{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T15:41:40Z","timestamp":1790264500329,"version":"4.1.0"},"reference-count":136,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,4]],"date-time":"2021-11-04T00:00:00Z","timestamp":1635984000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Hyponatremia, i.e., the presence of a serum sodium concentration ([Na+]) &lt; 136 mEq\/L, is the most frequent electrolyte imbalance in the elderly and in hospitalized patients. Symptoms of acute hyponatremia, whose main target is the central nervous system, are explained by the \u201cosmotic theory\u201d and the neuronal swelling secondary to decreased extracellular osmolality, which determines cerebral oedema. Following the description of neurological and systemic manifestations even in mild and chronic hyponatremia, in the last decade reduced extracellular [Na+] was associated with detrimental effects on cellular homeostasis independently of hypoosmolality. Most of these alterations appeared to be elicited by oxidative stress. In this review, we focus on the role of oxidative stress on both osmolality-dependent and -independent impairment of cell and tissue functions observed in hyponatremic conditions. Furthermore, basic and clinical research suggested that oxidative stress appears to be a common denominator of the degenerative processes related to aging, cancer progression, and hyponatremia. Of note, low [Na+] is able to exacerbate multiple manifestations of senescence and to decrease progression-free and overall survival in oncologic patients.<\/jats:p>","DOI":"10.3390\/antiox10111768","type":"journal-article","created":{"date-parts":[[2021,11,4]],"date-time":"2021-11-04T22:25:54Z","timestamp":1636064754000},"page":"1768","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Hyponatremia and Oxidative Stress"],"prefix":"10.3390","volume":"10","author":[{"given":"Benedetta","family":"Fibbi","sequence":"first","affiliation":[{"name":"Pituitary Diseases and Sodium Alterations Unit, AOU Careggi, 50139 Florence, Italy"},{"name":"Endocrinology, Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d, University of Florence, AOU Careggi, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6611-8103","authenticated-orcid":false,"given":"Giada","family":"Marroncini","sequence":"additional","affiliation":[{"name":"Pituitary Diseases and Sodium Alterations Unit, AOU Careggi, 50139 Florence, Italy"},{"name":"Endocrinology, Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d, University of Florence, AOU Careggi, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Anceschi","sequence":"additional","affiliation":[{"name":"Endocrinology, Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d, University of Florence, AOU Careggi, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Naldi","sequence":"additional","affiliation":[{"name":"Endocrinology, Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d, University of Florence, AOU Careggi, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Peri","sequence":"additional","affiliation":[{"name":"Pituitary Diseases and Sodium Alterations Unit, AOU Careggi, 50139 Florence, Italy"},{"name":"Endocrinology, Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d, University of Florence, AOU Careggi, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1056\/NEJM200005253422107","article-title":"Hyponatremia","volume":"342","author":"Madias","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1001\/archinternmed.2009.513","article-title":"Impact of hospital-associated hyponatremia on selected outcomes","volume":"170","author":"Wald","year":"2010","journal-title":"Arch. Intern. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Corona, G., Giuliani, C., Parenti, G., Norello, D., Verbalis, J.G., Forti, G., Maggi, M., and Peri, A. (2013). Moderate hyponatremia is associated with increased risk of mortality: Evidence from a meta-analysis. PLoS ONE, 8.","DOI":"10.1530\/endoabs.32.P864"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1016\/j.amjmed.2013.07.021","article-title":"Prevalence of hyponatremia and association with mortality: Results from NHANES","volume":"126","author":"Mohan","year":"2013","journal-title":"Am. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1002\/lt.21197","article-title":"An integrated MELD model including serum sodium and age improves the prediction of early mortality in patients with cirrhosis","volume":"13","author":"Luca","year":"2007","journal-title":"Liver Transpl."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/s11897-016-0295-7","article-title":"Pharmacologic approaches to electrolyte abnormalities in heart failure","volume":"13","author":"Grodin","year":"2016","journal-title":"Curr. Heart Fail. