Nrf2-Keap1 Activation as A Potential Target of The Antioxidant Defense System in Diabetes Mellitus

Yıl 2024, Cilt: 33 Sayı: 1, 48 - 57, 31.03.2024

Shireen Adil Alı Tuğçe Sapmaz Erçakallı Samet Kara Sait Polat

https://doi.org/10.17827/aktd.1435519

Öz

Diabetes mellitus (DM) is a chronic disease characterized by hyperglycemia and complications that include micro- and macrovascular disease. Nrf2 and its endogenous inhibitor, Keap1, function as a ubiquitous, evolutionarily conserved intracellular defense mechanism to counteract oxidative stress. Sequestered by cytoplasmic Keap1 and targeted to proteasomal degradation in basal conditions, in case of oxidative stress Nrf2 detaches from Keap1 and translocate to the nucleus, where it heterodimerizes with one of the small Maf proteins. The heterodimers recognize the AREs, that are enhancer sequences present in the regulatory regions of Nrf2 target genes, essential for the recruitment of key factors for transcription. Oxidative stress is the major pathogenic factor in diabetes and is mediated by Nrf2, a master regulator of the antioxidant protection response. This response involves a network of cooperating enzymes involved in drug detoxification and metabolic elimination of prooxidants. NRF2-induced antioxidant metabolic pathways include enzymes for the production, utilization, and regeneration of reduced glutathione (GSH). Nrf2 has been shown to have a protective effect on oxidative, inflammatory, and apoptotic. Keap1/Nrf2 signaling pathway can effectively suppress intracellular ROS overproduction and protect pancreatic β-cells from oxidative stress-induced DNA damage, contributing to the suppression of T1DM development. However, inhibition of the Keap1/Nrf2 signaling pathway significantly promoted the progression of T1DM. Diabetic complications can occur in long-term diabetes due to disturbances in metabolic balance, leading microvascular and macrovascular complication. It has been suggested that NRF2-related epigenetic changes reduce the occurrence and progression of diabetic complications by inhibiting oxidative stress. Various of antioxidant such as Vitamins like A, E, C vitamins, carotenoids, and minerals like zinc, manganese, copper, iron, and selenium are essential for the activity of NRF-2 also the natural antioxidants such as curcumin and flavonoids found in vegetables, fruits, and edible herbs also play an important role in activating the Nrf2 signaling pathway. In this review, we summarize the role of oxidative stress in diabetic pathogenesis and the role of antioxidants in the regulation of NRF-2 in the treatment of diabetic mellitus.

Anahtar Kelimeler

Diabetic Mellitus, Oxidative stress, NRF-2- Keap1, Antioxidant, Diabetic complication.

Diabetes Mellitus'ta Nrf2-Keap1 Aktivasyonu, Antioksidan Savunma Sisteminin Potansiyel Bir Hedefidir

Öz

Diabetes mellitus (DM), hiperglisemi ile karakterize kronik bir hastalıktır ve mikro- ve makrovasküler hastalıkları içeren komplikasyonları vardır. Nrf2 ve endojen inhibitörü Keap1, oksidatif stresle mücadele etmek için yaygın, evrimsel olarak korunmuş hücresel bir savunma mekanizması olarak işlev görür. Sitoplazmik Keap1 tarafından tutulur ve bazal koşullarda proteazomal bozulmaya hedeflenir, oksidatif stres durumunda Nrf2, Keap1'den ayrılır ve çekirdeğe taşınır, burada küçük Maf proteinlerinden biri ile heterodimer oluşturur. Heterodimerler, Nrf2 hedef genlerinin düzenleyici bölgelerinde bulunan güçlendirici dizileri (ARE'ler) tanır, transkripsiyon için önemli faktörlerin rekrütasyonu için gereklidir. Oksidatif stres, diyabetin ana patojenik faktörüdür ve Nrf2 tarafından iletilir, antioksidan koruma tepkisinin ana düzenleyicisidir. Bu yanıt, ilaç detoksifikasyonu ve prooksidanların metabolik eliminasyonunda yer alan bir dizi işbirliği yapan enzimi içeren bir ağa dahil olur. NRF2 tarafından indüklenen antioksidan metabolik yollar, azalmış glutatyonun (GSH) üretimi, kullanımı ve rejenerasyonu için enzimleri içerir. Nrf2'nin oksidatif, iltihaplı ve apoptotik etkileri koruyucu olduğu gösterilmiştir. Keap1/Nrf2 sinyal yolunun pankreatik β-hücreleri oksidatif stres kaynaklı DNA hasarından koruyarak T1DM gelişimini bastırmaya katkıda bulunduğu gösterilmiştir. Bununla birlikte, Keap1/Nrf2 sinyal yolunun inhibisyonu T1DM'nin ilerlemesini önemli ölçüde teşvik etmiştir. Uzun süreli diyabet sonucu diyabetik komplikasyonlar, metabolik dengesizliklerde meydana gelebilir, mikrovasküler ve makrovasküler komplikasyonlara yol açabilir. NRF2 ile ilişkili epigenetik değişikliklerin, oksidatif stresi inhibe ederek diyabetik komplikasyonların oluşumunu ve ilerlemesini azalttığı öne sürülmüştür. Ayrıca A, E, C vitaminleri ve karotenoidler gibi vitaminler ile çinko, mangan, bakır, demir ve selenyum gibi mineraller gibi çeşitli antioksidanlar NRF-2'nin aktivitesi için esastır, ayrıca sebzelerde, meyvelerde ve yenilebilir otlarda bulunan doğal antioksidanlar da Nrf2 sinyal yolunun aktive edilmesinde önemli bir rol oynar. Bu derlemede, diyabetik patogenezde oksidatif stresin rolünü ve diabetes mellitus tedavisinde NRF-2'nin düzenlenmesinde antioksidanların rolünü özetliyoruz.

Anahtar Kelimeler

Diabetes Mellitus, Oksidatif stres, NRF-2- Keap1, Antioksidan, Diyabetik komplikasyon.

Kaynakça

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