Lawsonia inermis Linn., Streptozotosinle İndüklenmiş Diyabetik Wistar Ratların Çeşitli İnflamatuar Sitokinler ve Apoptotik Hücre Ölümü Biyobelirteçlerinin Ekspresyonunu Olumlu Bir Şekilde Artırır

Öz

Diabetes mellitus, küresel ölçekte hastalığa ve ölüme önemli ölçüde katkıda bulunan bir durumdur. İnterlökinler, beta hücrelerin apoptozunu tetikleyebilecek ve insülin salgısını azaltabilecek potansiyel faktörler olarak tanımlanmıştır, bu da diabetes mellitus ile ilişkilendirilen çeşitli komplikasyonlara neden olmaktadır. Bu çalışma, streptozotosin ile indüklenmiş diyabetik ratlarda inflamatuar sitokinler, interlökinler ve apoptotik hücre ölüm belirteçlerini incelemeyi amaçlamaktadır. Lawsonia inermis yaprakları n-hekzan, etil asetat ve metanol kullanılarak sırasıyla ekstrakte edildi. Altmış beş erişkin erkek Wistar ratı, her biri 5 rat içeren 13 gruba ayrıldı. Streptozotosin ile indüklenmiş diyabetik ratlar şu şekilde tedavi edildi: metformin (500 mg kg–1), glibenklamidin (5 mg kg–1) üçe bölünmüş ekstrelerin her birinden 25, 50 ve 100 mg kg–1 dozu ve tedavi edilmemiş diyabetik ve nondiyabetik ratlarda ise damıtılmış su 28 gün boyunca tedavide kullanıldı. Tedavi edilmemiş diyabetik sıçanlar, interlökin 1, interlökin 6, interlökin 12 ve tümör nekroz faktörü alfa (TNF-α) gibi sitokinlerde artış gösterdi. Metanol fraksiyonu, diğer tedavi grupları ve diyabetik kontrolle karşılaştırıldığında interlökin 1, interlökin 6, interlökin 12, interlökin 18 ve TNF-α’yı önemli ölçüde azalttı. Ekstrenin metanol fraksiyonu, 2 standart ilaç ve kontrol grupları ile karşılaştırıldığında tTNF-α’da önemli bir azalma gösterdi. Nükleer faktör-kappa beta, hem tedavi edilen hem de tedavi edilmemiş diyabetik sıçanlarda önemsiz bir şekilde arttı. Tüm ekstre tedavi gruplarında kaspaz- 3, kaspaz-6 ve kaspaz-9’un ekspresyonunda önemli bir azalma gözlendi. Ayrıca, diyabetik tedavi edilmemiş sıçanlarda B-hücre lenfoma 2 seviyesinde hafif bir artış olduğu gözlendi. Bu çalışma ile, Lawsonia inermis Linn.’nin, diabetes mellitus’un patofizyolojisi ve patogenezinde rol oynayan çeşitli sitokinler, interlökinler ve esansiyel kaspazlar üzerinde önemli bir olumlu düzenleyici etkiye 123sahip olduğu sonucuna varıldı.

Anahtar Kelimeler

• Lawsonia inermis Lin
• enflamasyon
• sitokinler
• interlökinler
• diyabet

Lawsonia inermis Linn. Positively Improves the Expression of Various Inflammatory Cytokines and Apoptotic Cell Death Biomarkers of Streptozotocin- Induced Diabetic Wistar Rats

Öz

Diabetes mellitus is a significant contributor to illness and death on a global scale. Interleukins have been identified as potential factors that can induce apoptosis of beta cells and diminish insulin secretion, resulting in various complications associated with diabetes mellitus. This study investigated the inflammatory cytokines, interleukins, and apoptotic cell death markers in streptozotocin-induced diabetic rats. Lawsonia inermis leaves were sequentially extracted usingn-hexane, ethyl acetate, and methanol. Sixty-five male adult Wistar rats were grouped into 13, with 5 rats in each group. Streptozotocin-induced diabetic rats were treated as thus; 25, 50, and 100 mg kg–1 of each of the 3 partitioned extracts, metformin (500 mg kg–1), glibenclamide (5 mg kg–1), and untreated diabetic and nondiabetic rats were treated with distilled water for 28 days. Untreated diabetic rats showed an increased level of cytokines such as interleukin 1, interleukin 6, interleukin 12, and tumor necrosis factor alpha (TNF-α). The methanol fraction significantly decreased interleukin 1, interleukin 6, interleukin 12, interleukin 18, and TNF-α compared to other treatment groups and diabetic control. Methanol fraction of the extract showed a significant reduction in tTNF-α when compared to the 2 standard drugs and the controls. Nuclear factor-kappa beta increased nonsignificantly in both treated and untreated diabetic rats. There was a significant reduction in the expression of caspase-3, caspase-6, and caspase-9 in all the extract-treated groups. It was further noted that there is a slight increase level of B-cell lymphoma 2 in diabetic untreated rats. The study concluded that Lawsonia inermis Linn. has a significant positive modulatory effect on the expression of various cytokines, interleukins, and essential caspases that are implicated in the pathophysiology and pathogenesis of diabetes mellitus.

