Ratlara Malathion ve Rutin Uygulamaları Sonrası Akciğer Dokularında Metalloproteinaz Düzeyleri ile Oksidatif Stres ve Apoptoz Belirteçlerinin Değerlendirilmesi

Abstract

Malathion (MLT), organofosfat sınıfında önemli bir çevresel kirleticidir. Rutin (RUT) ise çeşitli toksik ajanlara karşı etkinliği yoğun olarak araştırılan flavonoid aile üyelerinden biridir. Bu çalışmada, MLT ve RUT tedavilerinin sıçanların akciğer dokularında oksidatif stres, apoptoz ve metalloproteinazlar üzerine etkileri araştırıldı. Çalışmada, sıçanlara 28 gün MLT ve/veya RUT tedavisi verildikten sonra akciğer dokularındaki MDA, GSH, Nrf2, HO-1, MMP2, MMP9 ve kaspaz-3 seviyeleri biyokimyasal veya RT-PCR yöntemi ile analiz edildi. Veriler, MLT ile indüklenen MDA seviyelerinin RUT tedavisinden sonra düştüğünü gösterdi. Ayrıca Nrf2 ve HO-1 mRNA transkript düzeyleri ile MLT tarafından baskılanan GSH düzeylerinin RUT tedavisi sonrası kontrol grubu düzeylerine yaklaştığı belirlendi. MLT, akciğer dokularında metalloproteinazların (MMP2 ve MMP9) ekspresyonunu yukarı doğru düzenlerken, RUT bu genlerin ekspresyonunu aşağı regüle etti. Ayrıca MLT'nin kaspaz-3 ekspresyonunu tetiklediği, RUT'nin ise kaspaz-3'ü baskılayarak anti-apoptotik etki gösterdiği gözlendi. Sonuç olarak, MLT'nin oksidatif stres, apoptoz ve metalloproteinazlar yoluyla sıçanların akciğer dokularında toksik etkiler gösterirken, RUT'nin bu toksik etkileri azaltabileceği belirlendi.

Keywords

• Akciğer
• Apoptoz
• Malathion
• Metalloproteinazlar
• Oksidatif stres
• Rutin

Evaluation of the Levels of Metalloproteinases as well as Markers of Oxidative Stress and Apoptosis in Lung Tissues After Malathion and Rutin Administrations to Rats

Abstract

Malathion (MLT) is an important environmental pollutant in the organophosphate class. Rutin (RUT), on the other hand, is one of the flavonoid family members whose effectiveness against various toxic agents has been extensively studied. In the present study, the effects of MLT and RUT treatments on oxidative stress, apoptosis and metalloproteinases in lung tissues of rats were investigated. In the study, MDA, GSH, Nrf2, HO-1, MMP2, MMP9 and caspase-3 levels in lung tissues were analyzed by biochemical or RT-PCR method after rats received MLT and/or RUT treatment for 28 days. The data showed that MLT-induced MDA levels decreased after RUT treatment. In addition, it was determined that Nrf2 and HO-1 mRNA transcript levels and GSH levels suppressed by MLT approached the control group levels after RUT treatment. MLT up-regulated the expression of metalloproteinases (MMP2 and MMP9) in lung tissues, while RUT down-regulated the expression of these genes. In addition, it was observed that MLT triggered caspase-3 expression, while RUT exerted an anti-apoptotic effect by suppressing caspase-3. As a result, it was determined that while MLT showed toxic effects in the lung tissues of rats through oxidative stress, apoptosis and metalloproteinases, RUT could alleviate these toxic effects.

