{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T12:06:23Z","timestamp":1772798783441,"version":"3.50.1"},"reference-count":58,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T00:00:00Z","timestamp":1655769600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Guangdong Basic and Applied Basic Research Foundation","award":["2022A1515010552"],"award-info":[{"award-number":["2022A1515010552"]}]},{"name":"Guangdong Basic and Applied Basic Research Foundation","award":["U1832101"],"award-info":[{"award-number":["U1832101"]}]},{"name":"Guangdong Basic and Applied Basic Research Foundation","award":["11335011"],"award-info":[{"award-number":["11335011"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2022A1515010552"],"award-info":[{"award-number":["2022A1515010552"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U1832101"],"award-info":[{"award-number":["U1832101"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["11335011"],"award-info":[{"award-number":["11335011"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Although direct damage to nuclear DNA is considered as the major contributing event that leads to radiation-induced effects, accumulating evidence in the past two decades has shown that non-target events, in which cells are not directly irradiated but receive signals from the irradiated cells, or cells irradiated at extranuclear targets, may also contribute to the biological consequences of exposure to ionizing radiation. With a beam diameter at the micrometer or sub-micrometer level, microbeams can precisely deliver radiation, without damaging the surrounding area, or deposit the radiation energy at specific sub-cellular locations within a cell. Such unique features cannot be achieved by other kinds of radiation settings, hence making a microbeam irradiator useful in studies of a radiation-induced bystander effect (RIBE) and cytoplasmic irradiation. Here, studies on RIBE and different responses to cytoplasmic irradiation using microbeams are summarized. Possible mechanisms related to the bystander effect, which include gap-junction intercellular communications and soluble signal molecules as well as factors involved in cytoplasmic irradiation-induced events, are also discussed.<\/jats:p>","DOI":"10.3390\/biology11070945","type":"journal-article","created":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T21:55:19Z","timestamp":1655848519000},"page":"945","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Radiation-Induced Bystander Effect and Cytoplasmic Irradiation Studies with Microbeams"],"prefix":"10.3390","volume":"11","author":[{"given":"Ziqi","family":"Zhang","sequence":"first","affiliation":[{"name":"College of Life Sciences, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kui","family":"Li","sequence":"additional","affiliation":[{"name":"College of Life Sciences, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9219-2844","authenticated-orcid":false,"given":"Mei","family":"Hong","sequence":"additional","affiliation":[{"name":"College of Life Sciences, South China Agricultural University, Guangzhou 510642, China"},{"name":"Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/s41416-020-0942-3","article-title":"Radiation-induced bystander and abscopal effects: Important lessons from preclinical models","volume":"123","author":"Daguenet","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1211\/jpp.60.8.0001","article-title":"Mechanism of radiation-induced bystander effects: A unifying model","volume":"60","author":"Hei","year":"2008","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"A59","DOI":"10.1269\/jrr.08120S","article-title":"Consequences of cytoplasmic irradiation: Studies from microbeam","volume":"50","author":"Zhou","year":"2009","journal-title":"J. Radiat. Res."},{"key":"ref_4","first-page":"6394","article-title":"Induction of sister chromatid exchanges by extremely low doses of alpha-particles","volume":"52","author":"Nagasawa","year":"1992","journal-title":"Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1089\/ars.2017.7267","article-title":"Targeted and off-target (bystander and abscopal) effects of radiation therapy: Redox mechanisms and risk\/benefit analysis","volume":"29","author":"Pouget","year":"2018","journal-title":"Antioxid. Redox Signal."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1667\/RR2757.1","article-title":"Intrachromosomal changes and genomic instability in site-specific microbeam-irradiated and bystander human-hamster hybrid cells","volume":"177","author":"Hu","year":"2012","journal-title":"Radiat. