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Syringic Acid Ameliorates Cardiac, Hepatic, Renal and Neuronal Damage Induced by Chronic Hyperglycaemia in Wistar Rats: A Behavioural, Biochemical and Histological Analysis. Molecules 2022; 27:molecules27196722. [PMID: 36235257 PMCID: PMC9573038 DOI: 10.3390/molecules27196722] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/29/2022] [Accepted: 10/04/2022] [Indexed: 11/16/2022] Open
Abstract
This study investigated the effects of syringic acid (SA) on renal, cardiac, hepatic, and neuronal diabetic complications in streptozotocin-induced neonatal (nSTZ) diabetic rats. STZ (110 mg/kg i.p) was injected into Wistar rat neonates as a split dose (second and third postnatal day). Diabetes mellitus was diagnosed in adults by measuring fasting blood glucose levels, urine volume, and food and water intake. The treatment of SA (25 mg/kg, 50 mg/kg p.o) was given from the 8th to 18th postnatal week. To assess the development of diabetic complications and the effect of therapy, biochemical indicators in serum and behavioural parameters were recorded at specific intervals during the study period. SA (25 mg/kg, 50 mg/kg p.o) treatment reduced hyperglycaemia, polydipsia, polyphagia, polyuria, relative organ weight, cardiac hypertrophic indices, inflammatory markers, cell injury markers, glycated haemoglobin, histopathological score, and oxidative stress, and increased Na/K ATPase activity. These findings suggest that SA might significantly alleviate diabetic complications and/or renal, neuronal, cardiac, and hepatic damage in nSTZ diabetic rats.
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Pinto L, Soares G, Próspero A, Stoppa E, Biasotti G, Paixão F, Santos A, Oliveira R, Miranda J. An easy and low-cost biomagnetic methodology to study regional gastrointestinal transit in rats. ACTA ACUST UNITED AC 2021; 66:405-412. [PMID: 33544465 DOI: 10.1515/bmt-2020-0202] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 01/19/2021] [Indexed: 12/12/2022]
Abstract
The identification of gastrointestinal (GI) motility disorders requires the evaluation of regional GI transit, and the development of alternative methodologies in animals has a significant impact on translational approaches. Therefore, the purpose of this study was to validate an easy and low-cost methodology (alternate current biosusceptometry - ACB) for the assessment of regional GI transit in rats through images. Rats were fed a test meal containing magnetic tracer and phenol red, and GI segments (stomach, proximal, medial and distal small intestine, and cecum) were collected to assess tracer's retention at distinct times after ingestion (0, 60, 120, 240, and 360 min). Images were obtained by scanning the segments, and phenol red concentration was determined by the sample's absorbance. The temporal retention profile, geometric center, gastric emptying, and cecum arrival were evaluated. The correlation coefficient between methods was 0.802, and the temporal retention of each segment was successfully assessed. GI parameters yielded comparable results between methods, and ACB images presented advantages as the possibility to visualize intrasegmental tracer distribution and the automated scan of the segments. The imaging approach provided a reliable assessment of several parameters simultaneously and may serve as an accurate and sensitive approach for regional GI research in rats.
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Affiliation(s)
- Leonardo Pinto
- Department of Biophysics and Pharmacology, São Paulo State University, Biosciences Institute of Botucatu, Botucatu, Brazil
| | - Guilherme Soares
- Department of Biophysics and Pharmacology, São Paulo State University, Biosciences Institute of Botucatu, Botucatu, Brazil
| | - André Próspero
- Department of Biophysics and Pharmacology, São Paulo State University, Biosciences Institute of Botucatu, Botucatu, Brazil
| | - Erick Stoppa
- Department of Biophysics and Pharmacology, São Paulo State University, Biosciences Institute of Botucatu, Botucatu, Brazil
| | - Gabriel Biasotti
- Department of Biophysics and Pharmacology, São Paulo State University, Biosciences Institute of Botucatu, Botucatu, Brazil
| | - Fabiano Paixão
- Science and Technology Institute, Federal University of São Paulo, São José dos Campos, Brazil
| | - Armênio Santos
- Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Brazil
| | - Ricardo Oliveira
- Ribeirão Preto Medical School, São Paulo University, Ribeirão Preto, Brazil
| | - José Miranda
- Department of Biophysics and Pharmacology, São Paulo State University, Biosciences Institute of Botucatu, Botucatu, Brazil
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Abstract
This review evaluates published studies regarding alpha-melanocyte stimulating hormone (α-MSH) in ghrelin-elicited feeding and gut motility. We have sought to integrate all available evidences to provide a complete review on the properties of melanocortin receptors (MCR) and the potential clinical treatment of α-MSH after ghrelin-elicited feeding and gut motility. The available studies were grouped into four categories: food intake, gastric emptying, small intestinal transit, and colonic transit. As we describe, the literature provides evidence of the ability of ghrelin to increase food intake, gastric emptying, small intestinal transit, and colonic transit. α-MSH, which displays high affinity for the MC3 and MC4 receptors, can competitively activate MCRs with agouti-related protein stimulated by ghrelin, and partly attenuates the effect of acyl ghrelin on food intake. Central ghrelin-induced acceleration of gastric emptying is not mediated by MCRs, but the acceleration of the small intestinal transit is at least partly mediated via MCRs in the brain. Similar to fecal pellets and total fecal weight, distal colonic motility and secretion are partly mediated by MCRs in the brain. The interplay between acyl ghrelin and MCRs may provide a new therapeutic avenue to ameliorate anorexia and constipation.
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Affiliation(s)
- Hsien-Hao Huang
- Department of Emergency Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Institute of Emergency and Critical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
| | - Chih-Yen Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
- Taiwan Association for the Study of Small Intestinal Diseases, Guishan, Taiwan, ROC
- Chinese Taipei Society for the Study of Obesity, Taipei, Taiwan, ROC
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Chen Y, Liu G, He F, Zhang L, Yang K, Yu H, Zhou J, Gan H. MicroRNA 375 modulates hyperglycemia-induced enteric glial cell apoptosis and Diabetes-induced gastrointestinal dysfunction by targeting Pdk1 and repressing PI3K/Akt pathway. Sci Rep 2018; 8:12681. [PMID: 30140011 PMCID: PMC6107553 DOI: 10.1038/s41598-018-30714-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 08/02/2018] [Indexed: 02/06/2023] Open
Abstract
Diabetic neuropathy can damage systemic nervous system, including alteration of enteric nervous system and subsequent gastrointestinal dysfunction. The effect of diabetes on enteric glia cell (EGC) is not clear. We investigated the effect of diabetes and hyperglycemia on EGC, and the role of microRNA375 in modulating EGC survival in vivo and in vitro. Streptozotocin-induced diabetic mice were intraperitoneally injected with microRNA375 inhibitor or its negative control. EGC was transfected with microRNA375 inhibitor or its mimic. Diabetes mice with gastrointestinal dysfunction showed increased apoptosis of EGC (no difference in cell numbers) and gene expression of micorRNA375 in the myenteric plexus. Hyperglycemia triggered apoptosis of EGC in vitro with decreased expression of Pdk1 and p-Akt, but increased expression of micorRNA375. MicorRNA375 mimic induced apoptosis of EGC in vitro with repressed Pdk1and p-Akt. MicorRNA375 inhibitor could both prevent hyperglycemia-induced apoptosis of EGC in vitro and diabetes-induced gastrointestinal dysfunction in vivo. Our results suggest that diabetes-induced gastrointestinal dysfunction is related to increased apoptosis of EGC in the myenteric plexus. Hyperglycemia can increase the expression of microRNA375 and damage EGC survival through PI3K/Akt pathway. MicroRNA375 specific inhibition can prevent hyperglycemia induced EGC damage and diabetes-induced gastrointestinal dysfunction.