Keywords

• Apoptosis
• Lung
• Malathion
• Metalloproteinases
• Oxidative stress
• Rutin

References

1. Referans1 Gupta VK, Siddiqi NJ, Ojha AK, Sharma B. Hepatoprotective effect of Aloe vera against cartap‐and malathion‐induced toxicity in Wistar rats. J Cell Physiol. 2019;234(10):18329-43.
2. Referans2 Pandit AA, Gandham RK, Mukhopadhyay CS, Verma R, Sethi R. Transcriptome analysis reveals the role of the PCP pathway in fipronil and endotoxin-induced lung damage. Respir res. 2019;20(1):1-16.
3. Referans3 Hassani S, Sepand M, Jafari A, Jaafari J, Rezaee R, Zeinali M, et al. Protective effects of curcumin and vitamin E against chlorpyrifos-induced lung oxidative damage. Hum Exp Toxicol. 2015;34(6):668-76.
4. Referans4 Jokanović M. Medical treatment of acute poisoning with organophosphorus and carbamate pesticides. Toxicol lett. 2009;190(2):107-15.
5. Referans5 Moore PD, Patlolla AK, Tchounwou PB. Cytogenetic evaluation of malathion-induced toxicity in Sprague-Dawley rats. MRGTEM. 2011;725(1-2):78-82.
6. Referans6 Abdel-Daim MM, Abushouk AI, Bungău SG, Bin-Jumah M, El-Kott AF, Shati AA, et al. Protective effects of thymoquinone and diallyl sulphide against malathion-induced toxicity in rats. Environ Sci Pollut Res. 2020;27(10):10228-35.
7. Referans7 Geng X, Shao H, Zhang Z, Ng JC, Peng C. Malathion-induced testicular toxicity is associated with spermatogenic apoptosis and alterations in testicular enzymes and hormone levels in male Wistar rats. Environ Toxicol Pharmacol. 2015;39(2):659-67.
8. Referans8 Uysal M, Karaman S. In vivo effects of intravenous lipid emulsion on lung tissue in an experimental model of acute malathion intoxication. Toxicol Ind. 2018;34(2):110-8.

