{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T09:20:46Z","timestamp":1775640046916,"version":"3.50.1"},"reference-count":99,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2020,8,19]],"date-time":"2020-08-19T00:00:00Z","timestamp":1597795200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2014\/50928-2"],"award-info":[{"award-number":["2014\/50928-2"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002924","name":"Federaci\u00f3n Espa\u00f1ola de Enfermedades Raras","doi-asserted-by":"publisher","award":["UIDB\/04469\/2020"],"award-info":[{"award-number":["UIDB\/04469\/2020"]}],"id":[{"id":"10.13039\/501100002924","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cachexia, a severe multifactorial condition that is underestimated and unrecognized in patients, is characterized by continuous muscle mass loss that leads to progressive functional impairment, while nutritional support cannot completely reverse this clinical condition. There is a strong need for more effective and targeted therapies for cachexia patients. There is a need for drugs that act on cachexia as a distinct and treatable condition to prevent or reverse excess catabolism and inflammation. Due to ghrelin properties, it has been studied in the cachexia and other treatments in a growing number of works. However, in the body, exogenous ghrelin is subject to very rapid degradation. In this context, the intranasal release of ghrelin-loaded liposomes to cross the blood-brain barrier and the release of the drug into the central nervous system may be a promising alternative to improve its bioavailability. The administration of nose-to-brain liposomes for the management of cachexia was addressed only in a limited number of published works. This review focuses on the discussion of the pathophysiology of cachexia, synthesis and physiological effects of ghrelin and the potential treatment of the diseased using ghrelin-loaded liposomes through the nose-to-brain route.<\/jats:p>","DOI":"10.3390\/ijms21175974","type":"journal-article","created":{"date-parts":[[2020,8,19]],"date-time":"2020-08-19T21:37:40Z","timestamp":1597873060000},"page":"5974","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Cachexia: Pathophysiology and Ghrelin Liposomes for Nose-to-Brain Delivery"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2253-6688","authenticated-orcid":false,"given":"Cecilia","family":"T. de Barros","sequence":"first","affiliation":[{"name":"Laboratory of Biomaterials and Nanotechnology (LaBNUS), University of Sorocaba, Sorocaba, 18078-005 S\u00e3o Paulo, Brazil"}]},{"given":"Alessandra C.","family":"Rios","sequence":"additional","affiliation":[{"name":"Laboratory of Biomaterials and Nanotechnology (LaBNUS), University of Sorocaba, Sorocaba, 18078-005 S\u00e3o Paulo, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3586-9457","authenticated-orcid":false,"given":"Tha\u00eds F. R.","family":"Alves","sequence":"additional","affiliation":[{"name":"Laboratory of Biomaterials and Nanotechnology (LaBNUS), University of Sorocaba, Sorocaba, 18078-005 S\u00e3o Paulo, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1822-0944","authenticated-orcid":false,"given":"Fernando","family":"Batain","sequence":"additional","affiliation":[{"name":"Laboratory of Biomaterials and Nanotechnology (LaBNUS), University of Sorocaba, Sorocaba, 18078-005 S\u00e3o Paulo, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8685-1946","authenticated-orcid":false,"given":"Kessi M. M.","family":"Crescencio","sequence":"additional","affiliation":[{"name":"Laboratory of Biomaterials and Nanotechnology (LaBNUS), University of Sorocaba, Sorocaba, 18078-005 S\u00e3o Paulo, Brazil"}]},{"given":"Laura J.","family":"Lopes","sequence":"additional","affiliation":[{"name":"Laboratory of Biomaterials and Nanotechnology (LaBNUS), University of Sorocaba, Sorocaba, 18078-005 S\u00e3o Paulo, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2603-1377","authenticated-orcid":false,"given":"Aleksandra","family":"Zieli\u0144ska","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, P\u00f3lo das Ci\u00eancias da Sa\u00fade, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal"},{"name":"Institute of Human Genetics, Polish Academy of Sciences, Strzeszy\u0144ska 32, 60-479 Pozna\u0144, Poland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6527-6612","authenticated-orcid":false,"given":"Patricia","family":"Severino","sequence":"additional","affiliation":[{"name":"Institute of Technology and Research, University of Tiradentes (UNIT), 49032-490 Aracaju, Sergipe, Brazil"},{"name":"Tiradentes Institute, 150 Mt Vernon St, Dorchester, MA 02125, USA"},{"name":"Center for Biomedical Engineering, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3795-8189","authenticated-orcid":false,"given":"Priscila","family":"G. Mazzola","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Science, University of Campinas (UNICAMP), Candido Portinari Street, Campinas, 13083-871 S\u00e3o Paulo, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9737-6017","authenticated-orcid":false,"given":"Eliana