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胃饥饿素对胃肠功能的影响：从基础研究到临床应用
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Abstract:
胃饥饿素是一种主要由胃内分泌细胞分泌的肽类激素，在胃肠道调节过程中具有重要作用。在基础研究方面，研究者们发现，胃饥饿素可通过刺激中枢神经系统增加人体食欲和食物的摄入量，也可直接作用于胃肠道平滑肌细胞增加胃肠蠕动的频率和幅度，同时相关研究发现其与胃肠道肿瘤的发病也存在一定联系。在临床应用方面，目前胃饥饿素被用于胃肠道手术术后、胃肠动力障碍及胃肠道肿瘤患者的治疗。本文从胃饥饿素的基础研究到临床应用展开讨论，综述了胃饥饿素对胃肠功能的影响，期望为胃肠道疾病的诊断和治疗提供新的思路和方法。
Ghrelin is a peptide hormone mainly secreted by gastric endocrine cells and plays an important role in the regulation of the gastrointestinal tract. In terms of basic research, researchers have found that ghrelin can increase human appetite and food intake by stimulating the central nervous system, and can also directly act on gastrointestinal smooth muscle cells to increase the frequency and amplitude of gastrointestinal peristalsis, and at the same time, studies have found that it is also associated with the incidence of gastrointestinal tumors system. In terms of clinical application, ghrelin is currently used in the treatment of patients with gastrointestinal motility disorders and gastrointestinal tumors after gastrointestinal surgery. In this paper, we discuss the effects of ghrelin on gastrointestinal function from the basic research to clinical application, hoping to provide new ideas and methods for the diagnosis and treatment of gastrointestinal diseases.
| [1] | Kojima, M., Hosoda, H., Date, Y., Nakazato, M., et al. (1999) Ghrelin Is a Growth-Hormone-Releasing Acylated Peptide from Stomach. Nature, 402, 656-660. https://doi.org/10.1038/45230 |
| [2] | Patterson, M., Murphy, K.G., Le Roux, C.W., Ghatei, M.A. and Bloom, S.R. (2005) Characterization of Ghrelin-Like Immunoreactivity in Human Plasma. The Journal of Clinical Endocrinology and Metabolism, 90, 2205-2211. https://doi.org/10.1210/jc.2004-1641 |
| [3] | Giorgioni, G., Del Bello, F., Quaglia, W., Botticelli, L., Cifani, C., Micioni Di Bonaventura, E., Micioni Di Bonaventura, M.V. and Piergentili, A. (2022) Advances in the Development of Nonpeptide Small Molecules Targeting Ghrelin Receptor. Journal of Medicinal Chemistry, 65, 3098-3118. https://doi.org/10.1021/acs.jmedchem.1c02191 |
| [4] | Deloose, E., Janssen, P., Depoortere, I. and Tack, J. (2012) The Migrating Motor Complex: Control Mechanisms and Its Role in Health and Disease. Nature Reviews Gastroenterology & Hepatology, 9, 271-285. https://doi.org/10.1038/nrgastro.2012.57 |
| [5] | Shin, A., Camilleri, M., Busciglio, I., Burton, D., Stoner, E., Noonan, P., Gottesdiener, K., Smith, S.A., Vella, A. and Zinsmeister, A.R. (2013) Randomized Controlled Phase Ib Study of Ghrelin Agonist, RM-131, in Type 2 Diabetic Women with Delayed Gastric Emptying: Pharmacokinetics and Pharmacodynamics. Diabetes Care, 36, 41-48. https://doi.org/10.2337/dc12-1128 |
| [6] | Dockray, G.J. (2014) Gastrointestinal Hormones and the Dialogue between Gut and Brain. The Journal of Physiology, 592, 2927-2941. https://doi.org/10.1113/jphysiol.2014.270850 |
| [7] | Giezenaar, C., Trahair, L.G., Luscombe-Marsh, N.D., Hausken, T., Standfield, S., Jones, K.L., Lange, K., Horowitz, M., Chapman, I. and Soenen, S. (2017) Effects of Randomized Whey-Protein Loads on Energy Intake, Appetite, Gastric Emptying, and Plasma Gut-Hormone Concentrations in Older Men and Women. The American Journal of Clinical Nutrition, 106, 865-877. https://doi.org/10.3945/ajcn.117.154377 |
| [8] | Cheung, C.K. and Wu, J.C. (2013) Role of Ghrelin in the Pathophysiology of Gastrointestinal Disease. Gut and Liver, 7, 505-512. https://doi.org/10.5009/gnl.2013.7.5.505 |
