The Effect of Chlorogenic Acid on Methotrexate-Induced Oxidative Stress and Inflammation in Lung Tissue of Rats

Ahmet Mentese; Selim Demir; Nihal Türkmen Alemdar; Elif Ayazoglu Demir; Yüksel Aliyazıcıoğlu

doi:10.59518/farabimedj.1504348

EN TR

The Effect of Chlorogenic Acid on Methotrexate-Induced Oxidative Stress and Inflammation in Lung Tissue of Rats

Abstract

Although methotrexate (MTX) is a widely used chemotherapeutic agent, lung toxicity remains a significant problem, limiting its use. The molecular mechanism of MTX-related lung toxicity is not fully understood. However, increased reactive oxygen species-induced oxidative stress (OS) and inflammation play an important role in lung injury. Chlorogenic acid (CHA) is a natural phenolic compound that has been shown in recent years to have beneficial effects in many pathologies associated with OS and inflammation. This study focused on investigating for the first time, the potential therapeutic effects of CHA in the lung tissue of rats exposed to MTX. After lung toxicity was induced in rats by MTX (20 mg/kg) injection on the first day, two different doses of CHA (1.5 and 3 mg/kg) were used for treatment for 3 days. The results showed that CHA treatment reduced the level of pulmonary lipid peroxidation, inflammation and apoptosis and promoted the pulmonary antioxidant system in rats subjected to MTX. Taken together, the antioxidant and anti-inflammatory properties of CHA may play a central role in attenuating MTX-induced lung injury, but the exact mechanism needs to be investigated in more extensive preclinical studies.

Keywords

Apoptosis , Chlorogenic acid , Inflammation , Lung toxicity , Methotrexate , Oxidative stress

Sıçanların Akciğer Dokusunda Metotreksat ile Oluşturulan Oksidatif Stres ve İnflamasyon Üzerine Klorojenik Asitin Etkisi

Öz

Metotreksat (MTX) yaygın olarak kullanılan bir kemoterapötik ajan olmasına rağmen, akciğer toksisitesi önemli bir sorun olmaya devam etmekte ve ilacın kullanımını sınırlamaktadır. MTX'e bağlı akciğer toksisitesinin moleküler mekanizması tam olarak anlaşılamamıştır. Ancak artan reaktif oksijen türlerinin neden olduğu oksidatif stres (OS) ve inflamasyon, akciğer hasarında önemli bir rol oynamaktadır. Klorojenik asit (CHA), son yıllarda OS ve inflamasyon ile ilişkili birçok patolojide yararlı etkilere sahip olduğu gösterilen doğal bir fenolik bileşiktir. Bu çalışma, MTX'e maruz bırakılan sıçanların akciğer dokusunda CHA'nın potansiyel terapötik etkilerinin ilk kez araştırılmasına odaklandı. Sıçanlarda ilk gün MTX (20 mg/kg) enjeksiyonu ile akciğer toksisitesi oluşturulduktan sonra, 3 gün boyunca iki farklı dozda CHA (1.5 ve 3 mg/kg) ile tedavi uygulandı. Sonuçlar, CHA tedavisinin, MTX'e maruz bırakılan sıçanlarda pulmoner lipid peroksidasyon, inflamasyon ve apoptoz seviyesini azalttığını ve pulmoner antioksidan sistemi desteklediğini gösterdi. Birlikte ele alındığında, CHA'nın antioksidan ve anti-inflamatuar özellikleri MTX'in neden olduğu akciğer hasarını hafifletmede merkezi bir rol oynayabilir, ancak kesin mekanizmanın daha kapsamlı klinik öncesi çalışmalarla araştırılması gerekmektedir.

Anahtar Kelimeler

Akciğer toksisitesi , Apoptoz , İnflamasyon , Klorojenik asit , Metotreksat , Oksidatif stres

