurons. Given the systemic anti-inflammatory role of cholinergic innervation, we hypothesized that enteric cholinergic neurons similarly possess anti-inflammatory properties and may represent a novel target to treat inflammatory bowel disease. METHODS Mice were fed 2.5% dextran sodium sulfate (DSS) for 7 days to induce colitis. Cholinergic enteric neurons, which express choline acetyltransferase (ChAT), were focally ablated in the midcolon of ChAT::Cre;R26-iDTR mice by local injection of diphtheria toxin before colitis induction. Activation of enteric cholinergic neurons was achieved using ChAT::Cre;R26-ChR2 mice, in which ChAT+ neurons express channelrhodopsin-2, with daily blue light stimulation delivered via an intracolonic probe during the 7 days of DSS treatment. Colitis severity, ENS structure, and smooth muscle contractility were assessed by histology, immunohistochemistry, quantitative polymerase chain reaction, organ bath, and electromyography. In vitro studies assessed the anti-inflammatory role of enteric cholinergic neurons on cultured muscularis macrophages. RESULTS Ablation of ChAT+ neurons in DSS-treated mice exacerbated colitis, as measured by weight loss, colon shortening, histologic inflammation, and CD45+ cell infiltration, and led to colonic dysmotility. Conversely, optogenetic activation of enteric cholinergic neurons improved colitis, preserved smooth muscle contractility, protected against loss of cholinergic neurons, and reduced proinflammatory cytokine production. Both acetylcholine and optogenetic cholinergic neuron activation in vitro reduced proinflammatory cytokine expression in lipopolysaccharide-stimulated muscularis macrophages. CONCLUSIONS These findings show that enteric cholinergic neurons have an anti-inflammatory role in the colon and should be explored as a potential inflammatory bowel disease treatment.
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Affiliation(s)
- Ahmed A Rahman
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Rhian Stavely
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Weikang Pan
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Leah Ott
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Kensuke Ohishi
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Drug Discovery Laboratory, Wakunaga Pharmaceuticals Company, Ltd, Akitakata, Hiroshima, Japan
| | - Takahiro Ohkura
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Christopher Han
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Ryo Hotta
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Allan M Goldstein
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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14
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Zhou L, Lian H, Yin Y, Zheng YS, Han YX, Liu GQ, Wang ZY. New insights into muscularis macrophages in the gut: from their origin to therapeutic targeting. Immunol Res 2023; 71:785-799. [PMID: 37219708 DOI: 10.1007/s12026-023-09397-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 05/15/2023] [Indexed: 05/24/2023]
Abstract
Muscularis macrophages, as the most abundant immune cells in the intestinal muscularis externa, exhibit tissue protective phenotype in the steady state. Owing to tremendous advances in technology, we now know the fact that muscularis macrophages are a heterogeneous population of cells which could be divided into different functional subsets depending on their anatomic niches. There is emerging evidence showing that these subsets, through molecular interactions with their neighbours, take part in a wide range of physiological and pathophysiological processes in the gut. In this review, we summarize recent progress (particularly over the past 4 years) on distribution, morphology, origin and functions of muscularis macrophages and, where possible, the characteristics of specific subsets in response to the microenvironment they occupy, with particular emphasis on their role in muscular inflammation. Furthermore, we also integrate their role in inflammation-related gastrointestinal disorders, such as post-operative ileus and diabetic gastroparesis, in order to propose future therapeutic strategies.
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Affiliation(s)
- Li Zhou
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
- Xinxiang Key Laboratory of Molecular Neurology, Xinxiang Medical University, Xinxiang, 453003, China
| | - Hui Lian
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
- Xinxiang Key Laboratory of Molecular Neurology, Xinxiang Medical University, Xinxiang, 453003, China
| | - Yue Yin
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Yuan-Sheng Zheng
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Yu-Xin Han
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Gao-Qi Liu
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Zhi-Yong Wang
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.
- Xinxiang Key Laboratory of Molecular Neurology, Xinxiang Medical University, Xinxiang, 453003, China.
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15
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Hamed K, El-Fiky SA, M Gawish A, R H Mohamed H, Khalil WKB, Huang X, Hasan M, Zafar A, Caprioli G. Assessing the Efficacy of Fenugreek Saponin Nanoparticles in Attenuating Nicotine-Induced Hepatotoxicity in Male Rats. ACS OMEGA 2023; 8:42722-42731. [PMID: 38024695 PMCID: PMC10653053 DOI: 10.1021/acsomega.3c05526] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 09/14/2023] [Indexed: 12/01/2023]
Abstract
During smoking, nicotine, the most bountiful compound in cigarettes, is absorbed into the body by the lungs and quickly metabolized in the liver, causing three major adverse impacts such as toxic, neoplastic, and immunomodulatory effects. Saponins extracted from several plants are reported to exhibit various biological actions, such as anticancer effects. So, the potential protective effect of fenugreek saponin and nanofenugreek saponin against toxicity induced by nicotine in male rats was investigated in this study. Animals were exposed to nicotine (1.5 mg/kg/day) and/or treated with fenugreek saponin (25, 50, and 100 mg/kg/day) and nanofenugreek saponin (20, 40, and 80 mg/kg/day). Comet assays, histopathological examination, and analyses for the expression levels of glutamate aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) genes in liver tissues as well as the activity of glutathione peroxidase (GPx) and glutathione-S-transferase (GST) were conducted. The results revealed that nicotine treatment induced a significant increase in DNA damage, decrease in the expression levels of (GLAST) and (GLT-1) genes, and increase in histopathological alterations in liver tissues. Moreover, nicotine treatment induced a significant reduction in the activity of antioxidant enzymes GPx and GST. On the other hand, administration of fenugreek saponin or nanofenugreek saponin with nicotine significantly decreased the DNA damage, increased the expression levels of (GLAST) and (GLT-1) genes, and decreased histopathological alterations in liver tissues. Additionally, a significant increase in the activities of GPx and GST was observed. The results suggested that DNA damage and histological injuries induced by nicotine were decreased by the administration of fenugreek saponin or nanofenugreek saponin; thus, fenugreek saponin and nanofenugreek saponin can be used as ameliorative agents against nicotine toxicity.
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Affiliation(s)
- Karima
A. Hamed
- Department
of Cell Biology, National Research Centre, 33 El-Bohous St, 12622 Dokki, Giza, P.O. 12622, Egypt
| | - Saima A. El-Fiky
- Department
of Cell Biology, National Research Centre, 33 El-Bohous St, 12622 Dokki, Giza, P.O. 12622, Egypt
| | - Azza M Gawish
- Department
of Zoology, Faculty of Science, Cairo University, Cairo 12622, Giza, Egypt
| | - Hanan R H Mohamed
- Department
of Zoology, Faculty of Science, Cairo University, Cairo 12622, Giza, Egypt
| | - Wagdy K. B. Khalil
- Department
of Zoology, Faculty of Science, Cairo University, Cairo 12622, Giza, Egypt
| | - Xue Huang
- School
of Chemistry and Chemical Engineering, Zhongkai
University of Agriculture and Engineering, Guangzhou 510225, P. R. China
| | - Murtaza Hasan
- Faculty
of Biological and Chemical Science, Department of Biotechnology, The Islamia University of Bahawalpur, Punjab 63100, Pakistan
- School
of Chemistry and Chemical Engineering, Zhongkai
University of Agriculture and Engineering, Guangzhou 510225, P. R. China
| | - Ayesha Zafar
- Department
of Biomedical Engineering, College of Future Technology, Peking University, Beijing 510225, P. R. China
| | - Giovanni Caprioli
- Chemistry
Interdisciplinary Project (CHip), School of Pharmacy, University of Camerino, Camerino 62032, Italy
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16
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van Baarle L, Stakenborg M, Matteoli G. Enteric neuro-immune interactions in intestinal health and disease. Semin Immunol 2023; 70:101819. [PMID: 37632991 DOI: 10.1016/j.smim.2023.101819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 07/19/2023] [Accepted: 08/11/2023] [Indexed: 08/28/2023]
Abstract
The enteric nervous system is an autonomous neuronal circuit that regulates many processes far beyond the peristalsis in the gastro-intestinal tract. This circuit, consisting of enteric neurons and enteric glial cells, can engage in many intercellular interactions shaping the homeostatic microenvironment in the gut. Perhaps the most well documented interactions taking place, are the intestinal neuro-immune interactions which are essential for the fine-tuning of oral tolerance. In the context of intestinal disease, compelling evidence demonstrates both protective and detrimental roles for this bidirectional neuro-immune signaling. This review discusses the different immune cell types that are recognized to engage in neuronal crosstalk during intestinal health and disease. Highlighting the molecular pathways involved in the neuro-immune interactions might inspire novel strategies to target intestinal disease.
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Affiliation(s)
- Lies van Baarle
- Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat 49, O&N1 box 701, 3000 Leuven, Belgium
| | - Michelle Stakenborg
- Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat 49, O&N1 box 701, 3000 Leuven, Belgium
| | - Gianluca Matteoli
- Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat 49, O&N1 box 701, 3000 Leuven, Belgium.
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17
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Ma T, Xue X, Tian H, Zhou X, Wang J, Zhao Z, Wang M, Song J, Feng R, Li L, Jing C, Tian F. Effect of the gut microbiota and their metabolites on postoperative intestinal motility and its underlying mechanisms. J Transl Med 2023; 21:349. [PMID: 37237321 DOI: 10.1186/s12967-023-04215-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 05/19/2023] [Indexed: 05/28/2023] Open
Abstract
Gut microbiota is closely related to human health and disease because, together with their metabolites, gut microbiota maintain normal intestinal peristalsis. The use of antibiotics or opioid anesthetics, or both, during surgical procedures can lead to dysbiosis and affect intestinal motility; however, the underlying mechanisms are not fully known. This review aims to discuss the effect of gut microbiota and their metabolites on postoperative intestinal motility, focusing on regulating the enteric nervous system, 5-hydroxytryptamine neurotransmitter, and aryl hydrocarbon receptor.
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Affiliation(s)
- TianRong Ma
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - XiaoLei Xue
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
- Department of Pharmacy, The Second Affiliated Hospital of Shandong First Medical University, Taian, 271000, China
| | - Hui Tian
- Department of Gastroenterology, Liaocheng People's Hospital, Shandong First Medical University, Liaocheng, 252000, China
| | - XinXiu Zhou
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - JunKe Wang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - ZhiWen Zhao
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - MingFei Wang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China
| | - JiYuan Song
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China
| | - RenXiang Feng
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China
| | - Leping Li
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China
| | - Changqing Jing
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China.
| | - Feng Tian
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China.
