{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T07:15:08Z","timestamp":1793085308192,"version":"4.5.0"},"reference-count":41,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,6,2]],"date-time":"2020-06-02T00:00:00Z","timestamp":1591056000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology","award":["MOST 108-2320-B-385-001 -"],"award-info":[{"award-number":["MOST 108-2320-B-385-001 -"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>The nephrotoxicity of aristolochic acids (AAs), p-cresyl sulfate (PCS) and indoxyl sulfate (IS) were well-documented, culminating in tubulointerstitial fibrosis (TIF), advanced chronic kidney disease (CKD) and fatal urothelial cancer. Nonetheless, information regarding the attenuation of AAs-induced nephropathy (AAN) and uremic toxin retention is scarce. Propolis is a versatile natural product, exerting anti-oxidant, anti-cancer and anti-fibrotic properties. We aimed to evaluate nephroprotective effects of propolis extract (PE) in a murine model. AAN was developed to retain circulating PCS and IS using C57BL\/6 mice, mimicking human CKD. The kidney sizes\/masses, renal function indicators, plasma concentrations of PCS\/IS, tissue expressions of TIF, \u03b1-SMA, collagen IaI, collagen IV and signaling pathways in transforming growth factor-\u03b2 (TGF-\u03b2) family were analyzed among the control, PE, AAN, and AAN-PE groups. PE ameliorated AAN-induced renal atrophy, renal function deterioration, TIF, plasma retention of PCS and IS. PE also suppressed \u03b1-SMA expression and deposition of collagen IaI and IV in the fibrotic epithelial-mesenchymal transition. Notably, PE treatment in AAN model inhibited not only SMAD 2\/3-dependent pathways but also SMAD-independent JNK\/ERK activation in the signaling cascades of TGF-\u03b2 family. Through disrupting fibrotic epithelial-mesenchymal transition and TGF-\u03b2 signaling transduction pathways, PE improves TIF and thereby facilitates renal excretion of PCS and IS in AAN. In light of multi-faced toxicity of AAs, PE may be capable of developing a new potential drug to treat CKD patients exposed to AAs.<\/jats:p>","DOI":"10.3390\/toxins12060364","type":"journal-article","created":{"date-parts":[[2020,6,3]],"date-time":"2020-06-03T04:12:09Z","timestamp":1591157529000},"page":"364","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Therapeutic Targeting of Aristolochic Acid Induced Uremic Toxin Retention, SMAD 2\/3 and JNK\/ERK Pathways in Tubulointerstitial Fibrosis: Nephroprotective Role of Propolis in Chronic Kidney Disease"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9903-7473","authenticated-orcid":false,"given":"Jia-Feng","family":"Chang","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan"},{"name":"Division of Nephrology, Department of Internal Medicine, En Chu Kong Hospital, New Taipei City 237, Taiwan"},{"name":"Graduate Institute of Aerospace and Undersea Medicine, Academy of Medicine, National Defense Medical Center, Taipei 114, Taiwan"},{"name":"Department of Nursing, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan"},{"name":"Renal Care Joint Foundation, New Taipei City 220, Taiwan"},{"name":"Graduate Institution of Biomedical and Pharmaceutical Science, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9770-6779","authenticated-orcid":false,"given":"Chih-Yu","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, En Chu Kong Hospital, New Taipei City 237, Taiwan"},{"name":"School of Biomedical Engineering, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuo-Cheng","family":"Lu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Fu Jen Catholic University Hospital, New Taipei City 242, Taiwan"},{"name":"Department of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue-Wen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Animal Science, National Ilan University, Yilan 260, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1437-177X","authenticated-orcid":false,"given":"Shih-Shin","family":"Liang","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung 804, Taiwan"},{"name":"Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Cheng","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Pharmaceutical, Yuanpei University, Hsinchu 300, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Feng","family":"Hung","sequence":"additional","affiliation":[{"name":"School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Chiun","family":"Liou","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai-Szu","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan"},{"name":"Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Jadot, I., Decl\u00e8ves, A.-E., Nortier, J., and Caron, N. 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