Saroglitazar ameliorates 5- Fluorouracil-induced hepatorenal damage in rats

IF 4.8 2区医学 Q2 IMMUNOLOGY International immunopharmacology Pub Date : 2024-10-17 DOI:10.1016/j.intimp.2024.113407

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Abstract

Rationale

Hepatotoxicity and nephrotoxicity are significant adverse effects caused in cancer patients treated with 5-Flurouracil (5-FU), a pyrimidine analogue anti-metabolite anticancer drug. The purpose of this research was to evaluate the impact of PPAR α/γ agonist (Saroglitazar; SARO) on 5-FU-induced hepatorenal damage in rats.

Methods

Male rats were randomly assigned to four groups: control, 5-FU, 5-FU + SARO (2 mg/kg), and 5-FU + SARO (4 mg/kg). Rats received 75 mg/kg 5-FU intraperitoneally once weekly for three weeks. Saroglitazar (2 and 4 mg/kg/day) was orally supplied by oral syringe for three consecutive weeks. On day 22, rats were euthanized and their livers and kidneys were subjected to morphological, biochemical, histological, and immunohistochemical analysis.

Results

Saroglitazar treatment significantly decreased serum liver and kidney function biomarkers. In addition, it successfully modulated liver and kidney levels of inflammatory mediators and markers (NF-κB P65, TNF-α, cleaved caspase-1, IL-1β and p-p38 MAPK) and oxidative stress-related parameters (MDA, GSH, SOD, Keap1, Nrf-2 and HO-1) in a dose dependent manner. Furthermore, SARO could attenuate 5-FU-induced activation of cleaved caspase-3 as well as improved histopathological examination of both liver and kidney tissues. Significance: Saroglitazar may be a viable therapy option for 5-FU toxicity as it halts the interaction network of NF-kB and Nrf2 signaling pathways and apoptosis.

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沙格列扎减轻 5-氟尿嘧啶诱发的大鼠肝肾损伤

理由肝毒性和肾毒性是癌症患者使用嘧啶类似物抗代谢抗癌药物 5-氟尿嘧啶（5-FU）治疗时产生的严重不良反应。本研究的目的是评估 PPAR α/γ 激动剂（沙格列扎；SARO）对 5-FU 诱导的大鼠肝肾损伤的影响。方法将雄性大鼠随机分为四组：对照组、5-FU 组、5-FU + SARO 组（2 毫克/千克）和 5-FU + SARO 组（4 毫克/千克）。大鼠每周一次腹腔注射 75 毫克/千克 5-FU，连续注射三周。沙格列扎尔（2 毫克和 4 毫克/千克/天）通过口服注射器连续口服三周。第 22 天，对大鼠实施安乐死，并对其肝脏和肾脏进行形态学、生物化学、组织学和免疫组化分析。此外，它还以剂量依赖的方式成功调节了肝脏和肾脏的炎症介质和标志物（NF-κB P65、TNF-α、裂解的卡巴酶-1、IL-1β和p-p38 MAPK）以及氧化应激相关参数（MDA、GSH、SOD、Keap1、Nrf-2和HO-1）的水平。此外，SARO 还能减轻 5-FU 诱导的裂解 Caspase-3 活化，并改善肝脏和肾脏组织的组织病理学检查。意义重大：Saroglitazar 可以阻止 NF-kB 和 Nrf2 信号通路的相互作用网络和细胞凋亡，因此可能是治疗 5-FU 毒性的一种可行疗法。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.