B.","family":"Souto","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, P\u00f3lo das Ci\u00eancias da Sa\u00fade, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal"},{"name":"CEB\u2014Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3618-8415","authenticated-orcid":false,"given":"Marco V.","family":"Chaud","sequence":"additional","affiliation":[{"name":"Laboratory of Biomaterials and Nanotechnology (LaBNUS), University of Sorocaba, Sorocaba, 18078-005 S\u00e3o Paulo, Brazil"},{"name":"Bioprocess and Biotechnology College, University of Sorocaba, Sorocaba, 18078-005 S\u00e3o Paulo, Brazil"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.clnu.2009.12.004","article-title":"Consensus definition of sarcopenia, cachexia and pre-cachexia: Joint document elaborated by Special Interest Groups (SIG) \u201ccachexia-anorexia in chronic wasting diseases\u201d and \u201cnutrition in geriatrics\u201d","volume":"29","author":"Muscaritoli","year":"2010","journal-title":"Clin. Nutr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/S1470-2045(10)70218-7","article-title":"Definition and classification of cancer cachexia: An international consensus","volume":"12","author":"Fearon","year":"2011","journal-title":"Lancet Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1358\/dot.2016.52.9.2545017","article-title":"Cachexia","volume":"52","author":"Graul","year":"2016","journal-title":"Drugs Today"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s13539-013-0105-y","article-title":"Cachexia as a major public health problem: Frequent, costly, and deadly","volume":"4","author":"Farkas","year":"2013","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"17105","DOI":"10.1038\/nrdp.2017.105","article-title":"Cancer-associated cachexia","volume":"4","author":"Baracos","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/s13539-014-0164-8","article-title":"Prevalence, incidence and clinical impact of cachexia: Facts and numbers-update 2014","volume":"5","author":"Anker","year":"2014","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.ctrv.2015.09.002","article-title":"Mechanisms of anorexia-cachexia syndrome and rational for treatment with selective ghrelin receptor agonist","volume":"41","author":"Esposito","year":"2015","journal-title":"Cancer Treat. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1097\/MCO.0000000000000075","article-title":"Ghrelin: From discovery to cancer cachexia therapy","volume":"17","author":"Molfino","year":"2014","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1002\/jcsm.12023","article-title":"Ghrelin prevents tumour- and cisplatin-induced muscle wasting: Characterization of multiple mechanisms involved","volume":"6","author":"Chen","year":"2015","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"80","DOI":"10.21037\/apm.2018.11.01","article-title":"Prokinetics and ghrelin for the management of cancer cachexia syndrome","volume":"8","author":"Malik","year":"2018","journal-title":"Ann. Palliat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cbi.2016.02.013","article-title":"Physiological roles for butyrylcholinesterase: A BChE-ghrelin axis","volume":"259","author":"Brimijoin","year":"2016","journal-title":"Chem. Biol. Interact."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/S0896-6273(03)00063-1","article-title":"The distribution and mechanism of action of ghrelin the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis","volume":"37","author":"Cowley","year":"2003","journal-title":"Neuron"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.drudis.2014.10.003","article-title":"Peptide therapeutics: Current status and future directions","volume":"20","author":"Fosgerau","year":"2015","journal-title":"Drug Discov. Today"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1111\/jphp.12607","article-title":"Oral delivery of insulin for treatment of diabetes: Status quo, challenges and opportunities","volume":"68","author":"Wong","year":"2016","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.3390\/molecules13051035","article-title":"Progress in drug delivery to the central nervous system by the prodrug approach","volume":"13","author":"Pavan","year":"2008","journal-title":"Molecules"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"75","DOI":"10.3109\/10717544.2013.838713","article-title":"Insights into direct nose to brain delivery: Current status and future perspective","volume":"21","author":"Mittal","year":"2014","journal-title":"Drug Deliv."