{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:29:19Z","timestamp":1792002559971,"version":"4.4.0"},"reference-count":42,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T00:00:00Z","timestamp":1613606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The aim of our study was to assess the sympathetic nervous system\u2019s involvement in the evolution of gastric carcinoma in patients by analyzing the mediators of this system (epinephrine and norepinephrine), as well as by analyzing the histological expression of the norepinephrine transporter (NET). We conducted an observational study including 91 patients diagnosed with gastric carcinoma and an additional 200 patients without cancer between November 2017 and October 2018. We set the primary endpoint as mortality from any cause in the first two years after enrolment in the study. The patients were monitored by a 24-h Holter electrocardiogram (ECG) to assess sympathetic or parasympathetic predominance. Blood was also collected from the patients to measure plasma free metanephrine (Meta) and normetanephrine (N-Meta), and tumor histological samples were collected for the analysis of NET expression. All of this was performed prior to the application of any antineoplastic therapy. Each patient was monitored for two years. We found higher heart rates in patients with gastric carcinoma than those without cancer. Regarding Meta and N-Meta, elevated levels were recorded in the patients with gastric carcinoma, correlating with the degree of tumor differentiation and other negative prognostic factors such as tumor invasion, lymph node metastasis, and distant metastases. Elevated Meta and N-Meta was also associated with a poor survival rate. All these data suggest that the predominance of the sympathetic nervous system\u2019s activity predicts increased gastric carcinoma severity.<\/jats:p>","DOI":"10.3390\/ijms22042042","type":"journal-article","created":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T20:56:21Z","timestamp":1613681781000},"page":"2042","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Assessment of Epinephrine and Norepinephrine in Gastric Carcinoma"],"prefix":"10.3390","volume":"22","author":[{"given":"Alina Maria","family":"Mehedin\u021beanu","sequence":"first","affiliation":[{"name":"Department of Oncology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Sfredel","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9748-1394","authenticated-orcid":false,"given":"Puiu Olivian","family":"Stovicek","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Nursing, T\u00e2rgu Jiu Subsidiary, Titu Maiorescu University, 04317 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Schenker","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7205-306X","authenticated-orcid":false,"given":"Georgic\u0103 Costinel","family":"T\u00e2rtea","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Octavian","family":"Istr\u0103toaie","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana-Maria","family":"Ciurea","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristin Constantin","family":"Vere","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,18]]},"reference":[{"key":"ref_1","unstructured":"(2020, September 15). Global Cancer Observatory. Available online: https:\/\/gco.iarc.fr\/today\/online-analysis-pie?v=2018&mode=cancer&mode_population=continents&population=900&populations=900&key=total&sex=0&cancer=39&type=0&statistic=5&prevalence=0&population_group=0&ages_group%5B%5D=0&ages_group%5B%5D=17&nb_items=7&group_cancer=1&include_nmsc=1&include_nmsc_other=1&half_pie=0&donut=0&population_group_globocan_id=."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"9600","DOI":"10.3748\/wjg.v20.i28.9600","article-title":"Gene-diet interactions in gastric cancer risk: A systematic review","volume":"20","author":"Kim","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.mehy.2006.01.015","article-title":"Neoneurogenesis: Tumors may initiate their own innervation by the release of neurotrophic factors in analogy to lymphangiogenesis and neoangiogenesis","volume":"67","author":"Entschladen","year":"2006","journal-title":"Med. Hypotheses"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2567","DOI":"10.3748\/wjg.v24.i24.2567","article-title":"Tumor heterogeneity of gastric cancer: From the perspective of tumor-initiating cell","volume":"24","author":"Gao","year":"2018","journal-title":"World J. Gastroenterol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.semcancer.2007.12.004","article-title":"The cancer\u2019s nervous tooth: Considering the neruronal crosstalk within tumors","volume":"18","author":"Entschladen","year":"2008","journal-title":"Semin. Cancer Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1002\/cncr.23231","article-title":"GABA B receptor is a novel drug target for pancreatic cancer","volume":"112","author":"Schuller","year":"2008","journal-title":"Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1177\/000348948509400420","article-title":"Nerves and neurotropic