ABSTRACT
BACKGROUND AND PURPOSE: Varicocele is a leading cause of male infertility. Melatonin is a highly pleiotropic neurohormone. We aimed to characterize the melatonin epigenetic potential in varicocele and the involved molecular mechanisms. EXPERIMENTAL APPROACH: Fifty-two male albino rats were randomly divided into four groups (13 rats each): control (I), melatonin (II), varicocele (III) and melatonin treated varicocele (IV) groups. Left varicocele was induced by partial left renal vein ligation. Reproductive hormones, epididymal sperm functional parameters, testicular 3/17 ß-hydroxysteroid dehydrogenases, antioxidant enzymes, malondialdehyde, nicotinamide adenine dinucleotide phosphate oxidase, 8-hydroxy-2'-deoxyguanosine and histopathological/Johnsen's score were evaluated. Flow cytometry and Comet were carried out to explore extent of sperm and testicular DNA damage. Testicular expression of silent information regulator 1 (SIRT1), forkhead transcription factors-class O (type1) (FOXO1), tumour suppressor gene, P53, cation channels of sperm (CatSper) and steroidogenic acute regulatory protein was evaluated by western blot technique. Testicular expression of Bcl-2 and its associated X protein and nuclear factor kappa-light-chain-enhancer of activated B cells were assayed by immunohistochemical staining. Testicular miR-34a expression was quantified by quantitative reverse transcription-polymerase chain reaction. KEY RESULTS: The varicocele induced testicular histological injury, enhanced oxidative stress, P53-mediated apoptosis, DNA damage and increased testicular miR-34a expression paralleled with down-regulated SIRT1/FOXO axis. Melatonin treatment of varicocele rats displayed antioxidant/anti-apoptotic efficacy and improved reproductive hormones axis, CatSper expression and fertility parameters. MiR-34a/SIRT1/FOXO1 epigenetic axis integrates testicular melatonin mediated intracellular transduction cascades in varicocele. CONCLUSION AND IMPLICATIONS: Melatonin can be used as an adjuvant therapy to improve varicocele and its complication.
Subject(s)
Melatonin , MicroRNAs , Sirtuin 1 , Varicocele , Animals , Antioxidants/metabolism , Antioxidants/pharmacology , Epigenesis, Genetic , Fertility , Male , Melatonin/pharmacology , MicroRNAs/metabolism , Oxidative Stress , Rats , Sirtuin 1/genetics , Sirtuin 1/metabolism , Tumor Suppressor Protein p53/metabolism , Varicocele/metabolism , Varicocele/pathologyABSTRACT
Sofosbuvir is a promising antiviral drug against chronic hepatitis C virus. Although it is characterized by its high efficacy, its adverse effects on nervous tissue are still unclear. Saffron is known for its neuroprotective property. This is a biochemical, histological and immunohistochemical study of the effect of sofosbuvir on the cerebellar cortex of rat and the possible ameliorating role of saffron's aqueous extract. Twenty-four adult male Wistar albino rats were equally divided into four groups; control, saffron extract-treated, sofosbuvir-treated (41.1 mg/kg/day for 6 weeks) and group concomitantly treated with saffron extract and sofosbuvir. Sofosbuvir-treated group recorded a significant increase in cerebellar malondialdehyde level coupling with a significant decrease in tissue glutathione and superoxide dismutase. Light microscopy revealed reduced number of Purkinje cells. The granular layer depicted many granular cells and Bergmann astrocytes with nuclear and cytoplasmic alterations. Electron microscopy revealed disorganized molecular layer with disarranged myelinated axons and disrupted mitochondria. Few shrunken Purkinje cells showed electron-dense cytoplasm and rarefied nuclei, indistinct nuclear envelope and dilated perinuclear space, areas of vacuolated cytoplasm, fragmented rough endoplasmic reticulum and few dark mitochondria. Some axons with tiny mitochondria were detected. A significant upregulation in immunohistochemical expression of GFAP-positive astrocytes was recorded. Concomitant administration of saffron extract significantly improved all studied parameters. Saffron extract is beneficial in ameliorating sofosbuvir-induced cerebellar morphological changes mainly through its antioxidant and neuroprotective properties.