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18
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Feng J, Xie Z, Hu H. Ion channel regulation of gut immunity. J Gen Physiol 2022; 155:213734. [PMID: 36459135 PMCID: PMC9723512 DOI: 10.1085/jgp.202113042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 08/15/2022] [Accepted: 11/17/2022] [Indexed: 12/03/2022] Open
Abstract
Mounting evidence indicates that gastrointestinal (GI) homeostasis hinges on communications among many cellular networks including the intestinal epithelium, the immune system, and both intrinsic and extrinsic nerves innervating the gut. The GI tract, especially the colon, is the home base for gut microbiome which dynamically regulates immune function. The gut's immune system also provides an effective defense against harmful pathogens entering the GI tract while maintaining immune homeostasis to avoid exaggerated immune reaction to innocuous food and commensal antigens which are important causes of inflammatory disorders such as coeliac disease and inflammatory bowel diseases (IBD). Various ion channels have been detected in multiple cell types throughout the GI tract. By regulating membrane properties and intracellular biochemical signaling, ion channels play a critical role in synchronized signaling among diverse cellular components in the gut that orchestrates the GI immune response. This work focuses on the role of ion channels in immune cells, non-immune resident cells, and neuroimmune interactions in the gut at the steady state and pathological conditions. Understanding the cellular and molecular basis of ion channel signaling in these immune-related pathways and initial testing of pharmacological intervention will facilitate the development of ion channel-based therapeutic approaches for the treatment of intestinal inflammation.
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Affiliation(s)
- Jing Feng
- Department of Anesthesiology, The Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO,Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai, China,Correspondence to Jing Feng:
| | - Zili Xie
- Department of Anesthesiology, The Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO
| | - Hongzhen Hu
- Department of Anesthesiology, The Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO,Hongzhen Hu:
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19
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Hussain Z, Park H. Inflammation and Impaired Gut Physiology in Post-operative Ileus: Mechanisms and the Treatment Options. J Neurogastroenterol Motil 2022; 28:517-530. [PMID: 36250359 PMCID: PMC9577567 DOI: 10.5056/jnm22100] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/08/2022] [Accepted: 08/31/2022] [Indexed: 11/20/2022] Open
Abstract
Post-operative ileus (POI) is the transient cessation of coordinated gastrointestinal motility after abdominal surgical intervention. It decreases quality of life, prolongs length of hospital stay, and increases socioeconomic costs. The mechanism of POI is complex and multifactorial, and has been broadly categorized into neurogenic and inflammatory phase. Neurogenic phase mediated release of corticotropin-releasing factor (CRF) plays a central role in neuroinflammation, and affects both central autonomic response as well hypothalamic-pituitary-adrenal (HPA) axis. HPA-stress axis associated cortisol release adversely affects gut microbiota and permeability. Peripheral CRF (pCRF) is a key player in stress induced gastric emptying and colonic transit. It functions as a local effector and interacts with the CRF receptors on the mast cell to release chemical mediators of inflammation. Mast cells proteases disrupt epithelial barrier via protease activated receptor-2 (PAR-2). PAR-2 facilitates cytoskeleton contraction to reorient tight junction proteins such as occludin, claudins, junctional adhesion molecule, and zonula occludens-1 to open epithelial barrier junctions. Barrier opening affects the selectivity, and hence permeation of luminal antigens and solutes in the gastrointestinal tract. Translocation of luminal antigens perturbs mucosal immune system to further exacerbate inflammation. Stress induced dysbiosis and decrease in production of short chain fatty acids add to the inflammatory response and barrier disintegration. This review discusses potential mechanisms and factors involved in the pathophysiology of POI with special reference to inflammation and interlinked events such as epithelial barrier dysfunction and dysbiosis. Based on this review, we recommend CRF, mast cells, macrophages, and microbiota could be targeted concurrently for efficient POI management.
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Affiliation(s)
- Zahid Hussain
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Hyojin Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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20
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Hatamnejad MR, Baradaran Ghavami S, Shirvani M, Asghari Ahmadabad M, Shahrokh S, Farmani M, Sherkat G, Asadzadeh Aghdaei H, Zali MR. Selective serotonin reuptake inhibitors and inflammatory bowel disease; Beneficial or malpractice. Front Immunol 2022; 13:980189. [PMID: 36275739 PMCID: PMC9583131 DOI: 10.3389/fimmu.2022.980189] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 09/22/2022] [Indexed: 11/21/2022] Open
Abstract
IBD, a chronic inflammatory disease, has been manifested as a growing health problem. No Crohn's and Colitis councils have officially ratified anti-depressants as a routine regimen for IBD patients. However, some physicians empirically prescribe them to rectify functional bowel consequences such as pain and alleviate psychiatric comorbidities. On the other side, SSRIs' prescription is accompanied by adverse effects such as sleep disturbances. Prolonged intermittent hypoxia throughout sleep disturbance such as sleep apnea provokes periodic reductions in the partial oxygen pressure gradient in the gut lumen. It promotes gut microbiota to dysbiosis, which induces intestinal inflammation. This phenomenon and evidence representing the higher amount of serotonin associated with Crohn's disease challenged our previous knowledge. Can SSRIs worsen the IBD course? Evidence answered the question with the claim on anti-inflammatory properties (central and peripheral) of SSRIs and illuminated the other substantial elements (compared to serotonin elevation) responsible for IBD pathogenesis. However, later clinical evidence was not all in favor of the benefits of SSRIs. Hence, in this review, the molecular mechanisms and clinical evidence are scrutinized and integrated to clarify the interfering molecular mechanism justifying both supporting and disproving clinical evidence. Biphasic dose-dependent serotonin behavior accompanying SSRI shifting function when used up for the long-term can be assumed as the parameters leading to IBD patients' adverse outcomes. Despite more research being needed to elucidate the effect of SSRI consumption in IBD patients, periodic prescriptions of SSRIs at monthly intervals can be recommended.
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Affiliation(s)
- Mohammad Reza Hatamnejad
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shaghayegh Baradaran Ghavami
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Marzieh Shirvani
- Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Shabnam Shahrokh
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Farmani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ghazal Sherkat
- Medicine Faculty of Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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21
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Pan PK, Wu TM, Tsai HY, Cho IC, Tseng HW, Lin TD, Nan FH, Wu YS. Acid external and internal environment exchange the Oreochromis niloticus tissue immune gene expression compared to the mouse macrophage polarization model. Front Immunol 2022; 13:1012078. [PMID: 36225935 PMCID: PMC9549756 DOI: 10.3389/fimmu.2022.1012078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 08/30/2022] [Indexed: 11/13/2022] Open
Abstract
The water environment plays an important role in animal physiology. In this study, we sought to evaluate the effect of the acid environment on the Oreochromis niloticus (Nile tilapia) internal microenvironment immune response compare to the mouse macrophage model (J77A.1). The acid environment treated mouse macrophage J774A.1 model have shown that acidic treatment is able to polarize macrophages into M2-like macrophages via an increase in Ym1, Tgm2, Arg1, Fizz1, and IL-10 expression. Metabolic analysis of mouse macrophages (J774A.1) at pH 2 vs. pH 7 and pH 4 vs. pH 7 have been shown to promote the expression of intracellular acetylcholine, choline, prochlorperazine, L-leucine, and bisphenol A,2-amino-3-methylimidazo[4,5-f] quinolone metabolites in the M2-like macrophage. Immune gene expression of the O. niloticus spleen and liver treated at pH 2, 4, and 7 was shown to reduce TNF-α, IL-1 β, IL-8, and IL-12 expression compared to pH 7 treatment. Immune gene was induced in O. niloticus following culture at pH 5, 6, and 7 fresh water environment. Taken together, we found that the acid internal environment polarizes tissues into an M2 macrophage developmental microenvironment. However, if the external environment is acid, tissues are exposed to an M1 macrophage developmental microenvironment.
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Affiliation(s)
- Po-Kai Pan
- Department of Aquaculture, National Pingtung University of Science and Technology, Pingtung, Taiwan
| | - Tsung-Meng Wu
- Department of Aquaculture, National Pingtung University of Science and Technology, Pingtung, Taiwan
| | - Hsin-Yuan Tsai
- Department of Aquaculture, National Pingtung University of Science and Technology, Pingtung, Taiwan
| | - I-Cheng Cho
- Department of Aquaculture, National Pingtung University of Science and Technology, Pingtung, Taiwan
| | - Hsin-Wei Tseng
- Department of Aquaculture, National Pingtung University of Science and Technology, Pingtung, Taiwan
| | - Tai-Du Lin
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, United States
| | - Fan-Hua Nan
- Department of Aquaculture, National Taiwan Ocean University, Keelung, Taiwan
| | - Yu-Sheng Wu
- Department of Aquaculture, National Pingtung University of Science and Technology, Pingtung, Taiwan
- *Correspondence: Yu-Sheng Wu,
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22
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Sui C, Tao L, Bai C, Shao L, Miao J, Chen K, Wang M, Hu Q, Wang F. Molecular and cellular mechanisms underlying postoperative paralytic ileus by various immune cell types. Front Pharmacol 2022; 13:929901. [PMID: 35991871 PMCID: PMC9385171 DOI: 10.3389/fphar.2022.929901] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 06/29/2022] [Indexed: 11/13/2022] Open
Abstract
Postoperative ileus (POI) is a well-known complication following gut manipulation or surgical trauma, leading to an impaired gut motility and prolonged postoperative recovery time. Few current therapeutic strategies can prevent POI, and this disorder remains to be a major clinical challenge for patients undergoing surgery. Comprehensive understanding of cellular and molecular mechanisms related to the pathogenesis of POI stimulates the discovery of more promising targets for treatment. POI is closely associated with a series of inflammatory events within the bowel wall, and as key components of inflammatory mechanisms, different types of immune cells, including macrophages, dendritic cells, and T lymphocytes, play significant roles during the development of POI. A variety of immune cells are recruited into the manipulation sites after surgery, contributing to early inflammatory events or impaired gut motility. Our review intends to summarize the specific relationship between different immune cells and POI, mainly focusing on the relevant mechanisms underlying this disorder.