References

Ali N, Rashid S, Nafees S, et al. Protective effect of chlorogenic acid against methotrexate induced oxidative stress, inflammation and apoptosis in rat liver: An experimental approach. Chem Biol Interact. 2017;272:80-91. doi:10.1016/j.cbi.2017.05.002
Hamed KM, Dighriri IM, Baomar AF, et al. Overview of methotrexate toxicity: A comprehensive literature review. Cureus. 2022;14(9):e29518. doi:10.7759/cureus.29518
Choy EH, Smith C, Doré CJ, Scott DL. A meta-analysis of the efficacy and toxicity of combining disease-modifying anti-rheumatic drugs in rheumatoid arthritis based on patient withdrawal. Rheumatology (Oxford). 2005;44(11):1414-1421. doi:10.1093/rheumatology/kei031
Schmiegelow K. Advances in individual prediction of methotrexate toxicity: A review. Br J Haematol. 2009;146(5):489-503. doi:10.1111/j.1365-2141.2009.07765.x
Solomon DH, Glynn RJ, Karlson EW, et al. Adverse effects of low-dose methotrexate: A randomized trial. Ann Intern Med. 2020;172(6):369-380. doi:10.7326/M19-3369
Ohbayashi M, Suzuki M, Yashiro Y, et al. Induction of pulmonary fibrosis by methotrexate treatment in mice lung in vivo and in vitro. J Toxicol Sci. 2010;35(5):653-661. doi:10.2131/jts.35.653
Çakır T, Özkan E, Dulundu E, et al. Caffeic acid phenethyl ester (CAPE) prevents methotrexate-induced hepatorenal oxidative injury in rats. J Pharm Pharmacol. 2011;63(12):1566-1571. doi:10.1111/j.2042-7158.2011.01359.x
Mukherjee S, Ghosh S, Choudhury S, et al. Pomegranate reverses methotrexate-induced oxidative stress and apoptosis in hepatocytes by modulating Nrf2-NF-κB pathways. J Nutr Biochem. 2013;24(12):2040-2050. doi:10.1016/j.jnutbio.2013.07.005
Roghani M, Kalantari H, Khodayar MJ, et al. Alleviation of liver dysfunction, oxidative stress and inflammation underlies the protective effect of ferulic acid in methotrexate-induced hepatotoxicity. Drug Des Devel Ther. 2020;14:1933-1941. doi:10.2147/DDDT.S237107
Babiak RM, Campello AP, Carnieri EG, Oliveira MB. Methotrexate: pentose cycle and oxidative stress. Cell Biochem Funct. 1998;16(4):283-293. doi:10.1002/(SICI)1099-0844(1998120)16:4<283::AID-CBF801>3.0.CO;2-E

