{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T02:32:12Z","timestamp":1789439532276,"version":"build-2803163510"},"reference-count":39,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2022,9,3]],"date-time":"2022-09-03T00:00:00Z","timestamp":1662163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["NIH-R03 CA180548"],"award-info":[{"award-number":["NIH-R03 CA180548"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["3P42ES023720-04S2"],"award-info":[{"award-number":["3P42ES023720-04S2"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["1P30 ES013508-02"],"award-info":[{"award-number":["1P30 ES013508-02"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Pennsylvania School of Medicine and the Office of the Vice Provost for Research","award":["NIH-R03 CA180548"],"award-info":[{"award-number":["NIH-R03 CA180548"]}]},{"name":"University of Pennsylvania School of Medicine and the Office of the Vice Provost for Research","award":["3P42ES023720-04S2"],"award-info":[{"award-number":["3P42ES023720-04S2"]}]},{"name":"University of Pennsylvania School of Medicine and the Office of the Vice Provost for Research","award":["1P30 ES013508-02"],"award-info":[{"award-number":["1P30 ES013508-02"]}]},{"DOI":"10.13039\/100000002","name":"pilot project","doi-asserted-by":"publisher","award":["NIH-R03 CA180548"],"award-info":[{"award-number":["NIH-R03 CA180548"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"pilot project","doi-asserted-by":"publisher","award":["3P42ES023720-04S2"],"award-info":[{"award-number":["3P42ES023720-04S2"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"pilot project","doi-asserted-by":"publisher","award":["1P30 ES013508-02"],"award-info":[{"award-number":["1P30 ES013508-02"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Although alveolar macrophages play a critical role in malignant transformation of mesothelial cells following asbestos exposure, inflammatory and oxidative processes continue to occur in the mesothelial cells lining the pleura that may contribute to the carcinogenic process. Malignant transformation of mesothelial cells following asbestos exposure occurs over several decades; however, amelioration of DNA damage, inflammation, and cell injury may impede the carcinogenic process. We have shown in an in vitro model of asbestos-induced macrophage activation that synthetic secoisolariciresinol diglucoside (LGM2605), given preventively, reduced inflammatory cascades and oxidative\/nitrosative cell damage. Therefore, it was hypothesized that LGM2605 could also be effective in reducing asbestos-induced activation and the damage of pleural mesothelial cells. LGM2605 treatment (50 \u00b5M) of huma n pleural mesothelial cells was initiated 4 h prior to exposure to asbestos (crocidolite, 20 \u00b5g\/cm2). Supernatant and cells were evaluated at 0, 2, 4, and 8 h post asbestos exposure for reactive oxygen species (ROS) generation, DNA damage (oxidized guanine), inflammasome activation (caspase-1 activity) and associated pro-inflammatory cytokine release (IL-1\u03b2, IL-18, IL-6, TNF\u03b1, and HMGB1), and markers of oxidative stress (malondialdehyde (MDA) and 8-iso-prostaglandin F2a (8-iso-PGF2\u03b1). Asbestos induced a time-dependent ROS increase that was significantly (p &lt; 0.0001) reduced (29.4%) by LGM2605 treatment. LGM2605 pretreatment also reduced levels of asbestos-induced DNA damage by 73.6% \u00b1 1.0%. Although levels of inflammasome-activated cytokines, IL-1\u03b2 and IL-18, reached 29.2 pg\/mL \u00b1 0.7 pg\/mL and 43.9 pg\/mL \u00b1 0.8 pg\/mL, respectively, LGM2605 treatment significantly (p &lt; 0.0001) reduced cytokine levels comparable to baseline (non-asbestos exposed) values (3.8 pg\/mL \u00b1 0.2 pg\/mL and 5.4 pg\/mL \u00b1 0.2 pg\/mL, respectively). Furthermore, levels of IL-6 and TNF\u03b1 in asbestos-exposed mesothelial cells were high (289.1 pg\/mL \u00b1 2.9 pg\/mL and 511.3 pg\/mL \u00b1 10.2 pg\/mL, respectively), while remaining undetectable with LGM2605 pretreatment. HMGB1 (a key inflammatory mediator and initiator of malignant transformation) release was reduced 75.3% \u00b1 0.4% by LGM2605. Levels of MDA and 8-iso-PGF2\u03b1, markers of oxidative cell injury, were significantly (p &lt; 0.001) reduced by 80.5% \u00b1 0.1% and 76.6% \u00b1 0.3%, respectively. LGM2605, given preventively, reduced ROS generation, DNA damage, and inflammasome-activated cytokine release and key inflammatory mediators implicated in asbestos-induced malignant transformation of normal mesothelial cells.<\/jats:p>","DOI":"10.3390\/ijms231710085","type":"journal-article","created":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T05:17:23Z","timestamp":1662441443000},"page":"10085","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Synthetic Secoisolariciresinol Diglucoside (LGM2605) Prevents Asbestos-Induced Inflammation and Genotoxic Cell Damage in Human Mesothelial Cells"],"prefix":"10.3390","volume":"23","author":[{"given":"Ralph A.","family":"Pietrofesa","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shampa","family":"Chatterjee","sequence":"additional","affiliation":[{"name":"Institute for Environmental Medicine, Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuwaraj","family":"Kadariya","sequence":"additional","affiliation":[{"name":"Cancer Signaling and Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1301-5175","authenticated-orcid":false,"given":"Joseph R.","family":"Testa","sequence":"additional","affiliation":[{"name":"Cancer Signaling and Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M.","family":"Albelda","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melpo","family":"Christofidou-Solomidou","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1158\/1078-0432.CCR-11-2259","article-title":"Molecular pathways: Targeting mechanisms of asbestos and erionite carcinogenesis in mesothelioma","volume":"18","author":"Carbone","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_2","first-page":"1005","article-title":"Chemoprevention of asbestos-linked cancers: A systematic review","volume":"32","author":"Neri","year":"2012","journal-title":"Anticancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1111\/j.1440-1843.2005.00714.x","article-title":"Advances in the diagnosis, evaluation, and management of malignant pleural mesothelioma","volume":"10","author":"Sterman","year":"2005","journal-title":"Respirology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1378\/chest.116.2.504","article-title":"Advances in the treatment of malignant pleural mesothelioma","volume":"116","author":"Sterman","year":"1999","journal-title":"Chest"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/S0165-6147(99)01367-X","article-title":"Potential drug targets: Small GTPases that regulate leukocyte function","volume":"20","author":"Benard","year":"1999","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Emmett, E.A. (2021). Asbestos in High-Risk Communities: Public Health Implications. Int. J. Environ. Res. Public Health, 18.","DOI":"10.3390\/ijerph18041579"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.canlet.2016.05.034","article-title":"Risk of second primary cancers after malignant mesothelioma and vice versa","volume":"379","author":"Chen","year":"2016","journal-title":"Cancer Lett."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1002\/jcb.20828","article-title":"Cellular and molecular parameters of mesothelioma","volume":"98","author":"Testa","year":"2006","journal-title":"J. Cell Biochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"16848","DOI":"10.18632\/oncotarget.4253","article-title":"Reactive oxygen species a double-edged sword for mesothelioma","volume":"6","author":"Benedetti","year":"2015","journal-title":"Oncotarget"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0165-4608(89)90105-2","article-title":"Specificity of asbestos-induced chromosomal aberrations in short-term cultured human mesothelial cells","volume":"41","author":"Olofsson","year":"1989","journal-title":"Cancer Genet. Cytogenet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1165\/ajrcmb.19.2.3111","article-title":"Asbestos fibers and interleukin-1 upregulate the formation of reactive nitrogen species in rat pleural mesothelial cells","volume":"19","author":"Choe","year":"1998","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1080\/01635581.2017.1296169","article-title":"Enterolactone Induces G1-phase Cell Cycle Arrest in Nonsmall Cell Lung Cancer Cells by Downregulating Cyclins and Cyclin-dependent Kinases","volume":"69","author":"Chikara","year":"2017","journal-title":"Nutr. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Chikara, S., Lindsey, K., Borowicz, P., Christofidou-Solomidou, M., and Reindl, K.M. (2017). Enterolactone alters FAK-Src signaling and suppresses migration and invasion of lung cancer cell lines. BMC Complementary Med. Ther., 17.","DOI":"10.1186\/s12906-016-1512-3"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1158\/1940-6207.CAPR-17-0119","article-title":"Flaxseed Consumption Inhibits Chemically Induced Lung Tumorigenesis and Modulates Expression of Phase II Enzymes and Inflammatory Cytokines in A\/J Mice","volume":"11","author":"Chikara","year":"2018","journal-title":"Cancer Prev. Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Pietrofesa, R.A., Chatterjee, S., Park, K., Arguiri, E., Albelda, S.M., and Christofidou-Solomidou, M. (2018). Synthetic Lignan Secoisolariciresinol Diglucoside (LGM2605) Reduces Asbestos-Induced Cytotoxicity in an Nrf2-Dependent and -Independent Manner. Antioxidants, 7.","DOI":"10.3390\/antiox7030038"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/1743-8977-10-39","article-title":"Asbestos and erionite prime and activate the NLRP3 inflammasome that stimulates autocrine cytokine release in human mesothelial cells","volume":"10","author":"Hillegass","year":"2013","journal-title":"Part. Fibre Toxicol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Pietrofesa, R.A., Velalopoulou, A., Albelda, S.M., and Christofidou-Solomidou, M. (2016). Asbestos Induces Oxidative Stress and Activation of Nrf2 Signaling in Murine Macrophages: Chemopreventive Role of the Synthetic Lignan Secoisolariciresinol Diglucoside (LGM2605). Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17030322"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7395238","DOI":"10.1155\/2017\/7395238","article-title":"The Synthetic Lignan Secoisolariciresinol Diglucoside Prevents Asbestos-Induced NLRP3 Inflammasome Activation in Murine Macrophages","volume":"2017","author":"Pietrofesa","year":"2017","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1093\/carcin\/bgv174","article-title":"Flaxseed lignans enriched in secoisolariciresinol diglucoside prevent acute asbestos-induced peritoneal inflammation in mice","volume":"37","author":"Pietrofesa","year":"2016","journal-title":"Carcinogenesis"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Velalopoulou, A., Tyagi, S., Pietrofesa, R.A., Arguiri, E., and Christofidou-Solomidou, M. (2016). The Flaxseed-Derived Lignan Phenolic Secoisolariciresinol Diglucoside (SDG) Protects Non-Malignant Lung Cells from Radiation Damage. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17010007"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1002\/ijc.11710","article-title":"Preclinical evaluation of the nonsteroidal anti-inflammatory agent celecoxib on malignant mesothelioma chemoprevention","volume":"109","author":"Catalano","year":"2004","journal-title":"Int. J. Cancer"},{"key":"ref_22","first-page":"21","article-title":"The flavonoid resveratrol suppresses growth of human malignant pleural mesothelioma cells through direct inhibition of specificity protein 1","volume":"30","author":"Lee","year":"2012","journal-title":"Int. J. Mol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.fct.2013.11.004","article-title":"Resveratrol contributes to chemosensitivity of malignant mesothelioma cells with activation of p53","volume":"63","author":"Lee","year":"2014","journal-title":"Food Chem. Toxicol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1080\/01635581.2015.1040516","article-title":"Anticarcinogenic Effects of Dietary Phytoestrogens and their Chemopreventive Mechanisms","volume":"67","author":"Hwang","year":"2015","journal-title":"Nutr Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"8979","DOI":"10.18632\/oncotarget.6924","article-title":"Multipolar mitosis and aneuploidy after chrysotile treatment: A consequence of abscission failure and cytokinesis regression","volume":"7","author":"Cortez","year":"2016","journal-title":"Oncotarget"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.freeradbiomed.2015.05.002","article-title":"Malignant mesothelioma as an oxidative stress-induced cancer: An update","volume":"86","author":"Chew","year":"2015","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2050","DOI":"10.1172\/JCI119010","article-title":"Asbestos induces apoptosis of human and rabbit pleural mesothelial cells via reactive oxygen species","volume":"98","author":"Broaddus","year":"1996","journal-title":"J. Clin. Investig."},{"key":"ref_28","first-page":"L1029","article-title":"Role of extracellular signal-regulated protein kinases in apoptosis by asbestos and H2O2","volume":"273","author":"Jimenez","year":"1997","journal-title":"Am. J. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"12611","DOI":"10.1073\/pnas.1006542107","article-title":"Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation","volume":"107","author":"Yang","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3290","DOI":"10.1158\/0008-5472.CAN-11-3481","article-title":"Cancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma","volume":"72","author":"Jube","year":"2012","journal-title":"Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"10397","DOI":"10.1073\/pnas.0604008103","article-title":"TNF-alpha inhibits asbestos-induced cytotoxicity via a NF-kappaB-dependent pathway, a possible mechanism for asbestos-induced oncogenesis","volume":"103","author":"Yang","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1126\/science.1156995","article-title":"Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica","volume":"320","author":"Dostert","year":"2008","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/nature00858","article-title":"Release of chromatin protein HMGB1 by necrotic cells triggers inflammation","volume":"418","author":"Scaffidi","year":"2002","journal-title":"Nature"},{"key":"ref_34","first-page":"260","article-title":"Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province","volume":"17","author":"Wagner","year":"1960","journal-title":"Br. J. Ind. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1080\/10937404.2016.1195322","article-title":"Environmental risk of mesothelioma in the United States: An emerging concern-epidemiological issues","volume":"19","author":"Baumann","year":"2016","journal-title":"J. Toxicol. Environ. Health Part B Crit. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"645","DOI":"10.15585\/mmwr.mm7119a1","article-title":"Malignant Mesothelioma Mortality in Women\u2014United States, 1999\u20132020","volume":"71","author":"Mazurek","year":"2022","journal-title":"MMWR Morb. Mortal. Wkly. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6863","DOI":"10.1158\/0008-5472.CAN-08-2852","article-title":"Advances in chemical carcinogenesis: A historical review and prospective","volume":"68","author":"Loeb","year":"2008","journal-title":"Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1089\/hum.2009.088","article-title":"Evaluation of an attenuated vesicular stomatitis virus vector expressing interferon-beta for use in malignant pleural mesothelioma: Heterogeneity in interferon responsiveness defines potential efficacy","volume":"21","author":"Saloura","year":"2010","journal-title":"Hum. Gene Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5325","DOI":"10.1016\/j.bmcl.2013.07.062","article-title":"Synthesis and antioxidant evaluation of (S,S)- and (R,R)-secoisolariciresinol diglucosides (SDGs)","volume":"23","author":"Mishra","year":"2013","journal-title":"Bioorganic Med. Chem. Lett."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/17\/10085\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:22:55Z","timestamp":1760142175000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/17\/10085"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,3]]},"references-count":39,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["ijms231710085"],"URL":"https:\/\/doi.org\/10.3390\/ijms231710085","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,3]]}}}