Crocin Protects Mice Pancreatic Islets from Oxidative Stress Induced by Methylglyoxal and Increases Insulin Secretion

Year 2023, Volume: 25 Issue: 3, 218 - 224, 30.12.2023

Vahid Radmehr , Akram Ahangarpour , Elnaz Haroonı , Reza Noeı Razlıqı

https://doi.org/10.18678/dtfd.1286026

Abstract

Aim: Islets of Langerhans are more sensitive to oxidative damage because of their low antioxidant capacity. In diabetes, methylglyoxal (MG) accumulates in the pancreas. The present study examined the effect of crocin on oxidative stress induced by MG in isolated Langerhans islets from male mice.
Material and Methods: Twenty-four male mice weighing 20 to 25 g were prepared. The isolated Langerhans islets were transferred to the culture medium. Oxidative stress was induced through MG administration for 30 min, and then 10, 20, 30, and 40 μM of crocin was used for 2 h. Samples were divided into seven groups with 2.8, 5.6, and 16.7 mM glucose concentrations: control, MG 300 μM, MG+glibenclamide 10 μM, and MG+crocin in four doses of 10, 20, 30, and 40 μM. At the end, the islet’s insulin, antioxidant levels, and lipid peroxidation were assessed by ELISA and calorimetry methods.
Results: Increased levels of malondialdehyde (MDA) in MG groups significantly decreased in 2.8 (p=0.008), 5.6 (p=0.004), and 16.7 (p˂0.001) mM glucose concentrations, with administration of 30 and 40 μM crocin. Total antioxidant capacity (TAC) was reduced in MG groups (p˂0.001) and significantly restored in all crocin-treated groups in 2.8, 5.6, and 16.7 mM glucose concentrations. Also, a significant decrease in insulin secretion and content was observed in MG groups of all three glucose concentrations (p˂0.001). Crocin at high doses improved these alterations.
Conclusion: MG caused oxidative damage and reduced insulin secretion in isolated islets. Crocin improved the antioxidant defense system, diminished MDA, and increased insulin secretion.

Keywords

beta-cell, crocin, diabetes, methylglyoxal, oxidative stress

Krosin, Fare Pankreas Adacıklarını Metilglioksal Tarafından İndüklenen Oksidatif Stresten Korur ve İnsülin Sekresyonunu Arttırır

Abstract

Amaç: Langerhans adacıkları, düşük antioksidan kapasiteleri nedeniyle oksidatif strese karşı daha duyarlıdır. Diyabette, pankreasta metilglioksal (MG) birikir. Bu çalışmada, erkek farelerden izole edilmiş olan Langerhans adacıklarında MG tarafından indüklenen oksidatif stres üzerinde krosinin etkisini araştırıldı.
Gereç ve Yöntemler: Ağırlıkları 20 ile 25 g arasında olan 24 adet erkek fare kullanıldı. İzole edilen Langerhans adacıkları kültür ortamına aktarıldı. 30 dakika boyunca MG uygulaması ile oksidatif stres indüklendi ve ardından 2 saat boyunca 10, 20, 30 ve 40 uM krosin kullanıldı. Örnekler, 2,8, 5,6 ve 16,7 mM glikoz konsantrasyonlarında yedi gruba ayrıldı: kontrol, MG 300 uM, MG+glibenclamide 10 uM ile 10, 20, 30 ve 40 μM'lik dört dozda MG+krosin. Son olarak adacığın insülin, antioksidan seviyeleri ve lipid peroksidasyonu ELISA ve kalorimetri yöntemleri ile değerlendirildi.
Bulgular: MG gruplarında artmış olan malondialdehit (MDA) düzeyleri, 30 ve 40 μM krosin uygulanmasıyla 2,8 (p=0,008), 5,6 (p=0,004) ve 16,7 (p˂0,001) mM glikoz konsantrasyonlarında anlamlı olarak azaldı. Toplam antioksidan kapasite (TAC), MG gruplarında azalmıştı (p˂0,001) ve krosinle tedavi edilen tüm gruplarda 2,8, 5,6 ve 16,7 mM glikoz konsantrasyonlarında önemli ölçüde düzeldi. Ayrıca MG gruplarında her üç glukoz konsantrasyonunda da insülin sekresyonu ve içeriğinde anlamlı azalma gözlendi (p˂0,001). Yüksek dozlarda krosin bu değişiklikleri iyileştirdi.
Sonuç: MG, izole adacıklarda oksidatif hasara neden olmuş ve sonuç olarak insülin sekresyonunu azaltmıştır. Krosin antioksidan savunma sistemini iyileştirdi, MDA üretimini baskıladı ve insülin sekresyonunu artırdı.

