PİNEALEKTOMİLİ RATLARDA AKRİLAMİD TARAFINDAN OLUŞTURULAN KARACİĞER HASARI ÜZERİNE EKZOJEN MELATONİNİN TERAPÖTİK ROLÜ: OKSİDATİF STRES, İNFLAMASYON VE APOPTOZİS ÜZERİNE ETKİLERİ
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2023-01
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info:eu-repo/semantics/openAccess
Özet
Akrilamid (AA), beyaz kristal yapıda, düşük molekül ağırlığında ve suda çözürlüğü yüksek olan bir maddedir. Doğada kendiliğinden bulunmamakta olup yüksek reaktiviteye sahiptir. Çok fazla endüstriyel alanda (kağıt, kimya gibi) kullanımı olan AA ısıl işlemler sonucunda gıdalarda da oluşabilmektedir. Gıdalarda kızartma ve fırınlama gibi pişirme yöntemleriyle ?120 ?C`de indirgeyici şekerler ve asparagin arasındaki Maillard reaksiyonu sonucunda oluşmaktadır. AA, hayvanlarda ve insanlarda toksik etkiye neden olabilmektedir. AA`nın karsinojenik, nörotoksik, genotoksik olması ve hidrofilik yapısı nedeniyle tüm organ ve dokulara kolaylıkla ulaşabilmesi sağlık açısından büyük endişe yaratmaktadır. Bu nedenle AA bilim insanları tarafından büyük ilgiyle araştırılmaktadır. Ksenobiyotiklerin detoksifikasyonunda rol oynayan karaciğer üzerinde de AA`nın toksik etkisi bulunmaktadır. AA`nın karaciğerde detoksifikasyonu, oksidatif strese neden olup, reaktif oksijen ve nitrojen radikallerin artışı ile sonuçlanabilmektedir. Bu artış karaciğerde glutatyonun tükenmesine, antioksidan enzimlerin azalmasına, hücre zarının oksidasyonuna neden olmaktadır. Buna bağlı olarak karaciğerde bulunan tüm hücrelerde inflamasyon, iskemi, fibroz, nekroz, apoptoz veya malign oluşumu meydana gelebilmektedir. Antioksidatif etkili ilaçların veya farmakolojik konsantrasyonlarda doğal olarak oluşan antioksidan takviyelerinin alınması oksidatif stresi değiştirmekte olup, bu takviyelerin çeşitli hastalıklarda morbiditeyi ve mortaliteyi azalttığı düşünülmektedir. İnsanlarda pineal bezden salgılanan melatonin (MLT) hormonu, endojen antioksidan olup ayrıca antiinflamatuar, antikanser gibi birçok fonsiyonel özelliği de bulunmaktadır. MLT ve metabolitleri hem oluşan serbest radikallerin ortadan kaldırılmasını sağlamakta hem de radikal oluşumunu azaltabilmektedir. Bu nedenle de lipid oksidasyonuna karşı koruyucu rol oynamaktadır. Aynı zamanda prooksidan enzimlerin azalmasını ve antioksidan enzim düzeylerinde de artış sağlamaktadır. Bu çalışmada amacımız hem pinealektomi işlemiyle MLT`den yoksun bırakılan ratlarda hemde pinealektomi yapılmayan ratlarda AA ile oksidatif stres, inflamasyona bağlı olarak karaciğer dokusundaki hepatotoktosisiteye karşı MLT`nin tedavi edici etkisini biyokimyasal, histopataloji ve immünohistokimyasal açıdan gözlemlemekti. Çalışmamızda, 60 adet erkek Wistar albino ratlar Sham ve PNX olmak üzere iki ana grup ve üçer alt grup olmak üzere 6 gruba ayrıldı. Ratlara etanol ve MLT uygulması intraperitonal (i.p.) yolla, AA uygulaması ise oral olarak gavajla uygulanmıştır. Çalışmada 21 gün boyunca; 1.gruba (Sham grubu) %0,5’lik etanol çözeltisi, 2. gruba (Sham+AA) 25 mg/kg/gün AA, 3. gruba (Sham+AA+MLT) 25 mg/kg/gün AA ve 10 mg/kg/gün MLT 0,5 ml hacminde, 4. gruba (PNX grubu) pinealektomi işleminden sonra %0,5’lik etanol çözeltisi, 5. gruba (PNX+AA grubu) pinealektomi işleminden sonra %0.5’lik etanol çözeltisi ve 25 mg/kg/gün AA, 6. gruba (PNX+AA+MLT) pinealektomi işlemi sonrasında %0,5 etonal çözeltisi ve 10 mg/kg/gün MLT, 25 mg/kg/gün AA uygulandı. Çalışmada hem Sham+AA hem de PNX+AA gruplarında Sham ve PNX gruplarına göre karaciğer dokusunda oksidan/antioksidan dengesinin oksidan lehine bozulmasına neden olarak total oksidan düzeyi (TOS) ve malondialdehit (MDA) düzeylerini arttırırken glutatyon (GSH), total antioksidan düzeyi (TAS), katalaz (CAT), süperoksit dismutaz (SOD) düzeylerini azalttı. PNX grubunda doğal antioksidan olan MLT yoksunluğuna bağlı olarak Sham grubuna göre TOS ve MDA düzeyleri daha fazla artarken, GSH, TAS, CAT ve SOD düzeyleri azaldı. Ekzojen MLT tedavisi sonucunda karaciğer dokusunda TOS ve MDA düzeyleri anlamlı derecede azalırken TAS ve GSH düzeyleri ile CAT, SOD aktivitilerinde artış gözlendi. AA uygulanan ratlarda karaciğer dokusunda inflamasyon artışı, nekroz oluşumu gözlendi, tümör nekroz faktör alfa (TNF-?) düzeylerinde anlamlı artış meydana geldi. MLT tedavisi sonrasında karaciğer dokusunda inflamasyonun azaldığı, apoptozun engellendiği ve hepatositlerde iyileşmelerin olduğu gözlendi. Çalışmamızın sonucu AA kaynaklı hepatotoksisite üzerinde MLT yoksunluğunda uygulanan ekzojen MLT`nin antioksidan, antiinflamatuar ve antiproliferatif etkisi sayesinde hepatositlerde oksidatif stresi, inflamasyonu, lipid peroksidasyonunu azaltabileceğini ve histopatolojik hasaları iyileştirebileceğini gösterdi.
