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Journals / Meandros Medical And Dental Journal / 2026 / Volume: 27 Issue: 2

An Approach to Attention Deficit Hyperactivity Disorder from the Perspective of Hypoxia and Apoptosis: CASP3, HIF1A, and VDR Gene Expression

Hipoksi ve Apoptoz Perspektifinden Dikkat Eksikliği Hiperaktivite Bozukluğuna Yaklaşım: CASP3, HIF1A ve VDR Gen Ekspresyonu

Reyhan Tahtasakal(ERCIYES UNIVERSITY)0000-0002-1347-0939
Halime Dana(ERCIYES UNIVERSITY)0000-0003-0829-8625
Melike Kevser Gül(ERCİYES ÜNİVERSİTESİ, TIP FAKÜLTESİ)0000-0002-0907-4503
Esra Demirci(ERCİYES ÜNİVERSİTESİ, TIP FAKÜLTESİ)0000-0002-8424-4947
Elif Funda Şener(ERCİYES ÜNİVERSİTESİ, TIP FAKÜLTESİ)0000-0002-5644-5442
Pages
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Publication Date
2026-06-24
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AI Summary & Key Takeaways

AI Insight
⚡ TL;DR(Too Long; Didn't Read)

Conclusion: Our findings provide new information to the literature to shed light on the hypoxia and apoptosis cascade in ADHD.

📌 3 Key Takeaways

🎯
Objective & Hypothesis:Aim: Attention deficit/hyperactivity disorder is a neurodevelopmental disorder.
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Key Findings & Data:Caspase-3 (CASP3) is a cysteine-aspartate protease that performs apoptosis.
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Conclusion & Impact:Conclusion: Our findings provide new information to the literature to shed light on the hypoxia and apoptosis cascade in ADHD.
🔬Design:Research Article
📍Scope:Comprehensive Sample
⚙️Variables:Attention Deficit Hyperactivity Disorder (ADHD) · Gene expression · VDR

Abstract

Aim: Attention deficit/hyperactivity disorder is a neurodevelopmental disorder. The combination of environmental and genetic factors plays a role in the etiology of ADHD. Caspase-3 (CASP3) is a cysteine-aspartate protease that performs apoptosis. After overexpression of hypoxia-inducible factor-1alpha (HIF1A) due to hypoxia, the cell enters apoptosis via a caspase-dependent cascade. It has been observed that the vitamin D receptor (VDR) is also fragmented and inactivated by caspases during apoptosis. This study aimed to reveal the relationship between VDR, HIF1A, and CASP3 gene expressions in ADHD. Materials and Methods: Forty patients and 40 healthy controls were enrolled in the study to assess the gene expression profiles. Results: HIF1A and CASP3 expressions were significantly higher in ADHD children, but there was no appreciable change in the VDR gene expression between ADHD children and healthy participants. In addition, HIF1A and CASP3 were also found to be higher in boys with ADHD. Conclusion: Our findings provide new information to the literature to shed light on the hypoxia and apoptosis cascade in ADHD.

Özet

Amaç: Dikkat eksikliği/hiperaktivite bozukluğu nörogelişimsel bir bozukluktur. Çevresel ve genetik faktörlerin birleşimi DEHB etiyolojisinde rol oynar. Kaspaz-3 (CASP3), apoptozu gerçekleştiren bir sistein-aspartat proteazdır. Hipoksiye bağlı olarak hipoksi ile indüklenebilir faktör-1 alfa (HIF1A) aşırı ekspresyonu sonrasında hücre, kaspaz bağımlı bir kaskad aracılığıyla apoptoza girer. Apoptoz sırasında D vitamini reseptörünün (VDR) de parçalandığı ve kaspazlar tarafından inaktive edildiği gözlenmiştir. Bu çalışma, DEHB'de VDR, HIF1A ve CASP3 gen ekspresyonları arasındaki ilişkiyi ortaya koymayı amaçlamıştır. Gereç ve Yöntemler: Gen ekspresyon profillerini değerlendirmek için çalışmaya 40 hasta ve 40 sağlıklı kontrol dahil edildi. Bulgular: HIF1A ve CASP3 ekspresyonları DEHB'li çocuklarda anlamlı derecede yüksekti, ancak VDR gen ekspresyonunda DEHB'li çocuklar ve sağlıklı katılımcılar arasında belirgin bir değişiklik yoktu. Ayrıca, HIF1A ve CASP3'ün DEHB'li erkek çocuklarda da daha yüksek olduğu bulundu. Sonuç: Bulgularımız, DEHB'deki hipoksi ve apoptozis kaskadı hakkında literatüre yeni bilgiler sunmaktadır.