Anahtar Kelimeler

• Lawsonia inermin Linn
• inflammation
• cytokines
• interleukins
• diabetes

Kaynakça

1. 1. Aremu A, Oridupa OA, Raufu IA, Ahmed OA. In vivo antihyperglycaemic activities of different solvent partitioned extract of Lawsonia inermis leaves in streptozotocin-induced diabetic rat model. Rom J Diab Nutri Meta Dis. 2022;29(3):323-334. http: //www .rjdn md.or g/ index.ph p/RJD NMD/a rticl e/vie w/114 3
2. 2. Jaganathan R, Ravindran R, Dhanasekaran S. Emerging role of adipocytokines in type 2 diabetes as mediators of insulin resistance and cardiovascular disease. Can J Diabetes. 2018;42(4):446-456.e1. [CrossRef]
3. 3. Yaribeygi H, Bo S, Ruscica M, Sahebkar A. Ceramides and diabetes mellitus: an update on the potential molecular relationships. Diabet Med. 2020;37(1):11-19. [CrossRef]
4. 4. Saeedi P, Halabian R, Imani Fooladi AA. A revealing review of mesenchymal stem cells therapy, clinical perspectives and Modification strategies. Stem Cell Investig. 2019;6(6:34):34. [CrossRef]
5. 5. Mielket K, Herdegen H. JNK and p38 stres skina ses-d egene rativ e effectors of signa l-tra nsduc tion- casca des in the nervous system. Prog Neurobiol. 2020;61(1):45-60. [CrossRef]
6. 6. Mohr S, Xi X, Tang J, Kern TS. Caspase activation in retinas of diabetic and galactosemic mice and diabetic patients. Diabetes. 2002;51(4): 1172-1179. [CrossRef]
7. 7. Muñoz-Pinedo C. Signaling pathways that regulate life and cell death: evolution of apoptosis in the context of self-defense. In: López-Larrea C., ed. Self and nonself. Advances in Experimental Medicine and Biology. Springer, New York, NY. 2012;738. [CrossRef]
8. 8. Nasoohi S, Ismael S, Ishrat T. Thior edoxi n-int eract ing protein (TXNIP) in cerebrovascular and neurodegenerative diseases: regulation and implication. Mol Neurobiol. 2018;55(10):7900-7920. [CrossRef]