Jahovic N, Çevik H, Şehirli AÖ, Yeğen BÇ, Şener G. Melatonin prevents methotrexate‐induced hepatorenal oxidative injury in rats. J Pineal Res. 2003;34(4):282-287. doi:10.1034/j.1600-079X.2003.00043.x
Demir S, Kazaz IO, Kerimoglu G, et al. Gallic acid attenuates torsion/detorsion-induced testicular injury in rats through suppressing of HMGB1/NF-κB axis and endoplasmic reticulum stress. Rev Int Androl. 2024;22(1):1-7. doi:10.22514/j.androl.2024.001
Khalifa MMA, Bakr AG, Osman AT. Protective effects of phloridzin against methotrexate-induced liver toxicity in rats. Biomed Pharmacother. 2017;95:529-535. doi:10.1016/j.biopha.2017.08.121
Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal. 2014;20(7):1126-1167. doi:10.1089/ars.2012.5149
Mammadov R, Suleyman B, Akturan S, et al. Effect of lutein on methotrexate-induced oxidative lung damage in rats: A biochemical and histopathological assessment. Korean J Intern Med. 2019;34:1279-1286. doi:10.3904/kjim.2018.145
Abosrea AM, Aboul Ezz HS, Mahmoud SM, Mousa MR, Ahmed NA. The potential role of pumpkin seeds oil on methotrexate-induced lung toxicity. Sci Rep. 2023;13(1):7321. doi:10.1038/s41598-023-34143-6
Abdalhameid E, Abd El-Haleim EA, Abdelsalam RM, Georgy GS, Fawzy HM, Kenawy SA. Cinnamic acid mitigates methotrexate-induced lung fibrosis in rats: comparative study with pirfenidone. Naunyn Schmiedebergs Arch Pharmacol. 2024;397(2):1071-1079. doi:10.1007/s00210-023-02652-w
Vardi N, Parlakpinar H, Ates B. Beneficial effects of chlorogenic acid on methotrexate-induced cerebellar Purkinje cell damage in rats. J Chem Neuroanat. 2012;43(1):43-47. doi:10.1016/j.jchemneu.2011.09.003
Shin HS, Satsu H, Bae MJ, et al. Anti-inflammatory effect of chlorogenic acid on the IL-8 production in Caco-2 cells and the dextran sulphate sodium-induced colitis symptoms in C57BL/6 mice. Food Chem. 2015;168:167-175. doi:10.1016/j.foodchem.2014.06.100
Lu H, Tian Z, Cui Y, Liu Z, Ma X. Chlorogenic acid: A comprehensive review of the dietary sources, processing effects, bioavailability, beneficial properties, mechanisms of action, and future directions. Compr Rev Food Sci Food Saf. 2020;19(6):3130-3158. doi:10.1111/1541-4337.12620
Liang N, Kitts DD. Role of chlorogenic acids in controlling oxidative and inflammatory stress conditions. Nutrients. 2015;8(1):16. doi:10.3390/nu8010016
Nguyen V, Taine EG, Meng D, Cui T, Tan W. Chlorogenic acid: A systematic review on the biological functions, mechanistic actions, and therapeutic potentials. Nutrients. 2024;16(7):924. doi:10.3390/nu16070924
Gupta A, Atanasov AG, Li Y, Kumar N, Bishayee A. Chlorogenic acid for cancer prevention and therapy: Current status on efficacy and mechanisms of action. Pharmacol Res. 2022;186:106505. doi:10.1016/j.phrs.2022.106505
Lv B, Guo J, Du Y, et al. Chlorogenic acid reduces inflammation by inhibiting the elevated expression of KAT2A to ameliorate lipopolysaccharide-induced acute lung injury. Br J Pharmacol. 2023;180(16):2156-2171. doi:10.1111/bph.16069
Larki-Harchegani A, Fayazbakhsh F, Nourian A, Nili-Ahmadabadi A. Chlorogenic acid protective effects on paraquat-induced pulmonary oxidative damage and fibrosis in rats. J Biochem Mol Toxicol. 2023;37(7):e23352. doi:10.1002/jbt.23352
Jain S, Saha P, Syamprasad NP, et al. Targeting TLR4/3 using chlorogenic acid ameliorates LPS+POLY I:C-induced acute respiratory distress syndrome via alleviating oxidative stress-mediated NLRP3/NF-κB axis. Clin Sci (Lond). 2023;137(10):785-805. doi:10.1042/CS20220625
Domitrović R, Cvijanović O, Šušnić V, Katalinić N. Renoprotective mechanisms of chlorogenic acid in cisplatin-induced kidney injury. Toxicology. 2014;324:98-107. doi:10.1016/j.tox.2014.07.004
Park SH, Baek SI, Yun J, et al. IRAK4 as a molecular target in the amelioration of innate immunity-related endotoxic shock and acute liver injury by chlorogenic acid. J Immunol. 2015;194(3):1122-1130. doi:10.4049/jimmunol.1402101
Ayazoglu Demir E, Mentese A, Livaoglu A, Alemdar NT, Aliyazicioglu Y, Demir S. Chlorogenic acid attenuates cisplatin-induced ovarian injury in rats. Drug Chem Toxicol. 2024;47(2):213-217. doi:10.1080/01480545.2023.2172181
Erboga M, Aktas C, Erboga ZF, Donmez YB, Gurel A. Quercetin ameliorates methotrexate-induced renal damage, apoptosis and oxidative stress in rats. Ren Fail. 2015;37(9):1492-1497. doi:10.3109/0886022X.2015.1074521
Yuksel Y, Yuksel R, Yagmurca M, et al. Effects of quercetin on methotrexate-induced nephrotoxicity in rats. Hum Exp Toxicol. 2017;36(1):51-61. doi:10.1177/0960327116637414
Sultana S. Protective effect of baicalin on methotrexate-induced mitochondrial damage in testicular tissues of rats. J King Saud Univ Sci. 2022;34:102343. doi:10.1016/j.jksus.2022.102343
Smith PK, Krohn RI, Hermanson GT, et al. Measurement of protein using bicinchoninic acid. Anal Biochem. 1985;150(1):76-85. doi:10.1016/0003-2697(85)90442-7
Mihara M, Uchiyama M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem. 1978;86(1):271-278. doi:10.1016/0003-2697(78)90342-1
Demir S, Kazaz IO, Kerimoglu G, et al. Propolis ameliorates ischemia/reperfusion-induced testicular damage by reducing oxidative stress. Rev Int Androl. 2023;21(3):100364. doi:10.1016/j.androl.2023.100364
Demir S, Mentese A, Livaoglu A, Demir EA, Alemdar NT, Aliyazicioglu Y. Therapeutic effect of sinapic acid against 5-fluorouracil-induced oxidative stress and inflammation in rat ovarium: An experimental approach. Farabi Med J. 2023;2(2):1-7. doi:10.59518/farabimedj.1221397
Islam MN, Rauf A, Fahad FI, et al. Superoxide dismutase: An updated review on its health benefits and industrial applications. Crit Rev Food Sci Nutr. 2022;62(26):7282-7300. doi:10.1080/10408398.2021.1913400
Van Loo G, Bertrand MJM. Death by TNF: A road to inflammation. Nat Rev Immunol. 2023;23(5):289-303. doi:10.1038/s41577-022-00792-3
Shalini S, Dorstyn L, Dawar S, Kumar S. Old, new and emerging functions of caspases. Cell Death Differ. 2015;22(4):526-539. doi:10.1038/cdd.2014.216.
Mentese A, Demir S, Alemdar NT, Aliyazicioglu Y, Deger O. The effect of chlorogenic acid on 5-fluorouracil-induced oxidative damage in rat ovarian tissue. Farabi Med J. 2022;1(1):1-7.
Ayazoglu Demir E, Mentese A, Kucuk H, Alemdar NT, Demir S, Aliyazicioglu Y. N-Acetylcysteine ameliorates 5-fluorouracil‐induced ovarian injury in rats. Clin Exp Health Sci. 2023;13(4):776-781. doi:10.33808/clinexphealthsci.1199615
Ayazoglu Demir E, Mentese A, Kucuk H, Alemdar NT, Demir S. The therapeutic effect of silibinin against 5-fluorouracil-induced ovarian toxicity in rats. J Biochem Mol Toxicol. 2023;37(9):e23408. doi:10.1002/jbt.23408
Kahraman H, Kurutaş E, Tokur M, et al. Protective effects of erythropoietin and N-acetylcysteine on methotrexate-induced lung injury in rats. Balkan Med J. 2013;30(1):99-104. doi:10.5152/balkanmedj.2012.078
Kalemci S, Dirican N, Cetin ES, et al. The efficacy of minocycline against methotrexate-induced pulmonary fibrosis in mice. Eur Rev Med Pharmacol Sci. 2013;17(24):3334-3340
Zaki SM, Hussein GHA, Khalil HMA, Abd Algaleel WA. Febuxostat ameliorates methotrexate-induced lung damage. Folia Morphol (Warsz). 2021;80(2):392-402. doi:10.5603/FM.a2020.0075
Wang JM, Chen RX, Zhang LL, et al. In vivo protective effects of chlorogenic acid against triptolide-induced hepatotoxicity and its mechanism. Pharm Biol. 2018;56(1):626-631. doi:10.1080/13880209.2018.1527370
Kazaz IO, Demir S, Kerimoglu G, et al. Chlorogenic acid ameliorates torsion/detorsion-induced testicular injury via decreasing endoplasmic reticulum stress. J Pediatr Urol. 2022;18(3):289.e1-289.e7. doi:10.1016/j.jpurol.2022.02.013
Ali YA, Ahmed AAE, Abd El-Raouf OM, Elkhoely A, Gad AM. Polydatin combats methotrexate-induced pulmonary fibrosis in rats: Involvement of biochemical and histopathological assessment. J Biochem Mol Toxicol. 2022;36(5):e23019. doi:10.1002/jbt.23019
Althagafy HS, Sharawi ZW, Batawi AH, et al. Buspirone attenuated methotrexate-induced hippocampal toxicity in rats by regulating Nrf2/HO-1, PPAR-γ, NF-κB/nNOS, and ROS/NLRP3/caspase-1 signaling pathways. J Biochem Mol Toxicol. 2023;37(9):e23414. doi:10.1002/jbt.23414
Kurt A, Tumkaya L, Turut H, et al. Protective effects of infliximab on lung injury induced by methotrexate. Arch Bronconeumol. 2015;51(11):551-557. doi:10.1016/j.arbres.2015.03.018
Xu Y, Chen J, Yu X, et al. Protective effects of chlorogenic acid on acute hepatotoxicity induced by lipopolysaccharide in mice. Inflamm Res. 2010;59(10):871-817. doi:10.1007/s00011-010-0199-z
Ji L, Jiang P, Lu B, et al. Chlorogenic acid, a dietary polyphenol, protects acetaminophen-induced liver injury and its mechanism. J Nutr Biochem. 2013;24(11):1911-1919. doi:10.1016/j.jnutbio.2013.05.007