9. Referans9 Jahan S, Munawar A, Razak S, Anam S, Ain QU, Ullah H, et al. Ameliorative effects of rutin against cisplatin-induced reproductive toxicity in male rats. BMC urology. 2018;18(1):1-11.
10. Referans10 Nafees S, Rashid S, Ali N, Hasan SK, Sultana S. Rutin ameliorates cyclophosphamide induced oxidative stress and inflammation in Wistar rats: role of NFκB/MAPK pathway. Chem Biol Interact. 2015;231:98-107.
11. Referans11 Zargar S, Wani TA, Alamro AA, Ganaie MA. Amelioration of thioacetamide-induced liver toxicity in Wistar rats by rutin. Int J Immunopathol Pharmacol. 2017;30(3):207-14.
12. Referans12 Yeh C-H, Yang J-J, Yang M-L, Li Y-C, Kuan Y-H. Rutin decreases lipopolysaccharide-induced acute lung injury via inhibition of oxidative stress and the MAPK–NF-κB pathway. Free Radic Biol Med. 2014;69:249-57.
13. Referans13 Kandemir FM, Caglayan C, Aksu EH, Yildirim S, Kucukler S, Gur C, et al. Protective effect of rutin on mercuric chloride-induced reproductive damage in male rats. Andrologia. 2020;52(3):e13524.
14. Referans14 Caglayan C, Kandemir FM, Darendelioğlu E, Yıldırım S, Kucukler S, Dortbudak MB. Rutin ameliorates mercuric chloride-induced hepatotoxicity in rats via interfering with oxidative stress, inflammation and apoptosis. J Trace Elem Med Biol. 2019;56:60-8.
15. Referans15 Akbel E, Arslan-Acaroz D, Demirel HH, Kucukkurt I, Ince S. The subchronic exposure to malathion, an organophosphate pesticide, causes lipid peroxidation, oxidative stress, and tissue damage in rats: the protective role of resveratrol. Toxicol res. 2018;7(3):503-12.
16. Referans16 Placer ZA, Cushman LL, Johnson BC. Estimation of product of lipid peroxidation [malonyl dialdehyde] in biochemical systems. Anal biochem. 1966;16(2):359-64.
17. Referans17 Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Anal biochem. 1968;25:192-205.
18. Referans18 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. methods. 2001;25(4):402-8.
19. Referans19 Farkhondeh T, Mehrpour O, Forouzanfar F, Roshanravan B, Samarghandian S. Oxidative stress and mitochondrial dysfunction in organophosphate pesticide-induced neurotoxicity and its amelioration: a review. Environ Sci Pollut Res. 2020;27(20):24799-814.
20. Referans20 Ranjbar A, Ghahremani MH, Sharifzadeh M, Golestani A, Ghazi-Khansari M, Baeeri M, et al. Protection by pentoxifylline of malathion-induced toxic stress and mitochondrial damage in rat brain. Hum Exp Toxicol. 2010;29(10):851-64.
21. Referans21 Caglayan C, Temel Y, Kandemir FM, Yildirim S, Kucukler S. Naringin protects against cyclophosphamide-induced hepatotoxicity and nephrotoxicity through modulation of oxidative stress, inflammation, apoptosis, autophagy, and DNA damage. Environ Sci Pollut Res. 2018;25(21):20968-84.
22. Referans22 Gur C, Kandemir O, Kandemir FM. Investigation of the effects of hesperidin administration on abamectin‐induced testicular toxicity in rats through oxidative stress, endoplasmic reticulum stress, inflammation, apoptosis, autophagy, and JAK2/STAT3 pathways. Environ Toxicol. 2022;37(3):401-12.
23. Referans23 Gur C, Kandemir FM, Darendelioglu E, Caglayan C, Kucukler S, Kandemir O, et al. Morin protects against acrylamide-induced neurotoxicity in rats: an investigation into different signal pathways. Environ Sci Pollut Res. 2021;28(36):49808-19.
24. Referans24 Kucukler S, Benzer F, Yildirim S, Gur C, Kandemir FM, Bengu AS, et al. Protective effects of chrysin against oxidative stress and inflammation induced by lead acetate in rat kidneys: a biochemical and histopathological approach. Biol Trace Elem Res. 2021;199(4):1501-14.
25. Referans25 Yıldız MO, Çelik H, Caglayan C, Kandemir FM, Gür C, Bayav İ, et al. Neuromodulatory effects of hesperidin against sodium fluoride-induced neurotoxicity in rats: Involvement of neuroinflammation, endoplasmic reticulum stress, apoptosis and autophagy. NeuroToxicology. 2022;90:197-204.
26. Referans26 Coban FK, Ince S, Kucukkurt I, Demirel HH, Hazman O. Boron attenuates malathion-induced oxidative stress and acetylcholinesterase inhibition in rats. Drug Chem Toxicol. 2015;38(4):391-9.
27. Referans27 Ince S, Arslan-Acaroz D, Demirel HH, Varol N, Ozyurek HA, Zemheri F, et al. Taurine alleviates malathion induced lipid peroxidation, oxidative stress, and proinflammatory cytokine gene expressions in rats. Biomed Pharmacother. 2017;96:263-8.
28. Referans28 Vanova N, Pejchal J, Herman D, Dlabkova A, Jun D. Oxidative stress in organophosphate poisoning: role of standard antidotal therapy. J Appl Toxicol. 2018;38(8):1058-70.
29. Referans29 Gür C, Genç A, Kandemir Ö. Ratlarda Deltametrin’in Neden Olduğu Dalak Toksisitesine Karşı Rutin’in Potansiyel Koruyucu Etkilerinin Oksidatif Stres, Apoptoz ve İnflamasyon Belirteçleri Üzerinden Araştırılması. Atatürk University J Vet Sci. 17(1):6-10.
30. Referans30 Caglayan C, Kandemir FM, Darendelioğlu E, Küçükler S, Ayna A. Hesperidin protects liver and kidney against sodium fluoride-induced toxicity through anti-apoptotic and anti-autophagic mechanisms. Life Sci. 2021;281:119730.
