{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T08:13:42Z","timestamp":1762071222805,"version":"build-2065373602"},"reference-count":38,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T00:00:00Z","timestamp":1666137600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Central Taiwan University of Science and Technology","award":["CTU107-C-021"],"award-info":[{"award-number":["CTU107-C-021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Many elderly individuals frequently experience cataracts that interfere with vision. After cataract surgery, the left lens epithelial cell (LEC) exhibited fibrosis and posterior capsule opacification (PCO). Sometimes, there is a need for a second surgery; nevertheless, people try other methods, such as a good pharmacological agent, to treat PCO to reduce transforming growth factor-\u03b22 (TGF-\u03b22) amounts to avoid secondary surgery. The aim of the present study was to explore the potential anti-PCO activity of five 2,4-dihydro-3H-pyrazol-3-one (DHPO) derivatives in a TGF-\u03b22-induced fibrogenesis SRA01\/04 cell model. The 2-phenyl-5-propyl-DHPO (TSE; no. 2: TSE-2) compound showed the best activity of reduced expression levels of TGF-\u03b22 among five derivatives and therefore was chosen to evaluate the anti-PCO activity and molecular mechanisms on the Sma and mad protein (SMAD) signaling pathway (including TGF-\u03b22, SMADs, and the inhibition of nuclear translocation of SMADs), non-SMAD pathway proteins, including p-extracellular, regulated protein kinases (ERK) 1\/2, or p-c-Jun N-terminal kinase (JUN) by Western blotting, PCR, or confocal immunofluorescence analyses. Following treatment with 10 \u03bcg\/mL of the five compounds, the cells displayed great viability by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTT) assay. In this study, the result of lactate dehydrogenase (LDH) activity measurement did not affect the cytotoxicity of the five compounds. In TGF-\u03b22-induced fibrogenesis in SRA01\/04 cells, treatment with the TSE compound decreased the TGF-\u03b22\/SMAD signaling genes, including reduced mRNA or expression levels of TGF-\u03b22, SMAD3, and SMAD4, leading to inhibition of TGF-\u03b22-induced fibrogenesis. Our confocal immunofluorescence analyses demonstrated that TSE treatment displays a suppressive effect on SMAD2\/3 or SMAD4 translocation to the nucleus. Furthermore, TSE treatment exhibits a reduction in the non-SMAD target gene expression levels of p- c-Jun N-terminal kinase (JUN), p- extracellular, regulated protein kinases (ERK)1\/2, p- p38 mitogen-activated protein kinase (p38), p-phosphatidylinositol 3-kinase (PI3K), p-mammalian target of rapamycin complex (mTORC), p-Akt (Ser473), and p-Akt (Thr308). The overall effect of TSE is to reduce the expression levels of collagen I and fibrinogen (FN), thus contributing to antifibrotic effects in cell models mimicking PCO. Our findings reveal the benefits of TSE by regulating TGF-\u03b2\/SMAD signaling and non-SMAD signaling-related gene proteins to display antifibrotic activity in cells for the possibility of preventing PCO after cataract surgery.<\/jats:p>","DOI":"10.3390\/cimb44100343","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T20:32:23Z","timestamp":1666211543000},"page":"5048-5066","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Protective Effects of One 2,4-Dihydro-3H-Pyrazol-3-one Derivative against Posterior Capsular Opacification by Regulation of TGF-\u03b22\/SMADs and Non-SMAD Signaling, Collagen I, and Fibronectin Proteins"],"prefix":"10.3390","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4264-2602","authenticated-orcid":false,"given":"Chun-Ching","family":"Shih","sequence":"first","affiliation":[{"name":"Department of Nursing, College of Nursing, Central Taiwan University of Science and Technology, No.666 Buzih Road, Beitun District, Taichung City 40601, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5719-0488","authenticated-orcid":false,"given":"Chia-Yi","family":"Lee","sequence":"additional","affiliation":[{"name":"Institute of Medicine, Chung Shan Medical University, Taichung City 40201, Taiwan"},{"name":"Nobel Eye Institute, Taipei 100008, Taiwan"},{"name":"Department of Ophthalmology, Jen-Ai Hospital Dali Branch, Taichung City 412224, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0012-1238","authenticated-orcid":false,"given":"Fung-Fuh","family":"Wong","sequence":"additional","affiliation":[{"name":"School of Pharmacy, China Medical University, No. 91 Hsueh-Shih Road, Taichung City 40402, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng-Hsiu","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Fengyuan Hospital, Ministry of Health and Welfare, Fengyuan District, Taichung City 42055, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.exer.2005.09.008","article-title":"Posterior capsule opacification-like changes in rat lens explants cultured with TGFbeta and FGF: Effects of cell coverage and reginal differences","volume":"82","author":"Symonds","year":"2006","journal-title":"Exp. Eye Res."