Details

Primary Language

English

Subjects

Pharmaceutical Biochemistry

Journal Section

Research Article

Authors

Ahmet Mentese
0000-0003-2036-5317
Türkiye

Selim Demir ^*
0000-0002-1863-6280
Türkiye

Nihal Türkmen Alemdar
0000-0002-8913-8692
Türkiye

Elif Ayazoglu Demir
0000-0001-7188-2176
Türkiye

Yüksel Aliyazıcıoğlu
0000-0001-9474-4307
Türkiye

Publication Date

October 1, 2024

Submission Date

June 24, 2024

Acceptance Date

September 4, 2024

Published in Issue

Year 2024 Volume: 3 Number: 3

DOI

https://doi.org/10.59518/farabimedj.1504348

IZ

https://izlik.org/JA79KJ34MG

APA

Mentese, A., Demir, S., Türkmen Alemdar, N., Ayazoglu Demir, E., & Aliyazıcıoğlu, Y. (2024). The Effect of Chlorogenic Acid on Methotrexate-Induced Oxidative Stress and Inflammation in Lung Tissue of Rats. Farabi Tıp Dergisi, 3(3), 71-78. https://doi.org/10.59518/farabimedj.1504348

Cited By

Chlorogenic acid protects against cisplatin-induced testicular damage: a biochemical and histological study

Archives of Industrial Hygiene and Toxicology

https://doi.org/10.2478/aiht-2025-76-3990

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