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Affiliation(s)
- Chao Sui
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Medical School of Nanjing University, Nanjing, China
| | - Liang Tao
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Chunhua Bai
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Medical School of Nanjing University, Nanjing, China
| | - Lihua Shao
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Ji Miao
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Kai Chen
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Medical School of Nanjing University, Nanjing, China
| | - Meng Wang
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- *Correspondence: Meng Wang, ; Qiongyuan Hu, ; Feng Wang,
| | - Qiongyuan Hu
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Medical School of Nanjing University, Nanjing, China
- *Correspondence: Meng Wang, ; Qiongyuan Hu, ; Feng Wang,
| | - Feng Wang
- Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- *Correspondence: Meng Wang, ; Qiongyuan Hu, ; Feng Wang,
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23
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Wei L, Singh R, Ghoshal UC. Enterochromaffin Cells-Gut Microbiota Crosstalk: Underpinning the Symptoms, Pathogenesis, and Pharmacotherapy in Disorders of Gut-Brain Interaction. J Neurogastroenterol Motil 2022; 28:357-375. [PMID: 35719046 PMCID: PMC9274469 DOI: 10.5056/jnm22008] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/16/2022] [Accepted: 04/04/2022] [Indexed: 11/20/2022] Open
Abstract
Disorders of gut-brain interaction (DGBIs) are common conditions in community and clinical practice. As specialized enteroendocrine cells, enterochromaffin (EC) cells produce up to 95% of total body serotonin and coordinate luminal and basolateral communication in the gastrointestinal (GI) tract. EC cells affect a broad range of gut physiological processes, such as motility, absorption, secretion, chemo/mechanosensation, and pathologies, including visceral hypersensitivity, immune dysfunction, and impaired gastrointestinal barrier function. We aim to review EC cell and serotonin-mediated physiology and pathophysiology with particular emphasis on DGBIs. We explored the knowledge gap and attempted to suggest new perspectives of physiological and pathophysiological insights of DGBIs, such as (1) functional heterogeneity of regionally distributed EC cells throughout the entire GI tract; (2) potential pathophysiological mechanisms mediated by EC cell defect in DGBIs; (3) cellular and molecular mechanisms characterizing EC cells and gut microbiota bidirectional communication; (4) differential modulation of EC cells through GI segment-specific gut microbiota; (5) uncover whether crosstalk between EC cells and (i) luminal contents; (ii) enteric nervous system; and (iii) central nervous system are core mechanisms modulating gut-brain homeostasis; and (6) explore the therapeutic modalities for physiological and pathophysiological mechanisms mediated through EC cells. Insights discussed in this review will fuel the conception and realization of pathophysiological mechanisms and therapeutic clues to improve the management and clinical care of DGBIs.
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Affiliation(s)
- Lai Wei
- Enteric NeuroScience Program, Mayo Clinic, Rochester, MN, USA
| | - Rajan Singh
- Department of Physiology and Cell Biology, University of Nevada, Reno, School of Medicine, NV, USA
| | - Uday C Ghoshal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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24
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Serafini MA, Paz AH, Nunes NS. Cholinergic immunomodulation in inflammatory bowel diseases. Brain Behav Immun Health 2022; 19:100401. [PMID: 34977822 PMCID: PMC8683952 DOI: 10.1016/j.bbih.2021.100401] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 11/29/2021] [Accepted: 12/04/2021] [Indexed: 12/28/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are chronic intestinal disorders characterized by dysregulated immune responses to resident microbiota in genetically susceptible hosts. The activation of the cholinergic system has been proposed for the treatment of IBD patients according to its potential anti-inflammatory effect in vivo. The α-7-nicotinic-acetylcholine receptor (α7nAChR) is involved in the inhibition of inflammatory processes, modulating the production of cytokines, suppressing dendritic cells and macrophage activity, leading to the suppression of T cells. In this review, we address the most recent studies and clinical trials concerning cholinergic signaling and its therapeutic potential for inflammatory bowel diseases.
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Affiliation(s)
- Michele A. Serafini
- Biological Sciences, Physiology Graduate Program, Federal University of Rio Grande do Sul, 90050170, Porto Alegre, Brazil
- Cells, Tissue and Genes Laboratory, Experimental Research Center, Hospital de Clinicas de Porto Alegre, 90035903, Porto Alegre, Brazil
| | - Ana H. Paz
- Morphological Sciences Department, Basic Health Sciences Institute, Federal University of Rio Grande do Sul, 90050170, Porto Alegre, Brazil
- Cells, Tissue and Genes Laboratory, Experimental Research Center, Hospital de Clinicas de Porto Alegre, 90035903, Porto Alegre, Brazil
| | - Natalia S. Nunes
- Experimental Transplantation Immunotherapy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 20852, Bethesda, MD, USA
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25
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Buscail E, Deraison C. Postoperative Ileus: a Pharmacological Perspective. Br J Pharmacol 2022; 179:3283-3305. [PMID: 35048360 DOI: 10.1111/bph.15800] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 12/31/2021] [Accepted: 01/05/2022] [Indexed: 11/29/2022] Open
Abstract
Post-operative ileus (POI) is a frequent complication after abdominal surgery. The consequences of POI can be potentially serious such as bronchial inhalation or acute functional renal failure. Numerous advances in peri-operative management, particularly early rehabilitation, have made it possible to decrease POI. Despite this, the rate of prolonged POI ileus remains high and can be as high as 25% of patients in colorectal surgery. From a pathophysiological point of view, POI has two phases, an early neurological phase and a later inflammatory phase, to which we could add a "pharmacological" phase during which analgesic drugs, particularly opiates, play a central role. The aim of this review article is to describe the phases of the pathophysiology of POI, to analyse the pharmacological treatments currently available through published clinical trials and finally to discuss the different research areas for potential pharmacological targets.
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Affiliation(s)
- Etienne Buscail
- IRSD, INSERM, INRAE, ENVT, University of Toulouse, CHU Purpan (University Hospital Centre), Toulouse, France.,Department of digestive surgery, colorectal surgery unit, Toulouse University Hospital, Toulouse, France
| | - Céline Deraison
- IRSD, INSERM, INRAE, ENVT, University of Toulouse, CHU Purpan (University Hospital Centre), Toulouse, France
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26
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Endo M, Oikawa T, Tonooka M, Hanawa T, Odaguchi H, Hori M. Hangekobokuto, a traditional Japanese herbal medicine, ameliorates postoperative ileus through its anti-inflammatory action. J Smooth Muscle Res 2022; 58:78-88. [PMID: 36216552 PMCID: PMC9537061 DOI: 10.1540/jsmr.58.78] [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] [Indexed: 11/07/2022] Open
Abstract
Background/Aims: Gastroprokinetic agents are used for patients with
postoperative ileus (POI), and the Japanese traditional herbal medicine daikenchuto (DKT)
is one such agent used in the clinical setting. POI is caused by inflammation. DKT and
rikkunshito have anti-inflammatory abilities in addition to their gastroprokinetic
effects. The efficacy of Kampo formulations, including hangekobokuto (HKT), in patients
with POI has been reported recently. Several authors have described the efficacy of
honokiol, the primary component of Magnoliae Cortex, in HKT in mouse
models of POI. We therefore analyzed the effect of HKT on POI model mice to determine the
similarities in the mechanism of action between HKT and DKT. Methods: HKT was administered orally to each mouse before and after
intestinal manipulation was performed on the distal ileum. The gastrointestinal transit
in vivo, leukocyte infiltration, and levels of inflammatory mediators,
such as cytokines and chemokines, were analyzed. Results: HKT significantly inhibited the infiltration of neutrophils and
macrophages and led to the recovery of delayed intestinal transit. In addition, it
significantly decreased inducible nitric oxide synthase (iNOS) as well as honokiol levels,
suggesting anti-inflammatory activity. However, it did not inhibit the increase in levels
of interleukin (IL)-1beta and IL-6, which are related to iNOS induction. In contrast, HKT
increased levels of nerve growth factor (NGF) and suppressed those of nuclear factor-κB
(NFκB), which are related to iNOS induction, suggesting the possibility of a neuronal
anti-inflammatory mechanism. Conclusions: HKT exerted a POI-relieving effect similar to DKT in a murine
POI model, and findings suggest that it may exert its anti-inflammatory activity through
NGF.
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Affiliation(s)
- Mari Endo
- Department of Clinical Research, Oriental Medicine Research
Center, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan
| | - Tetsuro Oikawa
- Center for Kampo Medicine, Tokyo Medical University Hospital,
6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
| | - Miki Tonooka
- Graduate School of Infection Control Sciences, Kitasato
University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan
| | - Toshihiko Hanawa
- Department of Clinical Research, Oriental Medicine Research
Center, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan
| | - Hiroshi Odaguchi
- Department of Clinical Research, Oriental Medicine Research
Center, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan,Oriental Medicine, Doctoral Program of Medical Science,
Kitasato University Graduate School, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642,
Japan
| | - Masatoshi Hori
- Department of Veterinary Pharmacology, Graduate School of
Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo
113-8657, Japan
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27
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Zhou L, Zheng LF, Zhang XL, Wang ZY, Yao YS, Xiu XL, Liu CZ, Zhang Y, Feng XY, Zhu JX. Activation of α7nAChR Protects Against Gastric Inflammation and Dysmotility in Parkinson's Disease Rats. Front Pharmacol 2021; 12:793374. [PMID: 34880768 PMCID: PMC8646045 DOI: 10.3389/fphar.2021.793374] [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: 10/12/2021] [Accepted: 11/03/2021] [Indexed: 12/14/2022] Open
Abstract
The cholinergic anti-inflammatory pathway (CAIP) has been proposed to regulate gastrointestinal inflammation via acetylcholine released from the vagus nerve activating α7 nicotinic receptor (α7nAChR) on macrophages. Parkinson’s disease (PD) patients and PD rats with substantia nigra (SN) lesions exhibit gastroparesis and a decayed vagal pathway. To investigate whether activating α7nAChR could ameliorate inflammation and gastric dysmotility in PD rats, ELISA, western blot analysis, and real-time PCR were used to detect gastric inflammation. In vitro and in vivo gastric motility was investigated. Proinflammatory mediator levels and macrophage numbers were increased in the gastric muscularis of PD rats. α7nAChR was located on the gastric muscular macrophages of PD rats. The α7nAChR agonists PNU-282987 and GTS-21 decreased nuclear factor κB (NF-κB) activation and monocyte chemotactic protein-1 mRNA expression in the ex vivo gastric muscularis of PD rats, and these effects were abolished by an α7nAChR antagonist. After treatment with PNU-282987 in vivo, the PD rats showed decreased NF-κB activation, inflammatory mediator production, and contractile protein expression and improved gastric motility. The present study reveals that α7nAChR is involved in the development of gastroparesis in PD rats and provides novel insight for the treatment of gastric dysmotility in PD patients.
