Elhadidy M G, Elmasry A I, El Nashar E M, Alghamdi M A, Al-Khater K M, Alasmari W A, Eladl A E, Hamed E M, Almohawes Z N, El-Kott A F, Shati A A, Rabei M R, Elalfy M M
Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Department of Medical Physiology, Faculty of Medicine, Al-Baha University, Al Baha, Kingdom of Saudi Arabia.
J Physiol Pharmacol. 2022 Oct;73(5). doi: 10.26402/jpp.2022.5.05. Epub 2023 Mar 16.
Liver fibrosis is a chronic progressive disease, its resolution still unclear, and the current study explored the role of melatonin in modulation of interleukin-6 (IL-6), interleukin-4 (IL-4), transforming growth factor beta1 (TGF-β1) and urokinase plasminogen activator receptor-associated protein/Endo180 (uPARAP/Endo180) pathway in thioacetamide (TAA)-induced hepatotoxicity. Thirty two adult Sprague-Dawley rats were divided into four groups: vehicle control group, TAA-induced liver fibrosis group that was left untreated, melatonin administration before and along with TAA and melatonin along with TAA group. TTA-induced massive liver necrosis, fibrosis around portal tract and increases serum levels of liver enzymes and total bilirubin when compared with control vehicle group. While both melatonin pretreatment and treatment retained liver parenchyma and liver enzymes quite similar to control group and reduced TAA-induced liver injury. Notably, melatonin pretreatment and treatment increased collagen degradation in TAA liver injury by19, 31.7-fold respectively evidence by collagen percentage area. Melatonin also decreased the amount of thiobarbituric acid reactive compounds and retained the reduced glutathione and superoxide dismutase to basal level quite similar to control group. Additionally, melatonin significantly (P value ≤0.05) decreased the levels of TGF-β1, epidermal growth factor (EGF), hydroxyproline, tissues IL-6, caspase-3, and receptor interacting serine/threonine kinase1 (RIPK1), fibrillin-1, and - smooth muscle actin in the liver tissues while significantly (P value ≤0.05) increasing the levels of IL-4 and uPARAP/Endo180. Due to its anti-inflammatory, anti-apoptotic, and antioxidant capabilities as well as its ability to decrease hepatic stellate cell activation and fibrogenesis, these data imply that melatonin has a powerful anti-fibrotic effect.
肝纤维化是一种慢性进行性疾病，其消退机制仍不清楚，目前的研究探讨了褪黑素在硫代乙酰胺（TAA）诱导的肝毒性中对白细胞介素-6（IL-6）、白细胞介素-4（IL-4）、转化生长因子β1（TGF-β1）和尿激酶型纤溶酶原激活物受体相关蛋白/内吞蛋白180（uPARAP/Endo180）通路的调节作用。32只成年Sprague-Dawley大鼠分为四组：溶剂对照组、未治疗的TAA诱导肝纤维化组、TAA给药前及给药时给予褪黑素组和TAA给药时给予褪黑素组。与溶剂对照组相比，TAA诱导了大量肝坏死、门管区周围纤维化，并增加了血清肝酶和总胆红素水平。而褪黑素预处理组和治疗组均保留了肝实质，肝酶水平与对照组相当，减轻了TAA诱导的肝损伤。值得注意的是，通过胶原百分比面积证明，褪黑素预处理组和治疗组分别使TAA肝损伤中的胶原降解增加了19倍和31.7倍。褪黑素还减少了硫代巴比妥酸反应性化合物的量，并使还原型谷胱甘肽和超氧化物歧化酶保留在与对照组相当的基础水平。此外，褪黑素显著（P值≤0.05）降低了肝组织中TGF-β1、表皮生长因子（EGF）、羟脯氨酸、组织IL-6、半胱天冬酶-3和受体相互作用丝氨酸/苏氨酸激酶1（RIPK1）、原纤蛋白-1和α-平滑肌肌动蛋白的水平，同时显著（P值≤0.05）增加了IL-4和uPARAP/Endo180的水平。由于其抗炎、抗凋亡和抗氧化能力以及降低肝星状细胞活化和纤维化形成的能力，这些数据表明褪黑素具有强大的抗纤维化作用。