| [9] | Mathur, N., Mehdi, S.F., Anipindi, M., Aziz, M., Khan, S.A., Kondakindi, H., Lowell, B., Wang, P. and Roth, J. (2021) Ghrelin as an Anti-Sepsis Peptide: Review. Frontiers in Immunology, 11, Article 610363. https://doi.org/10.3389/fimmu.2020.610363 |
| [10] | Bowers, C.Y. (1993) GH Releasing Peptides—Structure and Kinetics. Journal of Pediatric Endocrinology, 6, 21-31. https://doi.org/10.1515/JPEM.1993.6.1.21 |
| [11] | Hosoda, H., Doi, K., Nagaya, N., Okumura, H., Nakagawa, E., Enomoto, M., Ono, F. and Kangawa, K. (2004) Optimum Collection and Storage Conditions for Ghrelin Measurements: Octanoyl Modification of Ghrelin Is Rapidly Hydrolyzed to Desacyl Ghrelin in Blood Samples. Clinical Chemistry, 50, 1077-1080. https://doi.org/10.1373/clinchem.2003.025841 |
| [12] | Baldanzi, G., Filigheddu, N., Cutrupi, S., Catapano, F., Bonissoni, S., Fubini, A., Malan, D., Baj, G., Granata, R., Broglio, F., Papotti, M., Surico, N., Bussolino, F., Isgaard, J., Deghenghi, R., Sinigaglia, F., Prat, M., Muccioli, G., Ghigo, E. and Graziani, A. (2002) Ghrelin and Des-Acyl Ghrelin Inhibit Cell Death in Cardiomyocytes and Endothelial Cells through ERK1/2 and PI 3-Kinase/AKT. Journal of Cell Biology, 159, 1029-1037. https://doi.org/10.1083/jcb.200207165 |
| [13] | Porporato, P.E., Filigheddu, N., Reano, S., Ferrara, M., Angelino, E., Gnocchi, V.F., Prodam, F., Ronchi, G., Fagoonee, S., Fornaro, M., Chianale, F., Baldanzi, G., Surico, N., Sinigaglia, F., Perroteau, I., Smith, R.G., Sun, Y., Geuna, S. and Graziani, A. (2013) Acylated and Unacylated Ghrelin Impair Skeletal Muscle Atrophy in Mice. Journal of Clinical Investigation, 123, 611-622. https://doi.org/10.1172/JCI39920 |
| [14] | Nijenhuis, T., Hoenderop, J.G., Van der Kemp, A.W. and Bindels, R.J. (2003) Localization and Regulation of the Epithelial Ca2 Channel TRPV6 in the Kidney. Journal of the American Society of Nephrology, 14, 2731-2740. https://doi.org/10.1097/01.ASN.0000094081.78893.E8 |
| [15] | Tsch？p, M., Weyer, C., Tataranni, P.A., Devanarayan, V., Ravussin, E. and Heiman, M.L. (2001) Circulating Ghrelin Levels Are Decreased in Human Obesity. Diabetes, 50, 707-709. https://doi.org/10.2337/diabetes.50.4.707 |
| [16] | Shiiya, T., Nakazato, M., Mizuta, M., Date, Y., Mondal, M.S., Tanaka, M., Nozoe, S., Hosoda, H., Kangawa, K. and Matsukura, S. (2002) Plasma Ghrelin Levels in Lean and Obese Humans and the Effect of Glucose on Ghrelin Secretion. The Journal of Clinical Endocrinology and Metabolism, 87, 240-244. https://doi.org/10.1210/jcem.87.1.8129 |
| [17] | Date, Y., Kojima, M., Hosoda, H., Sawaguchi, A., Mondal, M.S., Suganuma, T., Matsukura, S., Kangawa, K. and Nakazato, M. (2000) Ghrelin, a Novel Growth Hormone-Releasing Acylated Peptide, Is Synthesized in a Distinct Endocrine Cell Type in the Gastrointestinal Tracts of Rats and Humans. Endocrinology, 141, 4255-4261. https://doi.org/10.1210/endo.141.11.7757 |
| [18] | Arvat, E., Maccario, M., Di Vito, L., Broglio, F., Benso, A., Gottero, C., Papotti, M., Muccioli, G., Dieguez, C., Casanueva, F.F., Deghenghi, R., Camanni, F. and Ghigo, E. (2001) Endocrine Activities of Ghrelin, a Natural Growth Hormone Secretagogue (GHS), in Humans: Comparison and Interactions with Hexarelin, a Nonnatural Peptidyl GHS, and GH-Releasing Hormone. The Journal of Clinical Endocrinology and Metabolism, 86, 1169-1174. https://doi.org/10.1210/jc.86.3.1169 |