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Affiliation(s)
- Li Zhou
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.,Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Li-Fei Zheng
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xiao-Li Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Zhi-Yong Wang
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Yuan-Sheng Yao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xiao-Lin Xiu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Chen-Zhe Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yue Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xiao-Yan Feng
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Jin-Xia Zhu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
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28
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Liu C, Wang T, Kang R, Huang L, Sun Z. Effect of multimodal preemptive analgesia on postoperative gastrointestinal function and clinical outcome in patients undergoing laparoscopic colorectal surgery. Int J Clin Pract 2021; 75:e14881. [PMID: 34529887 DOI: 10.1111/ijcp.14881] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 09/05/2021] [Accepted: 09/15/2021] [Indexed: 11/26/2022] Open
Abstract
OBJECTIVE This study aimed to investigate the effects of multimodal preemptive analgesia on postoperative gastrointestinal function and clinical outcomes in patients undergoing laparoscopic colorectal surgery. METHODS This prospective study included a total of 108 patients undergoing elective laparoscopic colorectal surgery from June 2019 to June 2020. The patients were divided into the control group and the study group according to the random number table method. Patients in the study group were given flurbiprofen axetil and oxycodone before skin incision combined with bilateral transverse abdominis plane block (TAPB) before anaesthesia induction. In the control group, patients were given sufentanil and flurbiprofen axetil combined with bilateral TAPB in postanaesthesia care unit (PACU). The incidence of postoperative gastrointestinal dysfunction (POGD), I-FEED score, inflammatory factor levels, rehabilitation indicators, postoperative pain assessment and other organ complications were observed and compared between the two groups. RESULTS The incidence of POGD in the study group was lower compared to the control group, and the difference was statistically significant (P < .05). The study group had lower total and mean scores of I-FEED at 24, 48, 72 and 96 hours after surgery; however, the differences were not statistically significant (P > .05). On the first and third day after operation, Lipopolysaccharide (LPS), C-reactive protein (CRP), Tumour necrosis factor (TNF-α) and Interleukins6 (IL-6) levels of the study group decreased significantly (P < .05). The reduction in inflammation factor levels from 1d to 3d was significantly greater than that of the control group (P < .05). CONCLUSION The strategy of multimodal preemptive analgesia can effectively prevent the onset of POGD and may accelerate rehabilitation. In short, multimodal preemptive analgesia provides a novel prevention strategy for patients undergoing laparoscopic colorectal surgery.
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Affiliation(s)
- Chaolei Liu
- Department of Anesthesiology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Tianlong Wang
- Department of Anesthesiology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Rongtian Kang
- Department of Anesthesiology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Lingning Huang
- Department of Anesthesiology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Zhangnan Sun
- Department of Anesthesiology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
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29
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Kim GM, Sohn HJ, Choi WS, Sohn UD. Improved motility in the gastrointestinal tract of a postoperative ileus rat model with ilaprazole. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2021; 25:507-515. [PMID: 34697261 PMCID: PMC8552821 DOI: 10.4196/kjpp.2021.25.6.507] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 07/06/2021] [Accepted: 08/02/2021] [Indexed: 11/15/2022]
Abstract
Postoperative ileus (POI), a symptom that occurs after abdominal surgery, reduces gastrointestinal motility. Although its mechanism is unclear, POI symptoms are known to be caused by inflammation 6 to 72 h after surgery. As proton pump inhibitors exhibit protective effect against acute inflammation, the purpose of this study was to determine the effect of ilaprazole on a POI rat model. POI was induced in rats by abdominal surgery. Rats were divided into six groups: control: normal rat + 0.5% CMC-Na, vehicle: POI rat + 0.5% CMC-Na, mosapride: POI rat + mosapride 2 mg/kg, ilaprazole 1 mg/kg: POI rat + ilaprazole 1 mg/kg, ilaprazole 3 mg/kg: POI rat + ilaprazole 3 mg/kg, and ilaprazole 10 mg/kg: POI rat + ilaprazole 10 mg/kg. Gastrointestinal motility was confirmed by measuring gastric emptying (GE) and gastrointestinal transit (GIT). In the small intestine, inflammation was confirmed by measuring TNF-α and IL-1β; oxidative stress was confirmed by SOD, GSH, and MDA levels; and histological changes were observed by H&E staining. Based on the findings, GE and GIT were decreased in the vehicle group and improved in the ilaprazole 10 mg/kg group. In the ilaprazole 10 mg/kg group, TNF-α and IL-1β levels were decreased, SOD and GSH levels were increased, and MDA levels were decreased. Histological damage was also reduced in the ilaprazole-treated groups. These findings suggest that ilaprazole prevents the decrease in gastrointestinal motility, a major symptom of postoperative ileus, and reduces inflammation and oxidative stress.
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Affiliation(s)
- Geon Min Kim
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 06974, Korea
| | - Hee Ju Sohn
- Department of Surgery, Chung-Ang University Hospital, Chung-Ang University, Seoul 06973, Korea
| | - Won Seok Choi
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 06974, Korea
| | - Uy Dong Sohn
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 06974, Korea
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30
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Kim YM, Hussain Z, Lee YJ, Park H. Altered Intestinal Permeability and Drug Repositioning in a Post-operative Ileus Guinea Pig Model. J Neurogastroenterol Motil 2021; 27:639-649. [PMID: 34642285 PMCID: PMC8521477 DOI: 10.5056/jnm21018] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 06/04/2021] [Accepted: 08/17/2021] [Indexed: 11/22/2022] Open
Abstract
Background/Aims The aim of this study is to identify the alteration in intestinal permeability with regard to the development of post-operative ileus (POI). Moreover, we investigated drug repositioning in the treatment of POI. Methods An experimental POI model was developed using guinea pigs. To measure intestinal permeability, harvested intestinal membranes of the ileum and proximal colon was used in an Ussing chamber. To identify the mechanisms associated with altered permeability, we measured leukocyte count and expression of calprotectin, claudin-1, claudin-2, and mast cell tryptase. We compared control, POI, and drug groups (mosapride [0.3 mg/kg and 1 mg/kg, orally], glutamine [500 mg/kg, orally], or ketotifen [1 mg/kg, orally] with regard to these parameters. Results Increased permeability after surgery significantly decreased after administration of mosapride, glutamine, or ketotifen. Leukocyte counts increased in the POI group and decreased significantly after administration of mosapride (0.3 mg/kg) in the ileum, and mosapride (0.3 mg/kg and 1 mg/kg), glutamine, or ketotifen in the proximal colon. Increased expression of calprotectin after surgery decreased after administration of mosapride (0.3 mg/kg), glutamine, or ketotifen in the ileum and proximal colon, and mosapride (1 mg/kg) in the ileum. The expression of claudin-1 decreased significantly and that of claudin-2 increased after operation. After administration of glutamine, the expression of both proteins was restored. Finally, mast cell tryptase levels increased in the POI group and decreased significantly after administration of ketotifen. Conclusions The alteration in intestinal permeability is one of the factors involved in the pathogenesis of POI. We repositioned 3 drugs (mosapride, glutamine, and ketotifen) as novel therapeutic agents for POI.
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Affiliation(s)
- Young Min Kim
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Zahid Hussain
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Young Ju Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hyojin Park
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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31
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Wells CI, Milne TGE, Seo SHB, Chapman SJ, Vather R, Bissett IP, O'Grady G. Post-operative ileus: definitions, mechanisms and controversies. ANZ J Surg 2021; 92:62-68. [PMID: 34676664 DOI: 10.1111/ans.17297] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 10/04/2021] [Accepted: 10/05/2021] [Indexed: 12/13/2022]
Abstract
Post-operative ileus (POI) is a syndrome of impaired gastrointestinal transit which occurs following abdominal surgery. There are few effective targeted therapies for ileus, and research has been limited by inconsistent definitions and an incomplete understanding of the underlying pathophysiology. Despite considerable effort, there remains no widely-adopted definition of ileus, and recent work has identified variation in outcome reporting is a major source of heterogeneity in clinical trials. Outcomes should be clearly-defined, clinically-relevant, and reflective of the underlying biology, impacts on hospital resources and quality of life. Further collaborative efforts will be needed to develop consensus definitions and a core outcome set for postoperative gastrointestinal recovery. Investigation into the pathophysiology of POI has been hindered by use of low-resolution techniques and difficulties linking cellular mechanisms to dysmotility patterns and clinical symptoms. Recent evidence has suggested the common assumption of post-operative GI paralysis is incorrect, and that the distal colon becomes hyperactive following surgery. The post-operative inflammatory response is important in the pathophysiology of ileus, but the time course of this in humans remains unclear, with the majority of evidence coming from animal models. Future work should investigate dysmotility patterns underlying ileus, and identify biomarkers which may be used to diagnose, monitor and stratify patients with ileus.
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Affiliation(s)
- Cameron I Wells
- Department of Surgery, The University of Auckland, Auckland, New Zealand
| | - Tony G E Milne
- Department of Surgery, The University of Auckland, Auckland, New Zealand.,Department of Surgery, Counties Manukau District Health Board, Auckland, New Zealand
| | - Sean Ho Beom Seo
- Department of Surgery, The University of Auckland, Auckland, New Zealand
| | | | - Ryash Vather
- Department of Surgery, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Ian P Bissett
- Department of Surgery, The University of Auckland, Auckland, New Zealand.,Department of Surgery, Auckland District Health Board, Auckland, New Zealand
| | - Greg O'Grady
- Department of Surgery, The University of Auckland, Auckland, New Zealand.,Department of Surgery, Auckland District Health Board, Auckland, New Zealand.,Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
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Stavely R, Abalo R, Nurgali K. Targeting Enteric Neurons and Plexitis for the Management of Inflammatory Bowel Disease. Curr Drug Targets 2021; 21:1428-1439. [PMID: 32416686 DOI: 10.2174/1389450121666200516173242] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 01/11/2020] [Accepted: 01/22/2020] [Indexed: 12/12/2022]
Abstract
Ulcerative colitis (UC) and Crohn's disease (CD) are pathological conditions with an unknown aetiology that are characterised by severe inflammation of the intestinal tract and collectively referred to as inflammatory bowel disease (IBD). Current treatments are mostly ineffective due to their limited efficacy or toxicity, necessitating surgical resection of the affected bowel. The management of IBD is hindered by a lack of prognostic markers for clinical inflammatory relapse. Intestinal inflammation associates with the infiltration of immune cells (leukocytes) into, or surrounding the neuronal ganglia of the enteric nervous system (ENS) termed plexitis or ganglionitis. Histological observation of plexitis in unaffected intestinal regions is emerging as a vital predictive marker for IBD relapses. Plexitis associates with alterations to the structure, cellular composition, molecular expression and electrophysiological function of enteric neurons. Moreover, plexitis often occurs before the onset of gross clinical inflammation, which may indicate that plexitis can contribute to the progression of intestinal inflammation. In this review, the bilateral relationships between the ENS and inflammation are discussed. These include the effects and mechanisms of inflammation-induced enteric neuronal loss and plasticity. Additionally, the role of enteric neurons in preventing antigenic/pathogenic insult and immunomodulation is explored. While all current treatments target the inflammatory pathology of IBD, interventions that protect the ENS may offer an alternative avenue for therapeutic intervention.