},{"key":"ref_2","first-page":"2301","article-title":"TGF-\u03b22-induced matrix modification and cell transdifferentiation in the human lens capsular bag","volume":"43","author":"Wormstone","year":"2002","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_3","first-page":"100905","article-title":"Posterior capsule opacification: What\u2019s in the bag?","volume":"22","author":"Wormstone","year":"2020","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.jcro.2018.11.001","article-title":"Rapid anterior capsule contraction after femtosecond laser-assisted cataract surgery in a patient with retinitis pigmentosa","volume":"7","author":"Johnson","year":"2019","journal-title":"JCRS Online Case Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2122","DOI":"10.1016\/j.jcrs.2007.07.041","article-title":"Safety and efficacy of intracapsular tranilast microspheres in experimental posterior capsule opacification","volume":"33","author":"Wang","year":"2007","journal-title":"J. Cataract. Refract. Surg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/S0886-3350(01)01069-0","article-title":"Intracapsular ring sustained 5-fluorouracil delivery system for the prevention of posterior capsule opacification in rabbits: A histological study","volume":"28","author":"Pandey","year":"2002","journal-title":"J. Cataract. Refract. Surg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5461784","DOI":"10.1155\/2018\/5461784","article-title":"Application of spectral domain optical coherence tomography to objectively evaluate posterior capsular opacity in vivo","volume":"2018","author":"Yu","year":"2018","journal-title":"J. Ophthalmol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1976","DOI":"10.1016\/j.jcrs.2008.07.029","article-title":"Intraocular lens design on posterior capsule opacification","volume":"34","author":"Buehl","year":"2008","journal-title":"J. Cataract. Refract. Surg."},{"key":"ref_9","first-page":"59","article-title":"Comparison of design of intraocular lens versus the material for PCO prevention","volume":"5","author":"Hazra","year":"2012","journal-title":"Int. J. Ophthalmol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Yang, Y., Ye, Y., Lin, X., Wu, K., and Yu, M. (2013). Inhibition of pirfenidone on TGF-beta2 induced proliferation, migration and epithelial-mesenchymal transition of human lens epithelial cells line SRA01\/04. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0056837"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"9089285","DOI":"10.1155\/2018\/9089285","article-title":"Retrospective analyses of potential risk factors for posterior capsule opacification after cataract surgery","volume":"2018","author":"Wu","year":"2018","journal-title":"J. Ophthalmol."},{"key":"ref_12","first-page":"2025","article-title":"Role of transforming growth factor-beta in transdifferentiation and fibrosis of lens epithelial cells","volume":"40","author":"Lee","year":"1999","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_13","first-page":"7343957","article-title":"Acceleration of bone regeneration in critical-size defect using BMP-9-loaded nHA\/ColI\/MWCNTs scaffolds seeded with bone marrow mesenchymal stem cells","volume":"2019","author":"Zhang","year":"2019","journal-title":"Biomed. Res. Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1016\/j.exer.2006.12.017","article-title":"TGFbeta isoform dependent SMAD2\/3 kinetics in human lens epithelial cells: A cellomics analysis","volume":"84","author":"Dawers","year":"2007","journal-title":"Exp. Eye Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"376","DOI":"10.2741\/s32","article-title":"TGF beta in fibroproliferative disease in the eye","volume":"1","author":"Saika","year":"2009","journal-title":"Front. Biosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"69","DOI":"10.2174\/187153008783928343","article-title":"Epithelial-mesenchymal transition as a therapeutic target for prevention of ocular tissue fibrosis","volume":"8","author":"Saika","year":"2008","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1097\/CCO.0b013e32835b6371","article-title":"TGF-\u03b2 signaling and epithelial-mesenchymal transition in cancer progression","volume":"25","author":"Katsuno","year":"2013","journal-title":"Curr. Opin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1111\/j.1752-699X.2012.00302.x","article-title":"Pirfenidone: Significant treatment effects in idiopathic pulmonary fibrosis","volume":"6","author":"Hilberg","year":"2012","journal-title":"Clin. Respir. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"9592","DOI":"10.1016\/j.tet.2009.09.055","article-title":"Efficient debromination of 5-pyrazolones and 5-hydroxypyrazoles by N-bromobenzamide","volume":"65","author":"Huang","year":"2009","journal-title":"Tetrahedron"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"412158","DOI":"10.1155\/2014\/412158","article-title":"Markers of inflammation and fibrosis in the orbital fat\/connective tissue of patients with Graves\u2019 orbitopathy: Clinical implications","volume":"2014","author":"Pawlowski","year":"2014","journal-title":"Mediat. Inflamm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1006\/exer.1998.0551","article-title":"Human lens epithelial cell line","volume":"67","author":"Ibaraki","year":"1998","journal-title":"Exp. Eye Res."