31. Referans31 Küçükler S, Çomaklı S, Özdemir S, Çağlayan C, Kandemir FM. Hesperidin protects against the chlorpyrifos‐induced chronic hepato‐renal toxicity in rats associated with oxidative stress, inflammation, apoptosis, autophagy, and up-regulation of PARP‐1/VEGF. Environ Toxicol. 2021;36(8):1600-17.
32. Referans32 Anwar M, Muhammad F, Akhtar B, Saleemi MK. Nephroprotective effects of curcumin loaded chitosan nanoparticles in cypermethrin induced renal toxicity in rabbits. Environ Sci Pollut Res. 2020;27(13):14771-9.
33. Referans33 Yardim A, Gur C, Comakli S, Ozdemir S, Kucukler S, Celik H, et al. Investigation of the effects of berberine on bortezomib-induced sciatic nerve and spinal cord damage in rats through pathways involved in oxidative stress and neuro-inflammation. Neurotoxicology. 2022;89:127-39.
34. Referans34 Yardim A, Kandemir FM, Ozdemir S, Kucukler S, Comakli S, Gur C, et al. Quercetin provides protection against the peripheral nerve damage caused by vincristine in rats by suppressing caspase 3, NF-κB, ATF-6 pathways and activating Nrf2, Akt pathways. Neurotoxicology. 2020;81:137-46.
35. Referans35 Hussein RM, Mohamed WR, Omar HA. A neuroprotective role of kaempferol against chlorpyrifos-induced oxidative stress and memory deficits in rats via GSK3β-Nrf2 signaling pathway. Pestic Biochem Physiol. 2018;152:29-37.
36. Referans36 Kong Y, Li M, Guo G, Yu L, Sun L, Yin Z, et al. Effects of dietary curcumin inhibit deltamethrin-induced oxidative stress, inflammation and cell apoptosis in Channa argus via Nrf2 and NF-κB signaling pathways. Aquaculture. 2021;540:736744.
37. Referans37 Shi W, Zhang D, Wang L, Sreeharsha N, Ning Y. Curcumin synergistically potentiates the protective effect of sitagliptin against chronic deltamethrin nephrotoxicity in rats: impact on pro‐inflammatory cytokines and Nrf2/Ho‐1 pathway. JBMT. 2019;33(10):e22386.
38. Referans38 Subbiah R, Tiwari RR. The herbicide paraquat-induced molecular mechanisms in the development of acute lung injury and lung fibrosis. Crit Rev Toxicol. 2021;51(1):36-64.
39. Referans39 Zhang W, Fievez L, Cheu E, Bureau F, Rong W, Zhang F, et al. Anti-inflammatory effects of formoterol and ipratropium bromide against acute cadmium-induced pulmonary inflammation in rats. Eur J Pharmacol. 2010;628(1-3):171-8.
40. Referans40 Yesildag K, Gur C, Ileriturk M, Kandemir FM. Evaluation of oxidative stress, inflammation, apoptosis, oxidative DNA damage and metalloproteinases in the lungs of rats treated with cadmium and carvacrol. Mol Biol Rep. 2022;49(2):1201-11.
41. Referans41 Zhang F, Hu L, Wu Y-x, Fan L, Liu W-t, Wang J, et al. Doxycycline alleviates paraquat-induced acute lung injury by inhibiting neutrophil-derived matrix metalloproteinase 9. Int Immunopharmacol. 2019;72:243-51.
42. Referans42 Liu M-w, Liu R, Wu H-y, Li Y-y, Su M-x, Dong M-n, et al. Radix puerariae extracts ameliorate paraquat-induced pulmonary fibrosis by attenuating follistatin-like 1 and nuclear factor erythroid 2p45-related factor-2 signalling pathways through downregulation of miRNA-21 expression. BMC Complement Altern Med. 2015;16(1):1-15.
43. Referans43 Yao R, Cao Y, He Y-r, Lau WB, Zeng Z, Liang Z-a. Adiponectin attenuates lung fibroblasts activation and pulmonary fibrosis induced by paraquat. PLoS One. 2015;10(5):e0125169.
44. Referans44 Yang X, Fang Y, Hou J, Wang X, Li J, Li S, et al. The heart as a target for deltamethrin toxicity: Inhibition of Nrf2/HO-1 pathway induces oxidative stress and results in inflammation and apoptosis. Chemosphere. 2022;300:134479.
45. Referans45 Hou W, Zhu X, Liu J, Map J. Inhibition of miR-153 ameliorates ischemia/reperfusion-induced cardiomyocytes apoptosis by regulating Nrf2/HO-1 signaling in rats. Biomed Eng Online. 2020;19(1):1-14.
46. Referans46 Semis HS, Kandemir FM, Kaynar O, Dogan T, Arikan SM. The protective effects of hesperidin against paclitaxel-induced peripheral neuropathy in rats. Life Sci. 2021;287:120104.
47. Referans47 Semis HS, Gur C, Ileriturk M, Kandemir FM, Kaynar O. Evaluation of therapeutic effects of quercetin against Achilles tendinopathy in rats via oxidative stress, inflammation, apoptosis, autophagy, and metalloproteinases. Am J Sports Med. 2022;50(2):486-98.
48. Referans48 Kandemir FM, Kucukler S, Caglayan C, Gur C, Batil AA, Gülçin İ. Therapeutic effects of silymarin and naringin on methotrexate‐induced nephrotoxicity in rats: Biochemical evaluation of anti‐inflammatory, antiapoptotic, and antiautophagic properties. J Food Biochem. 2017;41(5):e12398.
49. Referans49 Salama OA, Attia MM, Abdelrazek MA. Modulatory effects of swimming exercise against malathion induced neurotoxicity in male and female rats. Pestic Biochem Physiol. 2019;157:13-8.
50. Referans50 Dos Santos AA, Naime AA, de Oliveira J, Colle D, Dos Santos DB, Hort MA, et al. Long-term and low-dose malathion exposure causes cognitive impairment in adult mice: evidence of hippocampal mitochondrial dysfunction, astrogliosis and apoptotic events. Arch toxicol. 2016;90(3):647-60.