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Affiliation(s)
- Rhian Stavely
- Department of Pediatric Surgery, Pediatric Surgery Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA,Institute for Health and Sport, Victoria University; Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, Victoria, Australia
| | - Raquel Abalo
- Área de Farmacología y Nutrición, Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos (URJC), 28922 Alcorcón, Spain,Unidad Asociada I+D+i del Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas
(CSIC), Madrid, Spain,High Performance Research Group in Physiopathology and Pharmacology of the Digestive System NeuGut-URJC
| | - Kulmira Nurgali
- Institute for Health and Sport, Victoria University; Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, Victoria, Australia,Department of Medicine Western Health, Faculty of Medicine, Dentistry and Health Sciences,
The University of Melbourne, Melbourne, Victoria, Australia,Regenerative Medicine and Stem Cells Program, Australian Institute for Musculoskeletal Science (AIMSS), Melbourne, Victoria, Australia
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Buchmann Godinho D, da Silva Fiorin F, Schneider Oliveira M, Furian AF, Rechia Fighera M, Freire Royes LF. The immunological influence of physical exercise on TBI-induced pathophysiology: Crosstalk between the spleen, gut, and brain. Neurosci Biobehav Rev 2021; 130:15-30. [PMID: 34400178 DOI: 10.1016/j.neubiorev.2021.08.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/04/2021] [Accepted: 08/08/2021] [Indexed: 12/16/2022]
Abstract
Traumatic brain injury (TBI) is a non-degenerative and non-congenital insult to the brain and is recognized as a global public health problem, with a high incidence of neurological disorders. Despite the causal relationship not being entirely known, it has been suggested that multiorgan inflammatory response involving the autonomic nervous system and the spleen-gut brain axis dysfunction exacerbate the TBI pathogenesis in the brain. Thus, applying new therapeutic tools, such as physical exercise, have been described in the literature to act on the immune modulation induced by brain injuries. However, there are caveats to consider when interpreting the effects of physical exercise on this neurological injury. Given the above, this review will highlight the main findings of the literature involving peripheral immune responses in TBI-induced neurological damage and how changes in the cellular metabolism of the spleen-gut brain axis elicited by different protocols of physical exercise alter the pathophysiology induced by this neurological injury.
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Affiliation(s)
- Douglas Buchmann Godinho
- Laboratório de Bioquímica do Exercício, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil; Programa de Pós-Graduação em Bioquímica Toxicológica, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
| | - Fernando da Silva Fiorin
- Programa de Pós-Graduação em Neuroengenharia, Instituto Internacional de Neurociências Edmond e Lily Safra, Instituto Santos Dumont, Macaíba, RN, Brazil
| | - Mauro Schneider Oliveira
- Centro de Ciências da Saúde, Programa de Pós-Graduação em Farmacologia, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
| | - Ana Flavia Furian
- Centro de Ciências da Saúde, Programa de Pós-Graduação em Farmacologia, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
| | - Michele Rechia Fighera
- Laboratório de Bioquímica do Exercício, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil; Centro de Ciências da Saúde, Departamento de Clínica Médica e Pediatria, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
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Duan H, Cai X, Luan Y, Yang S, Yang J, Dong H, Zeng H, Shao L. Regulation of the Autonomic Nervous System on Intestine. Front Physiol 2021; 12:700129. [PMID: 34335306 PMCID: PMC8317205 DOI: 10.3389/fphys.2021.700129] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 06/22/2021] [Indexed: 12/12/2022] Open
Abstract
Intestine is composed of various types of cells including absorptive epithelial cells, goblet cells, endocrine cells, Paneth cells, immunological cells, and so on, which play digestion, absorption, neuroendocrine, immunological function. Intestine is innervated with extrinsic autonomic nerves and intrinsic enteric nerves. The neurotransmitters and counterpart receptors are widely distributed in the different intestinal cells. Intestinal autonomic nerve system includes sympathetic and parasympathetic nervous systems, which regulate cellular proliferation and function in intestine under physiological and pathophysiological conditions. Presently, distribution and functional characteristics of autonomic nervous system in intestine were reviewed. How autonomic nervous system regulates intestinal cell proliferation was discussed. Function of autonomic nervous system on intestinal diseases was extensively reviewed. It might be helpful to properly manipulate autonomic nervous system during treating different intestinal diseases.
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Affiliation(s)
- Hongyi Duan
- Medical College of Nanchang University, Nanchang, China
| | - Xueqin Cai
- Medical College of Nanchang University, Nanchang, China
| | - Yingying Luan
- Medical College of Nanchang University, Nanchang, China
| | - Shuo Yang
- Medical College of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, China
| | - Juan Yang
- Medical College of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, China
| | - Hui Dong
- Medical College of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Interdisciplinary Science, Nanchang University, Nanchang, China
| | - Huihong Zeng
- Medical College of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Interdisciplinary Science, Nanchang University, Nanchang, China
| | - Lijian Shao
- Medical College of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Interdisciplinary Science, Nanchang University, Nanchang, China
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35
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Ghezzi L, Cantoni C, Pinget GV, Zhou Y, Piccio L. Targeting the gut to treat multiple sclerosis. J Clin Invest 2021; 131:e143774. [PMID: 34196310 DOI: 10.1172/jci143774] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The gut-brain axis (GBA) refers to the complex interactions between the gut microbiota and the nervous, immune, and endocrine systems, together linking brain and gut functions. Perturbations of the GBA have been reported in people with multiple sclerosis (pwMS), suggesting a possible role in disease pathogenesis and making it a potential therapeutic target. While research in the area is still in its infancy, a number of studies revealed that pwMS are more likely to exhibit altered microbiota, altered levels of short chain fatty acids and secondary bile products, and increased intestinal permeability. However, specific microbes and metabolites identified across studies and cohorts vary greatly. Small clinical and preclinical trials in pwMS and mouse models, in which microbial composition was manipulated through the use of antibiotics, fecal microbiota transplantation, and probiotic supplements, have provided promising outcomes in preventing CNS inflammation. However, results are not always consistent, and large-scale randomized controlled trials are lacking. Herein, we give an overview of how the GBA could contribute to MS pathogenesis, examine the different approaches tested to modulate the GBA, and discuss how they may impact neuroinflammation and demyelination in the CNS.
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Affiliation(s)
- Laura Ghezzi
- Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.,University of Milan, Milan, Italy
| | - Claudia Cantoni
- Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Gabriela V Pinget
- Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
| | - Yanjiao Zhou
- Department of Medicine, School of Medicine, UConn Health, Farmington, Connecticut, USA
| | - Laura Piccio
- Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.,Brain and Mind Centre, School of Medical Sciences, University of Sydney, Sydney, New South Wales, Australia.,Hope Center for Neurological Disorders, Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA
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36
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Shi Y, Qiao CM, Zhou Y, Wu J, Cui C, Hong H, Jia XB, Huang SB, Yao L, Zhao WJ, Shen YQ. Protective effects of prucalopride in MPTP-induced Parkinson's disease mice: Neurochemistry, motor function and gut barrier. Biochem Biophys Res Commun 2021; 556:16-22. [PMID: 33836343 DOI: 10.1016/j.bbrc.2021.03.109] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 03/19/2021] [Indexed: 02/07/2023]
Abstract
Evidence suggests constipation precedes motor dysfunction and is the most common gastrointestinal symptom in Parkinson's disease (PD). 5-HT4 receptor (5-HT4R) agonist prucalopride has been approved to treat chronic constipation. Here, we reported intraperitoneal injection of prucalopride for 7 days increased dopamine and decreased dopamine turnover. Prucalopride administration improved motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-induced PD mouse models. Prucalopride treatment also ameliorated intestinal barrier impairment and increased IL-6 release in PD model mice. However, prucalopride treatment exerted no impact on JAK2/STAT3 pathway, suggesting that prucalopride may stimulate IL-6 via JAK2/STAT3-independent pathway. In conclusion, prucalopride exerted beneficial effects in MPTP-induced Parkinson's disease mice by attenuating the loss of dopamine, improving motor dysfunction and intestinal barrier.
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Affiliation(s)
- Yun Shi
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China; Department of Neurodegeneration and Injury, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Chen-Meng Qiao
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China; Department of Neurodegeneration and Injury, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Yu Zhou
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China; Department of Neurodegeneration and Injury, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Ji Wu
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China; Department of Neurodegeneration and Injury, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Chun Cui
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China; Department of Neurodegeneration and Injury, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Hui Hong
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China; Department of Neurodegeneration and Injury, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Xue-Bing Jia
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China; Department of Neurodegeneration and Injury, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Shu-Bing Huang
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China; Department of Neurodegeneration and Injury, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Li Yao
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China; Department of Neurodegeneration and Injury, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Wei-Jiang Zhao
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China; Department of Neurodegeneration and Injury, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
| | - Yan-Qin Shen
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China; Department of Neurodegeneration and Injury, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China.
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37
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Bowker B, Calabrese RO, Barber E. Postoperative Ileus. PHYSICIAN ASSISTANT CLINICS 2021. [DOI: 10.1016/j.cpha.2020.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Park JH, Lee KN, Lee OY, Choi MG, Chung H, Choi SC, Kim N, Park H, Sung IK, Sohn CI, Jee SR, Jang JY, Rhee PL, Park MI, Kwon JG, Park KS, Lee KJ, Lee JS. Efficacy and Safety of DWJ1252 Compared With Gasmotin in the Treatment of Functional Dyspepsia: A Multicenter, Randomized, Double-blind, Active-controlled Study. J Neurogastroenterol Motil 2021; 27:87-96. [PMID: 32792467 PMCID: PMC7786082 DOI: 10.5056/jnm20061] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 05/22/2020] [Accepted: 06/11/2020] [Indexed: 12/13/2022] Open
Abstract
Background/Aims Prokinetics such as mosapride citrate CR (conventional-release; Gasmotin) are commonly used in functional dyspepsia (FD). This study aims to evaluate the efficacy and safety of once-a-day mosapride citrate SR (DWJ1252), a sustained-release formulation of mosapride citrate, compared with mosapride citrate CR 3 times a day, in patients with FD. Methods In this multicenter, randomized, double-blind, active-controlled, non-inferiority study, 119 patients with FD (by the Rome III criteria, 60 for mosapride citrate SR and 59 for mosapride citrate CR) were randomly allocated to mosapride citrate SR once daily or mosapride citrate CR thrice daily for 4 weeks in 16 medical institutions. Primary end point was the change in gastrointestinal symptom (GIS) score from baseline, assessed by GIS questionnaires on 5-point Likert scale after 4-week treatment. Secondary end points and safety profiles were also analyzed. Results The study included 51 and 49 subjects in the mosapride citrate SR and mosapride citrate CR groups, respectively. GIS scores at week 4 were significantly reduced in both groups (mean ± SD: -10.04 ± 4.45 and -10.86 ± 5.53 in the mosapride citrate SR and mosapride citrate CR groups, respectively; P < 0.001), and the GIS changes from baseline did not differ between the 2 groups (difference, 0.82 point; 95% CI, -1.17, 2.81; P = 0.643). Changes in GIS at weeks 2 and 4 and quality of life at week 4, and the improvement rates of global assessments at weeks 2 and 4, did not differ between the groups. Adverse events were similar in the 2 groups, and there were no serious adverse events. Conclusion In patients with FD, mosapride citrate SR once daily is as effective as mosapride citrate CR thrice daily, with a similar safety profile.