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Affiliation(s)
- Yan Chen
- The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Gongxiang Liu
- The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Fuqian He
- The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Li Zhang
- Department of elderly digestive, Sichuan Provincial People's Hospital, Chengdu, 610072, China
| | - Kun Yang
- The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Huan Yu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jinqiu Zhou
- The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Huatian Gan
- The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Li Y, Zhang W, Ma J, Chen M, Lin B, Yang X, Li F, Tang X, Wang F. Study on the regulation of brain–gut peptide by Shenling Baizhu San in functional diarrhea rats. JOURNAL OF TRADITIONAL CHINESE MEDICAL SCIENCES 2018. [DOI: 10.1016/j.jtcms.2018.07.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Jang Y, Kim EK, Shim WS. Phytotherapeutic effects of the fruits of Poncirus trifoliata (L.) Raf. on cancer, inflammation, and digestive dysfunction. Phytother Res 2017; 32:616-624. [PMID: 29250842 DOI: 10.1002/ptr.6008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 10/24/2017] [Accepted: 11/14/2017] [Indexed: 12/15/2022]
Abstract
Poncirus trifoliata (L.) Raf. belongs to the family Rutaceae in the genus Poncirus. Its fruits are widely used to alleviate symptoms of various disorders. The mature fruit (MF) possesses anticancer and antiinflammatory activities. Extracts of the dried, immature fruit, Poncirus fructus (PF) are widely used as a traditional medicine for ameliorating symptoms of digestive dysfunction in East Asia. Molecular and cellular mechanisms underlying the effects of MF and PF extracts on cancer, inflammation, and gastrointestinal disorders have been extensively studied in the past decade. This review summarizes recent findings on the anticancer and antiinflammatory effects of MF and the prokinetic effects of PF. Although the therapeutic effects of MF and PF have been clearly elucidated, in-depth further clinical studies are still required to completely verify the clinical efficacy and safety of the fruits of P. trifoliata (L.) Raf.
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Affiliation(s)
- Yongwoo Jang
- McLean Hospital, Harvard Medical School, Belmont, MA, 02478, USA
| | - Eun-Kyung Kim
- Genosco, 767C Concord Ave, Cambridge, MA, 02138, USA
| | - Won-Sik Shim
- College of Pharmacy, Gachon University, Incheon, 21936, South Korea
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Nakato J, Ho YY, Omae R, Mizushige T, Uchida K, Tominaga M, Kim M, Goto T, Takahashi N, Kawada T, Akiduki S, Kanamoto R, Ohinata K. l-Ornithine and l-lysine stimulate gastrointestinal motility via transient receptor potential vanilloid 1. Mol Nutr Food Res 2017; 61. [PMID: 28722259 DOI: 10.1002/mnfr.201700230] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 06/15/2017] [Accepted: 07/04/2017] [Indexed: 01/09/2023]
Abstract
SCOPE The gastrointestinal (GI) tract senses and responds to intraluminal nutrients and these interactions often affect GI functions. We found that, among basic amino acids, l-ornithine (Orn) and l-lysine (Lys) stimulated but l-arginine (Arg) suppressed GI motility after oral administration (24 mmol/kg) in mice (Orn and Lys, 14.3 and 26.4% promotion; Arg, 7.7% suppression). We investigated the mechanism of the action of Orn and Lys on GI motility. METHODS AND RESULTS Orn-induced promotion of small intestinal transit was significantly inhibited (p<0.05) by oral administration of capsazepine, a transient receptor potential vanilloid 1 (TRPV1) antagonist. Moreover, the stimulatory effect of Orn and Lys was abolished in TRPV1-knockout mice. In TRPV1-transfected HEK293 cells, Orn and Lys (10 mM) evoked Ca2+ influx, which was blocked by ruthenium red, a TRP channel antagonist. These results suggest that Orn and Lys promote GI motility via activation of TRPV1. The GI motility stimulation by Orn and Lys was also blocked by atropine, a muscarinic acetylcholine receptor (mAChR) antagonist, or NG -nitro-l-arginine methyl ester, a nitric oxide (NO) synthase inhibitor. CONCLUSION Orally administered Orn and Lys stimulate GI motility via TRPV1, mAChR and NO synthase in mice.
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Affiliation(s)
- Junya Nakato
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan
| | - Yee Yin Ho
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan
| | - Ryo Omae
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan
| | - Takafumi Mizushige
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan.,Research Unit for Physiological Chemistry, C-PIER, Kyoto University, Kyoto, Japan
| | - Kunitoshi Uchida
- Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), Okazaki, Aichi, Japan.,Department of Physiological Sciences, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi, Japan
| | - Makoto Tominaga
- Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), Okazaki, Aichi, Japan.,Department of Physiological Sciences, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi, Japan
| | - Minji Kim
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan
| | - Tsuyoshi Goto
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan.,Research Unit for Physiological Chemistry, C-PIER, Kyoto University, Kyoto, Japan
| | - Nobuyuki Takahashi
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan.,Research Unit for Physiological Chemistry, C-PIER, Kyoto University, Kyoto, Japan
| | - Teruo Kawada
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan.,Research Unit for Physiological Chemistry, C-PIER, Kyoto University, Kyoto, Japan
| | - Saori Akiduki
- Healthcare Products Development Center, KYOWA HAKKO BIO CO., LTD., Tsukuba, Ibaraki, Japan
| | - Ryuhei Kanamoto
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan
| | - Kousaku Ohinata
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan
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Zhao M, Liao D, Zhao J. Diabetes-induced mechanophysiological changes in the small intestine and colon. World J Diabetes 2017; 8:249-269. [PMID: 28694926 PMCID: PMC5483424 DOI: 10.4239/wjd.v8.i6.249] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 04/05/2017] [Accepted: 05/05/2017] [Indexed: 02/05/2023] Open
Abstract
The disorders of gastrointestinal (GI) tract including intestine and colon are common in the patients with diabetes mellitus (DM). DM induced intestinal and colonic structural and biomechanical remodeling in animals and humans. The remodeling is closely related to motor-sensory abnormalities of the intestine and colon which are associated with the symptoms frequently encountered in patients with DM such as diarrhea and constipation. In this review, firstly we review DM-induced histomorphological and biomechanical remodeling of intestine and colon. Secondly we review motor-sensory dysfunction and how they relate to intestinal and colonic abnormalities. Finally the clinical consequences of DM-induced changes in the intestine and colon including diarrhea, constipation, gut microbiota change and colon cancer are discussed. The final goal is to increase the understanding of DM-induced changes in the gut and the subsequent clinical consequences in order to provide the clinicians with a better understanding of the GI disorders in diabetic patients and facilitates treatments tailored to these patients.