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1080\/17482940701210179","article-title":"Improvement in hyponatremia during hospitalization for worsening heart failure is associated with improved outcomes: Insights from the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Chronic Heart Failure (ACTIV in CHF) trial","volume":"9","author":"Rossi","year":"2007","journal-title":"Acute Card. Care"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1159\/000100866","article-title":"Hyponatremia in community-acquired pneumonia","volume":"27","author":"Nair","year":"2007","journal-title":"Am. J. Nephrol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"71.e1","DOI":"10.1016\/j.amjmed.2005.09.026","article-title":"Mild Chronic Hyponatremia is Associated with Falls, Unsteadiness, and Attention Deficits","volume":"119","author":"Renneboog","year":"2006","journal-title":"Am. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"S79","DOI":"10.1016\/j.amjmed.2006.05.013","article-title":"Is asymptomatic hyponatremia really asymptomatic?","volume":"119","author":"Decaux","year":"2006","journal-title":"Am. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2268","DOI":"10.2215\/CJN.00170115","article-title":"Mild chronic hyponatremia in the ambulatory setting: Significance and management","volume":"10","author":"Berl","year":"2015","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1822","DOI":"10.1002\/jbmr.380","article-title":"Mild hyponatremia as a risk factor for fractures: The Rotterdam Study","volume":"26","author":"Hoorn","year":"2011","journal-title":"J. Bone Miner. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.amjmed.2008.11.033","article-title":"Mild hyponatremia carries a poor prognosis in community subjects","volume":"122","author":"Sajadieh","year":"2009","journal-title":"Am. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1530\/EJE-15-0111","article-title":"Hyponatremia and mortality risk: A Danish cohort study of 279 508 acutely hospitalized patients","volume":"173","author":"Christiansen","year":"2015","journal-title":"Eur. J. Endocrinol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ma, Q.Q., Fan, X.D., Li, T., Hao, Y.Y., and Ma, F. (2018). Short- and long-term prognostic value of hyponatremia in patients with acute coronary syndrome: A systematic review and meta-analysis. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0193857"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1016\/j.jstrokecerebrovasdis.2013.07.011","article-title":"Hyponatremia in the prognosis of acute ischemic stroke","volume":"23","author":"Rodrigues","year":"2014","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.amjmed.2010.07.029","article-title":"Mortality associated with low serum sodium concentration in maintenance hemodialysis","volume":"124","author":"Curhan","year":"2011","journal-title":"Am. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"960","DOI":"10.2215\/CJN.10101110","article-title":"Mortality and serum sodium: Do patients die from or with hyponatremia?","volume":"6","author":"Chawla","year":"2011","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.ijcard.2008.08.004","article-title":"Predictors of short term mortality in hert failure\u2014insights from the Euro Heart Failure Survey","volume":"138","author":"Velavan","year":"2010","journal-title":"Int. J. Cardiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/BF01095898","article-title":"Prognostic value of spontaneous hyponatremia in cirrhosis with ascites","volume":"21","author":"Arroyo","year":"1976","journal-title":"Am. J. Dig. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"S47","DOI":"10.1016\/j.amjmed.2006.05.007","article-title":"Water and sodium retention in edematous disorders: Role of vasopressin and aldosterone","volume":"119","author":"Schrier","year":"2006","journal-title":"Am. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1111\/joim.12764","article-title":"Hyponatremia and activation of vasopressin secretion are both independently associated with 30-day mortality: Results of a multicenter, observational study","volume":"284","author":"Eckart","year":"2018","journal-title":"J. Intern. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e25","DOI":"10.1016\/j.ejim.2017.02.008","article-title":"Attention and postural balance are much more affected in older than in younger adults with mild or moderate chronic hyponatremia","volume":"41","author":"Renneboog","year":"2017","journal-title":"Eur. J. Intern. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"366","DOI":"10.2215\/CJN.07400717","article-title":"Serum sodium and cognition in older community-dwelling men","volume":"13","author":"Nowak","year":"2018","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.3233\/JAD-151118","article-title":"Copeptin, a marker of vasopressin, predicts vascular dementia but not Alzheimer\u2019s disease","volume":"52","author":"Nilsson","year":"2016","journal-title":"J. Alzheimers Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"313","DOI":"10.5414\/CN108335","article-title":"Mild hyponatremia is associated with functional and cognitive decline in chronic hemodialysis patients","volume":"82","author":"Shavit","year":"2014","journal-title":"Clin. Nephrol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.2215\/CJN.02240215","article-title":"Hyponatremia and cognitive impairment in patients treated with peritoneal dialysis","volume":"10","author":"Duan","year":"2015","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1111\/cen.13790","article-title":"Hyponatremia, falls and bone fractures: A systematic review and meta-analysis","volume":"89","author":"Corona","year":"2018","journal-title":"Clin. Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/s11154-016-9387-7","article-title":"Hyponatremia and bone disease","volume":"18","author":"Negri","year":"2017","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1093\/qjmed\/hcn061","article-title":"Mild hyponatremia and risk of fracture in the ambulatory elderly","volume":"101","author":"Gankam","year":"2008","journal-title":"QJM Int. J. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"275","DOI":"10.2215\/CJN.06120809","article-title":"Hyponatremia independent of osteoporosis is associated with fracture occurrence","volume":"5","author":"Kinsella","year":"2010","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Kuo, S.C., Kuo, P., Rau, C., Wu, S., Hsu, S., and Hsieh, C. (2017). Hyponatremia is associated with worse outcomes from fall injuries in the elderly. Int. J. Environ. Res. Public Health, 14.","DOI":"10.3390\/ijerph14050460"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3021","DOI":"10.1210\/jc.2015-1261","article-title":"Hyponatremia is associated with increased osteoporosis and bone fractures in a large US health system population","volume":"100","author":"Usala","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1007\/s001980200108","article-title":"The epidemiology of corticosteroid-induced osteoporosis: A meta-analysis","volume":"13","author":"Leufkens","year":"2002","journal-title":"Osteoporos. Int."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.bone.2015.12.002","article-title":"The effect of chronic mild hyponatremia on bone mineral loss evaluated by retrospective national Danish patient data","volume":"84","author":"Kruse","year":"2016","journal-title":"Bone"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1359\/jbmr.090827","article-title":"Hyponatremia-induced osteoporosis","volume":"25","author":"Verbalis","year":"2010","journal-title":"J. Bone Miner. Res."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Corona, G., Giuliani, C., Verbalis, J.G., Forti, G., Maggi, M., and Peri, A. (2015). Hyponatremia improvement is associated with a reduced risk of mortality: Evidence from a meta-analysis. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0124105"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.1056\/NEJMoa065181","article-title":"Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia","volume":"355","author":"Schrier","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1053\/j.ajkd.2015.12.024","article-title":"Tolvaptan and neurocognitive function in mild to moderate chronic hyponatremia: A randomized trial (INSIGHT)","volume":"67","author":"Verbalis","year":"2016","journal-title":"Am. J. Kidney Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1159\/000339100","article-title":"Hyponatremia in geriatric inhospital patients: Effects on results of a comprehensive geriatric assessment","volume":"58","author":"Gosch","year":"2012","journal-title":"Gerontology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3527","DOI":"10.1210\/jc.2014-1572","article-title":"Recovery from SIADH-associated osteoporosis: A case report","volume":"99","author":"Sejling","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1111\/cen.13937","article-title":"Hyponatraemia in patients with community-acquired pneumonia; prevalence and aetiology, and natural history of SIAD","volume":"90","author":"Cuesta","year":"2019","journal-title":"Clin. Endocrinol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1530\/EJE-20-1447","article-title":"Serum sodium alterations in SARS CoV-2 (COVID-19) infection: Impact on patient outcome","volume":"185","author":"Berni","year":"2021","journal-title":"Eur. J. Endocrinol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/S0140-6736(20)30628-0","article-title":"COVID19: Consider cytokine storm syndromes and immunosuppression","volume":"395","author":"Mehta","year":"2020","journal-title":"Lancet"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"519","DOI":"10.3345\/kjp.2013.56.12.519","article-title":"Inflammation and hyponatremia: An underrecognized condition?","volume":"56","author":"Park","year":"2013","journal-title":"Korean, J. Pediatr."