carcinomas","volume":"94","author":"Batsakis","year":"1985","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1772","DOI":"10.1002\/1097-0142(196710)20:10<1772::AID-CNCR2820201028>3.0.CO;2-#","article-title":"Nature of the perineural space invaded by prostatic carcinoma","volume":"20","author":"Rodin","year":"1967","journal-title":"Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1016\/S0360-3016(98)00167-9","article-title":"Perineural invasion and Gleason 7\u201310 tumors predict increased failure in prostate cancer patients with pretreatment PSA","volume":"41","author":"Anderson","year":"1998","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1002\/(SICI)1096-9861(20000501)420:2<211::AID-CNE5>3.0.CO;2-3","article-title":"Immunolocalization of the cocaine- and antidepressant-sensitive l-norepinephrine transporter","volume":"420","author":"Schroeter","year":"2000","journal-title":"J. Comp. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1017\/S1462399401003878","article-title":"Genetic or acquired deficits in the norepinephrine transporter: Current understanding of clinical implications","volume":"3","author":"Tellioglu","year":"2001","journal-title":"Expert Rev. Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1124\/pr.108.000869","article-title":"SLC6 neurotransmitter transporters. Structure, function and regulation","volume":"63","author":"Kristensen","year":"2011","journal-title":"Pharmacol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/nrn1008","article-title":"Plasma membrane monoamine transporters: Structure, regulation and function","volume":"4","author":"Torres","year":"2003","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1002\/cphy.c130055","article-title":"Central nervous system control of gastrointestinal motility and secretion and modulation of gastrointestinal functions","volume":"4","author":"Browning","year":"2014","journal-title":"Compr. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"188313","DOI":"10.1016\/j.bbcan.2019.188313","article-title":"Nervous system and gastric cancer","volume":"1873","author":"Wang","year":"2020","journal-title":"Biochim. Biophys. Acta (BBA) Rev. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1097\/PPO.0000000000000107","article-title":"Stress, metabolism and cancer: Integrated pathways contributing to immune suppression","volume":"21","author":"Repasky","year":"2015","journal-title":"Cancer J. (Sudbury Mass.)"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1002\/1097-0142(197704)39:4<1482::AID-CNCR2820390420>3.0.CO;2-P","article-title":"The influence of stress and stress hormones on the transplantability of a non-immunogenic syngeneic murine tumor","volume":"39","author":"Peters","year":"1977","journal-title":"Cancer"},{"key":"ref_18","first-page":"584","article-title":"Beta-adrenoceptor action on pancreatic cancer cell proliferation and tumor growth in mice","volume":"59","author":"Lin","year":"2012","journal-title":"Hepato Gastroenterol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.3748\/wjg.v23.i7.1250","article-title":"B2 adrenergic receptors and morphological changes of the enteric nervous system in colorectal adenocarcinoma","volume":"23","author":"Ciurea","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"10357","DOI":"10.1158\/0008-5472.CAN-06-2496","article-title":"Norepinephrine up-regulates the expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9 in nasopharyngeal carcinoma tumor cells","volume":"66","author":"Yang","year":"2006","journal-title":"Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1111\/cas.12438","article-title":"Novel regulatory program for norepinephrine-induced epithelial-mesenchymal transition in gastric adenocarcinoma cell lines","volume":"105","author":"Shan","year":"2014","journal-title":"Cancer Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/aps.2009.181","article-title":"HIF-1alpha links beta-adrenoceptor agonists and pancreatic cancer cells under normoxic condition","volume":"31","author":"Hu","year":"2010","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1186\/1476-4598-9-269","article-title":"Catecholamine up-regulates MMP-7 expression by activating AP-1 and STAT3 in gastric cancer","volume":"9","author":"Shi","year":"2010","journal-title":"Mol. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11010-015-2477-0","article-title":"Isoprenaline induces epithelial-mesenchymal transition in gastric cancer cells","volume":"408","author":"Lu","year":"2015","journal-title":"Mol. Cell. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"557","DOI":"10.3349\/ymj.2016.57.3.557","article-title":"Isoprenaline Induces Periostin Expression in Gastric Cancer","volume":"57","author":"Liu","year":"2016","journal-title":"Yonsei Med. J."