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Colldén G, Tschöp MH, Müller TD. Therapeutic Potential of Targeting the Ghrelin Pathway. Int J Mol Sci 2017; 18:ijms18040798. [PMID: 28398233 PMCID: PMC5412382 DOI: 10.3390/ijms18040798] [Citation(s) in RCA: 111] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 04/03/2017] [Accepted: 04/06/2017] [Indexed: 02/07/2023] Open
Abstract
Ghrelin was discovered in 1999 as the endogenous ligand of the growth-hormone secretagogue receptor 1a (GHSR1a). Since then, ghrelin has been found to exert a plethora of physiological effects that go far beyond its initial characterization as a growth hormone (GH) secretagogue. Among the numerous well-established effects of ghrelin are the stimulation of appetite and lipid accumulation, the modulation of immunity and inflammation, the stimulation of gastric motility, the improvement of cardiac performance, the modulation of stress, anxiety, taste sensation and reward-seeking behavior, as well as the regulation of glucose metabolism and thermogenesis. Due to a variety of beneficial effects on systems’ metabolism, pharmacological targeting of the endogenous ghrelin system is widely considered a valuable approach to treat metabolic complications, such as chronic inflammation, gastroparesis or cancer-associated anorexia and cachexia. The aim of this review is to discuss and highlight the broad pharmacological potential of ghrelin pathway modulation for the treatment of anorexia, cachexia, sarcopenia, cardiopathy, neurodegenerative disorders, renal and pulmonary disease, gastrointestinal (GI) disorders, inflammatory disorders and metabolic syndrome.
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Affiliation(s)
- Gustav Colldén
- Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
| | - Matthias H Tschöp
- Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
- Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany.
| | - Timo D Müller
- Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
- Institute for Diabetes and Obesity (IDO), Business Campus Garching-Hochbrück, Parkring 13, 85748 Garching, Germany.
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Robinson AM, Rahman AA, Carbone SE, Randall-Demllo S, Filippone R, Bornstein JC, Eri R, Nurgali K. Alterations of colonic function in the Winnie mouse model of spontaneous chronic colitis. Am J Physiol Gastrointest Liver Physiol 2017; 312:G85-G102. [PMID: 27881401 DOI: 10.1152/ajpgi.00210.2016] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Revised: 11/14/2016] [Accepted: 11/14/2016] [Indexed: 01/31/2023]
Abstract
UNLABELLED The Winnie mouse, carrying a missense mutation in Muc2, is a model for chronic intestinal inflammation demonstrating symptoms closely resembling inflammatory bowel disease (IBD). Alterations to the immune environment, morphological structure, and innervation of Winnie mouse colon have been identified; however, analyses of intestinal transit and colonic functions have not been conducted. In this study, we investigated in vivo intestinal transit in radiographic studies and in vitro motility of the isolated colon in organ bath experiments. We compared neuromuscular transmission using conventional intracellular recording between distal colon of Winnie and C57BL/6 mice and smooth muscle contractions using force displacement transducers. Chronic inflammation in Winnie mice was confirmed by detection of lipocalin-2 in fecal samples over 4 wk and gross morphological damage to the colon. Colonic transit was faster in Winnie mice. Motility was altered including decreased frequency and increased speed of colonic migrating motor complexes and increased occurrence of short and fragmented contractions. The mechanisms underlying colon dysfunctions in Winnie mice included inhibition of excitatory and fast inhibitory junction potentials, diminished smooth muscle responses to cholinergic and nitrergic stimulation, and increased number of α-smooth muscle actin-immunoreactive cells. We conclude that diminished excitatory responses occur both prejunctionally and postjunctionally and reduced inhibitory purinergic responses are potentially a prejunctional event, while diminished nitrergic inhibitory responses are probably due to a postjunction mechanism in the Winnie mouse colon. Many of these changes are similar to disturbed motor functions in IBD patients indicating that the Winnie mouse is a model highly representative of human IBD. NEW & NOTEWORTHY This is the first study to provide analyses of intestinal transit and whole colon motility in an animal model of spontaneous chronic colitis. We found that cholinergic and purinergic neuromuscular transmission, as well as the smooth muscle cell responses to cholinergic and nitrergic stimulation, is altered in the chronically inflamed Winnie mouse colon. The changes to intestinal transit and colonic function we identified in the Winnie mouse are similar to those seen in inflammatory bowel disease patients.
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Affiliation(s)
- Ainsley M Robinson
- College of Health and Biomedicine, Victoria University, Melbourne, Victoria, Australia
| | - Ahmed A Rahman
- College of Health and Biomedicine, Victoria University, Melbourne, Victoria, Australia
| | - Simona E Carbone
- College of Health and Biomedicine, Victoria University, Melbourne, Victoria, Australia
| | - Sarron Randall-Demllo
- University of Tasmania, School of Health Sciences, Launceston, Tasmania, Australia; and
| | - Rhiannon Filippone
- College of Health and Biomedicine, Victoria University, Melbourne, Victoria, Australia
| | - Joel C Bornstein
- Department of Physiology, Melbourne University, Melbourne, Victoria, Australia
| | - Rajaraman Eri
- University of Tasmania, School of Health Sciences, Launceston, Tasmania, Australia; and
| | - Kulmira Nurgali
- College of Health and Biomedicine, Victoria University, Melbourne, Victoria, Australia;
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Cheng Y, Wei Y, Yang W, Cai Y, Chen B, Yang G, Shang H, Zhao W. Ghrelin Attenuates Intestinal Barrier Dysfunction Following Intracerebral Hemorrhage in Mice. Int J Mol Sci 2016; 17:ijms17122032. [PMID: 27929421 PMCID: PMC5187832 DOI: 10.3390/ijms17122032] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 11/10/2016] [Accepted: 11/28/2016] [Indexed: 02/07/2023] Open
Abstract
Intestinal barrier dysfunction remains a critical problem in patients with intracerebral hemorrhage (ICH) and is associated with poor prognosis. Ghrelin, a brain-gut peptide, has been shown to exert protection in animal models of gastrointestinal injury. However, the effect of ghrelin on intestinal barrier dysfunction post-ICH and its possible underlying mechanisms are still unknown. This study was designed to investigate whether ghrelin administration attenuates intestinal barrier dysfunction in experimental ICH using an intrastriatal autologous blood infusion mouse model. Our data showed that treatment with ghrelin markedly attenuated intestinal mucosal injury at both histomorphometric and ultrastructural levels post-ICH. Ghrelin reduced ICH-induced intestinal permeability according to fluorescein isothiocyanate conjugated-dextran (FITC-D) and Evans blue extravasation assays. Concomitantly, the intestinal tight junction-related protein markers, Zonula occludens-1 (ZO-1) and claudin-5 were upregulated by ghrelin post-ICH. Additionally, ghrelin reduced intestinal intercellular adhesion molecule-1 (ICAM-1) expression at the mRNA and protein levels following ICH. Furthermore, ghrelin suppressed the translocation of intestinal endotoxin post-ICH. These changes were accompanied by improved survival rates and an attenuation of body weight loss post-ICH. In conclusion, our results suggest that ghrelin reduced intestinal barrier dysfunction, thereby reducing mortality and weight loss, indicating that ghrelin is a potential therapeutic agent in ICH-induced intestinal barrier dysfunction therapy.