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Affiliation(s)
- Jin Hwa Park
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Kang Nyeong Lee
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Oh Young Lee
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Myung-Gyu Choi
- Department of Internal Medicine, Catholic University College of Medicine, Seoul, Korea
| | - Hyunsoo Chung
- Department of Internal Medicine, Seoul National University, Seoul, Korea
| | - Suck-Chei Choi
- Department of Internal Medicine, Wonkwang University College of Medicine, Iksan, Jeollabuk-do, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea
| | - Hyojin Park
- Department of Internal Medicine, Yonsei University Gangnam Hospital, Seoul, Korea
| | - In-Kyung Sung
- Department of Internal Medicine, Konkuk University College of Medicine, Seoul, Korea
| | - Chong Il Sohn
- Department of Internal Medicine, Kangbuk Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sam Ryong Jee
- Department of Internal Medicine, Inje University College of Medicine, Busan, Korea
| | - Jae Young Jang
- Department of Internal Medicine, Kyunghee University College of Medicine, Seoul, Korea
| | - Poong-Lyul Rhee
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Moo In Park
- Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea
| | - Joong Goo Kwon
- Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, Korea
| | - Kyung Sik Park
- Department of Internal Medicine, Keimyung University College of Medicine, Daegu, Korea
| | - Kwang Jae Lee
- Department of Internal Medicine, Ajou University College of Medicine, Suwon, Gyeonggi-do, Korea
| | - Joon Seong Lee
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, Korea
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Guo Y, Wang B, Wang T, Gao L, Yang ZJ, Wang FF, Shang HW, Hua R, Xu JD. Biological characteristics of IL-6 and related intestinal diseases. Int J Biol Sci 2021; 17:204-219. [PMID: 33390844 PMCID: PMC7757046 DOI: 10.7150/ijbs.51362] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Accepted: 11/07/2020] [Indexed: 12/21/2022] Open
Abstract
The intestine serves as an important digestive and the largest immune organ in the body. Interleukin-6(IL-6), an important mediator of various pathways, participates in the interactions between different kinds of cells and closely correlates with intestinal physiological and pathological condition. In this review we summarize the signaling pathways of IL-6 and its functions in maintaining intestinal homeostasis. We also explored its relation with nervous system and highlight its potential role in Parkinson's disease. Based on its specialty of the double-side influences on intestinal tumors and inflammation, we summarize how they are done through distinctive process.
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Affiliation(s)
- Yuexin Guo
- Department of Oral Medicine, Basic Medical College, Capital Medical University, Beijing 100069, China
| | - Boya Wang
- Undergraduate Student of 2018 Eight Program of Clinical Medicine, Peking University Health Science Center, Beijing, 100081, China
| | - Tiantian Wang
- Department of Physiology and Pathophysiology, Basic Medical College, Capital Medical University, Beijing 100069, China
| | - Lei Gao
- Department of Bioinformatics, College of Bioengineering, Capital Medical University, Beijing 100069, China
| | - Ze-Jun Yang
- Department of Clinical Medicine, Basic Medical College, Capital Medical University, Beijing 100069, China
| | - Fei-Fei Wang
- Department of Clinical Medicine, Basic Medical College, Capital Medical University, Beijing 100069, China
| | - Hong-Wei Shang
- Experimental Center for Morphological Research Platform, Capital Medical University, Beijing 100069, China
| | - Rongxuan Hua
- Department of Clinical Medicine, Basic Medical College, Capital Medical University, Beijing 100069, China
| | - Jing-Dong Xu
- Department of Physiology and Pathophysiology, Basic Medical College, Capital Medical University, Beijing 100069, China
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Traditional Chinese Medicine Da-Cheng-Qi-Tang Ameliorates Impaired Gastrointestinal Motility and Intestinal Inflammatory Response in a Mouse Model of Postoperative Ileus. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:9074069. [PMID: 32802139 PMCID: PMC7415087 DOI: 10.1155/2020/9074069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 07/13/2020] [Indexed: 11/17/2022]
Abstract
This study was to explore the therapeutic effect and mechanism of the traditional Chinese medicine with the formula Da-Cheng-Qi-Tang (T-DCQT) and a modified Da-Cheng-Qi-Tang (M-DCQT) in a postoperative ileus (POI) mouse model. POI was induced via small bowel manipulation, and T-DCQT or M-DCQT was given by enema. The intestinal motility was measured with a charcoal mixture gavage. The intestinal tissues were collected for further studies by histopathological, qPCR, immunohistochemical staining, and Western blotting. Levels of inflammatory cytokines in blood were determined using a high-throughput liquid chip. We found that gastrointestinal dysfunction was alleviated after administration of either a T-DCQT or M-DCQT enema. Increased expression of NF-κB, p38 MAPK, and TLR4 in the intestinal tissues of POI mice were reversed following treatment. IL-1α, IL-6, MIP-1β, and IL-17 levels were significantly reduced at 24 h and 48 h following treatment, while the MCP-1 level was only observed to be reduced at 24 h after the treatment. Furthermore, compared with the T-DCQT effect, M-DCQT treatment was more effective in alleviating the increased IL-6, MIP-1β, and IL-1α levels. So, we draw a conclusion that T-DCQT or M-DCOT could ameliorate the POI-associated inflammatory response and improve GI motility in a POI mouse model.
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Bruschetta G, D'Ascola A, Medica P, Ferlazzo AM. Physical Exercise Affects Serotoninergic System in Horse Leukocytes. J Equine Vet Sci 2020; 88:102969. [PMID: 32303327 DOI: 10.1016/j.jevs.2020.102969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 02/20/2020] [Accepted: 02/22/2020] [Indexed: 11/18/2022]
Abstract
Serotonin (5-hydroxytryptamine [5-HT]) may induce metabolic effects in different cell types, including leukocytes. In horses, 5-HT is involved in physiological and behavioral functions. Physical exercise is known to increase the amounts of 5-HT both in brain and periphery, but so far, the signal mechanism in response to exercise is not known. The aim of the study was to investigate the effect of a racehorse intensive training session on plasma 5-HT levels, serotonin transporter (SERT), 5HT1A, 5-HT2A, 5-HT1B, 5-HT7 receptor, interleukin-1 beta, and tumor necrosis factor-alpha expression in horse peripheral blood mononuclear cells (PBMC). In particular, the research was carried out on 12 trained horses performing daily training. Plasma 5-HT levels were analyzed in platelet-poor plasma fraction by enzyme-linked immunosorbent assay at T0, T1, and T2 (pretraining, 30 minutes post-training, and 2 hours post-training session), respectively. Peripheral blood mononuclear cells were isolated to perform real-time polymerase chain reaction for the evaluation of SERT, 5-HT receptor, and cytokine mRNA levels. The results showed significantly increased levels of plasma 5-HT, 5HT1A, and 5-HT2A and significantly decreased levels of SERT, 5-HT1B, 5-HT7, and both cytokine mRNAs in PBMC at T1, compared with T0 and T2. The results were confirmed by in vitro experiment. Training may induce a lower degree of 5-HT storage and, therefore, a higher plasma 5-HT concentrations. Leukocyte 5-HT receptor mRNAs seem strongly influenced by the exercise. Observed changes suggest a transient neuroendocrinological response to the exercise. A better understanding of the influence of physical exercise on serotoninergic system could have potential application for the implementation of training protocols in racing horses.
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Affiliation(s)
- Giuseppe Bruschetta
- Department of Veterinary Sciences, Biochemistry Unit, University of Messina, Polo Universitario dell'Annunziata, Messina, Italy
| | - Angela D'Ascola
- Department of Clinical and Experimental Medicine, University of Messina, Policlinico Universitario, Messina, Italy
| | - Pietro Medica
- Department of Veterinary Sciences, Physiology Unit, University of Messina, Polo Universitario dell'Annunziata, Messina, Italy
| | - Alida Maria Ferlazzo
- Department of Veterinary Sciences, Biochemistry Unit, University of Messina, Polo Universitario dell'Annunziata, Messina, Italy.
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Agrawal L, Korkutata M, Vimal SK, Yadav MK, Bhattacharyya S, Shiga T. Therapeutic potential of serotonin 4 receptor for chronic depression and its associated comorbidity in the gut. Neuropharmacology 2020; 166:107969. [PMID: 31982703 DOI: 10.1016/j.neuropharm.2020.107969] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 01/14/2020] [Accepted: 01/16/2020] [Indexed: 12/19/2022]
Abstract
The latest estimates from world health organization suggest that more than 450 million people are suffering from depression and other psychiatric conditions. Of these, 50-60% have been reported to have progression of gut diseases. In the last two decades, researchers introduced incipient physiological roles for serotonin (5-HT) receptors (5-HTRs), suggesting their importance as a potential pharmacological target in various psychiatric and gut diseases. A growing body of evidence suggests that 5-HT systems affect the brain-gut axis in depressive patients, which leads to gut comorbidity. Recently, preclinical trials of 5-HT4R agonists and antagonists were promising as antipsychotic and prokinetic agents. In the current review, we address the possible pharmacological role and contribution of 5-HT4R in the pathophysiology of chronic depression and associated gut abnormalities. Physiologically, during depression episodes, centers of the sympathetic and parasympathetic nervous system couple together with neuroendocrine systems to alter the function of hypothalamic-pituitary-adrenal (HPA) axis and enteric nervous system (ENS), which in turn leads to onset of gastrointestinal tract (GIT) disorders. Consecutively, the ENS governs a broad spectrum of physiological activities of gut, such as visceral pain and motility. During the stages of emotional stress, hyperactivity of the HPA axis alters the ENS response to physiological and noxious stimuli. Consecutively, stress-induced flare, swelling, hyperalgesia and altered reflexes in gut eventually lead to GIT disorders. In summary, the current review provides prospective information about the role and mechanism of 5-HT4R-based therapeutics for the treatment of depressive disorder and possible consequences for the gut via brain-gut axis interactions. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.
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Affiliation(s)
- Lokesh Agrawal
- Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1, 305-8577, Tennodai, Tsukuba, Ibaraki, Japan.
| | - Mustafa Korkutata
- Department of Neurology, Division of Sleep Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Sunil Kumar Vimal
- Department of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, PR China
| | - Manoj Kumar Yadav
- School of Integrative and Global Majors, University of Tsukuba, 1-1-1, 305-8577, Tennodai, Tsukuba, Ibaraki, Japan; Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Sanjib Bhattacharyya
- Department of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, PR China
| | - Takashi Shiga
- Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1, 305-8577, Tennodai, Tsukuba, Ibaraki, Japan; Department of Neurobiology, Faculty of Medicine, University of Tsukuba,1-1-1, Tennodai, Tsukuba, 305-8577, Ibaraki, Japan.