},{"key":"ref_22","first-page":"185","article-title":"Antifibrotic effect of pirfenidone on orbital fibroblasts in patients with thyroid-associated ophthalmopathy and its mechanisms","volume":"58","author":"Li","year":"2019","journal-title":"Zhonghua Nei Ke Za Zhi"},{"key":"ref_23","first-page":"3964518","article-title":"Treatment with hyaluronic acid and collagen-polyvinylpyrrolidone improves extracellular matrix assembly for scarring after tracheal resection","volume":"2020","author":"Victoria","year":"2020","journal-title":"Biomed. Res. Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1111\/j.1600-0676.1994.tb00048.x","article-title":"Immunohistochemical analysis of S-phase cells in normal human and rat liver by PC10 monoclonal antibody","volume":"14","author":"Mancini","year":"1994","journal-title":"Liver Int."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1046\/j.1523-1755.1998.00962.x","article-title":"Pirfenidone improves renal function and fibrosis in the post-obstructed kidney","volume":"54","author":"Shimizu","year":"1998","journal-title":"Kidney Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"S24","DOI":"10.1016\/j.hrthm.2006.12.040","article-title":"Atrial fibrosis and the mechanisms of atrial fibrillation","volume":"4","author":"Everett","year":"2007","journal-title":"Heart Rhythm"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"482438","DOI":"10.1155\/2014\/482438","article-title":"Biological pathways and potential targets for prevention and therapy of chronic allograft nephropathy","volume":"2014","author":"Shrestha","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_28","first-page":"1010","article-title":"Pirfenidone inhibits transforming growth factor-\u03b21-induced fibrogenesis by blocking nuclear translocation of Smads in human retinal pigment epithelial cell line ARPE-19","volume":"18","author":"Choi","year":"2012","journal-title":"Mol. Vis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.mefs.2017.05.002","article-title":"The effect of genistein on TGF-\u03b2 signal, dysregulation of apoptosis, cyclooxygenase-2 pathway, and NF-\u03baB pathway in mice peritoneum of endometriosis model","volume":"22","author":"Sutrisno","year":"2017","journal-title":"Middle East Fertil. Soc. J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"a022137","DOI":"10.1101\/cshperspect.a022137","article-title":"Signaling cross talk between TGF-\u03b2\/ Smad and other signaling pathways","volume":"9","author":"Luo","year":"2017","journal-title":"Cold Spring Herb. Perspect. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Shu, D.Y., Butcher, E., and Saint-Geniez, M. (2020). EMT and EndMT: Emerging roles in age-related macular degeneration. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21124271"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.yexmp.2018.11.004","article-title":"Molecular biomarkers of Graves\u2019 ophthalmopathy","volume":"106","author":"Longo","year":"2019","journal-title":"Exp. Mol. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3028","DOI":"10.7150\/jca.20467","article-title":"MZF-1\/Elk-1\/PKC\u03b1 is associated with poor prognosis in patients with hepatocellular carcinoma","volume":"8","author":"Ye","year":"2017","journal-title":"J. Cancer"},{"key":"ref_34","first-page":"33021403","article-title":"The regulatory role of dietary factors in skeletal muscle development, regeneration and function","volume":"62","author":"Wang","year":"2020","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1639\/0007-2745-123.2.333","article-title":"Recent literature on bryophytes\u2212123(2)","volume":"123","author":"Atwood","year":"2020","journal-title":"Bryologist"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"20022","DOI":"10.3390\/ijms151120022","article-title":"Effects of Bofu-tsusho-san on diabetes and hyperlipidemia associated with AMP-activated protein kinase and glucose transporter 4 in high-fat-fed mice","volume":"15","author":"Lin","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"100755","DOI":"10.1016\/j.jbior.2020.100755","article-title":"The PKC universe keeps expanding: From cancer initiation to metastasis","volume":"78","author":"Rahimova","year":"2020","journal-title":"Adv. Biol. Regul."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.peptides.2017.04.008","article-title":"Liraglutide alleviates H2O2-induced retinal ganglion cells injury by inhibiting autophagy through mitochondrial pathways","volume":"92","author":"Ma","year":"2017","journal-title":"Peptides"}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/44\/10\/343\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:57:39Z","timestamp":1760144259000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/44\/10\/343"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,19]]},"references-count":38,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["cimb44100343"],"URL":"https:\/\/doi.org\/10.3390\/cimb44100343","relation":{},"ISSN":["1467-3045"],"issn-type":[{"type":"electronic","value":"1467-3045"}],"subject":[],"published":{"date-parts":[[2022,10,19]]}}}