| [19] | Tannenbaum, G.S., Epelbaum, J. and Bowers, C.Y. (2003) Interrelationship between the Novel Peptide Ghrelin and Somatostatin/Growth Hormone-Releasing Hormone in Regulation of Pulsatile Growth Hormone Secretion. Endocrinology, 144, 967-974. https://doi.org/10.1210/en.2002-220852 |
| [20] | González, C.R., Vázquez, M.J., López, M. and Diéguez, C. (2008) Influence of Chronic Undernutrition and Leptin on GOAT mRNA Levels in Rat Stomach Mucosa. Journal of Molecular Endocrinology, 41, 415-421. https://doi.org/10.1677/JME-08-0102 |
| [21] | Kirchner, H. and Nogueiras, R. (2008) GOAT: A Stomach Enzyme That Whets Our Appetite. Obesity Facts, 1, 123-126. https://doi.org/10.1159/000139141 |
| [22] | Bennett, P.A., Thomas, G.B., Howard, A.D., Feighner, S.D., Van der Ploeg, L.H., Smith, R.G. and Robinson, I.C. (1997) Hypothalamic Growth Hormone Secretagogue-Receptor (GHS-R) Expression Is Regulated by Growth Hormone in the Rat. Endocrinology, 138, 4552-4557. https://doi.org/10.1210/endo.138.11.5476 |
| [23] | Wren, A.M., Seal, L.J., Cohen, M.A., Brynes, A.E., Frost, G.S., Murphy, K.G., Dhillo, W.S., Ghatei, M.A. and Bloom, S.R. (2001) Ghrelin Enhances Appetite and Increases Food Intake in Humans. The Journal of Clinical Endocrinology and Metabolism, 86, 5992. https://doi.org/10.1210/jcem.86.12.8111 |
| [24] | Srisai, D., Yin, T.C., Lee, A.A., Rouault, A.A.J., Pearson, N.A., Grobe, J.L. and Sebag, J.A. (2017) MRAP2 Regulates Ghrelin Receptor Signaling and Hunger Sensing. Nature Communications, 8, Article No. 713. https://doi.org/10.1038/s41467-017-00747-6 |
| [25] | Sun, Y., Wang, P., Zheng, H. and Smith, R.G. (2004) Ghrelin Stimulation of Growth Hormone Release and Appetite Is Mediated through the Growth Hormone Secretagogue Receptor. Proceedings of the National Academy of Sciences of the United States of America, 101, 4679-4684. https://doi.org/10.1073/pnas.0305930101 |
| [26] | Hernández, M.A.G., Canfora, E.E., Jocken, J.W.E. and Blaak, E.E. (2019) The Short-Chain Fatty Acid Acetate in Body Weight Control and Insulin Sensitivity. Nutrients, 11, Article 1943. https://doi.org/10.3390/nu11081943 |
| [27] | Chaudhri, O., Small, C. and Bloom, S. (2006) Gastrointestinal Hormones Regulating Appetite. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 361, 1187-1209. https://doi.org/10.1098/rstb.2006.1856 |
| [28] | 李斌. 脑肠肽Ghrelin对脓毒症患者胃肠道功能障碍的机制研究[D]: [博士学位论文]. 兰州: 兰州大学, 2019. |
| [29] | Guzzetta, K.E., Cryan, J.F. and O’Leary, O.F. (2022) Microbiota-Gut-Brain Axis Regulation of Adult Hippocampal Neurogenesis. Brain Plasticity, 8, 97-119. https://doi.org/10.3233/BPL-220141 |
| [30] | Lee, J.C., Curtis, D., Williamson, J.B. and Ligato, S. (2021) Gastric Desmoid Fibromatosis—Report of a Rare Mimic of Gastrointestinal Stromal Tumor. Cureus, 13, e19614. https://doi.org/10.7759/cureus.19614 |
| [31] | Tack, J., Verbeure, W., Mori, H., Schol, J., Van den Houte, K., Huang, I.H., Balsiger, L., Broeders, B., Colomier, E., Scarpellini, E. and Carbone, F. (2021) The Gastrointestinal Tract in Hunger and Satiety Signalling. United European Gastroenterology Journal, 9, 727-734. https://doi.org/10.1002/ueg2.12097 |
| [32] | Drumm, B.T., Cobine, C.A. and Baker, S.A. (2022) Insights on Gastrointestinal Motility through the Use of Optogenetic Sensors and Actuators. The Journal of Physiology, 600, 3031-3052. https://doi.org/10.1113/JP281930 |
| [33] | Mahadeva, S. (2021) Non-Pharmacological Intervention in Functional Dyspepsia: Is This the Way Forward? Journal of Gastroenterology and Hepatology, 36, 2031-2032. https://doi.org/10.1111/jgh.15606 |