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Röszer T. Signal Mechanisms of M2 Macrophage Activation. PROGRESS IN INFLAMMATION RESEARCH 2020:73-97. [DOI: 10.1007/978-3-030-50480-9_4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Kimura H, Yoneya Y, Mikawa S, Kaji N, Ito H, Tsuchida Y, Komatsu H, Murata T, Ozaki H, Uchida R, Nishida K, Hori M. A new zinc chelator, IPZ-010 ameliorates postoperative ileus. Biomed Pharmacother 2019; 123:109773. [PMID: 31862476 DOI: 10.1016/j.biopha.2019.109773] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 11/29/2019] [Accepted: 12/04/2019] [Indexed: 12/26/2022] Open
Abstract
Zinc was discovered to be a novel second messenger in immunoreactive cells. We synthesized a novel free zinc chelator, IPZ-010. Here, we investigated the effects of IPZ-010 in a mouse postoperative ileus model and determined the effects of zinc signal inhibition as a new therapeutic strategy against postoperative ileus. Zinc waves were measured in bone marrow-derived mast cells (BMMCs) loaded with a zinc indicator, Newport green. Degranulation and cytokine expression were measured in BMMCs and bone marrow-derived macrophages (BMDMs). Postoperative ileus model mice were established with intestinal manipulation. Mice were treated with IPZ-010 (30 mg/kg, s.c. or p.o.) 1 h before and 2 h and 4 h after intestinal manipulation. Gastrointestinal transit, inflammatory cell infiltration, and expression of inflammatory mediators were measured. Free zinc waves occurred following antigen stimulation in BMMCs and were blocked by IPZ-010. IPZ-010 inhibited interleukin-6 secretion and degranulation in BMMCs. IPZ-010 inhibited tumor necrosis factor-α mRNA expression in BMMCs stimulated with lipopolysaccharide or adenosine triphosphate, whereas IPZ-010 had no effects on tumor necrosis factor-α mRNA expression in BMDMs stimulated with lipopolysaccharide or adenosine triphosphate. In postoperative ileus model mice, IPZ-010 inhibited leukocyte infiltration and cytokine expression, which ameliorated gastrointestinal transit. Furthermore, ketotifen (1 mg/kg) induced similar effects as IPZ-010. These effects were not amplified by co-administration of IPZ-010 and ketotifen. IPZ-010 inhibited zinc waves, resulting in inhibition of inflammatory responses in activated BMMCs in vitro. Targeting zinc waves in inflammatory cells may be a novel therapeutic strategy for treating postoperative ileus.
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Affiliation(s)
- Hitomi Kimura
- Department of Veterinary Pharmacology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Yutaka Yoneya
- Department of Veterinary Pharmacology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Shoma Mikawa
- Department of Veterinary Pharmacology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Noriyuki Kaji
- Department of Veterinary Pharmacology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Hiroki Ito
- Interprotein Corporation, 3-10-2 Toyosaki, Kita-ku, Osaka-city, Osaka 531-0072, Japan
| | - Yasuaki Tsuchida
- Department of Surgical Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya-city, Hyogo 663-8501, Japan
| | - Hirotsugu Komatsu
- Interprotein Corporation, 3-10-2 Toyosaki, Kita-ku, Osaka-city, Osaka 531-0072, Japan
| | - Takahisa Murata
- Department of Animal Radiology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Hiroshi Ozaki
- Department of Veterinary Pharmacology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Ryota Uchida
- Laboratory of Immune Regulation, Graduate School of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minamitamagaki-cho, Suzuka-city, Mie 513-8607, Japan
| | - Keigo Nishida
- Laboratory for Homeostatic Network, RCAI, RIKEN Research Center for Integrative Medical Sciences (IMS-RCAI), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama-city, Kanagawa 230-0045, Japan; Laboratory of Immune Regulation, Graduate School of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minamitamagaki-cho, Suzuka-city, Mie 513-8607, Japan
| | - Masatoshi Hori
- Department of Veterinary Pharmacology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
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Wedn AM, El-Gowilly SM, El-Mas MM. Nicotine reverses the enhanced renal vasodilator capacity in endotoxic rats: Role of α7/α4β2 nAChRs and HSP70. Pharmacol Rep 2019; 71:782-793. [PMID: 31377559 DOI: 10.1016/j.pharep.2019.04.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 04/10/2019] [Accepted: 04/13/2019] [Indexed: 01/13/2023]
Abstract
BACKGROUND Nicotine alleviates renal inflammation and injury induced by endotoxemia. This study investigated (i) the nicotine modulation of hemodynamic and renal vasodilatory responses to endotoxemia in rats, and (ii) roles of α7 or α4β2-nAChRs and related HSP70/TNFα/iNOS signaling in the interaction. METHODS Endotoxemia was induced by ip lipopolysaccharide (5 mg/kg/day, for 2 days) and changes in systolic blood pressure and vasodilator responsiveness of isolated perfused kidney to acetylcholine or 5'-N-ethylcarboxamidoadenosine (NECA, adenosine receptor agonist) were evaluated. RESULTS Lipopolysaccharide had no effect on serum creatinine, reduced blood pressure, and increased renal vasodilations induced by acetylcholine or NECA in male and female preparations. Immunohistochemical analyses showed that lipopolysaccharide reduced renal HSP70 expression, but increased α7-nAChRs, α4β2-nAChRs and iNOS expressions. The co-administration of aminoguanidine (iNOS inhibitor), pentoxifylline (TNFα inhibitor), or nicotine attenuated lipopolysaccharide mediation of renal vasodilations and elevations in α7/α4β2-nAChR and iNOS expressions. Nicotine also reversed the downregulating effect of lipopolysaccharide on HSP70 expression. α7-nAChRs (methyllycaconitine citrate, MLA) or α4β2-nAChRs (dihydro-β-erythroidine, DHβE) blockade potentiated the lipopolysaccharide enhancement of renal vasodilations, and abolished the depressant effect of nicotine on lipopolysaccharide responses. A similar abolition of nicotine effects was seen after HSP70 inhibition by quercetin. Alternatively, lipopolysaccharide hypotension was eliminated in rats treated with DHβE/nicotine or quercetin/nicotine regimen in contrast to no effect for nicotine alone or combined with MLA. CONCLUSIONS These findings establish that nicotine offsets lipopolysaccharide facilitation of renal vasodilations possibly through a crosstalk between HSP70 and nAChRs of the α7 and α4β2 types.
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Affiliation(s)
- Abdalla M Wedn
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Sahar M El-Gowilly
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Mahmoud M El-Mas
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
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Stakenborg N, Labeeuw E, Gomez-Pinilla PJ, De Schepper S, Aerts R, Goverse G, Farro G, Appeltans I, Meroni E, Stakenborg M, Viola MF, Gonzalez-Dominguez E, Bosmans G, Alpizar YA, Wolthuis A, D’Hoore A, Van Beek K, Verheijden S, Verhaegen M, Derua R, Waelkens E, Moretti M, Gotti C, Augustijns P, Talavera K, Vanden Berghe P, Matteoli G, Boeckxstaens GE. Preoperative administration of the 5-HT4 receptor agonist prucalopride reduces intestinal inflammation and shortens postoperative ileus via cholinergic enteric neurons. Gut 2019; 68:1406-1416. [PMID: 30472681 PMCID: PMC6691854 DOI: 10.1136/gutjnl-2018-317263] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 10/16/2018] [Accepted: 10/18/2018] [Indexed: 12/27/2022]
Abstract
OBJECTIVES Vagus nerve stimulation (VNS), most likely via enteric neurons, prevents postoperative ileus (POI) by reducing activation of alpha7 nicotinic receptor (α7nAChR) positive muscularis macrophages (mMφ) and dampening surgery-induced intestinal inflammation. Here, we evaluated if 5-HT4 receptor (5-HT4R) agonist prucalopride can mimic this effect in mice and human. DESIGN Using Ca2+ imaging, the effect of electrical field stimulation (EFS) and prucalopride was evaluated in situ on mMφ activation evoked by ATP in jejunal muscularis tissue. Next, preoperative and postoperative administration of prucalopride (1-5 mg/kg) was compared with that of preoperative VNS in a model of POI in wild-type and α7nAChR knockout mice. Finally, in a pilot study, patients undergoing a Whipple procedure were preoperatively treated with prucalopride (n=10), abdominal VNS (n=10) or sham/placebo (n=10) to evaluate the effect on intestinal inflammation and clinical recovery of POI. RESULTS EFS reduced the ATP-induced Ca2+ response of mMφ, an effect that was dampened by neurotoxins tetrodotoxin and ω-conotoxin and mimicked by prucalopride. In vivo, prucalopride administered before, but not after abdominal surgery reduced intestinal inflammation and prevented POI in wild-type, but not in α7nAChR knockout mice. In humans, preoperative administration of prucalopride, but not of VNS, decreased Il6 and Il8 expression in the muscularis externa and improved clinical recovery. CONCLUSION Enteric neurons dampen mMφ activation, an effect mimicked by prucalopride. Preoperative, but not postoperative treatment with prucalopride prevents intestinal inflammation and shortens POI in both mice and human, indicating that preoperative administration of 5-HT4R agonists should be further evaluated as a treatment of POI. TRIAL REGISTRATION NUMBER NCT02425774.
