{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T13:27:05Z","timestamp":1783344425487,"version":"3.54.6"},"reference-count":30,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,2,13]],"date-time":"2024-02-13T00:00:00Z","timestamp":1707782400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81473469"],"award-info":[{"award-number":["81473469"]}],"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":["31770131"],"award-info":[{"award-number":["31770131"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Environmental Toxicology"],"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Scutellaria baicalensis<\/jats:italic>\n                      (SB) and\n                      <jats:italic>Polygonatum Rhizoma<\/jats:italic>\n                      (PR), two traditional Chinese medicines, are both known to suppress cancer. However, the mechanism and effect of combined treatment of them for lung cancer are rarely known. Investigating the combined effect of SB and PR\u00a0(hereafter referred to as SP) in potential mechanism of lung cancer is required. This study was to evaluate the inhibitory effects of SP on A549 cell growth and to explore the underlying molecular mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      According to the theory of Chinese medicine and network pharmacology, in the in vivo experiment, a mouse model of carcinoma in situ was constructed, and lung carcinoma in situ tissues were collected for proteomics analysis, hematoxylin\u2010eosin staining, and CK19 immunohistochemistry. In the in vitro experiment, lung cancer A549 cells at logarithmic growth stage were taken, and the inhibitory effect of SP on the proliferation of A549 cells was detected by CCK8 method. The expression of PON\n                      <jats:sub>3<\/jats:sub>\n                      was detected by quantitative polymerase chain reaction and western blot. In addition, the effect of SP on the induction of apoptosis in A549 cells and the changes of membrane potential and reactive oxygen species (ROS) content were detected by flow cytometry. The changes of PON\n                      <jats:sub>3<\/jats:sub>\n                      content in endoplasmic reticulum (ER) are observed by laser confocal microscopy, whereas the effects of SP on the expression of apoptosis\u2010related proteins and ER stress\u2010related proteins in A549 cells were examined by western blot.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Result<\/jats:title>\n                    <jats:p>\n                      By searching the Traditional Chinese Medicines of Systems Pharmacology (TCMSP) (\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/www.tcmspe.com\/index.php\">https:\/\/www.tcmspe.com\/index.php<\/jats:ext-link>\n                      ) database and SymMap\u00a0database, the respective target genes of PR and SB were mapped into protein network interactions, and using Venn diagrams to show 38 genes in common between PR and SB and lung cancer, SP\u00a0was found to play a role in the treatment of lung cancer. In vivo experiments showed that in a lung carcinoma in situ model, lung tumor tissue was significantly lower in the SP group compared with the control group, and PON\n                      <jats:sub>3<\/jats:sub>\n                      was shown to be downregulated by lung tissue proteomics analysis. The combination of SP was able to inhibit the proliferation of A549 cells in a concentration\u2010dependent manner (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.0001). The expression levels of apoptosis\u2010related proteins and ER stress proteins were significantly increased and the expression levels of PON\n                      <jats:sub>3<\/jats:sub>\n                      and anti\u2010apoptosis\u2010related proteins were decreased in A549 cells. At the same time, knockdown of PON\n                      <jats:sub>3<\/jats:sub>\n                      could inhibit tumor cell proliferation (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.0001). The combination of different concentrations of SP significantly induced apoptosis in A549 cells (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.05;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.0001), increased ROS content (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.01), and damaged mitochondrial membrane potential of A549 cells (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.05;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.0001), and significantly increased the expression levels of apoptosis\u2010related proteins and ER stress proteins in lung cancer A549 cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      SP inhibits proliferation of lung cancer A549 cells by downregulating PON\n                      <jats:sub>3<\/jats:sub>\n                      \u2010induced apoptosis in the mitochondrial and ER pathways.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/tox.24148","type":"journal-article","created":{"date-parts":[[2024,2,13]],"date-time":"2024-02-13T04:30:05Z","timestamp":1707798605000},"page":"3172-3187","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Combination of\n                    <i>Polygonatum<\/i>\n                    <i>Rhizoma<\/i>\n                    and\n                    <i>Scutellaria baicalensis<\/i>\n                    triggers apoptosis through downregulation of\n                    <scp>\n                      PON\n                      <sub>3<\/sub>\n                    <\/scp>\n                    \u2010induced mitochondrial damage and endoplasmic reticulum stress in\n                    <scp>A549<\/scp>\n                    cells"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9196-0725","authenticated-orcid":false,"given":"Haitao","family":"Liu","sequence":"first","affiliation":[{"name":"Medical School Anhui University of Science &amp; Technology  Huainan China"},{"name":"Department of Respiratory Medicine, Shanghai Tenth People's Hospital Tongji University School of Medicine  Shanghai China"},{"name":"Institute of Energy Metabolism and Health Tongji University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liduo","family":"Yue","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Shanghai Tenth People's Hospital Tongji University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Shanghai Tenth People's Hospital Tongji University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiansheng","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Shanghai Tenth People's Hospital Tongji University School of Medicine  Shanghai China"},{"name":"Department of Integrated Traditional Chinese &amp; Western Medicine, Shanghai Tenth People's, Hospital Tongji University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjia","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Shanghai Tenth People's Hospital Tongji University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoqun","family":"Li","sequence":"additional","affiliation":[{"name":"School of Kinesiology Shanghai University of Sport  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbin","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Shanghai Tenth People's Hospital Tongji University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8660-7748","authenticated-orcid":false,"given":"Lihong","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Shanghai Tenth People's Hospital Tongji University School of Medicine  Shanghai China"},{"name":"Institute of Energy Metabolism and Health Tongji University School of Medicine  Shanghai China"},{"name":"Department of Integrated Traditional Chinese &amp; Western Medicine, Shanghai Tenth People's, Hospital Tongji University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,2,13]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21763"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2023.116296"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.815891"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1080\/10717544.2021.1977422"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.630921"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/jphp.13129"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1142\/S0192415X23500155"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2020.01.223"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.1c06729"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2017.11.013"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2012.35"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2016.11.084"},{"issue":"10","key":"e_1_2_11_14_1","first-page":"1989","article-title":"Research progress in chemical constituents in plants of polygonatum and their pharmacological effects","volume":"44","author":"Zhang J","year":"2019","journal-title":"Zhongguo Zhong Yao Za Zhi"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-018-0090-y"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2020.03.002"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2022.2030175"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-020-00312-2"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2022.10.010"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2016.03.007"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3270"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2010.11.005"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2007.07.006"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.8.23.10086"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401840"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3976"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.13616"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2012.10.021"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2022.105346"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2021.105728"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2022.2084862"}],"container-title":["Environmental Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/tox.24148","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T08:46:48Z","timestamp":1762591608000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/tox.24148"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,13]]},"references-count":30,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2024,5]]}},"alternative-id":["10.1002\/tox.24148"],"URL":"https:\/\/doi.org\/10.1002\/tox.24148","archive":["Portico"],"relation":{},"ISSN":["1520-4081","1522-7278"],"issn-type":[{"value":"1520-4081","type":"print"},{"value":"1522-7278","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,13]]},"assertion":[{"value":"2023-10-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-12-29","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-02-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}