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1096\/fj.02-1115com","article-title":"Bystander effect induced by counted high-LET particles in conflfluent human fifibroblasts: A mechanistic study","volume":"17","author":"Shao","year":"2003","journal-title":"FASEB J."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Seth, I., Schwartz, J.L., Stewart, R.D., Emery, R., Joiner, M.C., and Tucker, J.D. (2014). Neutron exposures in human cells: Bystander effect and relative biological effectiveness. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0098947"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.radonc.2011.11.002","article-title":"The importance of bystander effects in radiation therapy in melanoma skin-cancer cells and umbilical-cord stromal stem cells","volume":"102","author":"Katz","year":"2012","journal-title":"Radiother. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1007\/s13577-022-00668-7","article-title":"Bystander effects induced by the interaction between urothelial cancer cells and irradiated adipose tissue-derived stromal cells in urothelial carcinoma","volume":"35","author":"Kawasaki","year":"2022","journal-title":"Hum. Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"i120","DOI":"10.1093\/jrr\/rrt166","article-title":"Three-dimensional culture of HeLa-FUCCI cells for study of bystander cell-cycle effect of high LET particles","volume":"55","author":"Sakamoto","year":"2014","journal-title":"J. Radiat. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.mrfmmm.2011.12.007","article-title":"Bystander normal human fifibroblasts reduce damage response in radiation targeted cancer cells through intercellular ROS level modulation","volume":"731","author":"Widel","year":"2012","journal-title":"Mutat. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1093\/rpd\/ncl429","article-title":"Experimental techniques for studying bystander effects in vitro by high and low-LET ionising radiation","volume":"122","author":"Hill","year":"2006","journal-title":"Radiat. Prot. Dosim."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4959","DOI":"10.1073\/pnas.96.9.4959","article-title":"Targeted cytoplasmic irradiation with alpha particles induces mutations in mammalian cells","volume":"96","author":"Wu","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6700","DOI":"10.1158\/0008-5472.CAN-13-1411","article-title":"Cytoplasmic irradiation results in mitochondrial dysfunction and DRP1-dependent mitochondrial fission","volume":"73","author":"Zhang","year":"2013","journal-title":"Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.mrfmmm.2017.02.004","article-title":"Targeted cytoplasmic irradiation and autophagy","volume":"806","author":"Wu","year":"2017","journal-title":"Mutat. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1080\/09553002.2017.1364801","article-title":"Focus small to find big-the microbeam story","volume":"94","author":"Wu","year":"2018","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1667\/RR002CC.1","article-title":"50 Years of the radiological research accelerator facility (RARAF)","volume":"187","author":"Marino","year":"2017","journal-title":"Radiat. Res."},{"key":"ref_19","unstructured":"(2022, June 17). Available online: https:\/\/www.crr.columbia.edu\/raraf."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1667\/RR2847.1","article-title":"A focused scanning vertical beam for charged particle irradiation of living cells with single counted particles","volume":"178","author":"Merchant","year":"2012","journal-title":"Radiat. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1269\/jrr.07085","article-title":"Heavy-ion microbeam system at JAEA-Takasaki for microbeam biology","volume":"49","author":"Funayama","year":"2008","journal-title":"J. Radiat. Res."},{"key":"ref_22","first-page":"87","article-title":"The GSI heavy ion microbeam: A tool for the investigation of cellular response to high LET radiations","volume":"10950","author":"Barberet","year":"2006","journal-title":"Acta Phys. Pol. Ser. A"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s13014-015-0350-7","article-title":"Live cell imaging at the Munich ion microbeam SNAKE\u2014A status report","volume":"10","author":"Drexler","year":"2015","journal-title":"Radiat. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"055113","DOI":"10.1063\/1.4805067","article-title":"Focusing gigaelectronvolt heavy ions to micrometers at the Institute of Modern Physics","volume":"84","author":"Sheng","year":"2013","journal-title":"Rev. Sci. Instrum."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1093\/rpd\/ncv192","article-title":"Advances in microbeam technologies and applications to radiation biology","volume":"166","author":"Barberet","year":"2015","journal-title":"Radiat. Prot. Dosim."