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Affiliation(s)
- Yijun Cheng
- Department of Neurosurgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Yongxu Wei
- Department of Neurosurgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Wenlei Yang
- Department of Neurosurgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Yu Cai
- Department of Neurosurgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Bin Chen
- Department of Neurosurgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Guoyuan Yang
- Department of Neurology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
- Neuroscience and Neuroengineering Research Center, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China.
| | - Hanbing Shang
- Department of Neurosurgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Weiguo Zhao
- Department of Neurosurgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
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Mard SA, Ahmadi I, Ahangarpour A, Gharib-Naseri MK, Badavi M. Delayed gastric emptying in diabetic rats caused by decreased expression of cystathionine gamma lyase and H 2 S synthesis: in vitro and in vivo studies. Neurogastroenterol Motil 2016; 28:1677-1689. [PMID: 27324218 DOI: 10.1111/nmo.12867] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 05/04/2016] [Indexed: 01/09/2023]
Abstract
BACKGROUND This study aimed to evaluate the role of H2 S on gastric emptying rate (GER) and also to determine the effect of gastric distention on mRNA and protein expression of cystathionine β-lyase (CBS) and cystathionine γ-synthase (CSE) in diabetic-gastroparetic and normal rats. METHODS Adult normal rats intraperitoneally received either propargylglycine (PAG), L-cysteine or NaHS 30 min prior to GER marker (acetaminophen) to investigate H2 S involvement in GER and the same protocols were performed in diabetes-induced gastroparesis rats. The role of calcitonin gene related peptide (CGRP) neurons in the prokinetic effect of endogenous H2 S on GER was determined. The level of CBS and CSE expressions in response to gastric distention were also determined. The effect of H2 S on frequency and tension of spontaneous contractions of gastric smooth muscle strips was investigated. KEY RESULTS Our results showed that: (i) H2 S and L-cysteine increased GER in gastroparetic and normal rats. (ii) The increased levels of CSE expression in response to gastric distention in diabetic rats were lower than in normal rats. (iii) PAG inhibited the excitatory effect of capsaicin on GER and on tension of spontaneous contractions of strips. (iv) Hydrogen sulphide increased the frequency and tension of spontaneous contractions of gastric strip muscles in normal and diabetic rats. CONCLUSIONS & INFERENCES The results showed that delayed GER in diabetic rats can be due to down-regulation of H2 S biosynthesis enzyme, CSE and suggested that a potential prokinetic role for H2 S to treat the delayed gastric emptying in diabetic patients.
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Affiliation(s)
- S A Mard
- Physiology Research Center (PRC), Research Center for Infectious Diseases of Digestive System, Dept. of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. ,
| | - I Ahmadi
- Physiology Research Center (PRC), Research Center for Infectious Diseases of Digestive System, Dept. of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - A Ahangarpour
- Physiology Research Center (PRC), Dept. of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - M K Gharib-Naseri
- Physiology Research Center (PRC), Dept. of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - M Badavi
- Physiology Research Center (PRC), Dept. of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Georgiev T, Tolekova A, Kalfin R, Hadzhibozheva P. Short-term administration of melatonin or ghrelin on diabetic rats: effects on angiotensin II and vasopressin-induced uterine contractility. Physiol Res 2016; 66:125-133. [PMID: 27782742 DOI: 10.33549/physiolres.933337] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The aim of the present study was to investigate the effects of Angiotensin II (Ang II) and Arginin-Vasopressin (AVP) on contractility of non-pregnant uterus in diabetic Wistar rats and to explore whether one-week administration of Melatonin (MLT) or Ghrelin (GHR) will change the response of diabetic uterine muscle to AngII and AVP. Uterine horns, prepared by the method of isolated tissues were investigated as well as glycemic profile, blood pressure and body weight. The research of smooth muscle contractions was made by a new method of analysis, characterizing in detail the various phases of the myometrial activity. Differences in the development of the peptide-mediated smooth muscle contractions depending on the phase of the estrous cycle were observed. Experimental diabetes had a pronounced negative effect on force and time-parameters of AngII and AVP-stimulated uterine contractions. Administration of GHR or MLT had a beneficial effect on the glycemic status of diabetic rats and partially improved the response of uterine preparations to the peptides. The application of MLT increased both force and time-parameters of Ang II-and AVP-stimulated uterine contractions while treatment with GHR increased power characteristics and shortened contraction and relaxation of the smooth muscle process.
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Affiliation(s)
- T Georgiev
- Department of Physiology, Pathophysiology and Pharmacology, Medical Faculty, Trakia University, Stara Zagora, Bulgaria.
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Hao XK, Wu W, Wang CX, Xie GB, Li T, Wu HM, Huang LT, Zhou ML, Hang CH, Shi JX. Ghrelin alleviates early brain injury after subarachnoid hemorrhage via the PI3K/Akt signaling pathway. Brain Res 2014; 1587:15-22. [PMID: 25199591 DOI: 10.1016/j.brainres.2014.08.069] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 08/25/2014] [Accepted: 08/29/2014] [Indexed: 12/25/2022]
Abstract
Early brain injury (EBI) plays a key role in the pathogenesis of subarachnoid hemorrhage (SAH). Although the neuroprotective effects of ghrelin have been demonstrated in several studies, whether ghrelin reduces EBI after SAH remains unknown. In this study, we hypothesized that treatment with ghrelin would attenuate EBI after SAH, and that this protection would be mediated, at least in part, by activation of the PI3K/Akt signaling pathway. Adult male Sprague-Dawley rats (n=100) were randomly divided into the following groups: control group (n=20), SAH group (n=20), SAH+vehicle group (n=20), SAH+ghrelin group (n=20) and SAH+ghrelin+LY294002 group (n=20). The rats were injected with autologous blood (0.3mL) into the prechiasmatic cistern to induce SAH. Ghrelin (80μg/kg, IP), or an equal volume of vehicle, was administered immediately after surgery. The PI3K inhibitor, LY294002, was applied to manipulate the proposed pathway. Mortality, neurological scores, brain edema, cell apoptosis, and the expression of p-Akt, and cleaved caspase-3 proteins were assayed after 24h SAH. Ghrelin significantly improved neurological function and reduced neuronal apoptosis and brain edema at 24h after SAH. The level of p-Akt, expressed mainly in neurons, was markedly up-regulated. Additionally, the level of cleaved caspase-3 was decreased by ghrelin treatment. The beneficial effects of ghrelin in SAH rats were partially suppressed by LY294002. These results demonstrate that ghrelin may reduce EBI after SAH, via a mechanism involving the PI3K/Akt signaling pathway.