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1093\/cid\/ciaa248","article-title":"Dysregulation of immune response in patients with COVID-19 in Wuhan, China","volume":"71","author":"Qin","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_47","first-page":"934","article-title":"Hypothalamic-pituitary-adrenal axis activation and stimulation of systemic vasopressin secretion by recombinant interleukin-6 in humans: Potential implications for the syndrome of inappropriate vasopressin secretion","volume":"79","author":"Mastorakos","year":"1994","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"666949","DOI":"10.3389\/fmed.2021.666949","article-title":"The Prognostic Value of Hyponatremia for Predicting Poor Outcome in Patients With COVID-19: A Systematic Review and Meta-Analysis","volume":"14","author":"Akbar","year":"2021","journal-title":"Front. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1634\/theoncologist.2011-0400","article-title":"Diagnosis and management of hyponatremia in cancer patients","volume":"17","author":"Castillo","year":"2012","journal-title":"Oncologist"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1007\/BF03344188","article-title":"Hyponatremia and pituitary adenoma: Think twice about the etiopathogenesis","volume":"29","author":"Zogheri","year":"2006","journal-title":"J. Endocrinol. Investig."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1016\/0002-9343(76)90406-X","article-title":"Plasma arginine vasopressin in the syndrome of antidiuretic hormone excess associated with bronchogenic carcinoma","volume":"61","author":"Padfield","year":"1976","journal-title":"Am. J. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/1040-8428(94)00126-E","article-title":"Hyponatremia of malignancy","volume":"18","author":"Shapiro","year":"1995","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1111\/j.1365-2796.1995.tb00907.x","article-title":"Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in malignant disease","volume":"238","author":"Sorensen","year":"1995","journal-title":"J. Intern. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/bjc.1993.425","article-title":"Combination chemotherapy for intermediate and high grade non-Hodgkin\u2019s lymphoma","volume":"68","author":"Dhaliwal","year":"1993","journal-title":"Br. J. Cancer"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"S512","DOI":"10.4103\/0973-1482.172717","article-title":"Clinical outcome of 30 patients with bone marrow metastases","volume":"14","author":"Zhou","year":"2018","journal-title":"J. Cancer Res. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1111\/codi.12878","article-title":"Prognostic impact of hyponatraemia in patients with colorectal cancer","volume":"17","author":"Choi","year":"2015","journal-title":"Colorectal Dis."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1002\/hep.22418","article-title":"Hyponatremia in cirrhosis: Pathogenesis, clinical significance, and management","volume":"48","author":"Gines","year":"2008","journal-title":"Hepatology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1001\/archsurg.2008.522","article-title":"Indication of the extent of hepatectomy for hepatocellular carcinoma on cirrhosis by a simple algorithm based on preoperative variables","volume":"144","author":"Cescon","year":"2009","journal-title":"Arch. Surg."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1007\/s00520-014-2398-6","article-title":"Hyponatraemia is a predictor of clinical outcome for malignant pleural mesothelioma","volume":"23","author":"Berardi","year":"2015","journal-title":"Support Care Cancer"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1158\/1078-0432.CCR-07-1721","article-title":"Prognostic factors in renal cell carcinoma: Association of preoperative sodium concentration with survival","volume":"14","author":"Vasudev","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.eururo.2013.10.013","article-title":"The impact of low serum sodium on treatment outcome of targeted therapy in metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Cancer Database Consortium","volume":"65","author":"Schutz","year":"2014","journal-title":"Eur. Urol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"631","DOI":"10.6004\/jnccn.2006.0052","article-title":"Paraneoplastic syndromes associated with small cell lung cancer","volume":"4","author":"Gandhi","year":"2006","journal-title":"J. Natl. Compr. Canc. Netw."