{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T19:33:58Z","timestamp":1792956838405,"version":"4.5.0"},"reference-count":48,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:00:00Z","timestamp":1791849600000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The widespread use of titanium dioxide (TiO\n                    <jats:sub>2<\/jats:sub>\n                    ) nanoparticles (TNPs) in everyday products (ex; cosmetics, food additives) has growing concerns about their harmful effects on humans due to unavoidable exposure. We recently found that TNPs could stabilize both calcium phosphate (CaP) and uric acid (UA) crystals, implicating kidney stone formation. However, the impact of TNPs on the kidney, specifically on kidney tubular cells is unknown. Therefore, we investigated the effect of TiO\n                    <jats:sub>2<\/jats:sub>\n                    alone or in combination with UA\/CaP microcrystals on Ca\n                    <jats:sup>2+<\/jats:sup>\n                    dynamics by measuring Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transients, reactive oxygen species (ROS) production by H\n                    <jats:sub>2<\/jats:sub>\n                    DCFDA staining and H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    release, oxidative stress and inflammatory response by gene expression analysis, cell death by DAPI and Annexin V\/propidium iodide (PI) staining and cytotoxicity by lactate dehydrogenase (LDH) release in human kidney (HK\u20102) tubular cell line. The internalization of CaP\/UA crystals with TiO\n                    <jats:sub>2<\/jats:sub>\n                    in HK\u20102 cells resulted in an enhanced store\u2010operated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    entry (SOCE), which was blocked by Pyr6 (SOCE inhibitor). Indeed, the combination of CaP\/UA crystals with TiO\n                    <jats:sub>2<\/jats:sub>\n                    \u2010internalized HK\u20102 cells showed a pronounced increase in ROS production and LDH release compared to CaP and\/or UA crystals groups, which were reduced by SOCE inhibition. Analyses of nuclear morphology via DAPI staining indicated a greater cell injury\/death response in the presence of TiO\n                    <jats:sub>2<\/jats:sub>\n                    with CaP\/UA crystals. Annexin V\/PI staining revealed a greater percentage of apoptosis\/necrosis after internalization of CaP\/UA with TiO\n                    <jats:sub>2<\/jats:sub>\n                    , which was decreased upon preapplication of Pyr6. Gene expression analyses show that internalization of CaP\/UA+TiO\n                    <jats:sub>2<\/jats:sub>\n                    crystals evoked upregulation of oxidative stress (NOX4), inflammatory (MCP\u20101, TNF\u2010\u03b1), fibrotic (FN\u20101) and apoptotic (BCL2) genes. Taken together, TNPs, when combined with CaP\/UA, became the activator of SOCE to promote oxidative stress, inflammation, tubular injury and cytotoxicity, underscoring their implications in crystal\u2010induced nephropathy and stone formation.\n                  <\/jats:p>","DOI":"10.1002\/jbt.71133","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T18:00:21Z","timestamp":1791914421000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Titanium Dioxide Exacerbates Calcium Phosphate and Urate\u2010Induced Oxidative Stress, Injury and Inflammatory Response in Human Kidney\u20102 Cells"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9811-5334","authenticated-orcid":false,"given":"Samshritha R.","family":"Bikki","sequence":"first","affiliation":[{"name":"Calcium Signaling Laboratory, Research Service Veterans Affairs Medical Center  Washington DC USA"},{"name":"Department of Biomedical Engineering The Catholic University of America  Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2128-8797","authenticated-orcid":false,"given":"Aditi","family":"Mohapatra","sequence":"additional","affiliation":[{"name":"Calcium Signaling Laboratory, Research Service Veterans Affairs Medical Center  Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3461-2844","authenticated-orcid":false,"given":"Samuel","family":"Shin","sequence":"additional","affiliation":[{"name":"Calcium Signaling Laboratory, Research Service Veterans Affairs Medical Center  Washington DC USA"},{"name":"Department of Biomedical Engineering The Catholic University of America  Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2364-8945","authenticated-orcid":false,"given":"Bidhan C.","family":"Bandyopadhyay","sequence":"additional","affiliation":[{"name":"Calcium Signaling Laboratory, Research Service Veterans Affairs Medical Center  Washington DC USA"},{"name":"Department of Biomedical Engineering The Catholic University of America  Washington DC USA"},{"name":"Division of Renal Diseases &amp; Hypertension, Department of Medicine The George Washington University  Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,13]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/1743-8977-10-15"},{"issue":"5","key":"e_1_2_11_3_1","first-page":"481","article-title":"Toxicological Effects of Titanium Dioxide Nanoparticles: A Review of in Vitro Mammalian Studies","volume":"15","author":"Iavicoli I.","year":"2011","journal-title":"European Review for Medical and Pharmacological Sciences"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.2478\/v10019-011-0037-0"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/nano11092354"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/nano10081469"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ekir.2021.09.003"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells13121051"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2021.04.006"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.911968"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1159\/000487671"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25094787"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2023.09.017"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.10651110"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10059-010-0105-0"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2016.09.012"},{"key":"e_1_2_11_17_1","article-title":"Calcium Deposition and Other Renal Crystal Diseases","author":"Simhadri P. 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