{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T14:19:43Z","timestamp":1766067583402,"version":"3.37.3"},"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T00:00:00Z","timestamp":1662595200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012155","name":"National Institute for Medical Research Development","doi-asserted-by":"publisher","award":["973293"],"award-info":[{"award-number":["973293"]}],"id":[{"id":"10.13039\/501100012155","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"crossref","award":["310030_184662"],"award-info":[{"award-number":["310030_184662"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Cutaneous leishmaniasis (CL) is a Neglected Tropical Disease (NTD) that causes high morbidity in the tropics and sub-tropics. Despite the remarkable advancements in the treatment of CL, the available therapeutics are far from ideal and also cause serious adverse side effects. Negative air ions (NAIs) generators are widely available for domestic and industrial uses. Several studies have reported on positive effects of NAIs therapy on human health as a non-pharmaceutical treatment for respiratory disease, allergy, or stress-related health conditions, including infectious diseases. To our knowledge, no studies have examined the effectiveness of the NAIs therapy against <jats:italic>Leishmania<\/jats:italic> parasites. The aims of this study were to investigate the effect of NAIs therapy on <jats:italic>Leishmania major<\/jats:italic> (<jats:italic>L<\/jats:italic>. <jats:italic>major<\/jats:italic>) the causative agent of CL in <jats:italic>in vitro<\/jats:italic> and in a murine model.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methodology\/Principal findings<\/jats:title>\n<jats:p><jats:italic>In vitro<\/jats:italic> anti-leishmanial effects of NAIs therapy were measured by parasitological methods. NAIs therapy was assessed <jats:italic>in vivo<\/jats:italic> in <jats:italic>L<\/jats:italic>. <jats:italic>major<\/jats:italic> infected BALB\/c mice by measuring the footpad (FP) lesion size and parasite load using metric caliper tool and qPCR, respectively. Immune responses in treated and non-treated mice were assessed by measuring the levels of IFN-\u03b3, IL-4, NO and arginase activity. <jats:italic>In vitro<\/jats:italic> NAIs therapy significantly decreased the viability of <jats:italic>Leishmania<\/jats:italic> promastigotes and of amastigotes cultured in macrophages, but did not affect the host cells. NAIs therapy of <jats:italic>L<\/jats:italic>. <jats:italic>major<\/jats:italic> infected BALB\/c mice resulted in reduced FP lesion size, diminished parasite burden, and importantly decreased induction of IL-4 and arginase activity in the presence of NAIs. In contrast IFN-\u03b3 and NO levels were significantly enhanced. NAIs therapy significantly diminished the progression of disease compared to the control group, but was less effective than amphotericin B treatment.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Our study shows that NAIs treatment was effective <jats:italic>in vitro<\/jats:italic> and in <jats:italic>Leishmania<\/jats:italic>-infected mice, elicited a T-helper 1 (Th1) response and increased efficient cellular immunity, resulting in a diminished parasite load. Therefore, NAIs therapy can be considered as a useful and safe tool that can contribute to clearing <jats:italic>L<\/jats:italic>. <jats:italic>major<\/jats:italic> infections without inducing toxicity in host cells. The applications and mechanisms of NAIs therapy warrant further investigation especially in humans suffering from CL.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0274124","type":"journal-article","created":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T17:29:43Z","timestamp":1662658183000},"page":"e0274124","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Effects of negative air ions (NAIs) on Leishmania major: A novel tool for treatment of zoonotic cutaneous leishmaniasis (ZCL)"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5315-2559","authenticated-orcid":true,"given":"Alireza","family":"Badirzadeh","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mehdi","family":"Najm","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Hemphill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maryam","family":"Alipour","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hamid","family":"Hasanpour","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leila","family":"Masoori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Poorya","family":"Karimi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,9,8]]},"reference":[{"issue":"5","key":"pone.0274124.ref001","doi-asserted-by":"crossref","first-page":"e0009416","DOI":"10.1371\/journal.pntd.0009416","article-title":"Detection