{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T21:05:50Z","timestamp":1790715950536,"version":"4.1.0"},"reference-count":67,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2019,9,25]],"date-time":"2019-09-25T00:00:00Z","timestamp":1569369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Projects Funding and Granting Unit, Beni-Suef University, Egypt","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Mesoporous silica nanoparticles (MSNs) represent a promising inorganic platform for multiple biomedical applications. Previous studies have reported MSNs-induced hepatic and renal toxicity; however, the toxic mechanism remains unclear. This study aimed to investigate MSNs-induced hepatic and nephrotoxicity and test the hypothesis that altered TLR4\/MyD88\/NF-\u03baB, JAK2\/STAT3, and Nrf2\/ARE\/HO-1 signaling pathways mediate oxidative stress, inflammation, and fibrosis induced by MSNs. Rats were administered 25, 50, 100, and 200 mg\/kg MSNs for 30 days, and samples were collected for analyses. MSNs induced functional and histologic alterations, increased the levels of reactive oxygen species (ROS), lipid peroxidation and nitric oxide, suppressed antioxidants, and Nrf2\/HO-1 signaling in the liver and kidney of rats. MSNs up-regulated the expression of liver and kidney TLR4, MyD88, NF-\u03baB p65, and caspase-3 and increased serum pro-inflammatory cytokines. In addition, MSNs activated the JAK2\/STAT3 signaling pathway, down-regulated peroxisome proliferator activated receptor gamma (PPAR\u03b3), and promoted fibrosis evidenced by the increased collagen expression and deposition. In conclusion, this study conferred novel information on the role of ROS and deregulated TLR4\/MyD88\/NF-\u03baB, JAK2\/STAT3, PPAR\u03b3, and Nrf2\/ARE\/HO-1 signaling pathways in MSNs hepatic and nephrotoxicity. These findings provide experimental evidence for further studies employing genetic and pharmacological strategies to evaluate the safety of MSNs for their use in nanomedicine.<\/jats:p>","DOI":"10.3390\/biom9100528","type":"journal-article","created":{"date-parts":[[2019,9,26]],"date-time":"2019-09-26T03:06:51Z","timestamp":1569467211000},"page":"528","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":109,"title":["Mesoporous Silica Nanoparticles Trigger Liver and Kidney Injury and Fibrosis Via Altering TLR4\/NF-\u03baB, JAK2\/STAT3 and Nrf2\/HO-1 Signaling in Rats"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0279-6500","authenticated-orcid":false,"given":"Ayman M.","family":"Mahmoud","sequence":"first","affiliation":[{"name":"Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef 62514, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekram M.","family":"Desouky","sequence":"additional","affiliation":[{"name":"Biochemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef 62514, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1981-8382","authenticated-orcid":false,"given":"Walaa G.","family":"Hozayen","sequence":"additional","affiliation":[{"name":"Biochemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef 62514, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3017-9924","authenticated-orcid":false,"given":"May","family":"Bin-Jumah","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh 84428, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"El-Shaymaa","family":"El-Nahass","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef 62514, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanan A.","family":"Soliman","sequence":"additional","affiliation":[{"name":"Biochemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef 62514, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed A.","family":"Farghali","sequence":"additional","affiliation":[{"name":"Materials Science and Nanotechnology Department, Faculty of Postgraduate Studies for Advanced Sciences (PSAS), Beni-Suef University, Beni-Suef 62514, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,9,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.apsb.2018.01.007","article-title":"Mesoporous silica nanoparticles for drug and gene delivery","volume":"8","author":"Zhou","year":"2018","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Brinch, A., Hansen, S.F., Hartmann, N.B., and Baun, A. (2016). Eu regulation of nanobiocides: Challenges in implementing the biocidal product regulation (BPR). Nanomaterials, 6.","DOI":"10.3390\/nano6020033"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2967","DOI":"10.1007\/s00204-017-1993-y","article-title":"Toxicology of silica nanoparticles: An update","volume":"91","author":"Murugadoss","year":"2017","journal-title":"Arch. Toxicol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"393","DOI":"10.3109\/17435390.2010.519836","article-title":"Presence and risks of nanosilica in food products","volume":"5","author":"Dekkers","year":"2011","journal-title":"Nanotoxicology"},{"key":"ref_5","first-page":"e05088","article-title":"Re-evaluation of silicon dioxide (E 551) as a food additive","volume":"16","author":"Younes","year":"2018","journal-title":"EFSA J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1604634","DOI":"10.1002\/adma.201604634","article-title":"Degradability and clearance of silicon, organosilica, silsesquioxane, silica mixed oxide, and mesoporous silica nanoparticles","volume":"29","author":"Croissant","year":"2017","journal-title":"Adv. Mater."