Acrylamide (AA) is a white crystal structure, low molecular weight and highly soluble in water. It does not occur spontaneously in nature and has high reactivity. AA, which is used in many industrial areas (such as paper, chemistry), can also occur in foods as a result of heat treatments. It is formed as a result of the Maillard reaction between reducing sugars and asparagine in foods with cooking methods such as frying and baking at ?120 ?C. AA causes toxic effects in animals and humans. The fact that AA can easily reach all organs and tissues due to its carcinogenic, neurotoxic, genotoxic and hydrophilic structure creates a great concern in terms of health. For this reason, AA is being researched with great interest by scientists. AA has a toxic effect on the liver, which plays a role in the detoxification of xenobiotics. Detoxification of AA in the liver may cause oxidative stress and result in an increase in reactive oxygen and nitrogen radicals. This increase causes depletion of glutathione in the liver, a decrease in antioxidant enzymes, and oxidation of the cell membrane. Accordingly, inflammation, ischemia, fibrosis, necrosis, apoptosis, or malignant formation may occur in all cells in the liver. Taking antioxidative drugs or naturally occurring antioxidant supplements in pharmacological concentrations changes oxidative stress, and these supplements are thought to reduce morbidity and mortality in various diseases. The hormone melatonin (MLT) secreted from the pineal gland in humans is an endogenous antioxidant and also has many functional properties such as anti-inflammatory and anti-cancer. MLT and its metabolites can both eliminate free radicals and reduce radical formation. Therefore, it plays a protective role against lipid oxidation. At the same time, it provides a decrease in prooxidant enzymes and an increase in antioxidant enzyme levels. In this study, our aim was to observe the therapeutic effect of MLT against hepatotoxicity in liver tissue due to AA and oxidative stress and inflammation in terms of biochemical, histopathology and immunohistochemistry, both in rats deprived of MLT by pinealectomy procedure and in rats without pinealectomy. In our study, 60 male Wistar albino rats were divided into 6 groups, two main groups as Sham and PNX, and three subgroups each. Ethanol and MLT were administered intraperitoneally, while AA was administered orally by gavage to rats. During the 21 days in the study; 1st group (Sham group) 0.5% ethanol solution, 2nd group (Sham+AA) 25 mg/kg/day AA, 3rd group (Sham+AA+MLT) 25 mg/kg/day AA and 10 m/kg/day MLT, 0.5% ethanol solution after pinealectomy for group 4 (PNX group), 0.5% ethanol solution for group 5 (PNX+AA group) after pinealectomy, ethanol solution and 25 m/kg/day AA, group 6 (PNX+AA+MLT) after pinealectomy 0.5% etonal solution and 10 mg/kg/day MLT, 25 mg/kg by AA was applied. In the study, both the Sham+AA and PNX+AA groups increased the total oxidant level (TOS) and malondialdehyde (MDA) levels by causing the oxidant/antioxidant balance to deteriorate in favor of the oxidant in the liver tissue compared to the Sham and PNX groups, while glutathione (GSH) and total antioxidant level (TAS) increased. ), decreased catalase (CAT), superoxide dismutase (SOD) levels. In the PNX group, TOS and MDA levels increased more than in the Sham group due to MLT deprivation, which is a natural antioxidant, while GSH, TAS, CAT and SOD levels decreased. As a result of exogenous MLT treatment, TOS and MDA levels in liver tissue decreased significantly, while TAS and GSH levels and CAT, SOD activities increased. In rats treated with AA, increased inflammation and necrosis formation were observed in the liver tissue, and a significant increase in tumor necrosis factor alpha (TNF-?) levels occurred. After MLT treatment, it was observed that inflammation in the liver tissue decreased, apoptosis was prevented, and hepatocytes improved. The result of our study showed that exogenous MLT applied in MLT withdrawal on AA-induced hepatotoxicity can reduce oxidative stress, inflammation, lipid peroxidation and improve histopathological changes in hepatocytes thanks to its antioxidant, anti-inflammatory and antiproliferative effects."