of cutaneous leishmaniasis in three communities of Oti Region, Ghana.","volume":"15","author":"R Akuffo","year":"2021","journal-title":"PLOS Neglected Tropical Diseases"},{"issue":"1","key":"pone.0274124.ref002","doi-asserted-by":"crossref","first-page":"e0007843","DOI":"10.1371\/journal.pntd.0007843","article-title":"Antileishmanial activity of Urtica dioica extract against zoonotic cutaneous leishmaniasis","volume":"14","author":"A Badirzadeh","year":"2020","journal-title":"PLOS Neglected Tropical Diseases"},{"issue":"6","key":"pone.0274124.ref003","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1017\/S0031182021000160","article-title":"Potential therapeutic targets shared between leishmaniasis and cancer","volume":"148","author":"S Rashidi","year":"2021","journal-title":"Parasitology"},{"issue":"4","key":"pone.0274124.ref004","doi-asserted-by":"crossref","first-page":"e0232116","DOI":"10.1371\/journal.pone.0232116","article-title":"Deciphering the role of UBA-like domains in intraflagellar distribution and functions of myosin XXI in Leishmania.","volume":"15","author":"R Bajaj","year":"2020","journal-title":"PLOS ONE"},{"issue":"12","key":"pone.0274124.ref005","doi-asserted-by":"crossref","first-page":"e0242494","DOI":"10.1371\/journal.pone.0242494","article-title":"Psycho-social impacts, experiences and perspectives of patients with Cutaneous Leishmaniasis regarding treatment options and case management: An exploratory qualitative study in Tunisia.","volume":"15","author":"A Boukthir","year":"2020","journal-title":"PLOS ONE"},{"issue":"4","key":"pone.0274124.ref006","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1179\/2047773213Y.0000000097","article-title":"Cutaneous and post kala-azar dermal leishmaniasis caused by Leishmania infantum in endemic areas of visceral leishmaniasis, northwestern Iran 2002\u20102011: a case series.","volume":"107","author":"A Badirzadeh","year":"2013","journal-title":"Pathogens and global health"},{"issue":"3","key":"pone.0274124.ref007","doi-asserted-by":"crossref","first-page":"e0004495","DOI":"10.1371\/journal.pntd.0004495","article-title":"Treatment of Cutaneous Leishmaniasis Caused by Leishmania aethiopica: A Systematic Review","volume":"10","author":"J van Griensven","year":"2016","journal-title":"LOS Neglected Tropical Diseases."},{"issue":"11","key":"pone.0274124.ref008","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.pt.2003.09.008","article-title":"Leishmaniasis\u2013current chemotherapy and recent advances in the search for novel drugs","volume":"19","author":"SL Croft","year":"2003","journal-title":"Trends in parasitology"},{"issue":"2","key":"pone.0274124.ref009","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.actatropica.2011.02.007","article-title":"Systematic review of the adverse effects of cutaneous leishmaniasis treatment in the New World","volume":"118","author":"LF Oliveira","year":"2011","journal-title":"Acta tropica"},{"issue":"3","key":"pone.0274124.ref010","first-page":"117","article-title":"Selenium nanoparticles role in organ systems functionality and disorder","volume":"3","author":"SM Amini","year":"2018","journal-title":"Nanomedicine Research Journal"},{"key":"pone.0274124.ref011","doi-asserted-by":"crossref","first-page":"109809","DOI":"10.1016\/j.msec.2019.109809","article-title":"Preparation of antimicrobial metallic nanoparticles with bioactive compounds","volume":"103","author":"SM Amini","year":"2019","journal-title":"Materials Science and Engineering: C"},{"issue":"10","key":"pone.0274124.ref012","doi-asserted-by":"crossref","first-page":"2966","DOI":"10.3390\/ijms19102966","article-title":"Negative Air Ions and Their Effects on Human Health and Air Quality Improvement","volume":"19","author":"S-Y Jiang","year":"2018","journal-title":"International Journal of Molecular Sciences"},{"issue":"1","key":"pone.0274124.ref013","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s41664-017-0007-7","article-title":"Generation and determination of negative air ions","volume":"1","author":"H-F Lin","year":"2017","journal-title":"Journal of Analysis and Testing"},{"issue":"11","key":"pone.0274124.ref014","doi-asserted-by":"crossref","first-page":"e0242554","DOI":"10.1371\/journal.pone.0242554","article-title":"An inversion model for estimating the negative air ion concentration using MODIS images of the Daxing\u2019anling region.","volume":"15","author":"C