{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T18:09:15Z","timestamp":1767204555317,"version":"build-2238731810"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2019,2,12]],"date-time":"2019-02-12T00:00:00Z","timestamp":1549929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001849","name":"Defence Research and Development Organisation","doi-asserted-by":"publisher","award":["LSRB-271\/SH&amp;DD\/2015)"],"award-info":[{"award-number":["LSRB-271\/SH&amp;DD\/2015)"]}],"id":[{"id":"10.13039\/501100001849","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Accidental exposure to lethal doses of Gamma radiation leads to the systemic inflammatory syndrome which causes mortality. In view of this, management of hemopoietic syndrome by modulating pro-inflammatory response in clinically manageable time period seems to be the most appropriate strategy for encountering radiation induced damage and recovery. As both tissue and peripheral macrophages are critical for the management of radiation induced injuries, we have unraveled the immunomodulatory potential of radioprotective formulation (G-003M) on peripheral macrophages populations in this study. G-003M inhibited lethal radiation induced NO and Th1 effector cytokines in the exposed macrophages indicating its M1 dim polarizing capacity. In similar lines, conditioning of mice with G-003M before lethal irradiation (LR) inhibited LR induced titre of Th1 effector cytokines in both serums as well as in lung, small intestine, and spleen tissue confirming its immunomodulatory potential. G-003M potentially down modulated inflammatory response in LPS induced inflammatory model and enhanced M2 polarization of iNOS+ M1 effector macrophages providing a molecular hint on G-003M mechanism of action on macrophages. These observations revealed that G-003M potentially modulate pro-inflammatory programming of macrophages and mitigate radiation-induced inflammatory stress which is believed to contribute significantly to radioprotective attribute of G-003M. In this study, we demonstrate that Rutin and Podophyllotoxin drive M1\n                    <jats:sup>dim<\/jats:sup>\n                    \/M2 polarization of LR primed macrophages apart from protecting DNA from radiation. These drugs have the capacity to programme innate immune cells like macrophages which may be involved in homeostasis during recovery.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2019.00106","type":"journal-article","created":{"date-parts":[[2019,2,11]],"date-time":"2019-02-11T23:42:30Z","timestamp":1549928550000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["RETRACTED: Podophyllotoxin and Rutin Modulate M1 (iNOS+) Macrophages and Mitigate Lethal Radiation (LR) Induced Inflammatory Responses in Mice"],"prefix":"10.3389","volume":"10","author":[{"given":"Vinod","family":"Nadella","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rajiv","family":"Ranjan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Balasubramanian","family":"Senthilkumaran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S. S. Y. H.","family":"Qadri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suresh","family":"Pothani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ajay Kumar","family":"Singh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manju L.","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hridayesh","family":"Prakash","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2019,2,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"5473","DOI":"10.1158\/1078-0432.CCR-11-0774","article-title":"Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide","volume":"17","author":"Grossman","year":"2011","journal-title":"Clin Cancer Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/S0167-8140(85)80122-5","article-title":"Effect of dose-rate on total body irradiation: lethality and pathologic findings","volume":"4","author":"Travis","year":"1985","journal-title":"Radiother Oncol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1667\/0033-7587(2001)155[0409:TOOLRI]2.0.CO;2","article-title":"The outcome of local radiation injuries: 14 years of follow-up after the Chernobyl accident","volume":"155","author":"Gottl\u00f6ber","year":"2001","journal-title":"Radiat Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"8280","DOI":"10.4049\/jimmunol.180.12.8280","article-title":"Flagellin treatment protects against chemicals, bacteria, viruses, and radiation","volume":"180","author":"Vijay-Kumar","year":"2008","journal-title":"J Immunol."