Hipertiroidizmde MTOR ve NRF2 sinyalizasyonunun ferroptoz üzerine etkileri
Küçük Resim Yok
Tarih
2024
Yazarlar
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Düzce Üniversitesi
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Tiroit, vücuttaki tüm hücreler üzerinde gelişme, büyüme ve metabolizmayı düzenlemek için hareket eden tiroit hormonları tiroksin (T4) ve triiyodotironin (T3) üretiminden sorumlu bir endokrin bezdir. Hipertiroidizm, dokunun aşırı miktarda dolaşımdaki tiroit hormonuna maruz kaldığı patolojik bir sendromdur. Hipertiroidizm nedeniyle mitokondrinin oksidatif metabolizması hızlanmakta ve reaktif oksijen ürünlerini (ROS) arttırmaktadır. ROS'daki artış oksidatif strese neden olabilir. Nükleer faktör eritroid 2 ile ilişkili faktör 2 (NRF2), oksidatif strese karşı hücre koruyucu reaksiyonların başlatılması için redoks duyarlı olarak aktifleşen ilk ve en önemli transkripsiyonel aktivatör olup antioksidan tepkinin ana düzenleyicisi olarak kabul edilmektedir. Ferroptoz, demir şelatörleri ve lipofilik antioksidanlar tarafından kontrol edilen, hücrelerin antioksidan kapasitesi azaldığında hücre içi lipid ve ROS birikimi ile karakterize bir tür düzenlenmiş hücre ölümü şeklidir. Hücreler ferroptoza maruz kaldığında, antioksidan sistemde GPX4'ün hem ekspresyonu hem de aktivitesi azalacaktır. NRF2 hem lipid peroksidasyonunun hem de ferroptozun kritik bir hafifleticisidir. Ferroptoz düzenleyicileri arasında yer alan rapamisin proteininin memeli hedefi 1 (MTORC1), evrimsel olarak korunmuş serin-treonin kinaz enerji dengesi, büyüme faktörleri, besinler ve oksijendeki değişiklikleri algılayarak hücre döngüsü ilerlemesini ve büyümesini modüle eder. Rapamisin proteininin memeli hedefi (MTOR), tiroit hücrelerinde iyodür alımını da düzenleyen fosfatidilinositol-3 kinaz (PI3K)/Akt yolunun aşağı akış efektörüdür. Yürütmekte olduğumuz tez çalışmamızda hipertiroidizm hastalarında ferroptoz yolağının incelenmesi hedeflenmiştir. Çalışmamızda hipertiroidizm hastası 90 kişi ve kontrol grubu 90 kişi olmak üzere 180 kişi şeklinde toplamda iki grup oluşturulmuştur. Çalışmamızda kullandığımız biyokimyasal parametrelerimiz uzun zincirli yağ asidi-KoA ligaz 4 (ACSL4), glutatyon (GSH), malondialdehit (MDA), MTOR, NRF2, total antioksidan durumu (TAS) ve total oksidan durumu (TOS) şeklinde olup Enzim bağlı immünosorbent deneyi (ELİSA) metodu ile analizi yapılmıştır. Ulaşılan veriler ışığında hipertirodizmli hastaların serumlarında, kontrol grubunda yer alan hastaların serumlarına kıyas ile ACSL4, MDA, MTOR ve TOS biyokimyasal parametrelerde artış görülmüştür. Öte yandan GSH, NRF2 ve TAS biyokimyasal parametrelerinde kontrol grubuna göre düşüş olduğu bulunmuştur. Sonuçlarımıza göre hipertiroidizmli kişilerde yapılan serum analizlerine göre ferroptoz sinyal yolağının indüklendiği tespit edilmiştir. Yapılan bu çalışma ile hipertiroid koşullarının oluşturduğu ferroptozun baskılanması için MTOR yolağının inhibisyonu NRF2 yolağının indüksiyonu üzerine detaylı çalışmalar yapılarak hastalarda meydana gelen hasarlara katkı sağlayabileceği ön görülmektedir.
