Streptozotosin-Nikotinamid ile Oluşturulmuş Tip 2 Diyabetik Sıçanlarda Quercus ithaburensis subsp. macrolepis Meyve Ekstraktının Terapötik Potansiyeli

Abstract

Bu çalışmada; Quercus ithaburensis subsp. macrolepis meyve ekstraktının streptozotosin (STZ)-nikotinamid ile oluşturulan tip 2 diyabetli sıçanlarda kan glikozu ve oksidan-antioksidan sistemler üzerindeki etkisi araştırıldı. Sıçanlarda tip 2 diyabet, STZ (65 mg/kg)-nikotinamidin (45 mg/kg) intraperitoneal enjeksiyonuyla oluşturuldu. Sıçanlara 21 gün boyunca içme sularına 535mg/kg Q. ithaburensis meyve ekstraktı verildi. Sıçanlar dört gruba ayrıldı; Kontrol (K), Kontrol+Q. ithaburensis meyve ekstraktı (K+QIFE), Diyabet (D), Diyabet+Q.ithaburensis meyve ekstraktı (D+QIFE). Plazma ve doku malondialdehit (MDA) düzeyleri spektrofotometre ile ölçüldü. Tam kan glutatyon peroksidaz (GSH-Px), serum süperoksit dismutaz (SOD) enzim düzeyleri, serum paraoksonaz (PON) ve arilesteraz (ARE) enzim aktiviteleri ticari kitlerde belirlendi. Serum insülin düzeyleri ve kan glikozu sırasıyla bir Rat ELISA Kiti ve glukometre ile değerlendirildi. Ayrıca, lipid profilini değerlendirmek için otoanalizör kullanıldı. Kan şekeri ve serum total kolesterol (TK) düzeyleri K+QIFE ve D+ QIFE gruplarında (sırasıyla K ve D grupları) istatistiksel olarak anlamlı bir azalma gösterirken, serum insülin düzeyleri D+QIFE grubunda D grubuna kıyasla istatistiksel olarak anlamlı bir artış gösterdi. D+QIFE grubunda PON ve ARE enzim aktivitelerinde D grubuna kıyasla istatistiksel olarak anlamlı bir artış gözlendi, ancak K+QFE grubunda tam kan GSH-Px ve serum SOD düzeylerinde K grubuna kıyasla anlamlı bir artış bulundu. D+QIFE grubunda K grubuna kıyasla plazma, kalp, kas ve karaciğer doku MDA düzeylerinde istatistiksel olarak anlamlı bir azalma tespit edildi. Sonuç olarak, Q. ithaburensis meyve ekstraktının antihiperglisemik, antihiperlipidemik etkiye sahip olduğu, antioksidan sistemi güçlendirdiği, diyabete bağlı metabolik süreçleri ve buna bağlı komplikasyonları önleyen/iyileştiren iyi bir fitoterapötik ajan olduğu sonucuna varıldı.

Keywords

• Antioksidan
• lipid peroksidasyonu
• fitoterapötik ajan
• oksidatif stres

Supporting Institution

Bursa Uludağ Üniversitesi

Ethical Statement

Hayvan kullanımını içeren tüm deneysel prosedürler için Bursa Uludağ Üniversitesi Hayvan Deneyleri Yerel Etik Kurul Komisyonu izni (Etik onay numarası: 2018-04/11) sonrasında gerçekleştirilmiş ve tüm prosedürlere uyulmuştur.

Thanks

Bu çalışma, birinci yazarın yüksek Lisans tezinden (Bursa Uludağ Üniversitesi, Fen Bilimleri Enstitüsü, 2018) hazırlanmıştır.