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1038\/bjc.1990.133","article-title":"An overview of prognostic factors in small cell lung cancer. A report from the Subcommittee for the Management of Lung Cancer of the United Kingdom Coordinating Committee on Cancer Research","volume":"61","author":"Rawson","year":"1990","journal-title":"Br. J. Cancer"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Balachandran, K., Okines, A., Gunapala, R., Morganstein, D., and Popat, S. (2015). Resolution of severe hyponatraemia is associated with improved survival in patients with cancer. BMC Cancer, 15.","DOI":"10.1186\/s12885-015-1156-6"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.mehy.2012.05.023","article-title":"Proposing the use of hyponatremia as a marker to help identify high risk individuals for lung cancer","volume":"79","author":"Kasi","year":"2012","journal-title":"Med. Hypotheses"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"F619","DOI":"10.1152\/ajprenal.00502.2007","article-title":"Brain cell volume regulation in hyponatremia: Role of sex, age, vasopressin, and hypoxia","volume":"295","author":"Ayus","year":"2008","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/j.neuroscience.2004.07.033","article-title":"Water homeostasis in the brain: Basic concepts","volume":"129","author":"Kimelberg","year":"2004","journal-title":"Neuroscience"},{"key":"ref_68","first-page":"221","article-title":"Volume changes in neurons: Hyperexcitability and neuronal death","volume":"152","author":"Tuz","year":"2006","journal-title":"Contrib. Nephrol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.neuroscience.2004.09.053","article-title":"The neurobiology of glia in the context of water and ion homeostasis","volume":"129","author":"Simard","year":"2004","journal-title":"Neuroscience"},{"key":"ref_70","first-page":"2141","article-title":"Pathophysiology and puzzles of the volume-sensitive outwardly rectifying anion channel","volume":"15","author":"Okada","year":"2009","journal-title":"J. Physiol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1016\/j.neuroscience.2010.03.042","article-title":"Brain volume regulation in response to changes in osmolality","volume":"168","author":"Verbalis","year":"2010","journal-title":"Neuroscience"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/S0188-4409(02)00353-3","article-title":"Mechanisms Counteracting Swelling in Brain Cells During Hyponatremia","volume":"33","author":"Franco","year":"2002","journal-title":"Arch. Med. Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"C755","DOI":"10.1152\/ajpcell.1997.273.3.C755","article-title":"Volume expansion-sensing outward-rectifier Cl-channel: Fresh start to the molecular identity and volume sensor","volume":"273","author":"Okada","year":"1997","journal-title":"Am. J. Physiol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3355","DOI":"10.1113\/jphysiol.2010.190777","article-title":"Receptor regulation of osmolyte homeostasis in neural cells","volume":"18","author":"Fisher","year":"2010","journal-title":"J. Physiol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/0006-8993(91)90806-7","article-title":"Hyponatremia causes large sustained reductions in brain content of multiple organic osmolytes in rats","volume":"567","author":"Verbalis","year":"1991","journal-title":"Brain Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1677\/JOE-10-0050","article-title":"Chronic hyponatremia impairs memory in rats: Effects of vasopressin antagonist tolvaptan","volume":"206","author":"Miyazaki","year":"2010","journal-title":"J. Endocrinol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1016\/j.amjmed.2019.12.056","article-title":"Impairment of Neurocognitive Functioning, Motor Performance, and Mood Stability in Hospitalized Patients with Euvolemic Moderate and Profound Hyponatremia","volume":"133","author":"Norello","year":"2020","journal-title":"Am. J. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0301-0082(00)00067-8","article-title":"Glutamate uptake","volume":"65","author":"Danbolt","year":"2001","journal-title":"Prog. Neurobiol."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Haskew-Layton, R.E., Rudkouskaya, A., Jin, Y., Feustel, P.J., Kimelberg, H.K., and Mongin, A.A. (2008). Two distinct modes of hypoosmotic medium-induced release of excitatory amino acids and taurine in the rat brain in vivo. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0003543"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1681\/ASN.2014121196","article-title":"Chronic Hyponatremia Causes Neurologic and Psychologic Impairments","volume":"27","author":"Fujisawa","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1152\/physrev.2000.80.1.315","article-title":"Mitochondria and neuronal survival","volume":"80","author":"Nicholls","year":"2000","journal-title":"Physiol. Rev."