Keywords

beta hücresi, krosin, diyabet, metilglioksal, oksidatif stress

References

• Kasuga M. Insulin resistance and pancreatic β cell failure. J Clin Invest. 2006;116(7):1756-60.
• Jayachandran M, Vinayagam R, Ambati RR, Xu B, Chung SSM. Guava leaf extract diminishes hyperglycemia and oxidative stress, prevents β-cell death, inhibits inflammation, and regulates NF-kB signaling pathway in STZ induced diabetic rats. Biomed Res Int. 2018;2018:4601649.
• Moens C, Bensellam M, Himpe E, Muller CJ, Jonas JC, Bouwens L. Aspalathin protects insulin‐producing β cells against glucotoxicity and oxidative stress‐induced cell death. Mol Nutr Food Res. 2020;64(8):e1901009.
• Ma Q, Guo Y, Sun L, Zhuang Y. Anti-diabetic effects of phenolic extract from rambutan peels (Nephelium lappaceum) in high-fat diet and streptozotocin-induced diabetic mice. Nutrients. 2017;9(8):801.
• Al-Brakati A, Albarakati AJA, Daabo HMA, Baty RS, Salem FEH, Habotta OA, et al. Neuromodulatory effects of green coffee bean extract against brain damage in male albino rats with experimentally induced diabetes. Metab Brain Dis. 2020;35(7):1175-87.
• Shrilatha B, Muralidhara. Occurrence of oxidative impairments, response of antioxidant defences and associated biochemical perturbations in male reproductive milieu in the Streptozotocin‐diabetic rat. Int J Androl. 2007;30(6):508-18.
• Lenzen S. Oxidative stress: the vulnerable β-cell. Biochem Soc Trans. 2008;36(Pt 3):343-7.
• Dalle-Donne I, Rossi R, Colombo R, Giustarini D, Milzani A. Biomarkers of oxidative damage in human disease. Clin Chem. 2006;52(4):601-23.
• Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev. 2014;2014:360438.
• Desai K, Wu L. Methylglyoxal and advanced glycation endproducts: new therapeutic horizons? Recent Adv Cardiovasc Drug Discov. 2007;2(2):89-99.
• Schalkwijk CG, Stehouwer CDA. Methylglyoxal, a highly reactive dicarbonyl compound, in diabetes, its vascular complications, and other age-related diseases. Physiol Rev. 2020;100(1):407-61.
• Schalkwijk CG, Brouwers O, Stehouwer CD. Modulation of insulin action by advanced glycation endproducts: a new player in the field. Horm Metab Res. 2008;40(9):614-9.
• Mey JT, Haus JM. Dicarbonyl stress and glyoxalase-1 in skeletal muscle: implications for insulin resistance and type 2 diabetes. Front Cardiovasc Med. 2018;5:117.
• Kalapos MP. The tandem of free radicals and methylglyoxal. Chem Biol Interact. 2008;171(3):251-71.
• Chakraborty D, Samadder A, Dutta S, Khuda-Bukhsh AR. Antihyperglycemic potentials of a threatened plant, Helonias dioica: antioxidative stress responses and the signaling cascade. Exp Biol Med (Maywood). 2012;237(1):64-76.
• Lee SH, Park MH, Park SJ, Kim J, Kim YT, Oh MC, et al. Bioactive compounds extracted from Ecklonia cava by using enzymatic hydrolysis protects high glucose-induced damage in INS-1 pancreatic β-cells. Appl Biochem Biotechnol. 2012;167(7):1973-85.
• Baskar V, Venkatesh R, Ramalingam S. Flavonoids (antioxidants systems) in higher plants and their response to stresses. In: Gupta DK, Palma JM, Corpas FJ, editors. Antioxidants and antioxidant enzymes in higher plants. Switzerland: Springer, Cham; 2018. p.253-68.
• Adefegha SA, Dada FA, Oyeleye SI, Oboh G. Effects of berberine on cholinesterases and monoamine oxidase activities, and antioxidant status in the brain of streptozotocin (STZ)-induced diabetic rats. J Basic Clin Physiol Pharmacol. 2021;33(4):389-97.
• Radmehr V, Ahangarpour A, Khorsandi L, Omidi M. Protective effects of myricitrin and vitamin E on nephropathy of aging mice model induced by D-galactose. Duzce Med J. 2021;23(3):270-5.
• Caro-Ordieres T, Marín-Royo G, Opazo-Ríos L, Jiménez-Castilla L, Moreno JA, Gómez-Guerrero C, et al. The coming age of flavonoids in the treatment of diabetic complications. J Clin Med. 2020;9(2):346.
• Hussain T, Tan B, Murtaza G, Liu G, Rahu N, Saleem Kalhoro M, et al. Flavonoids and type 2 diabetes: Evidence of efficacy in clinical and animal studies and delivery strategies to enhance their therapeutic efficacy. Pharmacol Res. 2020;152:104629.
• Saribas GS, Tozak Yildiz H, Gorgulu O. Ellagic acid inhibits TGFβ1/smad-induced renal fibrosis in diabetic kidney injury. Duzce Med J. 2022;24(3):321-7.
• Patel S, Sarwat M, Khan TH. Mechanism behind the anti-tumour potential of saffron (Crocus sativus L.): The molecular perspective. Crit Rev Oncol Hematol. 2017;115:27-35.