Therapeutic Potential of Quercus İthaburensis Subsp. Macrolepis Fruit Extract in Stz-nicotinamide-induced Type 2 Diabetic Rats

Abstract

In this study; the effect of Quercus ithaburensis subsp. macrolepis fruit extract (QIFE) on blood glucose and oxidant-antioxidant systems in streptozotocin (STZ)-nicotinamide-induced type 2 diabetic rats was investigated. Type 2 diabetes was induced in rats by intraperitoneal injection of STZ (65mg/kg)-Nicotinamide (45 mg/kg). Rats were given 535mg/kg QIFE fruit extract in their drinking water for 21 days. Rats were divided into four groups; Control (C), Control+QIFE (C+QIFE), Diabetes (D), and Diabetes+QIFE (D+QIFE). Plasma and tissue malondialdehyde (MDA) levels were measured by spectrophotometry. Whole blood glutathione peroxidase (GSH-Px), serum superoxide dismutase (SOD) enzyme levels, serum paraoxonase (PON), and arylesterase (ARE) enzyme activities were determined using commercial kits. Serum insulin levels and blood glucose were evaluated using a Rat ELISA Kit and glucometer, respectively. Also, the autoanalyzer was used to assess the lipid profile. While blood sugar and serum total cholesterol (TC) levels showed a statistically significant decrease in the C+ QIFE and D+ QIFE groups (C and D groups, respectively), serum insulin levels showed a statistically significant increase in the D+QIFE group compared to the D group. In the D+QIFE group, a statistically significant increase was observed in PON and ARE enzyme activities compared to the D group, but in the C+QFE group, a significant increase was found in whole blood GSH-Px and serum SOD levels compared to the C group. A statistically significant decrease was detected in plasma, heart, muscle, and liver tissue MDA levels in the D+QIFE group compared to the C group. As a result, it was concluded that Q. ithaburensis fruit extract has anti-hyperglycemic, anti-hyperlipidemic effects, strengthens the antioxidant system, and is a good phytotherapeutic agent that prevents/improves metabolic processes and related complications related to diabetes mellitus.

Keywords

• Phytotherapeutic agents
• oxidative stress
• antioxidant
• lipid peroxidation

Supporting Institution

Bursa Uludag University

Ethical Statement

All experimental procedures involving animal use adhered to approved ethical policies and procedures. (Bursa Uludag University, Ethics approval number: 2018-04/11).

Thanks

This study covers the Master thesis of the first author (2018). (Bursa Uludag University Graduate School of Natural and Applied Science).

References

1. Abbott, C.A., Mackness, M.I., Kumar, S., Boulton, A. J., & Durrington, P.N. (1995). Serum paraoxonase activity, concentration, and phenotype distribution in diabetes mellitus and its relationship to serum lipids and lipoproteins. Arteriosclerosis, Thrombosis, and Vascular Biology, 15(11), 1812–1818. https://doi.org/10.1161/01.ATV.15.11.1812
2. Ahmed, S.I., Hayat, M.Q., Tahir, M., Mansoor, Q., Ismail, M., Keck, K., & Bates, R.B. (2016). Pharmacologically active flavonoids from the anticancer, antioxidant and antimicrobial extracts of Cassia Angustifolia Vahl. BMC Complementary. Alternative Medicine, 16, 460. https://doi.org/10.1186/s12906-016-1443-z
3. Ana, F.V., João, C.M.B., Anabela, S.G., Costa., & M Beatriz P.P. Oliveira (2016). A new age for Quercus spp. fruits: Review on nutritional and phytochemical composition and related biological activities of acorns. Comprehensive Reviews in Food Science and Food Safety, 15(6). https://doi.org/10.1111/1541-4337.12220
4. Anastasia, W.I., Sanro, T., Rizna, T.D., & Kazutaka, I. (2015). Antioxidant and α-glucosidase inhibitor activities of natural compounds isolated from Quercus gilva Blume leaves. Asian Pacific Journal of Tropical Biomedicine, 5(9), 748-755. https://doi.org/10.1016/j.apjtb.2015.07.004
5. Arora, S.K., Verma, P.R., Itankar, P. R., Prasad, S.K., & Nakhate, K.T. (2021). Evaluation of pancreatic regeneration activity of Tephrosia purpurea leaves in rats with streptozotocin-induced diabetes. Journal of Traditional and Complementary Medicine, 11, 435–445. https://doi.org/10.1016/j.jtcme.2020.05.008
6. Attanayake, A.P., Jayatilaka, K.A.P.W., & Pathirana, L.K.B. M. (2019). β-cell regenerative potential of selected herbal extracts in alloxan-induced diabetic rats. Current Drug Discovery Technologies, 16(3), 278–284. https://doi.org/10.2174/1570163815666180418153024
7. Bassalat, N., Taş, S., & Jaradat, N. (2020). Teucrium leucocladum: An effective tool for the treatment of hyperglycemia, hyperlipidemia, and oxidative stress in streptozotocin-induced diabetic rats. Evidence-Based Complementary and Alternative Medicine, 1–8. https://doi.org/10.1155/2020/1234567
8. Bhandari, M.R., Jong- Anurakkun N., Hong, G., & Kawabata, J. (2008). α-Glucosidase and α-amylase inhibitory activities of Nepalese medicinal herb Pakhanbhed (Bergenia ciliata, Haw.). Food Chemistry, 106(1), 247-252. https://doi.org/10.1016/j.foodchem.2007.05.077

