اخبار و اعلانات

 آمار

تعداد نشریات282
تعداد نشریات سازمان80
تعداد شماره‌ها3,251
تعداد مقالات35,918
تعداد مشاهده مقاله54,598,911
تعداد دریافت فایل اصل مقاله93,705,199
Alinejad Kasbakhi, Nasim, Vavrinec, Mgr. Peter. (1404). Benzylguanine Induces Cellular Senescence and Decreases Relaxation of Vascular Smooth Muscle in the Rat Aorta. سامانه مدیریت نشریات علمی, 80(6), 1581-1590. doi: 10.66224/ARI.80.6.3322
Nasim Alinejad Kasbakhi; Mgr. Peter Vavrinec. "Benzylguanine Induces Cellular Senescence and Decreases Relaxation of Vascular Smooth Muscle in the Rat Aorta". سامانه مدیریت نشریات علمی, 80, 6, 1404, 1581-1590. doi: 10.66224/ARI.80.6.3322
Alinejad Kasbakhi, Nasim, Vavrinec, Mgr. Peter. (1404). 'Benzylguanine Induces Cellular Senescence and Decreases Relaxation of Vascular Smooth Muscle in the Rat Aorta', سامانه مدیریت نشریات علمی, 80(6), pp. 1581-1590. doi: 10.66224/ARI.80.6.3322
Alinejad Kasbakhi, Nasim, Vavrinec, Mgr. Peter. Benzylguanine Induces Cellular Senescence and Decreases Relaxation of Vascular Smooth Muscle in the Rat Aorta. سامانه مدیریت نشریات علمی, 1404; 80(6): 1581-1590. doi: 10.66224/ARI.80.6.3322

Benzylguanine Induces Cellular Senescence and Decreases Relaxation of Vascular Smooth Muscle in the Rat Aorta

Archives of Razi Institute
مقاله 24، دوره 80، شماره 6، بهمن و اسفند 2025، صفحه 1581-1590    اصل مقاله (1.12 M)
نوع مقاله: Original Articles
شناسه دیجیتال (DOI): 10.66224/ARI.80.6.3322
نویسندگان
Nasim Alinejad Kasbakhi* ؛ Mgr. Peter Vavrinec
Department of Pharmacology and Toxicology, Faculty Of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia
چکیده
Introduction: Cellular senescence (CS) is defined as a condition of permanent cessation of growth, accompanied by distinct morphological and physiological alterations. This phenomenon is closely associated with DNA damage. Recently, our department identified that inhibition of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) by O-6-benzylguanine (O6-BG) induces CS in vascular smooth muscle cells (VSMCs). Consequently, we have resolved to validate these findings in an animal model. The objective of this study was to examine the impact of O6-BG on CS in vascular smooth muscle and to assess its influence on the relaxation response. 
Materials & Methods: Wistar rats were administered O6-BG by gavage with a dose of 12 mg/kg (two doses every 24 hours). After 12 weeks, animals were sacrificed, the aorta was removed and cleaned, and samples were prepared for Western blotting. Small aortic rings were the isolated for vascular response measurement. 
Results: Senescent markers p27Kip1 and p21 Cipl were significantly upregulated after O6-BG treatment, which confirms that MGMT inhibition leads to CS. We did not observe any statistically significant changes in the relative expression of the proteins p53 or ERK1/2. This means that the expression of cyclin-dependent kinase inhibitors is regulated independently of the cell cycle regulator p53 and the ERK1/2 branch of the MAPK signaling pathway. Furthermore, we observed significantly decreased relaxation response of aortic smooth muscle to sodium nitroprusside (SNP), which confirms known adverse effects of CS on the vascular system. 
Conclusion: To conclude, we found that treatment with O6-BG triggered an increase in the relative expression of p27, p21, and PCNA compared to healthy aortic tissues, acting as mediators and markers of senescence. Our findings provide new insights into the signaling of CS in a model of MGMT inhibition.
کلیدواژه‌ها
Aortic smooth muscle؛ Benzylguanine؛ Cellular senescence (CS)؛ Stress
سایر فایل های مرتبط با مقاله
مراجع