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1136\/hrt.24.3.257","article-title":"Diseases of the heart in the works of Hippocrates","volume":"24","author":"Katz","year":"1962","journal-title":"Br. Heart J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.2147\/TCRM.S196802","article-title":"Emerging treatment options for cancer-associated cachexia: A literature review","volume":"15","author":"Naito","year":"2019","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e47258","DOI":"10.15252\/embr.201847258","article-title":"Energy metabolism in cachexia","volume":"20","author":"Rohm","year":"2019","journal-title":"EMBO Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1038\/nrc3829","article-title":"Cancer cachexia: Understanding the molecular basis","volume":"14","author":"Busquets","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1002\/jcsm.12307","article-title":"Three cachexia phenotypes and the impact of fat-only loss on survival in FOLFIRINOX therapy for pancreatic cancer","volume":"9","author":"Kays","year":"2018","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1002\/jcsm.12388","article-title":"Cachexia as a common characteristic in multiple chronic disease","volume":"9","author":"Scherbakov","year":"2018","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1177\/2047487317730943","article-title":"An analysis of the types of recently published research in the field of cachexia","volume":"24","author":"Shewan","year":"2017","journal-title":"Eur. J. Prev. Cardiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1002\/jcsm.12528","article-title":"Cancer cachexia and its pathophysiology: Links with sarcopenia, anorexia and asthenia","volume":"11","author":"Santos","year":"2020","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1080\/17460441.2020.1724954","article-title":"Promising models for cancer-induced cachexia drug discovery","volume":"15","author":"Suzuki","year":"2020","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"61","DOI":"10.5770\/cgj.16.60","article-title":"Understanding and meeting the needs of the older population: A global challenge","volume":"16","author":"Bergman","year":"2013","journal-title":"Can. Geriatr. J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/B978-0-12-410473-0.00008-8","article-title":"Treatment of cachexia: Melanocortin and ghrelin interventions","volume":"92","author":"Steinman","year":"2013","journal-title":"Vitam Horm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s13539-010-0012-4","article-title":"Ghrelin and its potential in the treatment of eating\/wasting disorders and cachexia","volume":"1","author":"Tong","year":"2010","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3799","DOI":"10.1007\/s00018-014-1650-z","article-title":"Participation of the central melanocortin system in metabolic regulation and energy homeostasis","volume":"71","author":"Jeong","year":"2014","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/1475-2840-11-100","article-title":"GLUT4 content decreases along with insulin resistance and high levels of inflammatory markers in rats with metabolic syndrome","volume":"11","author":"Leguisamo","year":"2012","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1186\/s13075-014-0504-2","article-title":"The sympathetic nervous response in inflammation","volume":"16","author":"Pongratz","year":"2014","journal-title":"Arthritis Res. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"143","DOI":"10.3389\/fimmu.2014.00143","article-title":"Neuro-endocrine networks controlling immune system in health and disease","volume":"5","author":"Procaccini","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_33","first-page":"CD012229","article-title":"Ghrelin for the management of cachexia associated with cancer","volume":"2","author":"Khatib","year":"2018","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.jjcc.2011.11.002","article-title":"Ghrelin and cardiovascular diseases","volume":"59","author":"Kishimoto","year":"2012","journal-title":"J. Cardiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1016\/j.cmet.2018.02.008","article-title":"The Homeostatic Force of Ghrelin","volume":"27","author":"Yanagi","year":"2018","journal-title":"Cell Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.mce.2011.02.012","article-title":"Ghrelin and cachexia: Will treatment with GHSR-1a agonists make a difference for patients suffering from chronic wasting syndromes?","volume":"340","author":"DeBoer","year":"2011","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/45230","article-title":"Ghrelin is a growth-hormone-releasing acylated peptide from stomach","volume":"402","author":"Kojima","year":"1999","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2255","DOI":"10.1210\/en.2004-0695","article-title":"Ingested medium-chain fatty acids are directly utilized for the acyl modification of ghrelin","volume":"146","author":"Nishi","year":"2005","journal-title":"Endocrinology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.molmet.2015.03.005","article-title":"Ghrelin","volume":"4","author":"Nogueiras","year":"2015","journal-title":"Mol. Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7467","DOI":"10.1073\/pnas.1002271107","article-title":"Ghrelin O-acyltransferase (GOAT) is essential for growth hormone-mediated survival of calorie-restricted mice","volume":"107","author":"Zhao","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.nut.2009.07.003","article-title":"Update on melanocortin interventions for cachexia: Progress toward clinical application","volume":"26","author":"DeBoer","year":"2010","journal-title":"Nutrition"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4527980","DOI":"10.1155\/2017\/4527980","article-title":"The Impact of Ghrelin in Metabolic Diseases: An Immune Perspective","volume":"2017","author":"Pereira","year":"2017","journal-title":"J. Diabetes Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e11190","DOI":"10.7554\/eLife.11190","article-title":"Hippocampus ghrelin signaling mediates appetite through lateral hypothalamic orexin pathways","volume":"4","author":"Hsu","year":"2015","journal-title":"eLife"},{"key":"ref_44","first-page":"E1697","article-title":"Ghrelin inhibits sympathetic nervous activity in sepsis","volume":"293","author":"Wu","year":"2007","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"G1014","DOI":"10.1152\/ajpgi.2001.281.4.G1014","article-title":"Norepinephrine-induced hepatocellular dysfunction in early sepsis is mediated by activation of \u03b12-adrenoceptors","volume":"281","author":"Yang","year":"2001","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2554","DOI":"10.2174\/092986707782023334","article-title":"Sensory Signal Transduction in the vagal primary afferent neurons","volume":"14","author":"Ying","year":"2007","journal-title":"Curr. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1620\/tjem.222.155","article-title":"Vagal nerve regulation is essential for the increase in gastric motility in response to mild exercise","volume":"222","author":"Wang","year":"2010","journal-title":"Tohoku J. Exp. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1097\/SHK.0b013e3181f48a37","article-title":"Ghrelin Suppresses inflammation and neuronal nitric oxide synthase in focal cerebral ischemia via the vagus nerve","volume":"35","author":"Cheyuo","year":"2011","journal-title":"Shock"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1007\/s10753-011-9307-7","article-title":"Vagal stimulation modulates inflammation through a ghrelin mediated mechanism in traumatic brain injury","volume":"35","author":"Bansal","year":"2012","journal-title":"Inflammation"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1007\/s00005-014-0287-9","article-title":"Ghrelin gene products in acute and chronic inflammation","volume":"62","author":"Prodam","year":"2014","journal-title":"Arch. Immunol. Ther. Exp."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.bbcan.2017.02.002","article-title":"Ghrelin and cancer progression","volume":"1868","author":"Lin","year":"2017","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1111\/jne.12168","article-title":"Divergent neuronal circuitries underlying acute orexigenic effects of peripheral or central ghrelin: Critical role of brain accessibility","volume":"26","author":"Cabral","year":"2014","journal-title":"J. Neuroendocrinol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.phrs.2012.06.006","article-title":"Novel domain-selective ACE-inhibiting activity of synthetic growth hormone secretagogues","volume":"66","author":"Torsello","year":"2012","journal-title":"Pharmacol. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1053\/gast.2001.22158","article-title":"Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin","volume":"120","author":"Asakawa","year":"2001","journal-title":"Gastroenterology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1016\/j.peptides.2005.12.008","article-title":"Ghrelin gastrokinetic action in patients with neurogenic gastroparesis","volume":"27","author":"Binn","year":"2006","journal-title":"Peptides"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1007\/s00535-010-0269-6","article-title":"Comparison of the actions of acylated and desacylated ghrelin on acid secretion in the rat stomach","volume":"45","author":"Sakurada","year":"2010","journal-title":"J. Gastroenterol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1515\/hmbci-2016-0018","article-title":"The role of ghrelin in the regulation of glucose homeostasis","volume":"26","author":"Shin","year":"2016","journal-title":"Horm. Mol. Biol. Clin. Investig."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"42706","DOI":"10.1038\/srep42706","article-title":"Acyl ghrelin induces insulin resistance independently of GH, cortisol, and free fatty acids","volume":"7","author":"Vestergaard","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.regpep.2003.12.001","article-title":"Effects of ghrelin on insulin and glucagon secretion: A study of isolated pancreatic islets and intact mice","volume":"118","author":"Salehi","year":"2004","journal-title":"Regul. Pept."