9. Chatuphonprasert, W., Lao-Ong, T., & Jarukamjorn, K. (2013). Improvement of superoxide dismutase and catalase in streptozotocin-nicotinamide-induced type 2-diabetes in mice by berberine and glibenclamide. Pharmacology and Biology, 51(11), 1427–1433. https://doi.org/10.3109/13880209.2013.839714
10. de Gaetano, M., McEvoy, C., Andrews, D., Cacace, A., Hunter J., Brennan, E., & Godson, C. (2018). Specialized Pro-resolving Lipid Mediators: Modulation of Diabetes-Associated Cardio-,Reno-, and Retino-Vascular Complications. Frontiers in pharmacology, 9, 1488. https://doi.org/10.3389/fphar.2018.01488
11. Dogan, A., Celik, I., & Kaya, M.S. (2015). Antidiabetic properties of lyophilized extract of acorn (Quercus brantii Lindl.) on experimentally STZ-induced diabetic rats. Journal of Ethnopharmacology, 176, 243–251. https://doi.org/10.1016/j.jep.2015.01.031
12. Ema, B., Adrian, N., & Corneliu, T. (2020). A comprehensive review of phytochemistry and biological activities of Quercus species. Review. Forests, 11, 1-24. https://doi.org/10.3390/f11090904
13. Etxeberria, U., De La Garza, A.L., Campión, J., Martínez, J.A., & Milagro, F.I. (2012). Antidiabetic effects of natural plant extracts via inhibition of carbohydrate hydrolysis enzymes with emphasis on pancreatic alpha amylase. Expert Opinion on Therapeutic Targets, 16(3), 269–297. https://doi.org/10.1517/14728222.2012.669370
14. Eugene, H., Suk-Yong, J., Gyuri, K., Yong-Ho, L., Eun Yeong, C., Chung Mo, N., & Eun Seok, K. (2016). Rosiglitazone Use and the risk of bladder cancer in patients with type 2 diabetes. Medicine (Baltimore), 95(6), e2786. https://doi.org/10.1097/MD.0000000000002786
15. Faten, M., Boutheina, S., Sondes, F., Faten, A., Lassaad Ben, S., Riadh, Ksouric., & Khaldi A. (2022). Phenolic profile and in vitro anti-diabetic activity of acorn from four African Quercus species (Q. suber, Q. canariensis, Q. coccifera and Q. ilex). South African Journal of Botany, 146, 771-775. https://doi.org/10.1016/j.sajb.2021.12.023
16. Gezici, S., & Sekeroglu, N. (2019). Neuroprotective potential and phytochemical composition of acorn fruits. Industrial Crops and Products, 128, 13–17. https://doi.org/10.1016/j.indcrop.2018.10.039
17. Ghasemi, A., Khalifi, S., & Jedi, S. (2014). Streptozotocin-nicotinamide-induced rat model of type 2 diabetes (Review). Acta Physiologica Hungarica, 101(4), 408–420. https://doi.org/10.1556/APhysiol.101.2014.4.2
18. Gök, H.N., Deliorman Orhan, D., Gürbüz, İ., & Aslan, M. (2020). Activity-guided isolation of α-amylase, α-glucosidase, and pancreatic lipase inhibitory compounds from Rhus coriaria L. Journal of Food Science, 85(10), 3220–3228. https://doi.org/10.1111/1750-3841.15438
19. Huang, J., Wang, Y., Li, C., Wang, X., & He, X. (2016). Triterpenes isolated from acorns of Quercus serrata var. Brevipetiolata exert anti-inflammatory activity. Industrial Crops and Products, 91, 302–309. https://doi.org/10.1016/j.indcrop.2016.05.013
20. Hussain, S., Jan, F.G., Jan, G., Irfan, M., Musa, M., Rahman, S., …… & Ali, S. (2024). Evaluation of the Hypoglycemic and Hypolipidemic Potential of Extract Fraction of Quercus baloot Griff Seeds in Alloxan-induced Diabetic Mice Current Pharmaceutical Design, 30, 2978-2991. https://doi.org/10.2174/0113816128319184240827070016