},{"key":"B5","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1182\/blood.V81.2.324.324","article-title":"Inhibition of c-kit ligand\/steel factor by antibodies reduces survival of lethally irradiated mice","volume":"81","author":"Neta","year":"1993","journal-title":"Blood"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1084\/jem.173.5.1177","article-title":"Role of cytokines (interleukin 1, tumor necrosis factor, and transforming growth factor beta) in natural and lipopolysaccharide-enhanced radioresistance","volume":"173","author":"Neta","year":"1991","journal-title":"J Exp Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1007\/BF01972318","article-title":"Radioprotection of LPS-resistant C3H\/HeJ mice by RES-blockade","volume":"38","author":"Kumagai","year":"1982","journal-title":"Experientia"},{"key":"B8","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1189\/jlb.0413209","article-title":"Flagellin and LPS each restores rat lymphocyte populations after colorectal irradiation","volume":"95","author":"Lacave-Lapalun","year":"2014","journal-title":"J Leukoc Biol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1124\/jpet.113.204040","article-title":"Flagellin or lipopolysaccharide treatment modified macrophage populations after colorectal radiation of rats","volume":"346","author":"Lacave-Lapalun","year":"2013","journal-title":"J Pharmacol Exp Ther."},{"key":"B10","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1142\/S0192415X05002886","article-title":"Immune activation and radioprotection by propolis","volume":"33","author":"Takagi","year":"2005","journal-title":"Am J Chin Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1042\/BA20040164","article-title":"Podophyllum hexandrum (Himalayan mayapple) extract provides radioprotection by modulating the expression of proteins associated with apoptosis","volume":"42","author":"Kumar","year":"2005","journal-title":"Biotechnol Appl Biochem."},{"key":"B12","first-page":"OL1646","article-title":"Bioavailability, antioxidant and non toxic properties of a radioprotective formulation prepared from isolated compounds of Podophyllum hexandrum: a study in mouse model","volume":"58","author":"Dutta","year":"2012","journal-title":"Cell Mol Biol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"317","DOI":"10.3109\/10715762.2015.1004328","article-title":"The combination of the active principles of Podophyllum hexandrum supports early recovery of the gastrointestinal system via activation of Nrf2-HO-1 signaling and the hematopoietic system, leading to effective whole-body survival in lethally irradiated mice","volume":"49","author":"Dutta","year":"2015","journal-title":"Free Radic Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1002\/em.21853","article-title":"Modification of radiation-induced DNA double strand break repair pathways by chemicals extracted from Podophyllum hexandrum: an in vitro study in human blood leukocytes","volume":"55","author":"Srivastava","year":"2014","journal-title":"Environ Mol Mutagen."},{"key":"B15","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.fct.2016.03.007","article-title":"Countering effects of a combination of podophyllotoxin, podophyllotoxin beta-D-glucoside and rutin hydrate in minimizing radiation induced chromosomal damage, ROS and apoptosis in human blood lymphocytes","volume":"91","author":"Dutta","year":"2016","journal-title":"Food Chem Toxicol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"757","DOI":"10.3109\/09553002.2015.1062576","article-title":"Radiation-induced hematopoietic myelosuppression and genotoxicity get significantly countered by active principles of Podophyllum hexandrum: a study in strain 'A' mice","volume":"91","author":"Verma","year":"2015","journal-title":"Int J Radiat Biol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1179\/1351000212Y.0000000004","article-title":"Podophyllum hexandrum aqueous extract as a potential free radical scavenger","volume":"17","author":"Ganie","year":"2012","journal-title":"Redox Rep."},{"key":"B18","first-page":"29","article-title":"Protective efficacy of semi purified fraction of high altitude podophyllum hexandrum rhizomes in lethally irradiated Swiss albino mice","volume":"53","author":"Gupta","year":"2007","journal-title":"Cell Mol Biol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"183","DOI":"10.3389\/fimmu.2017.00183","article-title":"Podophyllotoxin and rutin modulates ionizing radiation-induced oxidative stress and apoptotic cell death in mice bone marrow and spleen","volume":"8","author":"Singh","year":"2017","journal-title":"Front Immunol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"658","DOI":"10.3389\/fimmu.2017.00658","article-title":"A combination of podophyllotoxin and rutin alleviates radiation-induced pneumonitis and fibrosis through modulation of lung inflammation in mice","volume":"8","author":"Verma","year":"2017","journal-title":"Front Immunol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"281","DOI":"10.2174\/1568010054022024","article-title":"Macrophages in inflammation","volume":"4","author":"Fujiwara","year":"2005","journal-title":"Curr Drug Targets Inflamm Allergy"},{"key":"B22","doi-asserted-by":"publisher","first-page":"4111","DOI":"10.1007\/s00018-015-1995-y","article-title":"Macrophage