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Cite This Article

Tahtasakal, R., Dana, H., Gül, M. K., Demirci, E., Şener, E. F., *, E. F. Ş. (2026). An Approach to Attention Deficit Hyperactivity Disorder from the Perspective of Hypoxia and Apoptosis: CASP3, HIF1A, and VDR Gene Expression. Meandros Medical And Dental Journal, Volume: 27 Issue: 2. https://doi.org/10.69601/meandrosmdj.1791577

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References (42)

  1. Faraone SV, Larsson H. Genetics of attention deficit hyperactivity disorder. Mol. Psychiatry 2019;24(4):562–575.
  2. Drechsler R, Brem S, Brandeis D, Grünblatt E, Berger G, Walitza S. ADHD: Current Concepts and Treatments in Children and Adolescents. Neuropediatrics. 2020;51(5):315–335.
  3. Luo Y, Weibman D, Halperin JM, Li X. A review of heterogeneity in attention deficit/hyperactivity disorder (ADHD). Front Hum Neurosci. 2019;13:42.
  4. LaBianca S, Brikell I, Helenius D, et al. Polygenic profiles define aspects of clinical heterogeneity in attention deficit hyperactivity disorder. Nat Genet. 2024;56(2):234–244.
  5. Hawi Z, Cummins TDR, Tong J, Johnson B, Lau R, Samarrai W et al. The molecular genetic architecture of attention deficit hyperactivity disorder. Mol Psychiatry. 2015;20(3):289–297.
  6. Curatolo P, D’Agati E, Moavero R. The neurobiological basis of ADHD. Ital. J Pediatr. 2010;36(1):1–7.
  7. Kranz TM, Grimm O. Update on genetics of attention deficit/hyperactivity disorder: current status 2023. Curr Opin Psychiatry. 2023;36(3):257-262.
  8. Schwabe I, Pelt DHM, Greven CU. Gene-environment interaction in ADHD traits: the role of school environment, personality, callousness-unemotional traits and satisfaction with life. Eur Child Adolesc Psychiatry. 2025;1-10.
  9. Bener A, Kamal M, Bener H, Bhugra D. Higher prevalence of iron deficiency as strong predictor of attention deficit hyperactivity disorder in children. Ann Med Health Sci Res. 2014;4(9):291.
  10. Eyles D, Burne T, McGrath J. Vitamin D in fetal brain development. Semin. Cell Dev Biol. 2011;22(6):629–636.
  11. Walbert T, Jirikowski GF, Prüfer K. Distribution of 1,25-dihydroxyvitamin D3 receptor immunoreactivity in the limbic system of the rat. Horm Metab. 2001;33(9):525–531.
  12. Sahin N, Altun H, Kurutas EB, Balkan D. Vitamin D and vitamin D receptor levels in children with attention-deficit/hyperactivity disorder. Neuropsychiatr Dis Treat. 2018;14:581–585.
  13. Ye X, Zhou Q, Ren P, Xiang W, Xiao L. The Synaptic and Circuit Functions of Vitamin D in Neurodevelopment Disorders. Neuropsychiatr Dis Treat. 2023;3(19):1515-1530.
  14. Wenger RH, Gassmann M. Oxygen(es) and the hypoxia-inducible factor-1. Biol Chem. 1997;378(7):609–616.
  15. Giannopoulou I, Pagida MA, Briana DD, Panayotacopoulou MT. Perinatal hypoxia as a risk factor for psychopathology later in life: the role of dopamine and neurotrophins. Hormones. 2018;17(1):25-32.
  16. da Costa NMM, de Siqueira AS, Ribeiro ALR, da Silva Kataoka MS, Jaeger RG, de Alves-Júnior SM et al. Role of HIF-1α and CASPASE-3 in cystogenesis of odontogenic cysts and tumors. Clin Oral Investig. 2018;22(1):141–149.
  17. Tahtasakal R, Hamurcu Z, Oz AB, et al. miR-484 as an “OncomiR” in Breast Cancer Promotes Tumorigenesis by Suppressing Apoptosis Genes. Ann Surg Oncol. 2025;32(4):2994-3008.
  18. Won S, Sayeed I, Peterson BL, Wali B, Kahn JS, Stein DG. Vitamin D prevents hypoxia/reoxygenation-induced blood-brain barrier disruption via vitamin D receptor-mediated NF-kB signaling pathways. PLoS One 2015;10(3):e0122821.
  19. Malloy PJ, Feldman D. Inactivation of the human vitamin D receptor by caspase-3. Endocrinology.2009;150(2):679–686.
  20. Réus GZ, Scaini G, Jeremias GC, Furlanetto CB, Morais MOS, Mello-Santos LM et al. Brain apoptosis signaling pathways are regulated by methylphenidate treatment in young and adult rats. Brain Res. 2014;1583:269–276.
  21. Lo S-C, Wang Y, Weber M, et al. Caspase-3 deficiency results in disrupted synaptic homeostasis and impaired attention control. J Neurosci. 2015;35(5):2118–2132.
  22. Demirci E, Erdogan A. Is emotion recognition the only problem in ADHD? effects of pharmacotherapy on face and emotion recognition in children with ADHD. Atten Defic Hyperact Disord. 2016 Dec;8(4):197-204.
