Asetaminofen ile oluşturulan karaciğer hasarı patojenezinde nitrik oksit sentaz (NOS) ve siklooksijenaz (COX) sistemlerinin rolünün araştırılması

Asetaminofen ile Oluşturulan Karaciğer Hasarı Patojenezinde Nitrik Oksit Sentaz (NOS) ve Siklooksijenaz (COX) Sistemlerinin Rolünün Araştırılması Giriş: Analjezik ve antipiretik olarak yaygın kullanılan asetaminofen (APAP) yüksek dozunda karaciğer hasarına yol açmaktadır. Amaç: Asetaminofen’e bağlı oluşan karaciğer hasarında nitrik oksit sentaz (NOS) ve siklooksijenaz (COX) sistemlerinin rolünü araştırmaktır. Yöntem: Sprague-Dawley sıçanlara (250-300 g) hepatotoksiste oluşturmak üzere APAP (500 mg/kg; intraperitoneal) uygulandı. Tedavi gruplarına APAP enjeksiyonundan önce 4 gün süreyle intraperitoneal non-selektif NOS inhibitörü L-NAME (20 mg/kg), iNOS inhibitörü aminoguanidin (8 mg/kg), non-selektif COX inhibitörü indometazin (5 mg/kg), COX-2 inhibitörü nimesulid (10 mg/kg) veya COX-1 inhibitörü ketorolak (5 mg/kg) uygulandı. 5. günde dekapitasyon sonrası kanda ALT ve AST, TNF-α, IL-1β ve IL-10 düzeyleri, karaciğer örneklerinde malondialdehid (MDA), glutatyon (GSH), miyeloperoksidaz (MPO) ve kemiluminisans ile oksidan düzeyleri ölçüldü. Dokuda immünohistokimyasal yöntemle iNOS, COX–2 ve nükleer faktör kappa B (NFκB) değerlendirildi ve mikroskopik skorlama yapıldı. Bulgular: Non-selektif NOS inhibisyonu ve selektif iNOS inhibisyonu karaciğerde oksidan oluşumunu, nötrofil infiltrasyonunu baskıladı ve GSH içeriğini korudu. İlaveten, iNOS inhibitörü ile tedavi dokuda lipid peroksidasyonu ve serumda artmış TNF- düzeyini geri döndürdü. Selektif ve non-selektif COX inhibitörleri de inflamasyonu baskılamakta etkili bulundu. İmmünhistokimya bulgularına göre, NOS inhibisyonu sadece NOS değil aynı zamanda COX enzimlerini de baskılamaktadur ve tersi durum da geçerlidir. Sonuç: Asetaminofen ile oluşan hepatotoksisite patogenezinde NOS ve COX sistemleri rol oynamakta ve bu sistemler birbirleriyle etkileşmektedirler. Anahtar Kelimeler: Asetaminofen, nitrik oksit sentaz, siklooksijenaz, karaciğer hasarı Roles of Nitric Oxide Synthase (NOS) and Cyclooxygenase (COX) Systems in the Pathogenesis of Acetaminophen Induced Liver InjuryIntroduction: Acetaminophen (APAP), a widely-used analgesic and antipyretic drug, can induce acute liver injury when used in high doses. Aim: To investigate the role of nitric oxide synthase (NOS) and cyclooxygenase (COX) systems and their interaction in the pathogenesis of APAP-induced liver injury in rats. Materials and methods: Sprague Dawley rats (250-300 g) received APAP (500 mg/kg) intraperitoneally for induction of hepatotoxicity. Treatment groups received non-selective NOS inhibitor L-NAME (20 mg/kg), iNOS inhibitor aminoguanidin (8 mg/kg), non-selective COX inhibitor indomethacin (5 mg/kg), COX-2 inhibitor nimesulid (10 mg/kg) or COX-1 inhibitor ketorolac (5 mg/kg) intraperitoneally for 4 consecutive days before APAP injection. All rats were decapitated on the 5th day. Trunk blood was collected for the measurement of ALT, AST, TNF-α, IL-1β and IL-10 levels. Liver samples were taken for the measurement of malondialdehyde (MDA) level, glutathione (GSH) content, myeloperoxidase (MPO) activity and NO-, luminol- and lucigenin-enhanced chemiluminescence values. Liver samples were also examined microscopically and iNOS, COX-2 and nuclear kappa factor B (NFκB) levels were evaluated immunohistochemically. Results: Non-selective NOS inhibition and selective iNOS inhibition suppressed oxidant production and neutrophil infiltration and restored GSH content in the liver. Additionally, treatment with the iNOS inhibitor reversed tissue lipid peroxidation and high serum TNF- levels. Selective and non-selective COX inhibitors were also effective in suppressing the extent of inflammation. According to immunohistochemical data, NOS inhibition suppresses not only NOS but also COX enzymes and vice versa. Conclusion: NOS and COX systems have a role in the pathogenesis of APAP induced liver injury and they interact with each other.Key words: Asetaminophen, nitric oxide synthase, cyclooxygenase, liver injur