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Affiliation(s)
- Xiao-Ke Hao
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Second Military Medical University, Shanghai, China
| | - Wei Wu
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Second Military Medical University, Shanghai, China; Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China
| | - Chun-Xi Wang
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China
| | - Guang-Bin Xie
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China
| | - Tao Li
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China
| | - He-Ming Wu
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Second Military Medical University, Shanghai, China
| | - Li-Tian Huang
- Department of Neurosurgery, School of Medicine, Southern Medical University (Guangzhou), Jinling Hospital, Nanjing, Jiangsu Province, China
| | - Meng-Liang Zhou
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China
| | - Chun-Hua Hang
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Second Military Medical University, Shanghai, China; Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China
| | - Ji-Xin Shi
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Second Military Medical University, Shanghai, China; Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China
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Murad HAS, Abdallah HM. Black tea extract and its thearubigins relieve the sildenafil-induced delayed gut motility in mice: a possible role of nitric oxide. Phytother Res 2014; 28:1687-91. [PMID: 24895242 DOI: 10.1002/ptr.5183] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 05/02/2014] [Accepted: 05/08/2014] [Indexed: 11/08/2022]
Abstract
In this study we hypothesize that a standardized black tea aqueous extract (BTE) and thearubigins, its main polyphenolic pigments, will improve sildenafil-induced delay in gastric emptying (GE) and small intestinal transit (SIT) in mice. Twenty groups of mice (n = 8) were given a phenol red meal, and three sets of experiments were performed. In the first and second sets, effects of different concentrations of BTE, thearubigins (TRs), and sildenafil (SLD), alone and in combinations, on GE and SIT were measured. In the third set, influence of nω -Nitro-l-arginine methyl ester hydrochloride (l-NAME) pretreatment on effects of these treatments was tested. Black tea extract (3% and 4.5%) and thearubigins (50 and 60 mg/kg) dose-dependently increased GE and SIT, whereas BTE 6% and thearubigins 70 mg/kg did not affect them. Sildenafil dose-dependently reduced both GE and SIT. Combination of metoclopramide, BTE 4.5%, thearubigins 60, or l-NAME with sildenafil (5 mg/kg) reversed its motility-delaying effects. Pretreatment with l-NAME followed by BTE 4.5%, thearubigins 60, BTE 4.5% + sildenafil 5, or thearubigins 60 + sildenafil 5 only partially affected the accelerating effects of BTE 4.5% and thearubigins 60. In conclusion, a standardized BTE and its thearubigins improve the sildenafil-induced delayed gut motility in mice. This improvement was partially blocked by l-NAME suggesting a possible role of nitric oxide. Thus, BTE 4.5% or TRs 60 mg/kg solution could be considered a reliever therapy for the sildenafil-induced dyspepsia.
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Affiliation(s)
- Hussam A S Murad
- Department of Pharmacology, Faculty of Medicine, Rabigh, King Abdulaziz University (KAU), Jeddah, 21589, Saudi Arabia; Department of Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, 11562, Egypt
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Avau B, Carbone F, Tack J, Depoortere I. Ghrelin signaling in the gut, its physiological properties, and therapeutic potential. Neurogastroenterol Motil 2013; 25:720-32. [PMID: 23910374 DOI: 10.1111/nmo.12193] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2013] [Accepted: 06/26/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND Ghrelin, an orexigenic hormone secreted from the stomach, was soon after its discovery hypothesized to be a prokinetic agent, due to its homology to motilin. Studies in animals and humans, using ghrelin and ghrelin receptor agonists, confirmed this hypothesis, suggesting a therapeutic potential for the ghrelin receptor in the treatment of gastrointestinal motility disorders. Precilinical studies demonstrated that ghrelin can act directly on ghrelin receptors on the enteric nervous system, but the predominant route of action under physiological circumstances is signaling via the vagus nerve in the upper gastrointestinal tract and the pelvic nerves in the colon. Different pharmaceutical companies have designed stable ghrelin mimetics that revealed promising results in trials for the treatment of diabetic gastroparesis and post-operative ileus. Nevertheless, no drug was able to reach the market so far, facing problems proving superiority over placebo treatment in larger trials. PURPOSE This review aims to summarize the road that led to the current knowledge concerning the prokinetic properties of ghrelin with a focus on the therapeutic potential of ghrelin receptor agonists in the treatment of hypomotility disorders. In addition, we outline some of the problems that could be at the basis of the negative outcome of the trials with ghrelin agonists and question whether the right target groups were selected. It is clear that a new approach is needed to develop marketable drugs with this class of gastroprokinetic agents.
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Affiliation(s)
- B Avau
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
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Shalaby MAF, Latif HAAE, Sayed MEE. Interaction of insulin with prokinetic drugs in STZ-induced diabetic mice. World J Gastrointest Pharmacol Ther 2013; 4:28-38. [PMID: 23667771 PMCID: PMC3644615 DOI: 10.4292/wjgpt.v4.i2.28] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2012] [Revised: 10/29/2012] [Accepted: 01/21/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the possible interactions of metoclopramide, domperidone and erythromycin in streptozotocin-induced diabetic mice treated with insulin by various parameters.
METHODS: Effects of the individual as well as combined drugs were studied in diabetic mice via estimation of the blood glucose and serum insulin levels, small intestinal transit (SIT), gastric emptying (GE), xylose absorption and glucose tolerance tests. Groups were given insulin 2 IU/kg s.c., metoclopramide 20 mg/kg p.o., domperidone 20 mg/kg p.o. and erythromycin 6 mg/kg p.o. individually and in combination. There were also normal and diabetic control groups. The first set of experiments was carried out to investigate the subchronic effect on blood glucose and serum insulin levels in diabetic mice of one week of daily dose administration of the tested drugs individually as well as the combination of insulin with each prokinetic drug. The other five sets of experiments were carried out to investigate the acute effect of a single dose of each drug individually and in combination on blood glucose and serum insulin levels, SIT, GE, oral xylose absorption and glucose tolerance tests.
RESULTS: The study included the prokinetic drugs metoclopramide (20 mg/kg), domperidone (20 mg/kg) and erythromycin (6 mg/kg), as well as insulin (2 IU/kg), which was individually effective in decreasing SIT, enhancing GE and increasing xylose absorption significantly in diabetic mice. Erythromycin tended to decrease blood glucose level and increase serum insulin level after 1 wk of daily administration in diabetic mice. Erythromycin potentiated the effect of insulin on blood glucose level and serum insulin level whereas other prokinetic agents failed to do so after repeated dose administration in diabetic mice. Metoclopramide or erythromycin in combination with insulin significantly decreased SIT, in diabetic mice, to lower levels than with insulin alone. Administration of prokinetic drugs along with insulin antagonized the action of insulin on xylose absorption. These combinations also increased the rate of glucose absorption from the gut.