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/364535a0","article-title":"NMDA-dependent superoxide production and neurotoxicity","volume":"364","author":"Pietri","year":"1993","journal-title":"Nature"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2282","DOI":"10.1046\/j.1471-4159.1996.67062282.x","article-title":"Mitochondria, calcium regulation, and acute glutamate excitotoxicity in cultured cerebellar granule cells","volume":"67","author":"Budd","year":"1996","journal-title":"J. Neurochem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2038","DOI":"10.1046\/j.1471-4159.1997.68052038.x","article-title":"Glutamate neurotoxicity in rat cerebellar granule cells: A major role for xanthine oxidase in oxygen radical formation","volume":"68","author":"Atlante","year":"1997","journal-title":"J. Neurochem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1046\/j.1471-4159.1999.721394.x","article-title":"Oxidative stress, mitochondrial function, and acute glutamate excitotoxicity in cultured cerebellar granule cells","volume":"72","author":"Castilho","year":"1999","journal-title":"J. Neurochem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/S0168-0102(00)00124-3","article-title":"Oxidative glutamate toxicity involves mitochondrial dysfunction and perturbation of intracellular Ca2+ homeostasis","volume":"37","author":"Pereira","year":"2000","journal-title":"Neurosci. Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/S0891-5849(00)00317-8","article-title":"Mitochondrial free radical generation, oxidative stress, and aging","volume":"29","author":"Cadenas","year":"2000","journal-title":"Free Radic. Biol. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1097\/00004647-200101000-00002","article-title":"Reactive oxygen radicals in signaling and damage in the ischemic brain","volume":"21","author":"Chan","year":"2001","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1016\/j.amjmed.2006.05.002","article-title":"Mechanisms of cell volume regulation in hypo-osmolality","volume":"119","author":"Lezama","year":"2006","journal-title":"Am. J. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1023\/B:NERE.0000010433.08577.96","article-title":"Regulation of the cellular content of the organic osmolyte taurine in mammalian cells","volume":"29","author":"Lambert","year":"2004","journal-title":"Neurochem. Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1111\/j.1471-4159.1987.tb10014.x","article-title":"Mechanism of kainate toxicity to cerebellar neurons in vitro is analogous to reperfusion tissue injury","volume":"49","author":"Dykens","year":"1987","journal-title":"J. Neurochem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1046\/j.1471-4159.1994.63020584.x","article-title":"Isolated cerebral and cerebellar mitochondria produce free radicals when exposed to elevated CA2+ and Na+: Implications for neurodegeneration","volume":"63","author":"Dykens","year":"1994","journal-title":"J. Neurochem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1016\/0896-6273(95)90186-8","article-title":"Glutamate-induced neuronal death: A succession of necrosis or apoptosis depending on mitochondrial function","volume":"15","author":"Ankarcrona","year":"1995","journal-title":"Neuron"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"7727","DOI":"10.1523\/JNEUROSCI.18-19-07727.1998","article-title":"Rapid Ca2+ entry through Ca2+-permeable AMPA\/Kainate channels triggers marked intracellular Ca2+ rises and consequent oxygen radical production","volume":"18","author":"Carriedo","year":"1998","journal-title":"J. Neurosci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0006-8993(96)00382-4","article-title":"Inhibition of free radical production or free radical scavenging protects from the excitotoxic cell death mediated by glutamate in cultures of cerebellar granule neurons","volume":"728","author":"Ciani","year":"1996","journal-title":"Brain Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"4904","DOI":"10.1046\/j.1432-1327.2000.01595.x","article-title":"Glutathione, oxidative stress and neurodegeneration","volume":"267","author":"Schulz","year":"2000","journal-title":"Eur. J. Biochem."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1172\/JCI115292","article-title":"Study of brain electrolytes and organic osmolytes during correction of chronic hyponatremia","volume":"88","author":"Lien","year":"1991","journal-title":"J. Clin. Invest."},{"key":"ref_98","first-page":"H313","article-title":"Depletion of brain glutathione by buthionine sulfoximine enhances cerebral ischemic injury in rats","volume":"262","author":"Mizui","year":"1992","journal-title":"Am. J. Physiol."},{"key":"ref_99","first-page":"L308","article-title":"Depletion of tissue glutathione with diethyl maleate enhances hyperbaric oxygen toxicity","volume":"258","author":"Weber","year":"1990","journal-title":"Am. J. Physiol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1038\/ki.1996.66","article-title":"Depletion of glutathione from brain cells in hyponatremia","volume":"49","author":"Clark","year":"1996","journal-title":"Kidney Int."