Modulatory Role of Saroglitazar on Novel Hematological Inflammatory Ratios and Metabolic Parameters in Animal Model of 5-Fluorouracil Toxicity

Authors

  • Hani Hadi Mohammed Department of Basic Medical Sciences, College of Medicine, University of Sulaimani, Kurdistan Region, Iraq https://orcid.org/0009-0007-2198-2655
  • Roza Haroon Rasheed Department of Pharmacology and Toxicology, College of Pharmacy, University of Sulaimani, Kurdistan Region, Iraq https://orcid.org/0009-0005-2198-3418
  • Tavga Ahmed Aziz Department of Pharmacology and Toxicology, College of Pharmacy, University of Sulaimani, Kurdistan Region, Iraq https://orcid.org/0000-0003-2742-6127

DOI:

https://doi.org/10.54133/ajms.v10i2.2325

Keywords:

Chemotherapy-induced toxicity, 5-FU, Hematological inflammatory ratios, Saroglitazar

Abstract

Background: 5-Fluorouracil (5-FU), a widely used chemotherapeutic agent, causes oxidative stress, inflammation, and multi-organ damage, particularly cardiotoxicity. Saroglitazar, a dual peroxisome proliferator-activated receptor α/γ agonist with lipid-lowering, insulin-sensitizing, and anti-inflammatory effects, may ameliorate these adverse outcomes. Objective: To evaluate how saroglitazar influences hematological inflammatory ratios and metabolic parameters in a rat model of 5-fluorouracil-induced toxicity. Methods: 35 adult males Wistar rats were categorized into five groups: Control (NC), 5-FU-treated positive control (PC), N-acetylcysteine (NAC) (100mg/kg) + 5-FU, SAR low (0.5mg/kg)+5-FU, and SAR high (5.0mg/kg)+5-FU. 150mg/kg 5-FU was given intraperitoneally on the 10th day of treatment. Biochemical markers were evaluated, including cholesterol, triglycerides, low-density lipoprotein (LDL), high-density lipoprotein (HDL), glucose, and HbA1c; inflammatory markers such as neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR); and hematological markers such as hemoglobin concentration (Hb), red blood cell count (RBC), and white blood cell count (WBC). Results: 5-FU treatment caused significant metabolic alteration, including dyslipidemia, hyperglycemia, systemic inflammation, and hematological suppression. Saroglitazar, on the other hand, improved lipid profiles by reducing cholesterol, triglycerides, and LDL and showed a glucose-lowering effect. It also reduced NLR and MLR, demonstrating their superior anti-inflammatory activity. Saroglitazar also improved RBC count and Hb levels, indicating its influence on erythropoiesis and bone marrow function. Conclusion: Saroglitazar mitigates 5-fluorouracil-induced metabolic, inflammatory, and hematological disturbances, supporting its potential as an adjunct to chemotherapy. Assessing its long-term effectiveness and practical use is recommended.

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References

Chrysostomou D, Roberts LA, Marchesi JR, Kinross JM. Gut microbiota modulation of efficacy and toxicity of cancer chemotherapy and immunotherapy. Gastroenterology. 2023;164(2):198-213. doi: 10.1053/j.gastro.2022.10.018.

Ali HH, Ahmed ZA, Aziz TA. Effect of telmisartan and quercetin in 5 fluorouracil-induced renal toxicity in rats. J Inflamm Res. 2022;15:6113–6124. doi: 10.2147/JIR.S389017.

da Silva MC, Fabiano LC, da Costa Salomão KC, de Freitas PLZ, Neves CQ, Borges SC, et al. A rodent model of human-dose-equivalent 5-fluorouracil: Toxicity in the liver, kidneys, and lungs. Antioxidants. 2023;12(5):1005. doi: 10.3390/antiox12051005.

Jungsuwadee P, Vore M, Clair DKS. Chemotherapy-induced oxidative stress in nontargeted normal tissues. In: Spitz DR, Dornfeld KJ, Krishnan K, Gius D, (eds.), Oxidative Stress in Cancer Biology and Therapy. Humana Press; 2012. p. 97–129. doi: 10.1007/978-1-61779-397-4_6.

Petak I, Tillman DM, Houghton JA. p53 dependence of Fas induction and acute apoptosis in response to 5-fluorouracil-leucovorin in human colon carcinoma cell lines1. Clini Cancer Res. 2000;6(11):4432–4441. PMID: 11106264.

Gelen V, Şengül E, Yıldırım S, Senturk E, Tekin S, Kükürt A. The protective effects of hesperidin and curcumin on 5-fluorouracil–induced nephrotoxicity in mice. Environ Sci Pollut Res [Internet]. 2021;28(34):47046–54705. doi: 10.1007/s11356-021-13969-5.