9. 9. Lewis AM, Varghese S, Xu H, Alexander HR. Interleukin-1 and cancer progression: the emerging role of interleukin-1 receptor antagonist as a novel therapeutic agent in cancer treatment. J Transl Med. 2006;4:48. [CrossRef]
10. 10. Kenneth Y, Gursharan D, Neil B, et al. Prevalence of diabetes in hypertensive patients. Am J Hypertens. 2013;26:159-162. [CrossRef]
11. 11. Marzena D, Saule I, Ewa K, Anna W, Yergen K, Grzegorz D. Alpha-lipoic acid modifies circulating angiogenic factors in patients with type 2 diabetes mellitus. Diab Res Clin Pract. 2015;107(2):273-279 0168-8227. [CrossRef]
12. 12. Ryba-Stanisławowska M, Rybarczyk-Kapturska K, Myśliwiec M, Jolanta M. Elevated Levels of Serum IL-12 and IL-18 are associated with lower frequencies of CD4+CD25highFOXP3+ regulatory T cells in young patients with Type 1 diabetes. J Inflamm. 2014;37:1513-1520. [CrossRef]
13. 13. Feng B, Chen S, Gordon AD, Chakrabarti S. miR-146a mediates inflammatory changes and fibrosis in the heart in diabetes. J Mol Cell Cardiol. 2017;105(3):70-76. [CrossRef]
14. 14. Zhang Y, He Z, Liu X, et al. Oral administration of Angelica sinensis polysaccharide protects against pancreatic islets failure in type 2 diabetic mice: pancreatic β-cell apoptosis inhibition. J Funct Foods. 2019;54:361-370. [CrossRef]
15. 15. Liu C, Whitener RL, Lin A, et al. Neutrophil cytosolic Factor 1 in dendritic cells promotes autoreactive CD8+ T cell activation via cross-presentation in Type 1 diabetes. Front Immunol. 2019;10:952. [CrossRef]
16. 16. Song L, Wang Luyao, Hou Y, et al. FGF4 protects the liver from nonalcoholic fatty liver disease by activating the AMP-activated protein kinase–caspase 6 signal axis. Hepatology. 2022;76(4):1105-1120. [CrossRef]
17. 17. Araya LE, Soni IV, Hardy JA, Julien O. Deorphanizing caspase-3 and caspase-9 substrates in and out of apoptosis with deep substrate profiling. ACS Chem Biol. 2021;16(11):2280-2296. [CrossRef]
18. 18. Aremu A, Olayinka AO, Akorede GJ, et al. Safety evaluation of Lawsonia inermis on physiological, andrological and haematological parameters of male Wistar rats. J Basic Med Vet. 2021;11(2):75-89. https ://e- journ al.un air.a c.id/ JBMV
19. 19. Opal SM, DePalo VA. Anti-inflammatory cytokines. Chest. 2000;117(4): 1162-1172. [CrossRef]
20. 20. DeFronzo RA, Reeves WB, Awad AS. Pathophysiology of diabetic kidney disease: impact of SGLT2 inhibitors. Nat Rev Nephrol. 2021;17(5):319-334. [CrossRef]
21. 21. Esser N, Paquot N, Scheen AJ. Anti-inflammatory agents to treat or prevent type 2 diabetes, metabolic syndrome and cardiovascular disease. Expert Opin Investig Drugs. 2015;24(3):283-307. [CrossRef]
22. 22. Spranger J, Kroke A, Möhlig M, et al. Inflammatory cytokines and the risk to develop type II diabetes: results from prospective populationbased; European Prospective Investigation into Cancer and Nutrition (EPIC); Potsdam study. J Diab. 2003;52:812-817.
23. 23. Alexandraki K, Piperi C, Kalofoutis C, Singh J, Alaveras A, Kalofoutis A. Inflammatory process in type II diabetes. Role of cytokines. Annal. New York of sci. Acad J. 2006;1084:89-117.
24. 24. Rabinovitch A, Suarez-Pinzon WL, Sorensen O, Bleackley RC, Power RF. INF-gamma gene expression in pancreatic islet-infiltrating mononuclear cells correlates with autoimmune diabetes in NOD mice. J Immuno. 2005;154:4874-4882.
25. 25. He S, Zhao Y, Wang G, et al. Pancreatic beta cell dysfunction and activated macrophage infiltration are early features in type 1 diabetes pathogenesis. Mol Med. 2023;29(1):31. [CrossRef]
26. 26. Pfeilschifter J, Pignat W, Vosbeck K, Märki F. Interleukin 1 and tumor necrosis factor synergistically stimulate prostaglandin synthesis and phospholipase A2 release from rat renal mesangial cells. Biochem Biophys Res Commun. 1989;159(2):385-394. [CrossRef]
27. 27. Suzuki D, Miyazaki M, Naka R, et al. In situ hybridization of IL-6 in diabetes nephropathy. J Diab. 2009;44:1233-1238.
28. 28. Nakamura A, Kenichi K, Shikata K, et al. Serum interleukin-18 are associated with neuropathy and atherosclerosis in Japanese patients with type II diabetes. Diab Care. 2005;31:157-165.
29. 29. McGettrick AJ, Feener EP, Kahn CR. Human IRS-1 polymorphism, G972R, causes IRS-1 to associate with the insulin receptor and inhibit receptor autophosphorylation. J Biol Chem. 2005;280:6441-6446.
30. 30. Rothe H, Burkart V, Faust A, Kolb H. IL-12 gene expression is associated with rapid development of diabetes mellitus in non-obese diabetic mice. Diabetologia. 1996;39(1):119-122. [CrossRef]
31. 31. Stadelmann C, Lassmann H. Detection of apoptosis in tissue sections. Cell Tissue Res. 2000;301(1):19-31. [CrossRef]
32. 32. Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Oxidative stress and stress-activating signaling pathways; a unifying theory of type II form of diabetes. Endocr Rev. 2002;23(5):599-622. [CrossRef]
33. 33. Ho FM, Liu SH, Liau CS, Huang PJ, Lin-Shiau SY. Hyperglycemic induced apoptosis in endothelial cells of human which is mediated by through sequential activations of JKN (C-J-NH 2-terminal kinase) and caspase-3 circulation. Diab Care. 2000;101:2618-2624. [CrossRef]
34. 34. Li L, Wang Faxuan, Zhang J, et al. Typical phthalic acid esters induce apoptosis by regulating the PI3K/Akt/Bcl-2 signaling pathway in rat insulinoma cells. Ecotoxicol Environ Saf. 2021;208(0147-6513):111461. [CrossRef]
35. 35. Baloğlu M, Deveci E. Bcl-2 expression in skeletal muscle in diabetic rats. Inter J Sci Res. 2018;7064:2319.