21. Jeremiah, O.U., & Sogolo, L.L. (2020). Antioxidant effects and mechanisms of medicinal plants and their bioactive compounds for the prevention and treatment of type 2 diabetes: An updated review. Oxidative Medicine and Cellular Longevity, 3, 2020. https://doi.org/10.1155/2020/1356893
22. Jianwei, Z., Shan, Z., Peipei, Y., Linlin, Y., Jin, H., Lingling, S., Xiaojing, Z., Yujun, L., & Chao, M. (2014). α-Glucosidase inhibitory activity of polyphenols from the burs of Castanea mollissima Blume. Molecules, 19, 8373-8386. https://doi.org/10.3390/molecules19068373
23. Katsiki, N., Banach, M., & Mikhailidis, D.P. (2019). Is type 2 diabetes mellitus a coronary heart disease equivalent or not? Do not just enjoy the debate and forget the patient! Archives of Medical Science, 15(6), 1357–1364. https://doi.org/10.5114/aoms.2019.89618
24. Kotur-Stevuljević, J., Vekić, J., Stefanović, A., Zeljković, A., Ninić, A., Ivanišević, J., ... & Spasojević-Kalimanovska, V. (2020). Paraoxonase 1 and atherosclerosis-related diseases. Biofactors, 46(2), 193–205. https://doi.org/10.1002/biof.1549
25. Lin, Y., Lu, Y., Song, Z., & Huang, D. (2018). Characterizations of the endogenous starch hydrolase inhibitors in acorns of Quercus fabri. Food Chemistry, 258, 111–117. https://doi.org/10.1016/j.foodchem.2018.03.136
26. Makhlouf, F.Z., Squeo, G., Barkat, M., Pasqualone, A., & Caponio, F. (2019). Comparative study of total phenolic content and antioxidant properties of Quercus fruit: Flour and oil. The North African Journal of Food and Nutrition Research, 3(5), 148–155. https://doi.org/10.51745/najfnr.3.5.148-155
27. Masiello, P., Broca, C., Gross, R., Roye, M., Manteghetti, M., Hillaire, B.D., …. & Ribes, G. (1998). Experimental NIDDM: Development of a new model in adult rats administered streptozotocin and nicotinamide. Diabetes, 47(2), 224–229. https://doi.org/10.2337/diab.47.2.224
28. Matacchione, G., Gurău, F., Baldoni, S., Prattichizzo, F., Silvestrini, A., Giuliani, A., … & Sabbatinelli, J. (2020). Pleiotropic effects of polyphenols on glucose and lipid metabolism: Focus on clinical trials. Ageing Research Reviews, 61, 101074. https://doi.org/10.1016/j.arr.2020.101074
29. Matsuda, H., Wang, T., Managi, H., & Yoshikawa, M. (2003). Structural requirements of flavonoids for inhibition of protein glycation and radical scavenging activities. Bioorganic & Medicinal Chemistry, 11, 5317–5323. http://doi.org/10.1016/j.bmc.2003.09.045
30. Mirza, B., Željan, M., Andrea, A., Ivana, B., & Maja, T. (2019). Antithrombotic activity of flavonoids and polyphenol-rich plant species. Acta Pharmaceutica, 69, 483-495. https://doi.org/10.2478/acph-2019-0050
31. Mithun, R.S.J., Khairnar, J.K., Abdulaziz, B.D., Mohammad, A.A, Mohammad, N.A., Fahad, M.A., … & Rajlakshmi, D. (2022). Dietary Polyphenols and Their Role in Oxidative Stress-Induced Human Diseases: Insights Into Protective Effects. Antioxidant Potentials and Mechanism(s) of Action. Frontiers in Pharmacology, 13, https://doi.org/10.3389/fphar.2022.806470