Kodama Y, Fumoto S, Nishi J, Nakashima M, Sasaki H, Nakamura J, et al. Absorption and distribution characteristics of 5-fluorouracil (5-FU) after an application to the liver surface in rats in order to reduce systemic side effects. Biol Pharm Bull. 2008;31(5):1049–1052. doi: 10.1248/bpb.31.1049.

Leocádio PCL, Antunes MM, Teixeira LG, Leonel AJ, Alvarez-Leite JI, Machado DCC, et al. L-arginine pretreatment reduces intestinal mucositis as induced by 5-FU in mice. Nutr Cancer. 2015;67(3):486–493. doi: 10.1080/01635581.2015.1004730.

Sara JD, Kaur J, Khodadadi R, Rehman M, Lobo R, Chakrabarti S, et al. 5-fluorouracil and cardiotoxicity: a review. Ther Adv Med Oncol. 2018;10:1758835918780140. doi: 10.1177/1758835918780140.

Madeddu C, Deidda M, Piras A, Cadeddu C, Demurtas L, Puzzoni M, et al. Pathophysiology of cardiotoxicity induced by nonanthracycline chemotherapy. J Cardiovasc Medicine. 2016;17:e12. doi: 10.2459/JCM.0000000000000376.

Jin X, Bai Y, Gao L, Wu S. Incidence of and risk factors for cardiotoxicity after fluorouracil-based chemotherapy in locally advanced or metastatic gastric cancer patients. Cancer Chemother Pharmacol. 2019;84(3):599–607. doi: 10.1007/s00280-019-03888-1.

Karakulak UN, Aladağ E, Maharjan N, Övünç K. Capecitabine-induced coronary artery vasospasm in a patient who previously experienced a similar episode with fluorouracil therapy. Turk Kardiyol Dern Ars. 2016;44(1):71-74. doi: 10.5543/tkda.2015.36005.

Yu X, Ruan Y, Shen T, Qiu Q, Yan M, Sun S, et al. Dexrazoxane Protects Cardiomyocyte from Doxorubicin-Induced Apoptosis by Modulating miR-17-5p. BioMed Res Int. 2020;2020(1):5107193. doi: 10.1155/2020/5107193.

Khan SA, Campbell AM, Lu Y, An L, Alpert JS, Chen QM. N-Acetylcysteine for cardiac protection during coronary artery reperfusion: A systematic review and meta-analysis of randomized controlled trials. Front Cardiovasc Med. 2021;8. doi: 10.3389/fcvm.2021.752939.

Pecoraro M, Marzocco S, Belvedere R, Petrella A, Franceschelli S, Popolo A. Simvastatin reduces doxorubicin-induced cardiotoxicity: Effects beyond its antioxidant activity. Int J Mol Sci. 2023;24(8):7573. doi: 10.3390/ijms24087573.

Kalliora C, Drosatos K. The Glitazars paradox: Cardiotoxicity of the metabolically beneficial dual PPARα and PPARγ activation. J Cardiovasc Pharmacol. 2020;76(5):514. doi: 10.1097/FJC.0000000000000891.

Jain N, Bhansali S, Kurpad AV, Hawkins M, Sharma A, Kaur S, et al. Effect of a dual PPAR α/γ agonist on insulin sensitivity in patients of type 2 diabetes with hypertriglyceridemia- randomized double-blind placebo-controlled trial. Sci Rep. 2019;9(1):19017. doi: 10.1038/s41598-019-55466-3.

Percie du Sert N, Hurst V, Ahluwalia A, Alam S, Avey MT, Baker M, et al. The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. J Cereb Blood Flow Metab. 2020;40(9):1769–1777. doi: 10.1177/0271678X20943823

Sharma A, S A, Kushwah DS, S R. Saroglitazar, a novel cardiometabolic agent for diabetic dyslipidemia - A Review. J Young Pharm. 2014;7(1):2–6. Available from: http://www.jyoungpharm.org/article/735

Haleagrahara N, Julian V, Chakravarthi S. N-acetylcysteine offers cardioprotection by decreasing cardiac lipid hydroperoxides and 8-isoprostane level in isoproterenol-induced cardiotoxicity in rats. Cardiovasc Toxicol. 2011;11(4):373–381. doi: 10.1007/s12012-011-9132-0.

Pan Y, Li Y, Fan H, Cui H, Chen Z, Wang Y, et al. Roles of the peroxisome proliferator-activated receptors (PPARs) in the pathogenesis of hepatocellular carcinoma (HCC). Biomed Pharmacother. 2024;177:117089. doi: 10.1016/j.biopha.2024.117089.