The thyroid is an endocrine gland responsible for the production of thyroid hormones, thyroxine (T4) and triiodothyronine (T3), which act on all cells in the body to regulate development, growth, and metabolism. Hyperthyroidism is a pathological syndrome where the tissue is exposed to excessive circulating thyroid hormones. Due to hyperthyroidism, mitochondrial oxidative metabolism accelerates, increasing reactive oxygen species (ROS). The increase in ROS can cause oxidative stress. Nuclear factor erythroid 2-related factor 2 (NRF2) is the primary and most important transcriptional activator that is redox-sensitive and activates to initiate cell-protective reactions against oxidative stress, being considered the main regulator of the antioxidant response. Ferroptosis is a type of regulated cell death characterized by intracellular lipid and ROS accumulation when the antioxidant capacity of cells decreases, and it is controlled by iron chelators and lipophilic antioxidants. When cells are subjected to ferroptosis, both the expression and activity of GPX4 in the antioxidant system will decrease. NRF2 is a critical mitigator of both lipid peroxidation and ferroptosis. Among the regulators of ferroptosis is the mammalian target of rapamycin complex 1 (MTORC1), an evolutionarily conserved serine-threonine kinase that modulates cell cycle progression and growth by sensing changes in energy balance, growth factors, nutrients, and oxygen. The mammalian target of rapamycin (MTOR) is a downstream effector of the phosphatidylinositol-3 kinase (PI3K) /Akt pathway, which also regulates iodide uptake in thyroid cells. Our ongoing thesis project aims to investigate the ferroptosis pathway in patients with hyperthyroidism. Our study comprises a total of two groups: 90 patients with hyperthyroidism and 90 individuals in the control group, making a total of 180 participants. The biochemical parameters used in our study include long-chain fatty acid-CoA ligase 4 (ACSL4), glutathione (GSH), malondialdehyde (MDA), MTOR, NRF2, total antioxidant status (TAS), and total oxidant status (TOS), all of which were analyzed using the Enzyme-Linked Immunosorbent Assay (ELISA) method. Based on the obtained data, it was observed that there was an increase in the biochemical parameters ACSL4, MDA, MTOR, and TOS in the serum of patients with hyperthyroidism compared to the serum of individuals in the control group. On the other hand, it was found that the biochemical parameters GSH, NRF2, and TAS decreased compared to the control group. According to our results, it was determined that the ferroptosis signaling pathway is induced based on the serum analyses conducted on individuals with hyperthyroidism. This study suggests that detailed studies on the inhibition of the MTOR pathway and the induction of the NRF2 pathway could contribute to mitigating the damage caused by ferroptosis under hyperthyroid conditions.
The thyroid is an endocrine gland responsible for the production of thyroid hormones, thyroxine (T4) and triiodothyronine (T3), which act on all cells in the body to regulate development, growth, and metabolism. Hyperthyroidism is a pathological syndrome where the tissue is exposed to excessive circulating thyroid hormones. Due to hyperthyroidism, mitochondrial oxidative metabolism accelerates, increasing reactive oxygen species (ROS). The increase in ROS can cause oxidative stress. Nuclear factor erythroid 2-related factor 2 (NRF2) is the primary and most important transcriptional activator that is redox-sensitive and activates to initiate cell-protective reactions against oxidative stress, being considered the main regulator of the antioxidant response. Ferroptosis is a type of regulated cell death characterized by intracellular lipid and ROS accumulation when the antioxidant capacity of cells decreases, and it is controlled by iron chelators and lipophilic antioxidants. When cells are subjected to ferroptosis, both the expression and activity of GPX4 in the antioxidant system will decrease. NRF2 is a critical mitigator of both lipid peroxidation and ferroptosis. Among the regulators of ferroptosis is the mammalian target of rapamycin complex 1 (MTORC1), an evolutionarily conserved serine-threonine kinase that modulates cell cycle progression and growth by sensing changes in energy balance, growth factors, nutrients, and oxygen. The mammalian target of rapamycin (MTOR) is a downstream effector of the phosphatidylinositol-3 kinase (PI3K) /Akt pathway, which also regulates iodide uptake in thyroid cells. Our ongoing thesis project aims to investigate the ferroptosis pathway in patients with hyperthyroidism. Our study comprises a total of two groups: 90 patients with hyperthyroidism and 90 individuals in the control group, making a total of 180 participants. The biochemical parameters used in our study include long-chain fatty acid-CoA ligase 4 (ACSL4), glutathione (GSH), malondialdehyde (MDA), MTOR, NRF2, total antioxidant status (TAS), and total oxidant status (TOS), all of which were analyzed using the Enzyme-Linked Immunosorbent Assay (ELISA) method. Based on the obtained data, it was observed that there was an increase in the biochemical parameters ACSL4, MDA, MTOR, and TOS in the serum of patients with hyperthyroidism compared to the serum of individuals in the control group. On the other hand, it was found that the biochemical parameters GSH, NRF2, and TAS decreased compared to the control group. According to our results, it was determined that the ferroptosis signaling pathway is induced based on the serum analyses conducted on individuals with hyperthyroidism. This study suggests that detailed studies on the inhibition of the MTOR pathway and the induction of the NRF2 pathway could contribute to mitigating the damage caused by ferroptosis under hyperthyroid conditions.
Açıklama
Anahtar Kelimeler
Biyokimya, Biochemistry
