Asetaminofen verilerek oluşturulan deneysel hepatotoksisitede rapamisinin hepatoprotektif etkisinin araştirilmasi
Küçük Resim Yok
Tarih
2025
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İnönü Üniversitesi
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Amaç: Tezin ana hedefi, sıçanlarda yüksek dozda asetaminofen ile oluşturulan hepatotoksisite modelinde rapamisin uygulamasının barsak florası ve hepatotoksisitedeki potansiyel etkilerinin detaylı bir biçimde araştırılmasıdır. Materyal ve Metot: Bu çalışmada; ortalama canlı ağırlıkları 200-260 g olan 30 adet Sprague Dawley türü sıçan kullanıldı. Oral yolla 835mg/kg tek doz asetaminofen verilerek deneysel hepatotoksisite modeli oluşturuldu, müteakiben 3 gün süreyle (1., 3. ve 5. günlerde) 1,5 mg/kg/gün dozunda rapamisin verilerek kan, ince bağırsak ve karaciğer doku örnekleri alındı. Kandan elde edilen serumlardan alkalin fosfataz, alanin transaminaz, aspartat aminotransferaz düzeyleri ölçüldü. Karaciğer ve ince bağırsak doku örneklerinin bir kısmı histolojik değerlendirmeler için kullanılırken diğer kısmıyla doku antioksidanları ve mTOR düzeyleri belirlendi. Ayrıca 16S rRNA temelli metagenomik analizler yapıldı. Bulgular: Asetaminofen uygulanan sıçanlarda karaciğer enzimlerinde yükselme, oksidatif stres belirteçlerinde bozulma ve belirgin histopatolojik hasar gözlenirken, asetaminofenle indüklenmiş hepatotoksisitede rapamisin uygulanması sonucu bu etkiler hafifledi. Biyokimyasal parametrelerde iyileşmeler görüldü. Histopatolojik değerlendirmelerde rapamisinin kısmen koruyucu etkiler gösterdiği saptandı. Mikrobiyota analizinde, asetaminofen uygulamasının bakteriyel çeşitlilik üzerinde olumsuz etkileri olduğu, rapamisinin ise bazı türlerde dengeleyici etkiler sağladığı belirlendi ancak tamamen iyileştirici olmadığı görüldü. Sonuç: Rapamisinin, deneysel hepatotoksisite modelinde karaciğer dokusunda hasarı azaltıcı ve bağırsak florasını koruyucu etkiler gösterdiği gözlemlendi. Bu bulgular, rapamisinin hepatoprotektif potansiyeliyle birlikte bağırsak-karaciğer ekseni üzerinden de etkili olabileceğini ortaya koymaktadır. Ancak bağırsak mikrobiyotasına yönelik etkiler sınırlı düzeyde kaldığı tespit edildi. Bu nedenle, rapamisinin hepatotoksisite ve bakteriyel translokasyon üzerindeki etkileri umut verici olmakla birlikte, bu etkinin sınırlı, doza ve/veya süreye ya da uygulama protokolüne bağlı olarak değişebileceği değerlendirildi. Konunun daha kapsamlı ve uzun süreli çalışmalarla desteklenmesi gerekmektedir.
Objective: This thesis aimed to establish a detailed rat model of hepatotoxicity induced by high-dose acetaminophen and to investigate the potential effects of rapamycin on intestinal microbiota and liver injury. Materials and Methods: Thirty Sprague Dawley rats (200–260 g) were used. An experimental hepatotoxicity model was induced by oral administration of a single dose of 835 mg/kg acetaminophen. The rats were given 1.5 mg/kg/day of rapamycin for 3 days, and blood, small intestine, and liver tissue samples were collected. Serum levels of alkaline phosphatase, alanine transaminase, and aspartate aminotransferase were measured from the blood samples. Some of the liver and small intestine tissue samples were used for histological evaluations, while others were used to determine tissue antioxidant and mTOR levels. 16S rRNA-based metagenomic analyses were also performed. Results: While acetaminophen-administered rats exhibited elevated liver enzymes, deterioration in oxidative stress markers, and significant histopathological damage, these effects were alleviated by rapamycin administration in acetaminophen-induced hepatotoxicity. Improvements were observed in biochemical parameters. Histopathological evaluations revealed that rapamycin had partially protective effects. Microbiota analysis revealed that acetaminophen administration had negative effects on bacterial diversity, while rapamycin provided stabilizing effects in some species, but was not fully curative. Conclusion: Rapamycin demonstrated partial hepatoprotective and microbiota-stabilizing effects in acetaminophen -induced hepatotoxicity. These beneficial outcomes were parameter-dependent and not completely restorative. The findings suggest that rapamycin's efficacy may depend on dose, treatment duration, and experimental protocol. Further long-term and dose-optimization studies are warranted to confirm its potential in mitigating hepatotoxicity and bacterial translocation.
Objective: This thesis aimed to establish a detailed rat model of hepatotoxicity induced by high-dose acetaminophen and to investigate the potential effects of rapamycin on intestinal microbiota and liver injury. Materials and Methods: Thirty Sprague Dawley rats (200–260 g) were used. An experimental hepatotoxicity model was induced by oral administration of a single dose of 835 mg/kg acetaminophen. The rats were given 1.5 mg/kg/day of rapamycin for 3 days, and blood, small intestine, and liver tissue samples were collected. Serum levels of alkaline phosphatase, alanine transaminase, and aspartate aminotransferase were measured from the blood samples. Some of the liver and small intestine tissue samples were used for histological evaluations, while others were used to determine tissue antioxidant and mTOR levels. 16S rRNA-based metagenomic analyses were also performed. Results: While acetaminophen-administered rats exhibited elevated liver enzymes, deterioration in oxidative stress markers, and significant histopathological damage, these effects were alleviated by rapamycin administration in acetaminophen-induced hepatotoxicity. Improvements were observed in biochemical parameters. Histopathological evaluations revealed that rapamycin had partially protective effects. Microbiota analysis revealed that acetaminophen administration had negative effects on bacterial diversity, while rapamycin provided stabilizing effects in some species, but was not fully curative. Conclusion: Rapamycin demonstrated partial hepatoprotective and microbiota-stabilizing effects in acetaminophen -induced hepatotoxicity. These beneficial outcomes were parameter-dependent and not completely restorative. The findings suggest that rapamycin's efficacy may depend on dose, treatment duration, and experimental protocol. Further long-term and dose-optimization studies are warranted to confirm its potential in mitigating hepatotoxicity and bacterial translocation.
Açıklama
Anahtar Kelimeler
Eczacılık ve Farmakoloji, Pharmacy and Pharmacology