• Hatziagapiou K, Kakouri E, Lambrou GI, Bethanis K, Tarantilis PA. Antioxidant properties of Crocus sativus L. and its constituents and relevance to neurodegenerative diseases; focus on Alzheimer’s and Parkinson’s disease. Curr Neuropharmacol. 2019;17(4):377-402.
• Radmehr V, Ahangarpour A, Mard SA, Khorsandi L. Crocin attenuates endoplasmic reticulum stress in methylglyoxal-induced diabetic nephropathy in male mice: MicroRNAs alterations and glyoxalase 1-Nrf2 signaling pathways. Iran J Basic Med Sci. 2022;25(11):1341-8.
• Rodriguez-Ruiz V, Barzegari A, Zuluaga M, Zunooni-Vahed S, Rahbar-Saadat Y, Letourneur D, et al. Potential of aqueous extract of saffron (Crocus sativus L.) in blocking the oxidative stress by modulation of signal transduction in human vascular endothelial cells. J Funct Foods. 2016;26:123-34.
• Wani MJ, Salman KA, Moin S, Arif A. Effect of crocin on glycated human low-density lipoprotein: A protective and mechanistic approach. Spectrochim Acta A Mol Biomol Spectrosc. 2023;286:121958.
• Pitsikas N, Boultadakis A, Georgiadou G, Tarantilis PA, Sakellaridis N. Effects of the active constituents of Crocus sativus L., crocins, in an animal model of anxiety. Phytomedicine. 2008;15(12):1135-9.
• Shoja M, Mehri S, Amin B, Askari VR, Hosseinzadeh H. The prophylactic and therapeutic effects of saffron extract and crocin on ethanol withdrawal syndrome in mice. J Pharmacopuncture. 2018;21(4):277-83.
• Khazdair MR, Boskabady MH, Hosseini M, Rezaee R, Tsatsakis AM. The effects of Crocus sativus (saffron) and its constituents on nervous system: A review. Avicenna J Phytomed. 2015;5(5):376-91.
• Elsherbiny NM, Salama MF, Said E, El-Sherbiny M, Al-Gayyar MM. Crocin protects against doxorubicin-induced myocardial toxicity in rats through down-regulation of inflammatory and apoptic pathways. Chem Biol Interact. 2016;247:39-48.
• Abou-Hany HO, Atef H, Said E, Elkashef HA, Salem HA. Crocin mediated amelioration of oxidative burden and inflammatory cascade suppresses diabetic nephropathy progression in diabetic rats. Chem Biol Interact. 2018;284:90-100.
• Margaritis I, Angelopoulou K, Lavrentiadou S, Mavrovouniotis IC, Tsantarliotou M, Taitzoglou I, et al. Effect of crocin on antioxidant gene expression, fibrinolytic parameters, redox status and blood biochemistry in nicotinamide-streptozotocin-induced diabetic rats. J Biol Res (Thessalon). 2020;27:4.
• O’Dowd JF, Stocker CJ. Isolation and purification of rodent pancreatic islets of Langerhans. Methods Mol Biol. 2020;2076:179-84.
• Ahangarpour A, Oroojan AA. Myricitrin and its solid lipid nanoparticle increase insulin secretion and content of isolated islets from the pancreas of male mice. Braz J Pharm Sci. 2022;58:e20065.
• Mohamad Shahi M, Haidari F, Shiri MR. Comparison of effect of resveratrol and vanadium on diabetes related dyslipidemia and hyperglycemia in streptozotocin induced diabetic rats. Adv Pharm Bull. 2011;1(2):81-6.
• Suh KS, Choi EM, Jung WW, Kim YJ, Hong SM, Park SY, et al. Deoxyactein protects pancreatic β-cells against methylglyoxal-induced oxidative cell damage by the upregulation of mitochondrial biogenesis. Int J Mol Med. 2017;40(2):539-48.
• Rains JL, Jain SK. Oxidative stress, insulin signaling, and diabetes. Free Radic Biol Med. 2011;50(5):567-75.
• Raafat K, Aboul-Ela M, El-Lakany A. Phytochemical and anti-neuropathic investigations of Crocus sativus via alleviating inflammation, oxidative stress and pancreatic beta-cells regeneration. Chin Herb Med. 2019;12(1):47-55.
• Samaha MM, Said E, Salem HA. A comparative study of the role of crocin and sitagliptin in attenuation of STZ-induced diabetes mellitus and the associated inflammatory and apoptotic changes in pancreatic β-islets. Environ Toxicol Pharmacol. 2019;72:103238.
• Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414(6865):813-20.
• Yaribeygi H, Atkin SL, Sahebkar A. A review of the molecular mechanisms of hyperglycemia-induced free radical generation leading to oxidative stress. J Cell Physiol. 2018;234(2):1300-12.
• Yaribeygi H, Noroozadeh A, Mohammadi MT, Johnston TP, Sahebkar A. Crocin improves oxidative stress by potentiating intrinsic anti-oxidant defense systems in pancreatic cells during uncontrolled hyperglycemia. J Pharmacopuncture. 2019;22(2):83-9.
• Oguntibeju OO. Type 2 diabetes mellitus, oxidative stress and inflammation: examining the links. Int J Physiol Pathophysiol Pharmacol. 2019;11(3):45-63.