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1111\/j.1471-4159.1990.tb08831.x","article-title":"Glutathione turnover in cultured astrocytes: Studies with [15N]glutamate","volume":"55","author":"Yudkoff","year":"1990","journal-title":"J. Neurochem."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1002\/ana.410270118","article-title":"Hyponatremia is associated with cerebral ischemia in patients with aneurysmal subarachnoid hemorrhage","volume":"27","author":"Hasan","year":"1990","journal-title":"Ann. Neurol."},{"key":"ref_103","first-page":"986","article-title":"Glutamate uptake is inhibited by arachidonic acid and oxygen radicals via two distinct and additive mechanisms","volume":"46","author":"Volterra","year":"1994","journal-title":"Mol. Pharmacol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"10864","DOI":"10.1074\/jbc.M110.155002","article-title":"Osteoclast response to low extracellular sodium and the mechanism of hyponatremia-induced bone loss","volume":"286","author":"Barsony","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1172\/JCI102959","article-title":"Bone as a sodium and potassium reservoir","volume":"33","author":"Bergstrom","year":"1954","journal-title":"J. Clin. Investig."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"R1429","DOI":"10.1152\/ajpregu.00676.2005","article-title":"Are large amounts of sodium stored in an osmotically inactive form during sodium retention? Balance studies in freely moving dogs","volume":"290","author":"Seeliger","year":"2006","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.abb.2003.09.013","article-title":"Zinc-induced sodium-dependent vitamin C transporter 2 expression: Potent roles in osteoblast differentiation","volume":"420","author":"Wu","year":"2003","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1007\/BF03345382","article-title":"Ascorbic acid inhibits osteoclastogenesis of RAW264.7 cells induced by receptor activated nuclear factor kappaB ligand (RANKL) in vitro","volume":"28","author":"Xiao","year":"2005","journal-title":"J. Endocrinol. Investig."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/s12020-015-0663-1","article-title":"Low extracellular sodium promotes adipogenic commitment of human mesenchymal stromal cells: A novel mechanism for chronic hyponatremia-induced bone loss","volume":"52","author":"Fibbi","year":"2016","journal-title":"Endocrine"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1111\/j.1582-4934.2004.tb00320.x","article-title":"Adult mesenchymal stem cells: Characterization, differentiation, and application in cell and gene therapy","volume":"8","author":"Baksh","year":"2004","journal-title":"J. Cell. Mol. Med."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1615\/CritRevEukarGeneExpr.v19.i2.20","article-title":"Marrow fat and the bone microenvironment: Developmental, functional and pathological implications","volume":"19","author":"Rosen","year":"2009","journal-title":"Crit. Rev. Eukariot. Gene Expr."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1126\/science.273.5271.59","article-title":"Oxidative stress, caloric restriction, and aging","volume":"273","author":"Sohal","year":"1996","journal-title":"Science"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1146\/annurev.pathmechdis.2.010506.092044","article-title":"The Aging Brain","volume":"3","author":"Yakner","year":"2008","journal-title":"Annu. Rev. Pathol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"S30","DOI":"10.1016\/j.amjmed.2006.05.005","article-title":"Incidence and prevalence of hyponatremia","volume":"119","author":"Upadhyay","year":"2006","journal-title":"Am. J. Med."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/s11357-011-9347-9","article-title":"Chronic hyponatremia exacerbates multiple manifestations of senescence in male rats","volume":"35","author":"Barsony","year":"2013","journal-title":"Age"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1111\/iep.12338","article-title":"Hyponatremia aggravates cardiac susceptibility to ischemia\/reperfusion injury","volume":"100","author":"Oniki","year":"2019","journal-title":"Int. J. Exp. Path."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1042\/bj3410233","article-title":"The mitochondrial permeability transition pore and its role in cell death","volume":"341","author":"Crompton","year":"1999","journal-title":"Biochem. J."},{"key":"ref_118","first-page":"187","article-title":"Cross-talk between reactive oxygen species and calcium in living cells. Biochemistry 2003, 68:1077-1080; Brookes PS. Mitochondrial nitric oxide synthase","volume":"3","author":"Goordeva","year":"2004","journal-title":"Mitochondrion"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1007\/s12017-013-8235-0","article-title":"Low extracellular sodium causes neuronal distress independently of reduced osmolality in an experimental model of chronic hyponatremia","volume":"15","author":"Benvenuti","year":"2013","journal-title":"Neuromol. Med."