CONCLUSION: The present study suggests that prokinetic drugs could potentially improve glycemic control in diabetic gastroparesis by allowing a more predictable absorption of nutrients, matched to the action of exogenous insulin. The use of prokinetics, such as erythromycin, may be interesting in the clinic in decreasing the need for insulin in diabetic patients. The dose of insulin may be safely decreased with erythromycin in chronic treatments.
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18
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In vivo characterization of intestinal effects of endomorphin-1 and endomorphin-2 in type 1 diabetic mice. Eur J Pharmacol 2013; 698:499-504. [DOI: 10.1016/j.ejphar.2012.10.044] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2012] [Revised: 10/27/2012] [Accepted: 10/31/2012] [Indexed: 11/21/2022]
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Lopez NE, Gaston L, Lopez KR, Coimbra RC, Hageny A, Putnam J, Eliceiri B, Coimbra R, Bansal V. Early ghrelin treatment attenuates disruption of the blood brain barrier and apoptosis after traumatic brain injury through a UCP-2 mechanism. Brain Res 2012; 1489:140-8. [PMID: 23099053 DOI: 10.1016/j.brainres.2012.10.031] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2012] [Revised: 09/11/2012] [Accepted: 10/16/2012] [Indexed: 01/04/2023]
Abstract
Ghrelin has been shown to be anti-inflammatory and neuroprotective in models of neurologic injury. We hypothesize that treatment with ghrelin will attenuate breakdown of the blood brain barrier (BBB) and apoptosis 24h following traumatic brain injury (TBI). We believe this protection is at least in part mediated by up-regulation of UCP-2, thereby stabilizing mitochondria and preventing up-regulation of caspase-3. A weight drop model was used to create severe TBI. Balb/c mice were divided into 3 groups. Sham: no TBI or ghrelin treatment; TBI: TBI only; TBI/ghrelin: 20μg (IP) ghrelin at the time of TBI. BBB permeability to 70kDa FITC-Dextran was measured 24h following injury and quantified in arbitrary integrated fluorescence (afu). Brain tissue was subjected to TUNEL staining and TUNEL positive cells were quantified. Immunohistochemistry was performed on injured tissue to reveal patterns of caspase-3 and UCP-2 expression. TBI increased cerebral vascular permeability by three-fold compared to sham. Ghrelin treatment restored vascular permeability to the level of shams. TUNEL staining showed that ghrelin mitigated the significant increase in apoptosis that follows TBI. TBI increased both caspase-3 compared to sham. Treatment with ghrelin significantly increased UCP-2 compared to TBI alone and this increase in UCP-2 expression was associated with a decrease in expression of caspase-3. Early ghrelin treatment prevents TBI induced BBB disruption and TBI mediated apoptosis 24h following injury. These results demonstrate the neuroprotective potential of ghrelin as a therapy in TBI.
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Affiliation(s)
- N E Lopez
- University of California San Diego, Department of Surgery, Division of Trauma, Surgical Critical Care and Burns, 200W. Arbor Drive #8896, San Diego, CA 92103, USA.
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Bansal V, Ryu SY, Lopez N, Allexan S, Krzyzaniak M, Eliceiri B, Baird A, Coimbra R. Vagal stimulation modulates inflammation through a ghrelin mediated mechanism in traumatic brain injury. Inflammation 2012; 35:214-20. [PMID: 21360048 PMCID: PMC3282000 DOI: 10.1007/s10753-011-9307-7] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Traumatic brain injury (TBI) releases a cascade of inflammatory cytokines. Vagal nerve stimulation (VNS) and ghrelin have known anti-inflammatory effects; furthermore, ghrelin release is stimulated by acetylcholine. We hypothesized VNS decreases post-TBI inflammation through a ghrelin-mediated mechanism. TBI was created in five groups of mice: sham, TBI, TBI/ghrelin, TBI/VNS, and TBI/VNS/ghrelin receptor antagonist (GRa). Serum and tissue ghrelin, and serum TNF-α were measured. Ghrelin increased following VNS 2 h post-TBI compared to sham or TBI. At 6 h, TBI and TBI/VNS/GRa had increased TNF-α compared to sham while TBI/VNS and TBI/ghrelin had TNF-α level comparable to sham. The highest ghrelin was measured in stomach where TBI decreased ghrelin in contrast to an increase by VNS. In conclusion, VNS increased serum ghrelin and decreased TNF-α following TBI. This was abrogated with GRa. Our data suggests that ghrelin plays an important role in the anti-inflammatory effects of VNS following TBI.
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Affiliation(s)
- Vishal Bansal
- Department of Surgery, Division of Trauma, Surgical Critical Care and Burns, University of California San Diego, 200 W. Arbor Drive #8896, San Diego, CA 92103 USA
| | - Seok Yong Ryu
- Department of Surgery, Division of Trauma, Surgical Critical Care and Burns, University of California San Diego, 200 W. Arbor Drive #8896, San Diego, CA 92103 USA
- Department of Emergency Medicine, Inje University, Sanggye Paik Hospital, Seoul, South Korea
| | - Nicole Lopez
- Department of Surgery, Division of Trauma, Surgical Critical Care and Burns, University of California San Diego, 200 W. Arbor Drive #8896, San Diego, CA 92103 USA
| | - Sarah Allexan
- Department of Surgery, Division of Trauma, Surgical Critical Care and Burns, University of California San Diego, 200 W. Arbor Drive #8896, San Diego, CA 92103 USA
| | - Michael Krzyzaniak
- Department of Surgery, Division of Trauma, Surgical Critical Care and Burns, University of California San Diego, 200 W. Arbor Drive #8896, San Diego, CA 92103 USA
| | - Brian Eliceiri
- Department of Surgery, Division of Trauma, Surgical Critical Care and Burns, University of California San Diego, 200 W. Arbor Drive #8896, San Diego, CA 92103 USA
| | - Andrew Baird
- Department of Surgery, Division of Trauma, Surgical Critical Care and Burns, University of California San Diego, 200 W. Arbor Drive #8896, San Diego, CA 92103 USA
| | - Raul Coimbra
- Department of Surgery, Division of Trauma, Surgical Critical Care and Burns, University of California San Diego, 200 W. Arbor Drive #8896, San Diego, CA 92103 USA
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Lopez NE, Krzyzaniak MJ, Blow C, Putnam J, Ortiz-Pomales Y, Hageny AM, Eliceiri B, Coimbra R, Bansal V. Ghrelin prevents disruption of the blood-brain barrier after traumatic brain injury. J Neurotrauma 2011; 29:385-93. [PMID: 21939391 DOI: 10.1089/neu.2011.2053] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Significant effort has been focused on reducing neuronal damage from post-traumatic brain injury (TBI) inflammation and blood-brain barrier (BBB)-mediated edema. The orexigenic hormone ghrelin decreases inflammation in sepsis models, and has recently been shown to be neuroprotective following subarachnoid hemorrhage. We hypothesized that ghrelin modulates cerebral vascular permeability and mediates BBB breakdown following TBI. Using a weight-drop model, TBI was created in three groups of mice: sham, TBI, and TBI/ghrelin. The BBB was investigated by examining its permeability to FITC-dextran and through quantification of perivascualar aquaporin-4 (AQP-4). Finally, we immunoblotted for serum S100B as a marker of brain injury. Compared to sham, TBI caused significant histologic neuronal degeneration, increases in vascular permeability, perivascular expression of AQP-4, and serum levels of S100B. Treatment with ghrelin mitigated these effects; after TBI, ghrelin-treated mice had vascular permeability and perivascular AQP-4 and S100B levels that were similar to sham. Our data suggest that ghrelin prevents BBB disruption after TBI. This is evident by a decrease in vascular permeability that is linked to a decrease in AQP-4. This decrease in vascular permeability may diminish post-TBI brain tissue damage was evident by decreased S100B.