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1210\/jc.2004-1069","article-title":"Ghrelin stimulates, whereas des-octanoyl ghrelin inhibits, glucose output by primary hepatocytes","volume":"90","author":"Gauna","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_61","first-page":"1","article-title":"Therapeutic potential of targeting the ghrelin pathway","volume":"18","year":"2017","journal-title":"Int. J. Mol. Sci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"8501","DOI":"10.1073\/pnas.1002941107","article-title":"Ghrelin and growth hormone: Story in reverse","volume":"107","author":"Nass","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1002\/jcsm.12084","article-title":"Novel mechanism of ghrelin therapy for cachexia","volume":"6","author":"Hatanaka","year":"2015","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1007\/s00520-016-3560-0","article-title":"Anamorelin for cancer anorexia-cachexia syndrome: A systematic review and meta-analysis","volume":"25","author":"Bai","year":"2017","journal-title":"Supportive Care Cancer"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.2217\/fon-2017-0141","article-title":"The emerging role of anamorelin hydrochloride in the management of patients with cancer anorexia-cachexia","volume":"13","author":"Currow","year":"2017","journal-title":"Future Oncol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/S1470-2045(14)71154-4","article-title":"Anamorelin for patients with cancer cachexia: An integrated analysis of two phase 2, randomised, placebo-controlled, double-blind trials","volume":"16","author":"Garcia","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"271","DOI":"10.3389\/fphar.2014.00271","article-title":"Rikkunshito, a ghrelin potentiator, ameliorates anorexia-cachexia syndrome","volume":"5","author":"Fujitsuka","year":"2014","journal-title":"Front. Pharmacol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"a020412","DOI":"10.1101\/cshperspect.a020412","article-title":"The blood-brain barrier","volume":"7","author":"Daneman","year":"2015","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"430","DOI":"10.2133\/dmpk.DMPK-10-RG-049","article-title":"Lack of a primary physicochemical determinant in the direct transport of drugs to the brain after nasal administration in rats: Potential involvement of transporters in the pathway","volume":"25","author":"Lee","year":"2010","journal-title":"Drug Metab. Pharmacokinet."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"325","DOI":"10.2147\/DDDT.S100075","article-title":"Drug delivery in overcoming the blood-brain barrier: Role of nasal mucosal grafting","volume":"11","author":"Marianecci","year":"2017","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"95","DOI":"10.2174\/1389200043489126","article-title":"Drug transport at the blood-brain barrier and the choroid plexus","volume":"5","author":"Candace","year":"2004","journal-title":"Curr. Drug Metab."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"124","DOI":"10.2500\/ajra.2015.29.4149","article-title":"The blood-brain barrier and nasal drug delivery to the central nervous system","volume":"29","author":"Miyake","year":"2015","journal-title":"Am. J. Rhinol. Allergy"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1210\/jc.2012-4247","article-title":"Clinical review: The human experience with ghrelin administration","volume":"98","author":"Garin","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.ejpb.2018.06.011","article-title":"Chitosan-coated liposome dry-powder formulations loaded with ghrelin for nose-to-brain delivery","volume":"129","author":"Salade","year":"2018","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"223","DOI":"10.3109\/10611860903386938","article-title":"Formulation of intranasal mucoadhesive temperature-mediated in situ gel containing ropinirole and evaluation of brain targeting efficiency in rats","volume":"18","author":"Khan","year":"2010","journal-title":"J. Drug Target."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1211\/0022357022539","article-title":"Is nose-to-brain transport of drugs in man a reality?","volume":"56","author":"Illum","year":"2004","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1002\/jps.21924","article-title":"Intranasal delivery to the central nervous system: Mechanisms and experimental considerations","volume":"99","author":"Dhuria","year":"2010","journal-title":"J. Pharm. Sci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"195","DOI":"10.4155\/tde.11.149","article-title":"Nasal-to-CNS drug delivery: Where are we now and where are we heading? An industrial perspective","volume":"3","author":"Landis","year":"2012","journal-title":"Ther. Deliv."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2755","DOI":"10.1021\/acs.molpharmaceut.5b00088","article-title":"Nose-to-brain delivery: Investigation of the transport of nanoparticles with different surface characteristics and sizes in excised porcine olfactory epithelium","volume":"12","author":"Mistry","year":"2015","journal-title":"Mol. Pharm."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.1124\/dmd.111.040782","article-title":"Systemic and direct nose-to-brain transport pharmacokinetic model for remoxipride after intravenous and intranasal administration","volume":"39","author":"Stevens","year":"2011","journal-title":"Drug Metab. Dispos."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2217\/14796708.3.1.1","article-title":"The nose may help the brain: Intranasal drug delivery for treating neurological diseases","volume":"3","author":"Ying","year":"2008","journal-title":"Future Neurol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1002\/jemt.1070230105","article-title":"Morphology of olfactory epithelium in humans and other vertebrates","volume":"23","author":"Morrison","year":"1992","journal-title":"Microsc. Res. Tech."