Botta M, Audano M, Sahebkar A, Sirtori CR, Mitro N, Ruscica M. PPAR agonists and metabolic syndrome: An established role? Int J Mol Sci. 2018;19(4):1197. doi: 10.3390/ijms19041197.

Cheng HS, Tan WR, Low ZS, Marvalim C, Lee JYH, Tan NS. Exploration and development of PPAR modulators in health and disease: An update of clinical evidence. Int J Mol Sci. 2019;20(20):5055. doi: 10.3390/ijms20205055.

Quintão NLM, Santin JR, Stoeberl LC, Corrêa TP, Melato J, Costa R. Pharmacological treatment of chemotherapy-induced neuropathic pain: PPARγ agonists as a promising tool. Front Neurosci. 2019;13. doi: 10.3389/fnins.2019.00907.

Alkabbani MA, Shatat AAS, Ghazy AN, Magdy K. Chemotherapy-induced liver injury: Unveiling emerging mechanisms and exploring mitigation strategies. ERU Res J. 2024. doi: 10.21608/erurj.2024.256957.1100.

Sun Z, Zhang S, Liang J, Li C, Yang X, Liu QS, et al. Effects of multiple novel bisphenol S analogs on adipogenesis in 3T3-L1 cells. J Hazard Mater. 2025;489:137689. doi: 10.1016/j.jhazmat.2025.137689.

Montaigne D, Butruille L, Staels B. PPAR control of metabolism and cardiovascular functions. Nat Rev Cardiol. 2021;18(12):809-823. doi: 10.1038/s41569-021-00569-6.

Sommer J, Mahli A, Freese K, Schiergens TS, Kuecuekoktay FS, Teufel A, et al. Analysis of molecular mechanisms of 5-fluorouracil-induced steatosis and inflammation in vitro and in mice. Oncotarget. 2017;8(8):13059-13072. doi: 10.18632/oncotarget.14371.

Trehan S, Singh G, Singh A, Bector G, Jain A, Antil P, et al. Chemotherapy and metabolic syndrome: A comprehensive review of molecular pathways and clinical outcomes. Cureus. 2024;16(8):e66354. doi: 10.7759/cureus.66354.

Jain MR, Giri SR, Trivedi C, Bhoi B, Rath A, Vanage G, et al. Saroglitazar, a novel PPARα/γ agonist with predominant PPARα activity, shows lipid-lowering and insulin-sensitizing effects in preclinical models. Pharmacol Res Perspect. 2015;3(3):e00136. doi: 10.1002/prp2.136.

Niu Y, Xiao H, Wang B, Wang Z, Du K, Wang Y, et al. Angelica sinensis polysaccharides alleviate the oxidative burden on hematopoietic cells by restoring 5-fluorouracil-induced oxidative damage in perivascular mesenchymal progenitor cells. Pharm Biol. 2023;61(1):768–778. doi: 10.1080/13880209.2023.2207592.

Fougerat A, Montagner A, Loiseau N, Guillou H, Wahli W. Peroxisome proliferator-activated receptors and their novel ligands as candidates for the treatment of non-alcoholic fatty liver disease. Cells. 2020;9(7):1638. doi: 10.3390/cells9071638.

Joharapurkar AA, Pandya VB, Patel VJ, Desai RC, Jain MR. Prolyl hydroxylase inhibitors: A breakthrough in the therapy of anemia associated with chronic diseases. J Med Chem. 2018;61(16):6964–6982. doi: 10.1021/acs.jmedchem.7b01686.

Wang Z, Wang Q, Gong X. Unveiling the mysteries of contrast-induced acute kidney injury: New horizons in pathogenesis and prevention. Toxics. 2024;12(8):620. doi: 10.3390/toxics12080620.

Balakumar P, Mahadevan N, Sambathkumar R. A contemporary overview of PPARα/γ dual agonists for the management of diabetic dyslipidemia. Curr Mol Pharmacol. 2019;12(3):195-201. doi: 10.2174/1874467212666190111165015.

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Published

2026-04-28

How to Cite

Mohammed, H. H., Rasheed, R. H., & Aziz, T. A. (2026). Modulatory Role of Saroglitazar on Novel Hematological Inflammatory Ratios and Metabolic Parameters in Animal Model of 5-Fluorouracil Toxicity. Al-Rafidain Journal of Medical Sciences ( ISSN 2789-3219 ), 10(2), 164–170. https://doi.org/10.54133/ajms.v10i2.2325

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