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Affiliation(s)
- Nicole E Lopez
- Department of Surgery, University of California-San Diego, San Diego, California, USA
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Shaikh AS, Somani RS. Animal models and biomarkers of neuropathy in diabetic rodents. Indian J Pharmacol 2011; 42:129-34. [PMID: 20871761 PMCID: PMC2937311 DOI: 10.4103/0253-7613.66833] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2009] [Revised: 02/24/2010] [Accepted: 06/09/2010] [Indexed: 02/07/2023] Open
Abstract
Diabetic neuropathy (DN) is a multifactor complication of diabetes. It is a late finding in type 1 diabetes, but can be an early finding in type 2 diabetes. The cause of DN is still unclear and, like other complications of diabetes, it may be the result of various pathological conditions. Animal models and biomarkers of DN have been extensively used in neuropathic research. The most useful model of DN should exhibit the key feature present in human pathology. Diabetic rodents show behavioral, functional, structural and molecular biomarkers and they are widely used as models to investigate the etiology of DN as well as to screen the efficacy of the potential therapeutic interventions. We have reviewed the different animal models and biomarkers of neuropathy in diabetic rodents of either type 1 or type 2 diabetes.
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Affiliation(s)
- A S Shaikh
- Department of Pharmacology, Sinhgad College of Pharmacy, Pune - 411 041, India
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Bansal V, Ryu SY, Blow C, Costantini T, Loomis W, Eliceiri B, Baird A, Wolf P, Coimbra R. The hormone ghrelin prevents traumatic brain injury induced intestinal dysfunction. J Neurotrauma 2010; 27:2255-60. [PMID: 20858122 PMCID: PMC3304249 DOI: 10.1089/neu.2010.1372] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Intestinal barrier breakdown following traumatic brain injury (TBI) is characterized by increased intestinal permeability, leading to bacterial translocation, and inflammation. The hormone ghrelin may prevent intestinal injury and have anti-inflammatory properties. We hypothesized that exogenous ghrelin prevents intestinal injury following TBI. A weight-drop model created severe TBI in three groups of anesthetized Balb/c mice. Group TBI: animals underwent TBI only; Group TBI/ghrelin: animals were given 10 μg of ghrelin intraperitoneally prior and 1 h following TBI; Group sham: no TBI or ghrelin injection. Intestinal permeability was measured 6 h following TBI by detecting serum levels of FITC-Dextran after injection into the intact ileum. The terminal ileum was harvested for histology, expression of the tight junction protein MLCK and inflammatory cytokine TNF-α. Permeability increased in the TBI group compared to the sham group (109.7 ± 21.8 μg/mL vs. 32.2 ± 10.1 μg/mL; p < 0.002). Ghrelin prevented TBI-induced permeability (28.3 ± 4.2 μg/mL vs. 109.7 ± 21.8 μg/mL; p < 0.001). The intestines of the TBI group showed blunting and necrosis of villi compared to the sham group, while ghrelin injection preserved intestinal architecture. Intestinal MLCK increased 73% compared to the sham group (p < 0.03). Ghrelin prevented TBI-induced MLCK expression to sham levels. Intestinal TNF-α increased following TBI compared to the sham group (46.2 ± 7.1 pg/mL vs. 24.4 ± 2.2 pg/mL p < 0.001). Ghrelin reduced TNF-α to sham levels (29.2 ± 5.0 pg/mL; p = NS). We therefore conclude that ghrelin prevents TBI-induced injury, as determined by intestinal permeability, histology, and intestinal levels of TNF-α. The mechanism for ghrelin mediating intestinal protection is likely multifactorial, and further studies are needed to delineate these possibilities.
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Affiliation(s)
- Vishal Bansal
- Department of Surgery, Division of Trauma, Surgical Critical Care and Burns, University of California San Diego, San Diego, California
| | - Seok Yong Ryu
- Department of Surgery, Division of Trauma, Surgical Critical Care and Burns, University of California San Diego, San Diego, California
- Department of Emergency Medicine, Inje University, Sanggye Paik Hospital, South Korea
| | - Chelsea Blow
- Department of Surgery, Division of Trauma, Surgical Critical Care and Burns, University of California San Diego, San Diego, California
| | - Todd Costantini
- Department of Surgery, Division of Trauma, Surgical Critical Care and Burns, University of California San Diego, San Diego, California
| | - William Loomis
- Department of Surgery, Division of Trauma, Surgical Critical Care and Burns, University of California San Diego, San Diego, California
| | - Brian Eliceiri
- Department of Surgery, Division of Trauma, Surgical Critical Care and Burns, University of California San Diego, San Diego, California
| | - Andrew Baird
- Department of Surgery, Division of Trauma, Surgical Critical Care and Burns, University of California San Diego, San Diego, California
| | - Paul Wolf
- Department of Pathology, University of California San Diego, San Diego, California
| | - Raul Coimbra
- Department of Surgery, Division of Trauma, Surgical Critical Care and Burns, University of California San Diego, San Diego, California
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25
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Sonnett TE, Levien TL, Gates BJ, Robinson JD, Campbell RK. Diabetes mellitus, inflammation, obesity: proposed treatment pathways for current and future therapies. Ann Pharmacother 2010; 44:701-11. [PMID: 20233909 DOI: 10.1345/aph.1m640] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE To review the pathophysiology, pharmacology, and current or future therapies under study for use in treating diabetes mellitus, inflammation associated with diabetes mellitus, and/or obesity related to diabetes mellitus, through 1 of 4 investigational pathways: adiponectin, ghrelin, resveratrol, or leptin. DATA SOURCES A literature search using MEDLINE (1966-December 12, 2009), PubMed (1950-December 12, 2009), Science Direct (1994-December 12, 2009), and International Pharmaceutical Abstracts (1970-December 12, 2009) was performed using the terms adiponectin, ghrelin, resveratrol, leptin, inflammation, obesity, and diabetes mellitus. English-language, original research, and review articles were examined, and citations from these articles were assessed as well. STUDY SELECTION AND DATA EXTRACTION Clinical studies and in vitro studies were included in addition to any Phase 1, 2, or 3 clinical trials. DATA SYNTHESIS Mechanistic pathways regarding adiponectin, ghrelin, resveratrol, and leptin are of interest as future treatment options for diabetes mellitus. Each of these pathways has produced significant in vitro and in vivo clinical data warranting further research as a possible treatment pathway for diabetes-related inflammation and/or obesity reduction. While research is still underway to determine the exact effects these pathways have on metabolic function, current data suggest that each of these compounds may be of interest for future therapies. CONCLUSIONS While several pathways under investigation may offer additional benefits in the treatment of diabetes mellitus and associated impairments, further investigation is necessary for both investigational and approved therapies to ensure that the impact in new pathways does not increase risks to patient safety and outcomes.