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1080\/095530098141087","article-title":"Studies of bystander effects in human fibroblasts using a charged particle microbeam","volume":"74","author":"Prise","year":"1998","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.1073\/pnas.030420797","article-title":"Induction of a bystander mutagenic effect of alpha particles in mammalian cells","volume":"97","author":"Zhou","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","first-page":"251","article-title":"The bystander effect in radiation oncogenesis; Trans-formation in C3HT1\/2 cells in vitro can be initiated in the un-irradiated neighbors of irradiated cells","volume":"156","author":"Swant","year":"2001","journal-title":"Radiat. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1080\/09553002.2016.1206237","article-title":"Cell cycle tracking for irradiated and unirradiated bystander cells in a single colony with exposure to a soft X-ray microbeam","volume":"92","author":"Kaminaga","year":"2016","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1080\/09553000600803904","article-title":"Apoptosis is initiated in human keratinocytes exposed to signalling factors from microbeam irradiated cells","volume":"82","author":"Lyng","year":"2006","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.mrfmmm.2014.03.004","article-title":"Damaging and protective bystander cross-talk between human lung cancer and normal cells after proton microbeam irradiation","volume":"763\u2013764","author":"Desai","year":"2014","journal-title":"Mutat. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"14203","DOI":"10.1073\/pnas.0505020102","article-title":"Biological effects in unirradiated human tissue induced by radiation damage up to 1 mm away","volume":"102","author":"Belyakov","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4295","DOI":"10.1158\/0008-5472.CAN-06-4442","article-title":"DNA double-strand breaks form in bystander cells after microbeam irradiation of three-dimensional human tissue models","volume":"67","author":"Sedelnikova","year":"2007","journal-title":"Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1080\/09553000600577821","article-title":"Cell cycle arrest and apoptosis in Caenorhabditis elegans germline cells following heavy-ion microbeam irradiation","volume":"82","author":"Sugimoto","year":"2006","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"A49","DOI":"10.1269\/jrr.08132S","article-title":"Microbeam irradiation of the C. elegans nematode","volume":"50","author":"Bertucci","year":"2009","journal-title":"J. Radiat. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1667\/RR3218.1","article-title":"Radiation-induced bystander signaling from somatic cells to germ cells in Caenorhabditis elegans","volume":"180","author":"Guo","year":"2013","journal-title":"Radiat. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1667\/RR14057.1","article-title":"A mouse ear model for bystander studies induced by microbeam irradiation","volume":"184","author":"Buonanno","year":"2015","journal-title":"Radiat. Res."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Yasuda, T., Kamahori, M., Nagata, K., Watanabe-Asaka, T., Suzuki, M., Funayma, T., Mitani, H., and Oda, S. (2017). Abscopal activation of microglia in embryonic fish brain following targeted irradiation with heavy-ion microbeam. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071428"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1097\/HP.0000000000000525","article-title":"Investigation of abscopal and bystander effects in immunocompromised mice after exposure to pencilbeam and microbeam","volume":"111","author":"Laissue","year":"2016","journal-title":"Health Phys."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1098\/rspb.1964.0043","article-title":"Effects of DNA synthesis of localized irradiation of cells in tissue culture by (i) a U.V. microbeam and (ii) an \u03b1-particle microbeam","volume":"160","author":"Dendy","year":"1964","journal-title":"Proc. R. Soc. Lond. B Biol. Sci."},{"key":"ref_41","first-page":"183","article-title":"Enhanced DNA double strand break repair triggered by microbeam irradiation induced cytoplasmic damage","volume":"9","author":"Konishi","year":"2018","journal-title":"J. Radiat. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1667\/RR15110.1","article-title":"Targeted nuclear irradiation with an X-ray microbeam enhances total JC-1 fluorescence from mitochondria","volume":"194","author":"Kaminaga","year":"2020","journal-title":"Radiat. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1667\/RR0006CC.1","article-title":"Cytoplasmic irradiation induces metabolic shift in human small airway epithelial cells via activation of Pim-1 kinase","volume":"187","author":"Wu","year":"2017","journal-title":"Radiat. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"13495","DOI":"10.1073\/pnas.0404930101","article-title":"Targeted cytoplasmic irradiation induces bystander responses","volume":"101","author":"Shao","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5872","DOI":"10.1158\/0008-5472.CAN-07-0188","article-title":"Cytoplasmic irradiation induces mitochondrial-dependent 53BP1 protein relocalization in irradiated and bystander cells","volume":"67","author":"Tartier","year":"2007","journal-title":"Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"96","DOI":"10.2174\/1874467211104020096","article-title":"Radiation induced non-targeted response: Mechanism and potential clinical implications","volume":"4","author":"Hei","year":"2011","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1667\/RR3111.1","article-title":"Gap junction communication and the propagation of bystander effects induced by microbeam irradiation in human fibroblast cultures: The impact of radiation quality","volume":"180","author":"Autsavapromporn","year":"2013","journal-title":"Radiat. Res."},{"key":"ref_48","first-page":"122","article-title":"Hypoxia and proton microbeam: Role of gap junction intercellular communication in inducing bystander responses on human lung cancer cells and normal Cells","volume":"197","author":"Autsavapromporn","year":"2022","journal-title":"Radiat. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1667\/RR15155.1","article-title":"Emerging role of secondary bystander effects induced by fractionated proton microbeam radiation","volume":"191","author":"Autsavapromporn","year":"2019","journal-title":"Radiat. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1667\/RR3600.1","article-title":"Calcium fluxes modulate the radiation-induced bystander responses in targeted glioma and fibroblast cells","volume":"166","author":"Shao","year":"2006","journal-title":"Radiat. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1158\/0008-5472.CAN-07-5278","article-title":"Mitochondrial function and nuclear factor-kappaB-mediated signaling in radiation-induced bystander effects","volume":"68","author":"Zhou","year":"2008","journal-title":"Cancer Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.lssr.2015.06.004","article-title":"Nitric oxide-mediated bystander signal transduction induced by heavy-ion microbeam irradiation","volume":"6","author":"Tomita","year":"2015","journal-title":"Life Sci. Space Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1667\/RR15469.1","article-title":"Role of endoplasmic reticulum and mitochondrion in proton microbeam radiation-induced bystander effect","volume":"193","author":"Dong","year":"2020","journal-title":"Radiat. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.exphem.2007.01.013","article-title":"Quantifying a bystander response following microbeam irradiation using single-cell RT-PCR analyses","volume":"35","author":"Ponnaiya","year":"2007","journal-title":"Exp. Hematol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.mrfmmm.2008.04.007","article-title":"Expression profiles are different in carbon ion-irradiated normal human fibroblasts and their bystander cells","volume":"642","author":"Iwakawa","year":"2008","journal-title":"Mutat. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.1093\/carcin\/bgq119","article-title":"MicroRNAome changes in bystander three-dimensional human tissue models suggest priming of apoptotic pathways","volume":"31","author":"Kovalchuk","year":"2010","journal-title":"Carcinogenesis"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1038\/sj.bjc.6605888","article-title":"Mechanism of genotoxicity induced by targeted cytoplasmic irradiation","volume":"103","author":"Hong","year":"2010","journal-title":"Br. J. Cancer"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/sj.onc.1210653","article-title":"Role of TGF-\u03b21 and nitric oxide in the bystander response of irradiated glioma cells","volume":"27","author":"Shao","year":"2008","journal-title":"Oncogene"}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/11\/7\/945\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:36:31Z","timestamp":1760139391000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/11\/7\/945"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,21]]},"references-count":58,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["biology11070945"],"URL":"https:\/\/doi.org\/10.3390\/biology11070945","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,21]]}}}