| [34] | Han, D., Kim, J.N., Kwon, M.J., Han, T., Kim, Y.T. and Kim, B.J. (2021) Salvia miltiorrhiza Induces Depolarization of Pacemaker Potentials in Murine Small Intestinal Interstitial Cells of Cajal via Extracellular Ca2 and Na Influx. Molecular Medicine Reports, 23, Article No. 348. https://doi.org/10.3892/mmr.2021.11987 |
| [35] | Mekjian, H.S., Phillips, S.F. and Hofmann, A.F. (1971) Colonic Secretion of Water and Electrolytes Induced by Bile Acids: Perfusion Studies in Man. The Journal of Clinical Investigation, 50, 1569-1577. https://doi.org/10.1172/JCI106644 |
| [36] | Smith, T.K., Park, K.J. and Hennig, G.W. (2014) Colonic Migrating Motor Complexes, High Amplitude Propagating Contractions, Neural Reflexes and the Importance of Neuronal and Mucosal Serotonin. Journal of Neurogastroenterology and Motility, 20, 423-446. https://doi.org/10.5056/jnm14092 |
| [37] | Zhao, Z., Sakata, I., Okubo, Y., Koike, K., Kangawa, K. and Sakai, T. (2008) Gastric Leptin, but Not Estrogen and Somatostatin, Contributes to the Elevation of Ghrelin mRNA Expression Level in Fasted Rats. The Journal of Endocrinology, 196, 529-538. https://doi.org/10.1677/JOE-07-0300 |
| [38] | Suzuki, K., Simpson, K.A., Minnion, J.S., Shillito, J.C. and Bloom, S.R. (2010) The Role of Gut Hormones and the Hypothalamus in Appetite Regulation. Endocrine Journal, 57, 359-372. https://doi.org/10.1507/endocrj.K10E-077 |
| [39] | Kowalski-Chauvel, A., Pradayrol, L., Vaysse, N. and Seva, C. (1996) Gastrin Stimulates Tyrosine Phosphorylation of Insulin Receptor Substrate 1 and Its Association with Grb2 and the Phosphatidylinositol 3-Kinase. The Journal of Biological Chemistry, 271, 26356-26361. https://doi.org/10.1074/jbc.271.42.26356 |
| [40] | Ginter, G., Ceranowicz, P. and Warzecha, Z. (2021) Protective and Healing Effects of Ghrelin and Risk of Cancer in the Digestive System. International Journal of Molecular Sciences, 22, Article 10571. https://doi.org/10.3390/ijms221910571 |
| [41] | Saleh, H.A., Yousef, M.H. and Abdelnaser, A. (2021) The Anti-Inflammatory Properties of Phytochemicals and Their Effects on Epigenetic Mechanisms Involved in TLR4/NF-κB-Mediated Inflammation. Frontiers in Immunology, 12, Article 606069. https://doi.org/10.3389/fimmu.2021.606069 |
| [42] | Jones, M.K., Tomikawa, M., Mohajer, B. and Tarnawski, A.S. (1999) Gastrointestinal Mucosal Regeneration: Role of Growth Factors. Frontiers in Bioscience, 4, 303-309. https://doi.org/10.2741/A428 |
| [43] | Talwar, B., Donnelly, R., Skelly, R. and Donaldson, M. (2016) Nutritional Management in Head and Neck Cancer: United Kingdom National Multidisciplinary Guidelines. The Journal of Laryngology and Otology, 130, S32-S40. https://doi.org/10.1017/S0022215116000402 |
| [44] | Camilleri, M., Papathanasopoulos, A. and Odunsi, S.T. (2009) Actions and Therapeutic Pathways of Ghrelin for Gastrointestinal Disorders. Nature Reviews Gastroenterology & Hepatology, 6, 343-352. https://doi.org/10.1038/nrgastro.2009.72 |
| [45] | Suzuki, H., Asakawa, A., Amitani, H., Nakamura, N. and Inui, A. (2013) Cancer Cachexia—Pathophysiology and Management. Journal of Gastroenterology, 48, 574-594. https://doi.org/10.1007/s00535-013-0787-0 |
| [46] | Blum, D., De Wolf-Linder, S., Oberholzer, R., Br？ndle, M., Hundsberger, T. and Strasser, F. (2021) Natural Ghrelin in Advanced Cancer Patients with Cachexia, a Case Series. Journal of Cachexia, Sarcopenia and Muscle, 12, 506-516. https://doi.org/10.1002/jcsm.12659 |