Yue","year":"2020","journal-title":"PLOS ONE"},{"issue":"1\u20133","key":"pone.0274124.ref015","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.scitotenv.2008.03.035","article-title":"Damage effects induced by electrically generated negative air ions in Caenorhabditis elegans","volume":"401","author":"K Cai","year":"2008","journal-title":"Science of The Total Environment"},{"issue":"4","key":"pone.0274124.ref016","first-page":"300","article-title":"Evaluation of Negative Air Ions in Bioaerosol Removal: Indoor Concentration of Airborne Bacterial and Fungal in Residential Building in Qom City, Iran.","volume":"12","author":"Z Asadgol","year":"2018","journal-title":"International Journal of Environmental and Ecological Engineering"},{"issue":"1","key":"pone.0274124.ref017","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1080\/26395940.2020.1728198","article-title":"Indoor and outdoor concentration of PM10, PM2. 5 and PM1 in residential building and evaluation of negative air ions (NAIs) in indoor PM removal","volume":"32","author":"A Nadali","year":"2020","journal-title":"Environmental Pollutants and Bioavailability"},{"issue":"6","key":"pone.0274124.ref018","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1046\/j.1365-2672.1999.00944.x","article-title":"Sensitivity of Candida albicans to negative air ion streams","volume":"87","author":"J Shargawi","year":"1999","journal-title":"Journal of applied microbiology"},{"issue":"2","key":"pone.0274124.ref019","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.canlet.2005.08.002","article-title":"Water-generated negative air ions activate NK cell and inhibit carcinogenesis in mice","volume":"239","author":"R Yamada","year":"2006","journal-title":"Cancer letters"},{"issue":"6","key":"pone.0274124.ref020","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1111\/j.1365-2672.2005.02729.x","article-title":"Interaction of air ions and bactericidal vapours to control micro\u2010organisms","volume":"99","author":"L Gaunt","year":"2005","journal-title":"Journal of applied microbiology"},{"issue":"5","key":"pone.0274124.ref021","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1007\/s10103-016-1928-5","article-title":"In vitro evaluation of photodynamic therapy using curcumin on Leishmania majo r and Leishmania braziliensis","volume":"31","author":"JG Pinto","year":"2016","journal-title":"Lasers in medical science"},{"issue":"11","key":"pone.0274124.ref022","doi-asserted-by":"crossref","first-page":"e49496","DOI":"10.1371\/journal.pone.0049496","article-title":"17-AAG Kills Intracellular Leishmania amazonensis while Reducing Inflammatory Responses in Infected Macrophages.","volume":"7","author":"Guedes CES Petersen ALdOA","year":"2012","journal-title":"PLOS ONE"},{"issue":"3","key":"pone.0274124.ref023","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.exppara.2006.01.008","article-title":"Leishmania amazonensis: participation of regulatory T and B cells in the in vitro priming (PIV) of CBA\/J spleen cells susceptible response","volume":"113","author":"PST Veras","year":"2006","journal-title":"Experimental parasitology"},{"issue":"1","key":"pone.0274124.ref024","doi-asserted-by":"crossref","first-page":"e12605","DOI":"10.1111\/pim.12605","article-title":"Sambucus ebulus extract stimulates cellular responses in cutaneous leishmaniasis","volume":"41","author":"M Heidari\u2010Kharaji","year":"2019","journal-title":"Parasite Immunology"},{"issue":"5","key":"pone.0274124.ref025","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1111\/j.1365-3024.1985.tb00098.x","article-title":"A limiting dilution assay for quantifying Leishmania major in tissues of infected mice","volume":"7","author":"RG Titus","year":"1985","journal-title":"Parasite immunology"},{"issue":"12","key":"pone.0274124.ref026","doi-asserted-by":"crossref","first-page":"e14394","DOI":"10.1371\/journal.pone.0014394","article-title":"DETC induces Leishmania parasite killing in human in vitro and murine in vivo models: a promising therapeutic alternative in Leishmaniasis.","volume":"5","author":"R Khouri","year":"2010","journal-title":"PloS one"},{"issue":"1","key":"pone.0274124.ref027","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1111\/1755-0998.12281","article-title":"The room temperature preservation of filtered environmental DNA samples and assimilation into a phenol\u2013chloroform\u2013isoamyl alcohol DNA extraction","volume":"15","author":"MA Renshaw","year":"2015","journal-title":"Molecular ecology resources"},{"issue":"9","key":"pone.0274124.ref028","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1128\/AAC.39.9.2167","article-title":"Culture