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Lu, Y., Xu, Q., Zuo, Y., Liu, L., Liu, S., Chen, L., Wang, K., Lei, Y., Zhao, X., and Li, Y. (2017). Isoprenaline\/\u03b22-AR activates Plexin-A1\/VEGFR2 signals via VEGF secretion in gastric cancer cells to promote tumor angiogenesis. BMC Cancer, 17.","DOI":"10.1186\/s12885-017-3894-0"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6839","DOI":"10.1158\/1078-0432.CCR-08-0230","article-title":"Biobehavioral influences on matrix metalloproteinase expression in ovarian carcinoma","volume":"14","author":"Lutgendorf","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1172\/JCI40802","article-title":"Adrenergic modulation of focal adhesion kinase protects human ovarian cancer cells from anoikis","volume":"120","author":"Sood","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5600","DOI":"10.4049\/jimmunol.1202364","article-title":"Catecholamine-Induced \u03b22-adrenergic receptor activation mediates desensitization of gastric cancer cells to trastuzumab by upregulating MUC4 expression","volume":"190","author":"Shi","year":"2013","journal-title":"J. Immunol."},{"key":"ref_30","first-page":"1669","article-title":"The \u03b2-adrenoceptor antagonist, propranolol, induces human gastric cancer cell apoptosis and cell cycle arrest via inhibiting nuclear factor \u03baB signaling","volume":"24","author":"Liao","year":"2010","journal-title":"Oncol. rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"13885","DOI":"10.1007\/s13277-016-5139-2","article-title":"Clinical significance of \u03b22-adrenergic receptor expression in patients with surgically resected gastric adenocarcinoma","volume":"37","author":"Takahashi","year":"2016","journal-title":"Tumour Biol. J. Int. Soc. Oncodev. Biol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"13833","DOI":"10.1038\/s41598-019-50358-y","article-title":"Nonlinear heart rate variability biomarkers for gastric cancer severity: A pilot study","volume":"9","author":"Shi","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Bastos, D.B., Sarafim-Silva, B., Sundefeld, M., Ribeiro, A.A., Brand\u00e3o, J., Biasoli, \u00c9.R., Miyahara, G.I., Casarini, D.E., and Bernab\u00e9, D.G. (2018). Circulating catecholamines are associated with biobehavioral factors and anxiety symptoms in head and neck cancer patients. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0202515"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Lamboy-Caraballo, R., Ortiz-Sanchez, C., Acevedo-Santiago, A., Matta, J., NA Monteiro, A., and N Armaiz-Pena, G. (2020). Norepinephrine-Induced DNA Damage in Ovarian Cancer Cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21062250"},{"key":"ref_35","first-page":"1932","article-title":"Epinephrine increases malignancy of breast cancer through p38 MAPK signaling pathway in depressive disorders","volume":"12","author":"Ouyang","year":"2019","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"424","DOI":"10.4149\/neo_2011_05_424","article-title":"Chemical sympathectomy suppresses fibrosarcoma development and improves survival of tumor-bearing rats","volume":"58","author":"Lackovicova","year":"2011","journal-title":"Neoplasma"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.ccell.2017.11.007","article-title":"\u03b22 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer","volume":"33","author":"Renz","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1016\/j.jhep.2014.02.025","article-title":"Monoamine oxidase A suppresses hepatocellular carcinoma metastasis by inhibiting the adrenergic system and its transactivation of EGFR signaling","volume":"60","author":"Li","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1002\/jcb.21802","article-title":"Epinephrine stimulates esophageal squamous-cell carcinoma cell proliferation via beta-adrenoceptor-dependent transactivation of extracellular signal-regulated kinase\/cyclooxygenase-2 pathway","volume":"105","author":"Liu","year":"2008","journal-title":"J. Cell. Biochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/s41388-019-1006-0","article-title":"Neurotransmitters: Emerging targets in cancer","volume":"39","author":"Jiang","year":"2020","journal-title":"Oncogene"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1161\/01.CIR.100.8.886","article-title":"ACC\/AHA guidelines for ambulatory electrocardiography: Executive summary and recommendations. A report of the American College of Cardiology\/American Heart Association task force on practice guidelines (committee to revise the guidelines for ambulatory electrocardiography)","volume":"100","author":"Crawford","year":"1999","journal-title":"Circulation"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1373\/clinchem.2014.224832","article-title":"Laboratory evaluation of pheochromocytoma and paraganglioma","volume":"60","author":"Eisenhofer","year":"2014","journal-title":"Clin. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/2042\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:25:56Z","timestamp":1760160356000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/2042"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,18]]},"references-count":42,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["ijms22042042"],"URL":"https:\/\/doi.org\/10.3390\/ijms22042042","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,18]]}}}