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Affiliation(s)
- Travis E Sonnett
- Department of Pharmacotherapy, Washington State University, Pullman, 99164, USA.
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Popescu I, Fleshner PR, Pezzullo JC, Charlton PA, Kosutic G, Senagore AJ. The Ghrelin agonist TZP-101 for management of postoperative ileus after partial colectomy: a randomized, dose-ranging, placebo-controlled clinical trial. Dis Colon Rectum 2010; 53:126-34. [PMID: 20087086 DOI: 10.1007/dcr.0b013e3181b54166] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE Ghrelin agonist TZP-101 is a potent prokinetic. This phase 2b study evaluated TZP-101 safety and efficacy in postoperative ileus management. METHODS Adults undergoing open partial colectomy were adaptively randomized to receive 20, 40, 80, 160, 320, 480 or 600 microg/kg TZP-101 (n = 168) or the placebo (n = 68) by 30-minute IV infusion within 1 hour of surgical closure and then daily for up to 7 days. The primary efficacy end point was the time to first bowel movement. Secondary end points included the percentage of patients with return of gastrointestinal function within 72 hours, and the time to readiness for discharge. RESULTS TZP-101 accelerated the time to first bowel movement in all groups, with Cox proportional hazard ratios of 1.57 (P = .056) for the low-efficacious dose (80 microg/kg) and 1.67 (P = .03) for the most efficacious dose (480 microg/kg). Using Kaplan-Meier analysis, the median time to first bowel movement was reduced in all TZP-101 groups by 10 to 22 hours vs. the placebo. A greater number of patients who received TZP-101 achieved recovery (P <or= .001) by 72 hours postsurgery compared with the placebo. The median time to readiness for hospital discharge was significantly accelerated by 20.4 hours at the 480 microg/kg TZP-101 dose compared with the placebo (hazard ratio = 1.69; P = .03). The most common treatment-emergent adverse events were nausea and vomiting, which were reduced in the TZP-101 group compared with the placebo group. CONCLUSION In patients undergoing major abdominal surgery, the first-in-class ghrelin agonist TZP-101 was well-tolerated and accelerated recovery of the upper and lower gastrointestinal tract, with a large proportion of subjects recovering within 72 hours compared with the placebo.
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De Smet B, Mitselos A, Depoortere I. Motilin and ghrelin as prokinetic drug targets. Pharmacol Ther 2009; 123:207-23. [DOI: 10.1016/j.pharmthera.2009.04.004] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2009] [Accepted: 04/09/2009] [Indexed: 12/13/2022]
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Charoenthongtrakul S, Giuliana D, Longo KA, Govek EK, Nolan A, Gagne S, Morgan K, Hixon J, Flynn N, Murphy BJ, Hernández AS, Li J, Tino JA, Gordon DA, DiStefano PS, Geddes BJ. Enhanced gastrointestinal motility with orally active ghrelin receptor agonists. J Pharmacol Exp Ther 2009; 329:1178-86. [PMID: 19252061 DOI: 10.1124/jpet.108.150193] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2025] Open
Abstract
The orexigenic peptide ghrelin has been shown to have prokinetic activity in the gastrointestinal (GI) system of several species, including humans. In this series of experiments, we have evaluated the prokinetic activity of novel, small-molecule ghrelin receptor (GhrR) agonists after parenteral and peroral dosing in mice and rats. Gastric emptying, small intestinal transport, and fecal output were determined after intraperitoneal and intracerebroventricular dosing of GhrR agonists, using ghrelin as a positive control. These same parameters were evaluated after oral gavage dosing of the synthetic agonists. Regardless of dose route, GhrR agonist treatment increased gastric emptying, small intestinal transit, and fecal output. However, fecal output was only increased by GhrR agonist treatment if mice were able to feed during the stimulatory period. Thus, GhrR agonists can stimulate upper GI motility, and the orexigenic action of the compounds can indirectly contribute to prokinetic activity along the entire GI tract. The orexigenic and prokinetic effects of either ghrelin or small-molecule GhrR agonists were selective for the GhrR because they were absent when evaluated in GhrR knockout mice. We next evaluated the efficacy of the synthetic GhrR agonists dosed in a model of opiate-induced bowel dysfunction induced by a single injection of morphine. Oral dosing of a GhrR agonist normalized GI motility in opiate-induced dysmotility. These data demonstrate the potential utility of GhrR agonists for treating gastrointestinal hypomotility disorders.
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Zheng Q, Qiu WC, Yan J, Wang WG, Yu S, Wang ZG, Ai KX. Prokinetic effects of a ghrelin receptor agonist GHRP-6 in diabetic mice. World J Gastroenterol 2008; 14:4795-9. [PMID: 18720542 PMCID: PMC2739343 DOI: 10.3748/wjg.14.4795] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To investigate the effects of a ghrelin receptor agonist GHRP-6 on delayed gastrointestinal transit in alloxan-induced diabetic mice.
METHODS: A diabetic mouse model was established by intraperitoneal injection with alloxan. Mice were randomized into two main groups: normal mice and diabetic mice treated with GHRP-6 at doses of 0, 20, 50, 100 and 200 μg/kg ip. Gastric emptying (GE), intestinal transit (IT), and colonic transit (CT) were studied in mice after they had a phenol red meal following injection of GHRP-6. Based on the most effective GHRP-6 dosage, atropine was given at 1 mg/kg for 15 min before the GHRP-6 injection for each measurement. The mice in each group were sacrificed 20 min later and the percentages of GE, IT, and CT were calculated.
RESULTS: Percentages of GE, IT, and CT were significantly decreased in diabetic mice as compared to control mice. In the diabetic mice, GHRP-6 improved both GE and IT, but not CT. The most effective dose of GHRP-6 was 200 μg/kg and atropine blocked the prokinetic effects of GHRP-6 on GE and IT.
CONCLUSION: GHRP-6 accelerates delayed GE and IT, but has no effect on CT in diabetic mice. GHRP-6 may exert its prokinetic effects via the cholinergic pathway in the enteric nervous system, and therefore, has therapeutic potential for diabetic patients with delayed upper gastrointestinal transit.
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Banta CA, Clemens ET, Krinsky MM, Sheffy BE. Sites of organic acid production and patterns of digesta movement in the gastrointestinal tract of dogs. J Nutr 1979; 738:1-7. [PMID: 39123 DOI: 10.1016/j.ejphar.2014.05.025] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2013] [Revised: 04/29/2014] [Accepted: 05/12/2014] [Indexed: 12/12/2022] Open
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