microtitration: a sensitive method for quantifying Leishmania infantum in tissues of infected mice","volume":"39","author":"P Buffet","year":"1995","journal-title":"Antimicrobial agents and chemotherapy"},{"issue":"10","key":"pone.0274124.ref029","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1111\/pim.12340","article-title":"Enhanced paromomycin efficacy by solid lipid nanoparticle formulation against Leishmania in mice model","volume":"38","author":"M Heidari\u2010Kharaji","year":"2016","journal-title":"Parasite immunology"},{"issue":"1","key":"pone.0274124.ref030","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s12639-020-01279-5","article-title":"Arginase\/nitric oxide modifications using live non-pathogenic Leishmania tarentolae as an effective delivery system inside the mammalian macrophages","volume":"45","author":"A Badirzadeh","year":"2021","journal-title":"Journal of Parasitic Diseases"},{"key":"pone.0274124.ref031","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.exppara.2019.05.004","article-title":"Cytokine profile and nitric oxide levels in macrophages exposed to Leishmania infantum FML","volume":"203","author":"R Shafiei","year":"2019","journal-title":"Experimental Parasitology"},{"issue":"4259","key":"pone.0274124.ref032","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1126\/science.959834","article-title":"Biological impact of small air ions","volume":"193","author":"AP Krueger","year":"1976","journal-title":"Science"},{"issue":"3","key":"pone.0274124.ref033","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.ijfoodmicro.2010.08.023","article-title":"Antimicrobial action of essential oil vapours and negative air ions against Pseudomonas fluorescens","volume":"143","author":"AK Tyagi","year":"2010","journal-title":"International Journal of Food Microbiology"},{"key":"pone.0274124.ref034","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/S0076-6879(84)05031-X","article-title":"[28] Survey of the methodology for evaluating negative air ions: Relevance to biological studies","volume":"105","author":"R. Pethig","year":"1984","journal-title":"Methods in enzymology"},{"issue":"101","key":"pone.0274124.ref035","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1364\/AO.8.S1.000106","article-title":"Nature of charge carriers in negative coronas","volume":"8","author":"M. Shahin","year":"1969","journal-title":"Applied Optics"},{"issue":"1","key":"pone.0274124.ref036","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/1471-2180-7-32","article-title":"Bactericidal action of positive and negative ions in air","volume":"7","author":"LA Fletcher","year":"2007","journal-title":"BMC microbiology"},{"issue":"1","key":"pone.0274124.ref037","first-page":"1","article-title":"Phenotypic and functional analyses of natural killer cells: impaired NK activity partly due to the CD56+ cell dysfunction in cancer patients","volume":"15","author":"A Kishi","year":"1999","journal-title":"International journal of immunotherapy"},{"issue":"14","key":"pone.0274124.ref038","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1017\/S0031182011001363","article-title":"The interplay between Leishmania promastigotes and human Natural Killer cells in vitro leads to direct lysis of Leishmania by NK cells and modulation of NK cell activity by Leishmania promastigotes","volume":"138","author":"T Lieke","year":"2011","journal-title":"Parasitology"},{"issue":"12","key":"pone.0274124.ref039","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1111\/pim.12007","article-title":"Tissue damage and immunity in cutaneous leishmaniasis","volume":"34","author":"S Nyl\u00e9n","year":"2012","journal-title":"Parasite immunology"},{"article-title":"Assesment of \u03b2-lapachone loaded in lecithin-chitosan nanoparticles for the topical treatment of cutaneous leishmaniasis in L. major infected BALB\/c mice","year":"2015","author":"S Espuelas","key":"pone.0274124.ref040"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0274124","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T17:30:24Z","timestamp":1662658224000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0274124"}},"subtitle":[],"editor":[{"given":"Maritza","family":"Jaramillo","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2022,9,8]]},"references-count":40,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,9,8]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0274124","relation":{},"ISSN":["1932-6203"],"issn-type":[{"type":"electronic","value":"1932-6203"}],"subject":[],"published":{"date-parts":[[2022,9,8]]}}}