Granisetron ameliorates doxorubicin-evoked nephrotoxicity via modulation of Nrf2 and TLR4/p38 MAPK/NLRP3 signals in rats

IF 2.5 4区生物学 Q1 ANATOMY & MORPHOLOGY Tissue & cell Pub Date : 2025-04-01 Epub Date: 2025-01-15 DOI:10.1016/j.tice.2025.102744

Marwa M. Khalaf , Emad H.M. Hassanein , Hamada S. Qebesy , Abdullatif A. Ahmed , Heba M. Mahmoud

{"title":"Granisetron ameliorates doxorubicin-evoked nephrotoxicity via modulation of Nrf2 and TLR4/p38 MAPK/NLRP3 signals in rats","authors":"Marwa M. Khalaf , Emad H.M. Hassanein , Hamada S. Qebesy , Abdullatif A. Ahmed , Heba M. Mahmoud","doi":"10.1016/j.tice.2025.102744","DOIUrl":null,"url":null,"abstract":"<div><div>Doxorubicin (DOX) is an anthracycline chemotherapy employed in treating malignancies. Unfortunately, the clinical application of DOX is limited due to its nephrotoxicity. Granisetron (GRAN) is a 5-HT3 receptor blocker used widely to manage post-chemotherapy nausea and vomiting with anti-inflammatory, anti-oxidant, and anti-apoptotic bioactivities. We plan to examine the renoprotective effect of GRAN against DOX-associated renal toxicity. In this investigation, twenty-four adult male Wistar rats were allocated to control, DOX (30 mg/kg, i.p), and GRAN (2.5 mg/kg, p.o) + DOX groups. GRAN attenuated renal impairment induced by DOX in rats by decreasing the BUN, creatinine, KIM-1, and Cys-C levels, and such finding is supported by attenuating histological alterations caused by DOX. GRAN combated oxidative stress proved by decreasing MDA content and elevating GSH and CAT levels mediated by Nrf2 activation. GRAN suppressed inflammation evidenced by decreasing IL-6 and TNF-α levels mediated by downregulation of inflammatory sensitive controllers TLR-4, NLRP3, and p38 MAPK. GRAN prevented apoptosis by controlling renal expression of BAX, caspase-3 and Bcl2. Therefore, GRAN holds promise agent against DOX-induced renal toxicity by upregulating Nrf2 and suppressing apoptosis and inflammatory cascadeTLR4/p38 MAPK/ NLRP3.</div></div>","PeriodicalId":23201,"journal":{"name":"Tissue & cell","volume":"93 ","pages":"Article 102744"},"PeriodicalIF":2.5000,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Tissue & cell","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0040816625000242","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/15 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"ANATOMY & MORPHOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Doxorubicin (DOX) is an anthracycline chemotherapy employed in treating malignancies. Unfortunately, the clinical application of DOX is limited due to its nephrotoxicity. Granisetron (GRAN) is a 5-HT3 receptor blocker used widely to manage post-chemotherapy nausea and vomiting with anti-inflammatory, anti-oxidant, and anti-apoptotic bioactivities. We plan to examine the renoprotective effect of GRAN against DOX-associated renal toxicity. In this investigation, twenty-four adult male Wistar rats were allocated to control, DOX (30 mg/kg, i.p), and GRAN (2.5 mg/kg, p.o) + DOX groups. GRAN attenuated renal impairment induced by DOX in rats by decreasing the BUN, creatinine, KIM-1, and Cys-C levels, and such finding is supported by attenuating histological alterations caused by DOX. GRAN combated oxidative stress proved by decreasing MDA content and elevating GSH and CAT levels mediated by Nrf2 activation. GRAN suppressed inflammation evidenced by decreasing IL-6 and TNF-α levels mediated by downregulation of inflammatory sensitive controllers TLR-4, NLRP3, and p38 MAPK. GRAN prevented apoptosis by controlling renal expression of BAX, caspase-3 and Bcl2. Therefore, GRAN holds promise agent against DOX-induced renal toxicity by upregulating Nrf2 and suppressing apoptosis and inflammatory cascadeTLR4/p38 MAPK/ NLRP3.

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

格拉司琼通过调节Nrf2和TLR4/p38 MAPK/NLRP3信号改善大鼠阿霉素引起的肾毒性。

阿霉素（DOX）是一种用于治疗恶性肿瘤的蒽环类化疗药物。不幸的是，由于其肾毒性，DOX的临床应用受到限制。格拉司琼（Granisetron， GRAN）是一种5-HT3受体阻滞剂，具有抗炎、抗氧化和抗凋亡的生物活性，广泛用于化疗后恶心和呕吐。我们计划研究GRAN对dox相关肾毒性的保护作用。将24只成年雄性Wistar大鼠分为对照组、DOX组（30 mg/kg, i.p）和GRAN组（2.5 mg/kg, p.o） + DOX组。GRAN通过降低BUN、肌酐、KIM-1和Cys-C水平来减轻DOX引起的大鼠肾损害，这一发现得到了减轻DOX引起的组织学改变的支持。GRAN通过降低MDA含量，提高GSH和CAT水平，通过Nrf2激活来对抗氧化应激。GRAN通过下调炎症敏感控制因子TLR-4、NLRP3和p38 MAPK介导的IL-6和TNF-α水平降低来抑制炎症。GRAN通过控制BAX、caspase-3和Bcl2的表达来阻止细胞凋亡。因此，GRAN通过上调Nrf2，抑制细胞凋亡和炎症级联反应lr4 /p38 MAPK/ NLRP3，有望对抗dox诱导的肾毒性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Tissue & cell 医学-解剖学与形态学

CiteScore

3.90

自引率

0.00%

发文量

234

期刊介绍： Tissue and Cell is devoted to original research on the organization of cells, subcellular and extracellular components at all levels, including the grouping and interrelations of cells in tissues and organs. The journal encourages submission of ultrastructural studies that provide novel insights into structure, function and physiology of cells and tissues, in health and disease. Bioengineering and stem cells studies focused on the description of morphological and/or histological data are also welcomed. Studies investigating the effect of compounds and/or substances on structure of cells and tissues are generally outside the scope of this journal. For consideration, studies should contain a clear rationale on the use of (a) given substance(s), have a compelling morphological and structural focus and present novel incremental findings from previous literature.