Lebda Mohamed A, Sadek Kadry M, Abouzed Tarek K, Tohamy Hossam G, El-Sayed Yasser S
Department of Biochemistry, Faculty of Veterinary Medicine, Alexandria University, Egypt.
Department of Biochemistry, Faculty of Veterinary Medicine, Damanhur University, Egypt.
Life Sci. 2018 Jan 1;192:136-143. doi: 10.1016/j.lfs.2017.11.036. Epub 2017 Nov 24.
The potential antifibrotic effects of melatonin against induced hepatic fibrosis were explored.
Rats were allocated into four groups: placebo; thioacetamide (TAA) (200mg/kg bwt, i.p twice weekly for two months); melatonin (5mg/kgbwt, i.p daily for a week before TAA and continued for an additional two months); and melatonin plus TAA. Hepatic fibrotic changes were evaluated biochemically and histopathologically. Hepatic oxidative/antioxidative indices were assessed. The expression of hepatic proinflammatory cytokines (tumor necrosis factor-α, and interleukin-1β), fibrogenic-related genes (transforming growth factor-1β, collagen I, collagen, III, laminin, and autotaxin) and an antioxidant-related gene (thioredoxin-1) were detected by qRT-PCR.
In fibrotic rats, melatonin lowered serum aspartate aminotransferase, alanine aminotransferase, and autotaxin activities, bilirubin, hepatic hydroxyproline and plasma ammonia levels. Melatonin displayed hepatoprotective and antifibrotic potential as indicated by mild hydropic degeneration of some hepatocytes and mild fibroplasia. In addition, TAA induced the depletion of glutathione, glutathione s-transferase, glutathione peroxidase, superoxide dismutase, catalase, and paraoxonase-1 (PON-1), while inducing the accumulation of malondialdehyde, protein carbonyl (C=O) and nitric oxide (NO), and DNA fragmentation. These effects were restored by melatonin pretreatment. Furthermore, melatonin markedly attenuated the expression of proinflammatory cytokines and fibrogenic genes via the upregulation of thioredoxin-1 mRNA transcripts.
Melatonin exhibits potent anti-inflammatory, antioxidant and fibrosuppressive activities against TAA-induced hepatic fibrogenesis via the suppression of oxidative stress, DNA damage, proinflammatory cytokines and fibrogenic gene transcripts. In addition, we demonstrate that the antifibrotic activity of melatonin is mediated by the induction of thioredoxin-1 with attenuation of autotaxin expressions.
探讨褪黑素对诱导性肝纤维化的潜在抗纤维化作用。
将大鼠分为四组：安慰剂组；硫代乙酰胺（TAA）组（200mg/kg体重，腹腔注射，每周两次，共两个月）；褪黑素组（5mg/kg体重，在TAA注射前腹腔注射一周，然后持续两个月）；褪黑素加TAA组。通过生化和组织病理学方法评估肝脏纤维化变化。评估肝脏氧化/抗氧化指标。通过qRT-PCR检测肝脏促炎细胞因子（肿瘤坏死因子-α和白细胞介素-1β）、纤维化相关基因（转化生长因子-1β、胶原蛋白I、胶原蛋白III、层粘连蛋白和自分泌运动因子）以及抗氧化相关基因（硫氧还蛋白-1）的表达。
在纤维化大鼠中，褪黑素降低了血清天冬氨酸转氨酶、丙氨酸转氨酶和自分泌运动因子活性、胆红素、肝脏羟脯氨酸和血浆氨水平。一些肝细胞的轻度水样变性和轻度纤维增生表明褪黑素具有肝脏保护和抗纤维化潜力。此外，TAA导致谷胱甘肽、谷胱甘肽S-转移酶、谷胱甘肽过氧化物酶、超氧化物歧化酶、过氧化氢酶和对氧磷酶-1（PON-1）耗竭，同时诱导丙二醛、蛋白质羰基（C=O）和一氧化氮（NO）积累以及DNA片段化。褪黑素预处理可恢复这些效应。此外，褪黑素通过上调硫氧还蛋白-1 mRNA转录本显著减弱促炎细胞因子和纤维化基因的表达。
褪黑素通过抑制氧化应激、DNA损伤、促炎细胞因子和纤维化基因转录本，对TAA诱导的肝纤维化表现出强大的抗炎、抗氧化和纤维抑制活性。此外，我们证明褪黑素的抗纤维化活性是通过诱导硫氧还蛋白-1并减弱自分泌运动因子表达来介导的。