References

  1. Muthamil S, Kim HY, Jang HJ, Lyu JH, Shin UC, Go Y, et al. Biomarkers of cellular senescence and aging: current state‐of‐the‐art, challenges and future perspectives. Adv Biol (Weinh). 2024; 8(9):e2400079. [DOI:10.1002/adbi.202400079] [PMID]
  2. Guan L, Eisenmenger A, Crasta KC, Sandalova E, Maier AB. Therapeutic effect of dietary ingredients on cellular senescence in animals and humans: A systematic review. Ageing Res Rev. 2024; 95:102238. [DOI:10.1016/j.arr.2024.102238] [PMID]
  3. Zhang L, Pitcher LE, Yousefzadeh MJ, Niedernhofer LJ, Robbins PD, Zhu Y. Cellular senescence: A key therapeutic target in aging and diseases. J Clin Invest. 2022; 132(15):e158450. [DOI:10.1172/JCI158450] [PMID]
  4. Zhang L, Pitcher LE, Prahalad V, Niedernhofer LJ, Robbins PD. Targeting cellular senescence with senotherapeutics: Senolytics and senomorphics. FEBS J. 2023; 290(5):1362-83. [DOI:10.1111/febs.16350] [PMID]
  5. Kumari R, Jat P. Mechanisms of cellular senescence: Cell cycle arrest and senescence associated secretory phenotype. Front Cell Dev Biol. 2021; 9:645593. [DOI:10.3389/fcell.2021.645593] [PMID]
  6. Herranz N, Gil J. Mechanisms and functions of cellular senescence. J Clin Invest. 2018; 128(4):1238-46. [DOI:10.1172/JCI95148] [PMID]
  7. Wang B, Han J, Elisseeff JH, Demaria M. The senescence-associated secretory phenotype and its physiological and pathological implications. Nat Rev Mol Cell Biol. 2024; 25(12):958-78. [DOI:10.1038/s41580-024-00727-x] [PMID]
  8. Zou J, Lei T, Guo P, Yu J, Xu Q, Luo Y, et al. Mechanisms shaping the role of ERK1/2 in cellular senescence (Review). Mol Med Rep. 2019; 19(2):759-70. [DOI:10.3892/mmr.2018.9712]
  9. Sabharwal A, Middleton MR. Exploiting the role of O6-methylguanine-DNA-methyltransferase (MGMT) in cancer therapy. Curr Opin Pharmacol. 2006; 6(4):355-63. [DOI:10.1016/j.coph.2006.03.011] [PMID]
  10. Friedman HS, Keir S, Pegg AE, Houghton PJ, Colvin OM, Moschel RC, et al. O6-benzylguanine-mediated enhancement of chemotherapy. Mol Cancer Ther. 2002; 1(11):943-8. [PMID]
  11. Li HF, Wang LD, Qu SY. Phytoestrogen genistein decreases contractile response of aortic artery in vitro and arterial blood pressure in vivo. Acta Pharmacol Sin. 2004; 25(3):313-8. [PMID]
  12. Konduri SD, Ticku J, Bobustuc GC, Sutphin RM, Colon J, Isley B, et al. Blockade of MGMT expression by O6 benzyl guanine leads to inhibition of pancreatic cancer growth and induction of apoptosis. Clin Cancer Res. 2009; 15(19):6087-95. [DOI:10.1158/1078-0432.CCR-09-0887] [PMID]
  13. Imawari Y, Nakanishi M. Senescence and senolysis in cancer: The latest findings. Cancer Sci. 2024; 115(7):2107-16. [DOI:10.1111/cas.16184] [PMID]
  14. Broustas CG, Lieberman HB. DNA damage response genes and the development of cancer metastasis. Radiat Res. 2014; 181(2):111-30. [DOI:10.1667/RR13515.1] [PMID]
  15. El-Deiry WS. p21(WAF1) Mediates Cell-Cycle Inhibition, Relevant to Cancer Suppression and Therapy. Cancer Res. 2016; 76(18):5189-91. [DOI:10.1158/0008-5472.CAN-16-2055] [PMID]
  16. Wang H, Guo M, Wei H, Chen Y. Targeting p53 pathways: Mechanisms, structures, and advances in therapy. Signal Transduct Target Ther. 2023; 8(1):92. [DOI:10.1038/s41392-023-01347-1] [PMID]
  17. Kim J, Wong PK. Loss of ATM impairs proliferation of neural stem cells through oxidative stress-mediated p38 MAPK signaling. Stem Cells. 2009; 27(8):1987-98. [DOI:10.1002/stem.125] [PMID]
  18. Aliouat-Denis CM, Dendouga N, Van den Wyngaert I, Goehlmann H, Steller U, van de Weyer I, et al. p53-independent regulation of p21Waf1/Cip1 expression and senescence by Chk2. Mol Cancer Res. 2005; 3(11):627-34. [DOI:10.1158/1541-7786.MCR-05-0121] [PMID]