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Affiliation(s)
- Nathalie Stakenborg
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium
| | - Evelien Labeeuw
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium
| | - Pedro J Gomez-Pinilla
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium
| | - Sebastiaan De Schepper
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium
| | - Raymond Aerts
- Department of Abdominal Surgery, University Hospital of Leuven, Leuven, Belgium
| | - Gera Goverse
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders, Laboratory for Mucosal Immunology, University of Leuven, Leuven, Belgium
| | - Giovanna Farro
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium
| | - Iris Appeltans
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium
| | - Elisa Meroni
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium
| | - Michelle Stakenborg
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders, Laboratory for Mucosal Immunology, University of Leuven, Leuven, Belgium
| | - Maria Francesca Viola
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium
| | - Erika Gonzalez-Dominguez
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium
| | - Goele Bosmans
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium
| | - Yeranddy A Alpizar
- Department of Cellular and Molecular Medicine, Laboratory of Ion Channel Research, KU Leuven; VIB Center for Brain & Disease Research, Leuven, Belgium
| | - Albert Wolthuis
- Department of Abdominal Surgery, University Hospital of Leuven, Leuven, Belgium
| | - Andre D’Hoore
- Department of Abdominal Surgery, University Hospital of Leuven, Leuven, Belgium
| | - Kim Van Beek
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium
| | - Simon Verheijden
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium
| | - Marleen Verhaegen
- Department of Anesthesiology, University Hospital of Leuven, Leuven, Belgium
| | - Rita Derua
- Department of Cellular and Molecular Medicine, Laboratory of Protein Phosphorylation and Proteomics, Universitiy of Leuven, Leuven, Belgium
| | - Etienne Waelkens
- Department of Cellular and Molecular Medicine, Laboratory of Protein Phosphorylation and Proteomics, Universitiy of Leuven, Leuven, Belgium
| | - Milena Moretti
- CNR, Neuroscience Institute-Milano, Biometra University of Milan, Milan, Italy
| | - Cecilia Gotti
- CNR, Neuroscience Institute-Milano, Biometra University of Milan, Milan, Italy
| | - Patrick Augustijns
- Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Drug Delivery and Disposition, University of Leuven, Leuven, Belgium
| | - Karel Talavera
- Department of Cellular and Molecular Medicine, Laboratory of Ion Channel Research, KU Leuven; VIB Center for Brain & Disease Research, Leuven, Belgium
| | - Pieter Vanden Berghe
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders, Laboratory for Enteric Neuroscience, University of Leuven, Leuven, Belgium
| | - Gianluca Matteoli
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders, Laboratory for Mucosal Immunology, University of Leuven, Leuven, Belgium
| | - Guy E Boeckxstaens
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for GastroIntestinal Disorders, Intestinal Neuroimmune Interactions, University of Leuven, Leuven, Belgium
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Nunes NS, Chandran P, Sundby M, Visioli F, da Costa Gonçalves F, Burks SR, Paz AH, Frank JA. Therapeutic ultrasound attenuates DSS-induced colitis through the cholinergic anti-inflammatory pathway. EBioMedicine 2019; 45:495-510. [PMID: 31253515 PMCID: PMC6642284 DOI: 10.1016/j.ebiom.2019.06.033] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 06/05/2019] [Accepted: 06/18/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Ulcerative Colitis (UC) is an Inflammatory Bowel Disease (IBD) characterized by uncontrolled immune response, diarrhoea, weight loss and bloody stools, where sustained remission is not currently achievable. Dextran Sulphate Sodium (DSS)-induced colitis is an animal model that closely mimics human UC. Ultrasound (US) has been shown to prevent experimental acute kidney injury through vagus nerve (VN) stimulation and activation of the cholinergic anti-inflammatory pathway (CAIP). Since IBD patients may present dysfunctional VN activity, our aim was to determine the effects of therapeutic ultrasound (TUS) in DSS-induced colitis. METHODS Acute colitis was induced by 2% DSS in drinking water for 7 days and TUS was administered to the abdominal area for 7 min/day from days 4-10. Clinical symptoms were analysed, and biological samples were collected for proteomics, macroscopic and microscopic analysis, flow cytometry and immunohistochemistry. FINDINGS TUS attenuated colitis by reducing clinical scores, colon shortening and histological damage, inducing proteomic tolerogenic response in the gut during the injury phase and early recovery of experimental colitis. TUS did not improve clinical and pathological outcomes in splenectomised mice, while α7nAChR (α7 nicotinic acetylcholine receptor - indicator of CAIP involvement) knockout animals presented with disease worsening. Increased levels of colonic F4/80+α7nAChR+ macrophages in wild type mice suggest CAIP activation. INTERPRETATION These results indicate TUS improved DSS-induced colitis through stimulation of the splenic nerve along with possible contribution by VN with CAIP activation. FUND: Intramural Research Programs of the Clinical Centre, the National Institute of Biomedical Imaging and Bioengineering at the NIH and CAPES/Brazil.
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Affiliation(s)
- Natalia Schneider Nunes
- Frank Laboratory, Radiology and Imaging Sciences, Clinical Centre, NIH, Bethesda, MD, United States; Gastroenterology and Hepatology Sciences Graduate Program, UFRGS, Porto Alegre, RS, Brazil.
| | - Parwathy Chandran
- Frank Laboratory, Radiology and Imaging Sciences, Clinical Centre, NIH, Bethesda, MD, United States
| | - Maggie Sundby
- Frank Laboratory, Radiology and Imaging Sciences, Clinical Centre, NIH, Bethesda, MD, United States
| | - Fernanda Visioli
- Faculty of Dentistry, Oral Pathology, UFRGS, Porto Alegre, RS, Brazil
| | | | - Scott Robert Burks
- Frank Laboratory, Radiology and Imaging Sciences, Clinical Centre, NIH, Bethesda, MD, United States
| | - Ana Helena Paz
- Gastroenterology and Hepatology Sciences Graduate Program, UFRGS, Porto Alegre, RS, Brazil
| | - Joseph Alan Frank
- Frank Laboratory, Radiology and Imaging Sciences, Clinical Centre, NIH, Bethesda, MD, United States; National Institute of Biomedical Imaging and Bioengineering, NIH, Bethesda, MD, United States
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May M, Beauchemin M, Vary C, Barlow D, Houseknecht KL. The antipsychotic medication, risperidone, causes global immunosuppression in healthy mice. PLoS One 2019; 14:e0218937. [PMID: 31242264 PMCID: PMC6594635 DOI: 10.1371/journal.pone.0218937] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 06/12/2019] [Indexed: 01/19/2023] Open
Abstract
Atypical antipsychotic medications such as risperidone are widely prescribed for diverse psychiatric indications including schizophrenia, bipolar disorder and depression. These medications have complex pharmacology and are associated with significant endocrine and metabolic side effects. This class of medications also carries FDA black box warnings due to increased risk of death in elderly patients. Clinical reports indicate that patients treated with these medications are more susceptible to infections; however, the underlying mechanisms/pharmacology are unclear. We have previously reported that risperidone and it’s active metabolite distributes to the bone marrow in clinically relevant concentrations in preclinical species, leading us to hypothesize that the hematopoietic system may be impacted by these medications. To test this hypothesis, using proteomic and cytokine array technology, we evaluated the expression of genes involved in inflammatory and immune function following short term (5 days) and longer term (4 weeks) treatment in healthy animals. We report that low-dose risperidone treatment results in global immunosuppression in mice, observed following 5 days of dosing and exacerbated with longer term drug treatment (4 weeks). These data are consistent with increased susceptibility to infection in patients administered these medications and have profound implications for the increasing off-label prescribing to vulnerable patient populations including children and the elderly.
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Affiliation(s)
- Meghan May
- Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, ME, United States of America
| | - Megan Beauchemin
- Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, ME, United States of America
| | - Calvin Vary
- Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME, United States of America
| | - Deborah Barlow
- Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, ME, United States of America
| | - Karen L. Houseknecht
- Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, ME, United States of America
- * E-mail:
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Neural anti-inflammatory action mediated by two types of acetylcholine receptors in the small intestine. Sci Rep 2019; 9:5887. [PMID: 30971711 PMCID: PMC6458176 DOI: 10.1038/s41598-019-41698-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 03/15/2019] [Indexed: 12/14/2022] Open
Abstract
Gastrointestinal prokinetic agents function as serotonin-4 receptor (5-HT4R) agonists to activate myenteric plexus neurons to release acetylcholine (ACh), which then induce anti-inflammatory action. Details of this pathway, however, remain unknown. The aim of this study is to clarify the anti-inflammatory mechanism underlying the 5-HT4R agonist, mosapride citrate (MOS)-induced anti-inflammatory action on postoperative ileus (POI). POI models were generated from wild-type C57BL6/J (WT), 5-HT4R knock-out (S4R KO), α7 nicotinic AChR KO (α7 R KO), and M2 muscarinic ACh receptor KO (M2R KO) mice. MOS attenuated leukocyte infiltration in WT. MOS-induced anti-inflammatory action was completely abolished in both S4R KO and S4R KO mice upon wild-type bone marrow transplantation. MOS-induced anti-inflammatory action against macrophage infiltration, but not neutrophil infiltration, was attenuated in α7 R KO mice. Selective α7nAChR agonists (PNU-282987 and AR-R17779) also inhibited only macrophage infiltration in POI. MOS-mediated inhibition of neutrophil infiltration was diminished by atropine, M2AChR antagonist, methoctramine, and in M2R KO mice. Stimulation with 5-HT4R inhibits leukocyte infiltration in POI, possibly through myenteric plexus activation. Released ACh inhibited macrophage and neutrophil infiltration likely by activation of α7nAChR on macrophages and M2AChR. Thus, macrophage and neutrophil recruitment into inflamed sites is regulated by different types of AChR in the small intestine.
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Castello A, Bruschetta G, Giunta RP, Marino AMF, Ferlazzo AM. The effect of Toxoplasma gondii on plasma serotonin concentration in sheep. Vet World 2018; 11:1500-1505. [PMID: 30532508 PMCID: PMC6247880 DOI: 10.14202/vetworld.2018.1500-1505] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 09/19/2018] [Indexed: 11/16/2022] Open
Abstract
Background and Aim Toxoplasma gondii is an intracellular parasite that commonly infects warm-blooded animals, including humans. Virtually all species can be infected, but a species-specific variability is evident, in terms of both type and severity of the symptoms encountered. As serotonin (5-hydroxytryptamine [5-HT]) plays an important regulatory role in both physiological and immune responses, the aim of this research was to assess whether toxoplasmosis disease could affect plasma 5-HT concentration and/or hematochemical parameters in a particularly susceptible species to infection as sheep. Materials and Methods 5-HT plasma levels were analyzed in platelet-poor plasma fraction by enzyme-linked immunosorbent assay. Blood count and hematochemical parameters were evaluated. Total proteins (TPs), glucose (Glu), and lactate dehydrogenase were determined by a spectrophotometer. Results Results showed significantly higher levels in plasma 5-HT, monocytes, and TP and significantly lower levels of Glu, in infected sheep compared to the control group. Conclusion Results could support the hypothesis of an effect of toxoplasmosis infection on plasma 5-HT concentrations in sheep. More research is needed to assess the function of 5-HT in the regulation of infected sheep's immune responses.
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Affiliation(s)
- Annamaria Castello
- Italian National Reference Center for Toxoplasmosis (Ce.Tox) - Experimental Zooprophylactic Institute of Sicily (IZS), Via Passo Gravina 195, 95125 Catania, Italy
| | - Giuseppe Bruschetta
- Department of Veterinary Sciences, University of Messina, Polo Universitario dell'Annunziata, 98168 Messina, Italy
| | - Renato Paolo Giunta
- Italian National Reference Center for Toxoplasmosis (Ce.Tox) - Experimental Zooprophylactic Institute of Sicily (IZS), Via Passo Gravina 195, 95125 Catania, Italy
| | - Anna Maria Fausta Marino
- Italian National Reference Center for Toxoplasmosis (Ce.Tox) - Experimental Zooprophylactic Institute of Sicily (IZS), Via Passo Gravina 195, 95125 Catania, Italy
| | - Alida Maria Ferlazzo
- Department of Veterinary Sciences, University of Messina, Polo Universitario dell'Annunziata, 98168 Messina, Italy
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