32. Neumann, A., Weill, A., Ricordeau, P., Fagot, J. P., All, F., & Allemand, H. (2012). Pioglitazone and risk of bladder cancer among diabetic patients in France: A population-based cohort study. Diabetologia, 55(7), 1953–1962. https://doi.org/10.1007/s00125-012-2538-9
33. Ngan, T., Bao, P., & Ly, L. (2020). Bioactive compounds in anti-diabetic plants: From herbal medicine to modern drug discovery. Biology, 9(9), 252. https://doi.org/10.3390/biology9090252
34. Nissen, S. E., & Wolski, K. (2007). Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. The New England Journal of Medicine, 356(24), 2457–2471. https://doi.org/10.1056/NEJMoa072761
35. Ohkawa, H., Ohishi, N., & Yagi, K. (1979). Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Analytical Biochemistry, 95(2), 351–358. https://doi.org/10.1016/0003-2697(79)90738-3
36. Özcan, T. (2007). Characterization of Turkish Quercus L. taxa based on fatty acid compositions of the acorns. Journal of the American Oil Chemists' Society, 84(7), 653–662. https://doi.org/10.1007/s11746-007-1087-8
37. Özcan, T., & Baycu, G. (2005). Some elemental concentrations in the acorns of Turkish Quercus L. (Fagaceae) taxa. Pakistan Journal of Botany, 37(2), 361–371.
38. Özcan, T. (2006). Total protein and amino acid compositions in the acorns of Turkish Quercus L. taxa. Genetic Resources and Crop Evolution, 53(3), 419–429. https://doi.org/10.1007/s10722-004-1337-7
39. Saini, R., & PatilI, S.M. (2012). Anti-Diabetic Activity of Roots of Quercus Infectoria Olivier in Alloxan Induced Diabetic Rats. International Journal Of Pharmaceutical Sciences And Research, 3(4),1318-1321 ISSN: 0975-8232
40. Pisoschi, A. M., & Pop, A. (2015). The role of antioxidants in the chemistry of oxidative stress: A review. European Journal of Medicinal Chemistry, 97, 55–74. https://doi.org/10.1016/j.ejmech.2015.04.040
41. Rakic, S., Povrenovic, D., Tešević, V., Simić, M., & Maletić, R. (2006). Oak acorn, polyphenols and antioxidant activity in functional food. Journal of Food Engineering, 74(3), 416–423. https://doi.org/10.1016/j.jfoodeng.2005.03.057
42. Ralph, A. D. F., Ele, F., Leif, G., Robert, R. H., William, H. H., Jens, J., … Ram, W. (2015). Type 2 diabetes mellitus. Nature Reviews Disease Primers, 1, 15019. https://doi.org/10.1038/nrdp.2015.19
43. Ramesh, C.G., Dennis, C., Srinivas, N., Alan, B., Kellie, B., & Basil, D.R. (2017). Interactions between antidiabetic drugs and herbs: an overview of mechanisms of action and clinical implications. Diabetology & Metabolic Syndrome, 9(59). https://doi.org/10.1186/s13098-017-0254-9
44. Saini, R., & PatilI, S.M. (2012). Anti-Diabetic Activity of Roots of Quercus Infectoria Olivier in Alloxan Induced Diabetic Rats. International Journal Of Pharmaceutical Sciences And Research, 3(4),1318-1321. ISSN: 0975-8232.
45. Sarandol, E., Taş, S., Serdar, Z., & Dirican, M. (2020). Effects of thiamine treatment on oxidative stress in experimental diabetes. Bratislava Medical Journal, 121(3), 235–241. https://doi.org/10.4149/BLL_2020_036
46. Sen, S., Chakraborty R., Sridhar C., Reddy Y.S.R., & De B. (2010). Free radicals, antioxidants, diseases and phytomedicines: Current status and future prospect. International Journal of Pharmaceutical Sciences Review and Research, 3(1), 91-100. ISSN 0976 – 044X