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"10309","DOI":"10.1021\/acsami.6b16505","article-title":"Progress in nanotheranostics based on mesoporous silica nanomaterial platforms","volume":"9","author":"Singh","year":"2017","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3236","DOI":"10.1039\/b701744h","article-title":"Mesoporous silica nanoparticle based controlled release, drug delivery, and biosensor systems","volume":"31","author":"Trewyn","year":"2007","journal-title":"Chem. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10549","DOI":"10.1002\/anie.201304026","article-title":"Mesoporous silica nanoparticle pretargeting for pet imaging based on a rapid bioorthogonal reaction in a living body","volume":"52","author":"Lee","year":"2013","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1016\/j.biopha.2018.10.167","article-title":"Mesoporous silica nanoparticles for therapeutic\/diagnostic applications","volume":"109","author":"Jafari","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Rascol, E., Pisani, C., Dorandeu, C., Nyalosaso, J.L., Charnay, C., Daurat, M., Da Silva, A., Devoisselle, J.-M., Gaillard, J.-C., and Armengaud, J. (2018). Biosafety of mesoporous silica nanoparticles. Biomimetics, 3.","DOI":"10.3390\/biomimetics3030022"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.2217\/nnm-2018-0076","article-title":"The toxicity of silica nanoparticles to the immune system","volume":"13","author":"Chen","year":"2018","journal-title":"Nanomedicine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1016\/S0140-6736(12)60235-9","article-title":"Silicosis","volume":"379","author":"Leung","year":"2012","journal-title":"Lancet"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2527","DOI":"10.1016\/j.biopha.2018.11.093","article-title":"Cardiac and pulmonary toxicity of mesoporous silica nanoparticles is associated with excessive ros production and redox imbalance in wistar rats","volume":"109","author":"Hozayen","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6045","DOI":"10.2147\/IJN.S132304","article-title":"Silica nanoparticles induce liver fibrosis via TGF-\u03b2(1)\/Smad3 pathway in icr mice","volume":"12","author":"Yu","year":"2017","journal-title":"Int. J. Nanomed."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1093\/toxsci\/kfn250","article-title":"Macrophage responses to silica nanoparticles are highly conserved across particle sizes","volume":"107","author":"Waters","year":"2009","journal-title":"Toxicol. Sci. Off. J. Soc. Toxicol."},{"key":"ref_17","first-page":"1","article-title":"Renal interstitial fibrosis induced by high-dose mesoporous silica nanoparticles via the NF-\u03baB signaling pathway","volume":"10","author":"Chen","year":"2015","journal-title":"Int. J. Nanomed."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.bbadis.2016.11.005","article-title":"Nrf2 signaling pathway: Pivotal roles in inflammation","volume":"1863","author":"Ahmed","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s12989-017-0202-8","article-title":"MyD88-dependent pro-interleukin-1\u03b2 induction in dendritic cells exposed to food-grade synthetic amorphous silica","volume":"14","author":"Winkler","year":"2017","journal-title":"Part. Fibre Toxicol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/nrm909","article-title":"Stats: Transcriptional control and biological impact","volume":"3","author":"Levy","year":"2002","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2520","DOI":"10.1038\/sj.onc.1209281","article-title":"Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-\u03b21 production","volume":"25","author":"Ogata","year":"2006","journal-title":"Oncogene"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1002\/jlb.66.5.733","article-title":"The peroxisome proliferator-activated receptor (PPAR\u03b3) as a regulator of monocyte\/macrophage function","volume":"66","author":"Ricote","year":"1999","journal-title":"J. Leukoc. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1016\/j.cellsig.2011.05.018","article-title":"Peroxisome proliferator-activated receptor gamma (PPAR\u03b3) plays a critical role in the development of tgfbeta resistance of H460 cell","volume":"23","author":"Lin","year":"2011","journal-title":"Cell. Signal."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"519","DOI":"10.2353\/ajpath.2009.080574","article-title":"Rosiglitazone abrogates bleomycin-induced scleroderma and blocks profibrotic responses through peroxisome proliferator-activated receptor-gamma","volume":"174","author":"Wu","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"26466","DOI":"10.18632\/oncotarget.25470","article-title":"Folic acid-conjugated mesoporous silica particles as nanocarriers of natural prodrugs for cancer targeting and antioxidant action","volume":"9","author":"AbouAitah","year":"2018","journal-title":"Oncotarget"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3311","DOI":"10.1016\/j.bbagen.2016.08.013","article-title":"A novel role for small molecule glycomimetics in the protection against lipid-induced endothelial dysfunction: Involvement of akt\/enos and Nrf2\/are signaling","volume":"1861","author":"Mahmoud","year":"2017","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2\u2212\u0394\u0394CT method","volume":"25","author":"Livak","year":"2011","journal-title":"Methods"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1016\/j.bbrc.2007.12.001","article-title":"Adipose