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.ejpb.2018.05.009","article-title":"Recent advances in carrier mediated nose-to-brain delivery of pharmaceutics","volume":"128","author":"Bourganis","year":"2018","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"709","DOI":"10.4155\/tde.14.41","article-title":"The nasal approach to delivering treatment for brain diseases: An anatomic, physiologic, and delivery technology overview","volume":"5","author":"Djupesland","year":"2014","journal-title":"Ther. Deliv."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0169-409X(97)00059-8","article-title":"Nasal mucociliary clearance as a factor in nasal drug delivery","volume":"29","author":"Marttin","year":"1998","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.plipres.2017.07.001","article-title":"Beyond liposomes: Recent advances on lipid based nanostructures for poorly soluble\/poorly permeable drug delivery","volume":"68","author":"Teixeira","year":"2017","journal-title":"Prog. Lipid Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.colsurfb.2018.07.049","article-title":"Mixed cationic liposomes for brain delivery of drugs by the intranasal route: The acetylcholinesterase reactivator 2-PAM as encapsulated drug model","volume":"171","author":"Pashirova","year":"2018","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"155","DOI":"10.3389\/fimmu.2018.00155","article-title":"The multirole of liposomes in therapy and prevention of infectious diseases","volume":"9","author":"Nisini","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/S0022-2275(20)43097-4","article-title":"Phospholipid spherules (liposomes) as a model for biological membranes","volume":"9","author":"Sessa","year":"1968","journal-title":"J. Lipid Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"118953","DOI":"10.1016\/j.ijpharm.2019.118953","article-title":"Synthesis, structure-activity relationship and biological evaluation of tetracationic gemini Dabco-surfactants for transdermal liposomal formulations","volume":"575","author":"Pashirova","year":"2019","journal-title":"Int. J. Pharm."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"5381","DOI":"10.2147\/IJN.S117210","article-title":"Getting into the brain: Liposome-based strategies for effective drug delivery across the blood-brain barrier","volume":"11","author":"Vieira","year":"2016","journal-title":"Int. J. Nanomed."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.tibtech.2013.09.007","article-title":"Ligand-targeted liposome design: Challenges and fundamental considerations","volume":"32","author":"Noble","year":"2014","journal-title":"Trends Biotechnol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"975","DOI":"10.2147\/IJN.S68861","article-title":"Liposomes as nanomedical devices","volume":"10","author":"Bozzuto","year":"2015","journal-title":"Int. J. Nanomed."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"8531","DOI":"10.2147\/IJN.S147650","article-title":"Development of coated liposomes loaded with ghrelin for nose-to-brain delivery for the treatment of cachexia","volume":"12","author":"Salade","year":"2017","journal-title":"Int. J. Nanomed."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.ijpharm.2017.11.051","article-title":"Sustained-release multiparticulates for oral delivery of a novel peptidic ghrelin agonist: Formulation design and in vitro characterization","volume":"536","author":"Howick","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s11060-014-1584-1","article-title":"Cationic surface charge enhances early regional deposition of liposomes after intracarotid injection","volume":"120","author":"Joshi","year":"2014","journal-title":"J. Neurooncol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"105","DOI":"10.2174\/138920012798356934","article-title":"PEGylation of Proteins and Liposomes: A powerful and flexible strategy to improve the drug delivery","volume":"13","author":"Paola","year":"2012","journal-title":"Curr. Drug Metab."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1146\/annurev-pharmtox-010814-124852","article-title":"Targeting receptor-mediated transport for delivery of biologics across the blood-brain barrier","volume":"55","author":"Lajoie","year":"2015","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1602\/neurorx.2.1.108","article-title":"Drug transport to brain with targeted nanoparticles","volume":"2","author":"Olivier","year":"2005","journal-title":"NeuroRx"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/17\/5974\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:03:32Z","timestamp":1760177012000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/17\/5974"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,19]]},"references-count":99,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["ijms21175974"],"URL":"https:\/\/doi.org\/10.3390\/ijms21175974","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,19]]}}}