Sıçanda gentamisin ile oluşturulan akut nefrotoksisite üzerine alfa melanosit stimülan hormonunun etkisi

1. Gentamisin’e bağlı nefrotoksisitenin patojenezinde oksidan hasarın rolü olduğu gösterilmiştir. Bu çalışmada, sıçanda gentamisin ile indüklenen nefrotoksisite üzerinde -melanosit stimülan hormonun (-MSH) olası yararlı etkilerini araştırmak amaçlanmıştır. Gereç ve Yöntemler: Her iki cinsiyetten Sprague-Dawley sıçanlara (200-220 gr), 7 gün süreyle intraperitoneal (i.p.) fizyolojik tuzlu su (kontrol grubu; n=8) veya gentamisin sülfat (80 mg/kg/gün; n=8) uygulandı. Tedavi grubuna, 7 gün boyunca -MSH (25 g/sıçan/gün; i.p.) verildi. Sıçanlar 7. günde 24 saatlik idrar toplamak için metabolik kafeslere yerleştirildiler ve 8. günde dekapite edildiler. Hayvanlardan kan ve böbrek örnekleri alındı. Kanda üre nitrojeni (BUN) ve kreatinin düzeyi ölçümleri yapıldı. Böbrek örneklerinde lipid peroksidasyonu (LP), glutatyon (GSH) düzeyi ve myeloperoksidaz aktivitesi (MPO) ölçümleri ve histolojik değerlendirme yapıldı. 24 saatlik idrar örneklerinde, idrar hacmi ve kreatinin ölçümleri yapıldı ve kreatinin klirensi hesaplandı. Sonuçlar: Gentamisin grubunda BUN ve kreatinin düzeyleri kontrol grubuna göre anlamlı derecede yüksek bulunurken kreatinin klirensi değerleri azalma gösterdi. -MSH tedavisi, bu parametreleri değiştirmedi. Histolojik incelemede, kontrol grubunda normal morfoloji, gentamisin grubunda yaygın lökosit infiltrasyonu, yoğun vazokonjesyon, glomerüllerde şiddetli hasarla beraber yaygın tubuler nekroz gözlendi. -MSH tedavisi böbrek hasarını ve tubuler nekrozun şiddetini azalttı. -MSH tedavisi böbrekde gentamisin’e bağlı artmış mikroskopik skor değerini, LP düzeyini ve MPO aktivitesini anlamlı derecede azalttı. Gentamisin grubunda kontrol grubuna göre azalmış olan böbrek GSH değeri de -MSH tedavisiyle kontrol düzeyine yükseldi. Tartışma: -MSH tedavisi gentamisin ile indüklenen renal hasarda koruyucu etki gösterdi. -MSH tedavisi gentamisin ile indüklenmiş doku nötrofil infiltrasyonu ve LP’deki artış ile glutatyondaki azalmayı da engelledi. Ancak, peptid gentamisin’e bağlı böbrekteki fonksiyonel bozulma üzerine anlamlı bir etki göstermedi. 1. SUMMARY It has been demonstrated that oxidant damage is involved in the pathogenesis of gentamicin-induced nephrotoxicity. The study aimed to investigate the putative beneficial effect of -MSH on gentamicin-induced nephrotoxicity in rats. Materials and Methods: Sprague Dawley rats of both sexes (200-220 g) received saline intraperitoneally (i.p.) (control group; n=8) or gentamicin sulphate (80 mg/kg/day) (n=8) alone or with -MSH (25 g/rat/day; i.p.) for 7 days. All rats were placed in metabolic cages to collect urine for 24 hours and were decapitated on the 8th day. Blood was collected to measure blood urea nitrogen (BUN) and creatinine levels. Kidney samples were taken to determine lipid peroxidation (LP), glutathione (GSH) levels, myeloperoxidase (MPO) activity and for microscopic evaluation. Urine volume and creatinine levels were measured to calculate the creatinine clearance. Results: In gentamicin group, the serum BUN and creatinine levels were significantly higher and the creatinine clearance values were lower than those of the control group. -MSH treatment did not change these parameters. The microscopic examination revealed a normal morphology in the control group, whereas there was widespread leukocyte infiltration, vasocongestion and severe injury in the glomeruli along with tubuler necrosis in gentamicin group. Kidney MPO activity and LP levels and the micrsocopic score of gentamicin group which were significantly higher than those of the control group, were all reversed by -MSH. Decreased kidney GSH level in gentamicin group was also attenuated by -MSH. Discussion: -MSH has a protective effect on gentamicin-induced renal injury. It prevents the increase in kidney neutrophil infiltration and LP, also the decrease in tissue GSH content. However, the peptide does not seem to show any significant effect on gentamicin-induced kidney dysfunction