expression of catalase is regulated via a novel remote PPAR\u03b3-responsive region","volume":"366","author":"Okuno","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.nano.2008.01.001","article-title":"Nanotoxicology and nanomedicine: Making hard decisions","volume":"4","author":"Linkov","year":"2008","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1021\/nn901146y","article-title":"In vivo biodistribution and clearance studies using multimodal organically modified silica nanoparticles","volume":"4","author":"Kumar","year":"2010","journal-title":"ACS Nano"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Yu, Y., Li, Y., Wang, W., Jin, M., Du, Z., Li, Y., Duan, J., Yu, Y., and Sun, Z. (2013). Acute toxicity of amorphous silica nanoparticles in intravenously exposed ICR mice. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0061346"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1016\/j.ejpb.2009.02.005","article-title":"Silica nanoparticles as hepatotoxicants","volume":"72","author":"Nishimori","year":"2009","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1016\/j.nano.2015.07.004","article-title":"Biodistribution, excretion, and toxicity of mesoporous silica nanoparticles after oral administration depend on their shape","volume":"11","author":"Li","year":"2015","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1016\/j.tiv.2011.06.012","article-title":"Cytotoxicity and mitochondrial damage caused by silica nanoparticles","volume":"25","author":"Sun","year":"2011","journal-title":"Toxicol. In Vitro"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.colsurfb.2016.05.006","article-title":"Amphipathic silica nanoparticles induce cytotoxicity through oxidative stress mediated and p53 dependent apoptosis pathway in human liver cell line HL-7702 and rat liver cell line BRL-3a","volume":"145","author":"Zuo","year":"2016","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/1743-8977-7-39","article-title":"The nanosilica hazard: Another variable entity","volume":"7","author":"Napierska","year":"2010","journal-title":"Part. Fibre Toxicol."},{"key":"ref_38","first-page":"2891","article-title":"Sio(2) nanoparticle-induced impairment of mitochondrial energy metabolism in hepatocytes directly and through a kupffer cell-mediated pathway in vitro","volume":"9","author":"Xue","year":"2014","journal-title":"Int. J. Nanomed."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1016\/S0891-5849(03)00149-7","article-title":"Reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation by silica in inflammation and fibrosis","volume":"34","author":"Fubini","year":"2003","journal-title":"Free Radic. Biol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.tox.2014.03.008","article-title":"Purinergic signaling via p2x7 receptor mediates IL-1\u03b2 production in kupffer cells exposed to silica nanoparticle","volume":"321","author":"Kojima","year":"2014","journal-title":"Toxicology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"9237263","DOI":"10.1155\/2017\/9237263","article-title":"The role of NrfF2 in cardiovascular function and disease","volume":"2017","author":"Satta","year":"2017","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1006\/bbrc.1997.6943","article-title":"An Nrf2\/small maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements","volume":"236","author":"Itoh","year":"1997","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.biopha.2018.06.171","article-title":"Commiphora molmol protects against methotrexate-induced nephrotoxicity by up-regulating Nrf2\/ARE\/HO-1 signaling","volume":"106","author":"Mahmoud","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.cbi.2017.04.009","article-title":"Methotrexate hepatotoxicity is associated with oxidative stress, and down-regulation of PPAR\u03b3 and Nrf2: Protective effect of 18beta-glycyrrhetinic acid","volume":"270","author":"Mahmoud","year":"2017","journal-title":"Chem. Biol. Interact."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.cbi.2017.04.012","article-title":"Commiphora molmol resin attenuates diethylnitrosamine\/phenobarbital-induced hepatocarcinogenesis by modulating oxidative stress, inflammation, angiogenesis and Nrf2\/ARE\/HO-1 signaling","volume":"270","author":"Mahmoud","year":"2017","journal-title":"Chem. Biol. Interact."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1016\/j.biopha.2018.12.112","article-title":"Olea europaea leaf extract up-regulates Nrf2\/ARE\/HO-1 signaling and attenuates cyclophosphamide-induced oxidative stress, inflammation and apoptosis in rat kidney","volume":"111","author":"ALHaithloul","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4593","DOI":"10.1039\/C9FO00114J","article-title":"Ferulic acid protects against methotrexate nephrotoxicity via activation of Nrf2\/ARE\/HO-1 signaling and PPAR\u03b3, and suppression of NF-\u03baB\/NLRP3 inflammasome axis","volume":"10","author":"Mahmoud","year":"2019","journal-title":"Food Funct."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Aladaileh, S.H., Abukhalil, M.H., Saghir, S.A.M., Hanieh, H., Alfwuaires, M.A., Almaiman, A.A., Bin-Jumah, M., and Mahmoud, A.M. (2019). Galangin activates Nrf2 signaling and attenuates oxidative damage, inflammation, and apoptosis in a rat model of cyclophosphamide-induced hepatotoxicity. Biomolecules, 9.","DOI":"10.3390\/biom9080346"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2626","DOI":"10.4049\/jimmunol.1003930","article-title":"Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury","volume":"187","author":"Xu","year":"2011","journal-title":"J. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1097\/MNH.0b013e32832a1d5f","article-title":"Toll-like receptors in kidney disease","volume":"18","author":"Smith","year":"2009","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.cellsig.2011.01.014","article-title":"Nuclear factor p65 interacts with keap1 to repress the Nrf2-are pathway","volume":"23","author":"Yu","year":"2011","journal-title":"Cell. Signal."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1042\/BST20150014","article-title":"Dissecting molecular cross-talk between Nrf2 and NF-\u03baB response pathways","volume":"43","author":"Wardyn","year":"2015","journal-title":"Biochem. Soc. Trans."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"11624","DOI":"10.1038\/ncomms11624","article-title":"Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription","volume":"7","author":"Kobayashi","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1743-8977-11-8","article-title":"Sub-chronic toxicity study in rats orally exposed to nanostructured silica","volume":"11","author":"Vandebriel","year":"2014","journal-title":"Part. Fibre Toxicol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1007\/s00441-011-1246-y","article-title":"TGF-\u03b2 in progression of liver disease","volume":"347","author":"Dooley","year":"2012","journal-title":"Cell Tissue Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1007\/s10753-019-00973-8","article-title":"Umbelliferone ameliorates CCL4-induced liver fibrosis in rats by upregulating PPAR\u03b3 and attenuating oxidative stress, inflammation, and TGF-\u03b21\/Smad3 signaling","volume":"42","author":"Mahmoud","year":"2019","journal-title":"Inflammation"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1091\/mbc.E17-06-0342","article-title":"Stat3 controls COL1A2 enhancer activation cooperatively with junb, regulates type i collagen synthesis posttranscriptionally, and is essential for lung myofibroblast differentiation","volume":"29","author":"Papaioannou","year":"2018","journal-title":"Mol. Biol. Cell"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3422","DOI":"10.4049\/jimmunol.1401779","article-title":"Noncanonical Stat3 activation regulates excess TGF-\u03b21 and collagen i expression in muscle of stricturing crohn\u2019s disease","volume":"194","author":"Li","year":"2015","journal-title":"J. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1016\/j.kint.2016.06.038","article-title":"Fyn deficiency attenuates renal fibrosis by inhibition of phospho-Stat3","volume":"90","author":"Seo","year":"2016","journal-title":"Kidney Int."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"F25","DOI":"10.1152\/ajprenal.00311.2016","article-title":"Mesenchymal stem cells protect against obstruction-induced renal fibrosis by decreasing Stat3 activation and Stat3-dependent MMP-9 production","volume":"312","author":"Matsui","year":"2017","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1096\/fj.03-1273rev","article-title":"TGF-\u03b2 signaling and the fibrotic response","volume":"18","author":"Leask","year":"2004","journal-title":"FASEB J."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1038\/s41467-017-01236-6","article-title":"Activation of Stat3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis","volume":"8","author":"Chakraborty","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1084\/jem.20040104","article-title":"Early growth response gene 1-mediated apoptosis is essential for transforming growth factor \u03b21-induced pulmonary fibrosis","volume":"200","author":"Lee","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1053\/j.gastro.2004.07.019","article-title":"Hepatocyte-specific disruption of Bcl-xL leads to continuous hepatocyte apoptosis and liver fibrotic responses","volume":"127","author":"Takehara","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.1038\/labinvest.2010.123","article-title":"Kupffer cells are associated with apoptosis, inflammation and fibrotic effects in hepatic fibrosis in rats","volume":"90","author":"Liu","year":"2010","journal-title":"Lab. Investig."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"G902","DOI":"10.1152\/ajpgi.00124.2006","article-title":"Regulation of peroxisome proliferator-activated receptor-\u03b3 in liver fibrosis","volume":"291","author":"Yang","year":"2006","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"64690","DOI":"10.18632\/oncotarget.11811","article-title":"Renal tubular epithelium-targeted peroxisome proliferator-activated receptor-\u03b3 maintains the epithelial phenotype and antagonizes renal fibrogenesis","volume":"7","author":"Zhao","year":"2016","journal-title":"Oncotarget"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/9\/10\/528\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:24:10Z","timestamp":1760189050000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/9\/10\/528"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,25]]},"references-count":67,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2019,10]]}},"alternative-id":["biom9100528"],"URL":"https:\/\/doi.org\/10.3390\/biom9100528","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,25]]}}}