47. Sheweita, S.A., Mashaly, S., Newairy, A.A., Abdou, H.M., & Eweda, S.M. (2016). Changes in oxidative stress and antioxidant enzyme activities in streptozotocin-induced diabetes mellitus in rats: Role of Alhagi maurorum extracts. Oxidative Medicine and Cellular Longevity, 2016, 5264064. https://doi.org/10.1155/2016/5264064
48. Shiyi, T., Lintong, Yu., Jun, L., Li, H., Tiantian, X., Deshuang, Y.,…… & Chao M. (2024). Multiple triglyceride-derived metabolic indices and incident cardiovascular outcomes in patients with type 2 diabetes and coronary heart disease. Cardiovascular Diabetology, 23, 359. https://doi.org/10.1186/s12933-024-02446-1
49. Shweta, P., Aleena M., Hinal, C., Shiv, K., & Rahul, M. (2021). Classifications of polyphenols and their potential application in human health and diseases. International Journal of Physiology, Nutrition and Physical Education, 6(1), 293-301. https://doi.org/10.22271/journalofsport.2021.v6.i1e.2236
50. Soran, H., Schofield, J.D., & Durrington, P.N. (2015). Antioxidant properties of HDL. Frontiers in Pharmacology, 6, 222. https://doi.org/10.3389/fphar.2015.00222
51. Sugiyama, H., Akazome, Y., Shoji, T., Yamaguchi, A., Yasue, M., Kanda, T., & Ohtake, Y. (2007). Oligomeric procyanidins in apple polyphenol are main active components for inhibition of pancreatic lipase and triglyceride absorption. Journal of Agricultural and Food Chemistry, 55(11), 4604–4609. https://doi.org/10.1021/jf070569k
52. Sun, C., Wang, L., Sun, J., Wang, Z., & Tang, Z. (2020). Hypoglycemic and hypolipidemic effects of rutin on hyperglycemic rats. Journal of Traditional Chinese Medicine, 40(4), 640–645. https://doi.org/10.19852/j.cnki.jtcm.2020.04.012
53. Sun, T., Hu, J., Yin, Z., Xu, Z., Zhang, L., Fa, L., & Li, Y. (2017). Low serum paraoxonase1 activity levels predict coronary artery disease severity. Oncotarget, 8(12), 19443–19456. https://doi.org/10.18632/oncotarget.15525
54. Surapon, T. (2015). Oxidative stress, insulin resistance, dyslipidemia, and type 2 diabetes mellitus. World Journal of Diabetes, 6(3), 456–480. https://doi.org/10.4239/wjd.v6.i3.456
55. Szkudelski, T. (2012). Streptozotocin–nicotinamide-induced diabetes in the rat: Characteristics of the experimental model. Experimental Biology and Medicine, 237(5), 481–490. https://doi.org/10.1258/ebm.2012.011372
56. Taib, M., Rezzak, Y., Bouyazza, L., & Lyoussi, B. (2020). Medicinal uses, phytochemistry, and pharmacological activities of Quercus species. Evidence-Based Complementary and Alternative Medicine, https://doi.org/10.1155/2020/1920683
57. Tarique, H., Bie, T., Ghulam, M., Gang, L., Najma, R., Muhammad, S.K., ….& Yulong, Y. (2020). Flavonoids and type 2 diabetes: Evidence of efficacy in clinical and animal studies and delivery strategies to enhance their therapeutic efficacy. Pharmacological Research, 152, 104629. https://doi.org/10.1016/j.phrs.2020.104629
58. Taş, S., Sarandöl, E., & Dirican, M. (2014). Vitamin B6 supplementation improves oxidative stress and enhances serum paraoxonase/arylesterase activities in streptozotocin-induced diabetic rats. Scientific World Journal, 2014, 351598. http://doi.org/10.1155/2014/351598