},{"key":"ref_120","first-page":"878","article-title":"Heme oxygenase and its products in the nervous system","volume":"6","author":"Mancuso","year":"2004","journal-title":"Antioxid. Redox Signal"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1046\/j.1471-4159.2000.0750304.x","article-title":"Neurons overexpressing heme oxygenase-1 resist oxidative stress-mediated cell death","volume":"75","author":"Chen","year":"2000","journal-title":"J. Neurochem."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1097\/00004647-199805000-00011","article-title":"Induction of heme oxygenase protein protects neurons in cortex and striatum, but not in hippocampus, against transient forebrain ischemia","volume":"18","author":"Takizawa","year":"1998","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.neulet.2006.06.052","article-title":"Heme oxygenase protects hippocampal neurons from ethanol-induced neurotoxicity","volume":"405","author":"Ku","year":"2006","journal-title":"Neurosci. Lett."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/s40618-015-0352-1","article-title":"Neuronal distress induced by low extracellular sodium in vitro is partially reverted by the return to normal sodium","volume":"39","author":"Benvenuti","year":"2016","journal-title":"J. Endocrinol. Investig."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1007\/s10495-010-0491-y","article-title":"Neurogenesis in the aged and neurodegenerative brain","volume":"15","author":"Shruster","year":"2010","journal-title":"Apoptosis"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1007\/s12020-019-02135-0","article-title":"Effects of low extracellular sodium on proliferation and invasive activity of cancer cells in vitro","volume":"67","author":"Marroncini","year":"2020","journal-title":"Endocrine"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"e2253","DOI":"10.1038\/cddis.2016.105","article-title":"ROS homeostasis and metabolism: A dangerous liason in cancer cells","volume":"7","author":"Panieri","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.biotechadv.2018.01.007","article-title":"Targeting of stress response pathways in the prevention and treatment of cancer","volume":"36","author":"Zelenka","year":"2018","journal-title":"Biotechnol. Adv."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1093\/carcin\/21.3.361","article-title":"Oxyradicals and DNA damage","volume":"21","author":"Marnett","year":"2000","journal-title":"Carcinogenesis"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1038\/nrd4002","article-title":"Modulation of oxidative stress as an anticancer strategy","volume":"12","author":"Gorrini","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1038\/nature07733","article-title":"Association of reactive oxygen species levels and radioresistance in cancer stem cells","volume":"458","author":"Diehn","year":"2009","journal-title":"Nature"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1245\/s10434-011-2040-5","article-title":"Increased CD13 expression reduces reactive oxygen species, promoting survival of liver cancer stem cells via an epithelial-mesenchymal transition-like phenomenon","volume":"19","author":"Kim","year":"2012","journal-title":"Ann. Surg. Oncol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1038\/sj.bjc.6605563","article-title":"Hyponatremia as a prognostic and predictive factor in metastatic renal cell carcinoma","volume":"102","author":"Jeppesen","year":"2010","journal-title":"Br. J. Cancer"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1080\/0284186X.2018.1477256","article-title":"Hyponatremia associates with poor outcome in metastatic renal cell carcinoma patients treated with everolimus: Prognostic impact","volume":"57","author":"Penttila","year":"2018","journal-title":"Acta Oncol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"23871","DOI":"10.18632\/oncotarget.13372","article-title":"Hyponatremia normalization as an independent prognostic factor in patients with advanced non-small cell lung cancer treated with first-line therapy","volume":"8","author":"Berardi","year":"2017","journal-title":"Oncotarget"}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/10\/11\/1768\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:26:05Z","timestamp":1760167565000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/10\/11\/1768"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,4]]},"references-count":136,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["antiox10111768"],"URL":"https:\/\/doi.org\/10.3390\/antiox10111768","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,4]]}}}