  23. Tahtasakal R, Sener EF, Delibasi N, et al. Overexpression of the PTEN Gene in Myocardial Tissues of Coronary Bypass Surgery Patients. Arq Bras Cardiol. 2023;120(4):1–9.
  24. Shibata T, Yamagata H, Uchida S, Otsuki K, Hobara T, Higuchi F et al. The alteration of hypoxia inducible factor-1 (HIF-1) and its target genes in mood disorder patients. Prog. Neuro-Psychopharmacology Biol Psychiatry. 2013;43:222–229.
  25. Şimşek F, Işık Ü, Aktepe E, Kılıç F, Şirin FB, Bozkurt M. Comparison of Serum VEGF, IGF-1, and HIF-1α Levels in Children with Autism Spectrum Disorder and Healthy Controls. J Autism Dev Disord. 2021;51(10):3564–3574.
  26. García-Domínguez I, Suárez-Pereira I, Santiago M, Pérez-Villegas EM, Bravo L, López-Martín C, et al. Selective deletion of Caspase-3 gene in the dopaminergic system exhibits autistic-like behaviour. Prog Neuro-Psychopharmacology Biol Psychiatry. 2021;104:110030.
  27. Getahun D, Rhoads GG, Demissie K, Lu SE, Quinn VP, Fassett MJ et al. In utero exposure to ischemic-hypoxic conditions and attention-deficit/ hyperactivity disorder. Pediatrics. 2013;131(1):e53-61.
  28. Amor L Ben, Grizenko N, Schwartz G, et al. Perinatal complications in children with attention-deficit hyperactivity disorder and their unaffected siblings. J Psychiatry Neurosci. 2005;30(2):120-6.
  29. Pagida MA, Konstantinidou AE, Korelidou A, Katsika D, Tsekoura E, Patsouris E, et al. The Effect of Perinatal Hypoxic/Ischemic Injury on Tyrosine Hydroxylase Expression in the Locus Coeruleus of the Human Neonate. Dev Neurosci. 2016;38(1):41–53.
  30. Viktor M, Melinda B, Mária SS, Gergely K. Dopamine D4 receptor hypoxia sensitivity and child psychiatric disorders. Neuropsychopharmacol Hung. 2010;12(1):289–293.
  31. Huang X, Wang M, Zhang Q, Chen X, Wu J. The role of glutamate receptors in attention-deficit/hyperactivity disorder: From physiology to disease. Am J Med Genet. Part B Neuropsychiatr. Genet. 2019;180(4):272–286.
  32. Lou HC. Etiology and pathogenesis of Attention-deficit Hyperactivity Disorder (ADHD): Significance of prematurity and perinatal hypoxic-haemodynamic encephalopathy. Acta Paediatr. Int. J Paediatr. 1996;85(11):1266–1271.
  33. Gill R, Soriano M, Blomgren K, Hagberg H, Wybrecht R, Miss MT, et al. Role of caspase-3 activation in cerebral ischemia-induced neurodegeneration in adult and neonatal brain. J Cereb Blood Flow Metab. 2002;22(4):420–430.
  34. Carvalho GF da S, Costa TVMM, Nascimento AM, Wolff BM, Damasceno JG, Vieira LL, et al. DNA methylation epi-signature and biological age in attention deficit hyperactivity disorder patients. Clin Neurol Neurosurg. 2023;228:107714.
  35. Ong LTC, Booth DR, Parnell GP. Vitamin D and its Effects on DNA Methylation in Development, Aging, and Disease. Mol Nutr Food Res. 2020;64(23):1–11.
  36. Siniscalco D, Cirillo A, Bradstreet JJ, Antonucci N. Epigenetic findings in autism: New perspectives for therapy. Int J Environ Res Public Health. 2013;10(9):4261–4273.
  37. Pertile RAN, Cui X, Eyles DW. Vitamin D signaling and the differentiation of developing dopamine systems. Neuroscience. 2016;333:193–203.
  38. Chang JPC, Su KP, Mondelli V, Pariante CM. Cortisol and inflammatory biomarker levels in youths with attention deficit hyperactivity disorder (ADHD): evidence from a systematic review with meta-analysis. Transl Psychiatry. 2021;11(1).
  39. Vanderhaeghen T, Vandewalle J, Libert C. Hypoxia-inducible factors in metabolic reprogramming during sepsis. FEBS J. 2020;287(8):1478–1495.
  40. Xue G, Gao R, Liu Z, Xu N, Cao Y, Zhao B, et al. Vitamin D/VDR signaling inhibits colitis by suppressing HIF-1a activation in colonic epithelial cells. Am J Physiol. - Gastrointest Liver Physiol. 2021;320(5):G837–G846.
  41. Oliveira ALMB, Rodrigues GD, Silva BM, Rohan PA, Soares PPDS. Sex differences in cardiorespiratory control under hypoxia: the roles of oxygen desaturation and hypoxic exposure time. Front Cardiovasc Med. 2025;12:1473910.
  42. Li Y, Wang Z, Ma H, Wang N. Moderating role of gender in brain structural changes of long-term high-altitude hypoxia-exposed individuals. Brain Res Bull. 2025;230:111531.