Ferulic Acid Treats Gastric Ulcer via Suppressing Oxidative Stress and Inflammation

(1) Background: The aim of the present study was to evaluate the gastroprotective potential of ferulic acid (FA) on indomethacin-induced gastric ulcers in rats with macroscopic and microscopic examinations along with biochemical assays. (2) Methods: After 24 h starvation, the ulcer was induced in male Sprague-Dawley rats by subcutaneous indomethacin (25 mg/kg) injection. Fifteen minutes after ulcer induction, rats were treated with either tween 80 or FA. FA was given by oral gavage at 100 mg/kg, 250 mg/kg, and 500 mg/kg. In the fourth hour, rats were euthanized and collected gastric samples were evaluated macroscopically and microscopically. Antioxidant parameters including malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), and inflammatory parameters comprising of myeloperoxidase (MPO), Tumor Necrosis Factor (TNF)-α, Interleukin (IL)-1β, IL-6 and Nuclear Factor Kappa-B (NF-κB) p65 levels were also determined. (3) Results: Indomethacin injection significantly increased the macroscopic and microscopic scores. In addition, it increased the gastric MDA, MPO, TNF-α, IL-1β, IL-6, and NF-κB p65 levels but reduced SOD and GSH content. Treatment with FA significantly improved the gastric injury macroscopically and microscopically. Moreover, FA displayed a marked decrease in the gastric levels of MDA, MPO, TNF-α, IL-1β, IL-6, and NF-κB p65 and a significant increase in SOD and GSH compared to the INDO group. Ultimately, 250 mg/kg FA was determined as the most effective dose. (4) Conclusion: Our results revealed that FA has a gastroprotective effect against indomethacin-induced gastric ulcers in rats due to its antioxidant and anti-inflammatory properties. As a result, FA may be a potential treatment choice for gastric ulcers

Ferulic Acid Treats Gastric Ulcer via Suppressing Oxidative Stress and Inflammation

(1) Background: The aim of the present study was to evaluate the gastroprotective potential of ferulic acid (FA) on indomethacin-induced gastric ulcers in rats with macroscopic and microscopic examinations along with biochemical assays. (2) Methods: After 24 h starvation, the ulcer was induced in male Sprague-Dawley rats by subcutaneous indomethacin (25 mg/kg) injection. Fifteen minutes after ulcer induction, rats were treated with either tween 80 or FA. FA was given by oral gavage at 100 mg/kg, 250 mg/kg, and 500 mg/kg. In the fourth hour, rats were euthanized and collected gastric samples were evaluated macroscopically and microscopically. Antioxidant parameters including malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), and inflammatory parameters comprising of myeloperoxidase (MPO), Tumor Necrosis Factor (TNF)-α, Interleukin (IL)-1β, IL-6 and Nuclear Factor Kappa-B (NF-κB) p65 levels were also determined. (3) Results: Indomethacin injection significantly increased the macroscopic and microscopic scores. In addition, it increased the gastric MDA, MPO, TNF-α, IL-1β, IL-6, and NF-κB p65 levels but reduced SOD and GSH content. Treatment with FA significantly improved the gastric injury macroscopically and microscopically. Moreover, FA displayed a marked decrease in the gastric levels of MDA, MPO, TNF-α, IL-1β, IL-6, and NF-κB p65 and a significant increase in SOD and GSH compared to the INDO group. Ultimately, 250 mg/kg FA was determined as the most effective dose. (4) Conclusion: Our results revealed that FA has a gastroprotective effect against indomethacin-induced gastric ulcers in rats due to its antioxidant and anti-inflammatory properties. As a result, FA may be a potential treatment choice for gastric ulcers