Acrylamide (AA) is a white crystal structure, low molecular weight and highly soluble in water. It does not occur spontaneously in nature and has high reactivity. AA, which is used in many industrial areas (such as paper, chemistry), can also occur in foods as a result of heat treatments. It is formed as a result of the Maillard reaction between reducing sugars and asparagine in foods with cooking methods such as frying and baking at ?120 ?C. AA causes toxic effects in animals and humans. The fact that AA can easily reach all organs and tissues due to its carcinogenic, neurotoxic, genotoxic and hydrophilic structure creates a great concern in terms of health. For this reason, AA is being researched with great interest by scientists. AA has a toxic effect on the liver, which plays a role in the detoxification of xenobiotics. Detoxification of AA in the liver may cause oxidative stress and result in an increase in reactive oxygen and nitrogen radicals. This increase causes depletion of glutathione in the liver, a decrease in antioxidant enzymes, and oxidation of the cell membrane. Accordingly, inflammation, ischemia, fibrosis, necrosis, apoptosis, or malignant formation may occur in all cells in the liver. Taking antioxidative drugs or naturally occurring antioxidant supplements in pharmacological concentrations changes oxidative stress, and these supplements are thought to reduce morbidity and mortality in various diseases. The hormone melatonin (MLT) secreted from the pineal gland in humans is an endogenous antioxidant and also has many functional properties such as anti-inflammatory and anti-cancer. MLT and its metabolites can both eliminate free radicals and reduce radical formation. Therefore, it plays a protective role against lipid oxidation. At the same time, it provides a decrease in prooxidant enzymes and an increase in antioxidant enzyme levels. In this study, our aim was to observe the therapeutic effect of MLT against hepatotoxicity in liver tissue due to AA and oxidative stress and inflammation in terms of biochemical, histopathology and immunohistochemistry, both in rats deprived of MLT by pinealectomy procedure and in rats without pinealectomy. In our study, 60 male Wistar albino rats were divided into 6 groups, two main groups as Sham and PNX, and three subgroups each. Ethanol and MLT were administered intraperitoneally, while AA was administered orally by gavage to rats. During the 21 days in the study; 1st group (Sham group) 0.5% ethanol solution, 2nd group (Sham+AA) 25 mg/kg/day AA, 3rd group (Sham+AA+MLT) 25 mg/kg/day AA and 10 m/kg/day MLT, 0.5% ethanol solution after pinealectomy for group 4 (PNX group), 0.5% ethanol solution for group 5 (PNX+AA group) after pinealectomy, ethanol solution and 25 m/kg/day AA, group 6 (PNX+AA+MLT) after pinealectomy 0.5% etonal solution and 10 mg/kg/day MLT, 25 mg/kg by AA was applied. In the study, both the Sham+AA and PNX+AA groups increased the total oxidant level (TOS) and malondialdehyde (MDA) levels by causing the oxidant/antioxidant balance to deteriorate in favor of the oxidant in the liver tissue compared to the Sham and PNX groups, while glutathione (GSH) and total antioxidant level (TAS) increased. ), decreased catalase (CAT), superoxide dismutase (SOD) levels. In the PNX group, TOS and MDA levels increased more than in the Sham group due to MLT deprivation, which is a natural antioxidant, while GSH, TAS, CAT and SOD levels decreased. As a result of exogenous MLT treatment, TOS and MDA levels in liver tissue decreased significantly, while TAS and GSH levels and CAT, SOD activities increased. In rats treated with AA, increased inflammation and necrosis formation were observed in the liver tissue, and a significant increase in tumor necrosis factor alpha (TNF-?) levels occurred. After MLT treatment, it was observed that inflammation in the liver tissue decreased, apoptosis was prevented, and hepatocytes improved. The result of our study showed that exogenous MLT applied in MLT withdrawal on AA-induced hepatotoxicity can reduce oxidative stress, inflammation, lipid peroxidation and improve histopathological changes in hepatocytes thanks to its antioxidant, anti-inflammatory and antiproliferative effects."
Açıklama
Anahtar Kelimeler
Pinealektomi, Karaciğer Hasarı, Melatonin, Akrilamid, Oksidatif Stres, İnflamasyon, Apoptoz, Pinealectomy, Liver Injury, Melatonin, Acrylamide, Oxidative Stress, Inflammation, Apoptosis