  19. Razavipour SF, Harikumar KB, Slingerland JM. p27 as a transcriptional regulator: New roles in development and cancer. Cancer Res. 2020; 80(17):3451-8. [DOI:10.1158/0008-5472.CAN-19-3663] [PMID]
  20. Villanueva J, Yung Y, Walker JL, Assoian RK. ERK activity and G1 phase progression: Identifying dispensable versus essential activities and primary versus secondary targets. Mol Biol Cell. 2007; 18(4):1457-63. [DOI:10.1091/mbc.e06-10-0908] [PMID]
  21. Timmerbeul I, Garrett-Engele CM, Kossatz U, Chen X, Firpo E, Grünwald V, et al. Testing the importance of p27 degradation by the SCFskp2 pathway in murine models of lung and colon cancer. Proc Natl Acad Sci U S A. 2006; 103(38):14009-14. [DOI:10.1073/pnas.0606316103] [PMID]
  22. Kroeger PT Jr, Shoue DA, Mezzacappa FM, Gerlach GF, Wingert RA, Schulz RA. Knockdown of SCF(Skp2) function causes double-parked accumulation in the nucleus and DNA re-replication in Drosophila plasmatocytes. PLoS One. 2013; 8(10):e79019. [DOI:10.1371/journal.pone.0079019] [PMID]
  23. Choi BK, Fujiwara K, Dayaram T, Darlington Y, Dickerson J, Goodell MA, et al. WIP1 dephosphorylation of p27Kip1 Serine 140 destabilizes p27Kip1 and reverses anti-proliferative effects of ATM phosphorylation. Cell Cycle. 2020; 19(4):479-91. [DOI:10.1080/15384101.2020.1717025] [PMID]
  24. Besse S, Tanguy S, Boucher F, Bulteau AL, Riou B, de Leiris J, et al.Aortic vasoreactivity during prolonged hypoxia and hypoxia-reoxygenation in senescent rats. Mech Ageing Dev. 2002; 123(4):275-85. [DOI:10.1016/S0047-6374(01)00327-X] [PMID]
  25. Lönnrot K, Pörsti I, Alho H, Wu X, Hervonen A, Tolvanen JP. Control of arterial tone after long-term coenzyme Q10 supplementation in senescent rats. Br J Pharmacol. 1998; 124(7):1500-6. [DOI:10.1038/sj.bjp.0701970] [PMID]
  26. Roskoski R Jr. Targeting ERK1/2 protein-serine/threonine kinases in human cancers. Pharmacol Res. 2019; 142:151-68. [DOI:10.1016/j.phrs.2019.01.039] [PMID]
  27. Roskoski R Jr. ERK1/2 MAP kinases: Structure, function, and regulation. Pharmacol Res. 2012; 66(2):105-43.[DOI:10.1016/j.phrs.2012.04.005] [PMID]
  28. Chambard JC, Lefloch R, Pouysségur J, Lenormand P. ERK implication in cell cycle regulation. Biochim Biophys Acta. 2007; 1773(8):1299-310. [DOI:10.1016/j.bbamcr.2006.11.010] [PMID]
  29. Kaboutari J, Ghorbani M, Karimi B, Javdai M, Khosraviyan P. Effects of the Slow-release Curcumin-loaded Selenium Nanoparticles on Experimental Peritonitis. Iran J Vet Med. 2024; 18(4):555-66. [DOI:10.32598/ijvm.18.4.1005414]
  30. Toussaint O, Royer V, Salmon M, Remacle J. Stress-induced premature senescence and tissue ageing. Biochem Pharmacol. 2002; 64(5-6):1007-9. [DOI:10.1016/S0006-2952(02)01170-X] [PMID]
  31. Flores JM, Martín-Caballero J, García-Fernández RA. p21 and p27 a shared senescence history. Cell Cycle. 2014; 13(11):1655-6. [DOI:10.4161/cc.29147] [PMID]
  32. Simard FA, Cloutier A, Ear T, Vardhan H, McDonald PP. MEK-independent ERK activation in human neutrophils and its impact on functional responses. J Leukoc Biol. 2015; 98(4):565-73. [DOI:10.1189/jlb.2MA1214-599R] [PMID]
  33. Fan L, Bi T, Wang L, Xiao W. DNA-damage tolerance through PCNA ubiquitination and sumoylation. Biochem J. 2020; 477(14):2655-77. [DOI:10.1042/BCJ20190579] [PMID]
  34. Zarei H, Tajik A. Garlic powder supplementary diet prevents pulmonary hypertension syndrome by reducing apoptosis in broiler chickens. Iran J Vet Med. 2024; 18(4):589-98. [DOI:10.32598/ijvm.18.4.1005496]

 

آمار
تعداد مشاهده مقاله: 159
تعداد دریافت فایل اصل مقاله: 235


counter
سامانه مدیریت نشریات علمی. طراحی و پیاده سازی از سیناوب