polarization in pathology","volume":"72","author":"Sica","year":"2015","journal-title":"Cell Mol Life Sci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1189\/jlb.0211095","article-title":"The innate immune system and the clearance of apoptotic cells","volume":"90","author":"Devitt","year":"2011","journal-title":"J Leukoc Biol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/j.bbamcr.2014.09.020","article-title":"Transglutaminase 2 interacts with syndecan-4 and CD44 at the surface of human macrophages to promote removal of apoptotic cells","volume":"1853","author":"Nadella","year":"2015","journal-title":"Biochim Biophys Acta"},{"key":"B25","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1016\/S0923-2494(99)80039-X","article-title":"The role of the macrophage in immune regulation","volume":"149","author":"Gordon","year":"1998","journal-title":"Res Immunol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1161\/CIRCRESAHA.115.306256","article-title":"Macrophage phenotype and function in different stages of atherosclerosis","volume":"118","author":"Tabas","year":"2016","journal-title":"Circ Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"13","DOI":"10.12703\/P6-13","article-title":"The M1 and M2 paradigm of macrophage activation: time for reassessment","volume":"6","author":"Martinez","year":"2014","journal-title":"F1000Prime Rep."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.1038\/ni.2109","article-title":"Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils","volume":"12","author":"Galli","year":"2011","journal-title":"Nat Immunol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"514","DOI":"10.3389\/fimmu.2014.00514","article-title":"From monocytes to M1\/M2 macrophages: phenotypical vs. functional differentiation","volume":"5","author":"Italiani","year":"2014","journal-title":"Front Immunol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"2596","DOI":"10.1016\/j.ajpath.2015.06.001","article-title":"Monocyte and macrophage plasticity in tissue repair and regeneration","volume":"185","author":"Das","year":"2015","journal-title":"Am J Pathol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1172\/JCI59643","article-title":"Macrophage plasticity and polarization: in vivo veritas","volume":"122","author":"Sica","year":"2012","journal-title":"J Clin Invest."},{"key":"B32","first-page":"107","article-title":"Anti-inflammatory effects of Podophyllum hexandrum (RP-1) against lipopolysaccharides induced inflammation in mice","volume":"8","author":"Prakash","year":"2005","journal-title":"J Pharm Pharm Sci."},{"key":"B33","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1667\/RR3031.1","article-title":"Cytokines in radiobiological responses: a review","volume":"178","author":"Schaue","year":"2012","journal-title":"Radiat Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s12950-015-0058-3","article-title":"Portrait of inflammatory response to ionizing radiation treatment","volume":"12","author":"Di","year":"2015","journal-title":"J Inflamm."},{"key":"B35","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1007\/s11010-006-9277-5","article-title":"Podophyllum hexandrum modulates gamma radiation-induced immunosuppression in Balb\/c mice: implications in radioprotection","volume":"295","author":"Goel","year":"2007","journal-title":"Mol Cell Biochem."},{"key":"B36","doi-asserted-by":"publisher","first-page":"320","DOI":"10.2307\/3576688","article-title":"Radiation-induced hemopoietic death in mice as a function of photon energy and dose rate","volume":"105","author":"Gengozian","year":"1986","journal-title":"Radiat Res."},{"key":"B37","doi-asserted-by":"publisher","first-page":"614","DOI":"10.3389\/fimmu.2014.00614","article-title":"Molecular mechanisms that influence the macrophage m1-m2 polarization balance","volume":"5","author":"Wang","year":"2014","journal-title":"Front Immunol."}],"updated-by":[{"DOI":"10.3389\/fimmu.2022.899504","type":"retraction","label":"Retraction","source":"retraction-watch","updated":{"date-parts":[[2022,3,30]],"date-time":"2022-03-30T00:00:00Z","timestamp":1648598400000},"record-id":"36624"},{"DOI":"10.3389\/fimmu.2022.899504","type":"retraction","label":"Retraction","source":"publisher","updated":{"date-parts":[[2022,3,30]],"date-time":"2022-03-30T00:00:00Z","timestamp":1648598400000}}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2019.00106\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,5]],"date-time":"2024-04-05T10:04:25Z","timestamp":1712311465000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2019.00106\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,12]]},"references-count":37,"alternative-id":["10.3389\/fimmu.2019.00106"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2019.00106","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,12]]},"article-number":"106"}}