59. Taş, S., Taş, B., Bassalat, N., & Jaradat, N. (2018). In-vivo, hypoglycemic, hypolipidemic and oxidative stress inhibitory activities of Myrtus communis L. fruits hydroalcoholic extract in normoglycemic and streptozotocin-induced diabetic rats. Biomedical Research, 29, 2727–2734. http://doi.org/10.4066/biomedicalresearch.29-18-708
60. Taş, S., Sarandöl, E., Tekin, C.N., Tosunoğlu, A., Vatan, Ö., Hürriyet, H., … & Dirican, M. (2022). Monofloral Brassica nigra pollen improves oxidative stress and metabolic parameters in streptozotocin-induced diabetic rats. Journal of Applied Biological Sciences, 16(3), 563–574. https://doi.org/10.5281/zenodo.7114334
61. Taş, S; Tosunoğlu, A; Dirican, m., Tekin, C. N., & Sarandöl, E. (2024). Ameliorative effects of monofloral Cistus creticus bee pollen on the oxidant-antioxidant systems in streptozotocin-i̇nduced diabetic rats. Palestinian Medical and Pharmaceutical Journal, 9(3), 337-346. https://doi.org/10.59049/2790-0231.1215
62. Tsikas, D. (2017). Assessment of lipid peroxidation by measuring malondialdehyde (MDA) and relatives in biological samples: Analytical and biological challenges. Analytical Biochemistry, 524, 13–30. https://doi.org/10.1016/j.ab.2016.10.021
63. Vinayagam, R., & Xu, B. (2015). Antidiabetic properties of dietary flavonoids: A cellular mechanism. Nutrition & Metabolism, 12, 60. https://doi.org/10.1186/s12986-015-0042-5
64. Vinha, A., Barreira, J., Ferreira, I., & Oliveira, M. (2019). Therapeutic, phytochemistry, and pharmacology of acorns (Quercus nuts): A review. In Bioactive Compounds in Underutilized Fruits and Nuts, pp. 1–15.
65. Wereski, R., Kimenai, D.M., Bularga, A., Taggart, C., Lowe, D.J., Mills, N.L., & Chapman, A. R. (2022). Risk factors for type 1 and type 2 myocardial infarction. European Heart Journal, 43(2), 127–135. https://doi.org/10.1093/eurheartj/ehab581
66. Yin, P., Wang, Y., Yang, L., Sui, J., & Liu, Y. (2018). Hypoglycemic effects in alloxan-induced diabetic rats of the phenolic extract from Mongolian oak cups enriched in ellagic acid, kaempferol and their derivatives. Molecules, 23(5), 1046. https://doi.org/10.3390/molecules23051046
67. Young, I., & Trimble, E. (1991). Measurement of malondialdehyde in plasma by high performance liquid chromatography with fluorimetric detection. Annals of Clinical Biochemistry, 57(3), 318–325. https://doi.org/10.1177/0004563220911639
68. Zanza, C., Thangathurai J., Audo, A., Muir, H.A., Candelli, M., Pignataro, G., Thangathurai D., Cicchinelli, S., & Franceschi, F. (2019). Oxidative stress in critical care and vitamins supplement therapy: "a beneficial care enhancing" European Review for Medical and Pharmacological Sciences, 23(17), 7703-7712. https://doi.org/10.26355/eurrev_201909_18894
69. Zehra, B., Ahmed, A., Sarwar, R., Khan, A., Farooq, U., Ali, S.A., & Al-Harrasi, A. (2019). Apoptotic and antimetastatic activities of betulin isolated from Quercus incana against non-small cell lung cancer cells. Cancer Management and Research, 11, 1667–1683. https://doi.org/10.2147/CMAR.S186956