Ilimaquinone (marine sponge metabolite) as a novel inhibitor of SARS-CoV-2 key target proteins in comparison with suggested COVID-19 drugs: designing,docking and molecular dynamics simulation study

The outbreak of novel coronavirus, SARS-CoV-2, has infected more than 36 million people and caused approximately 1 million deaths around the globe as of 9 October 2020. The escalating outspread of the virus and rapid rise in the number of cases require the instantaneous development of effectual drugs and vaccines. Presently, there are no approved drugs or vaccine available to treat the infection. In such scenario, one of the propitious therapeutic approaches against viral infection is to explore enzyme inhibitors amidst natural compounds, utilizing computational approaches aiming to get products with negligible side effects. In the present study, the inhibitory prospects of ilimaquinone (marine sponge metabolite) were assessed in comparison with hydroxychloroquine, azithromycin, favipiravir, ivermectin and remdesivir at the active binding pockets of nine different vital SARS-CoV-2 target proteins (spike receptor binding domain, RNA-dependent RNA polymerase, Nsp10, Nsp13, Nsp14, Nsp15, Nsp16, main protease, and papain-like-protease), employing an in silico molecular interaction based approach. In addition, molecular dynamics (MD) simulations of the SARS-CoV-2 papain-like protease (PLpro)–ilimaquinone complex were also carried out to calculate various structural parameters including root mean square fluctuation (RMSF), root mean square deviation (RMSD), radius of gyration (R_g) and hydrogen bond interactions. PLpro is a promising drug target, due to its imperative role in viral replication and additional function of stripping ubiquitin and interferon-stimulated gene 15 (ISG15) from host-cell proteins. In light of the possible inhibition of all vital SARS-CoV-2 target proteins, our study has emphasized the importance to study in depth ilimaquinone actions in vivo.

Inhibitory potential of ilimaquinone (marine sponge metabolite) against nine essential SARS-CoV-2 target proteins, employing a molecular interaction and dynamics simulation approach.     

Association of IL-8 (-251)T/A polymorphism with susceptibility to and aggressiveness of nasopharyngeal carcinoma

Interleukin-8 (IL-8) is an angiogenic chemokine that plays a potent role in both development and progression of many human malignancies including nasopharyngeal carcinoma (NPC). In the present study, we evaluated the susceptibility and prognostic implications of the (-251) T/A genetic variation in IL-8 in NPC. We used the allele-specific polymerase chain reaction to characterize the variation of the IL-8 promoter region for 160 unrelated Tunisian patients with NPC and 169 healthy control subjects. There was a significant association between the homozygotes IL-8 (-251) AA genotype and nasopharyngeal carcinoma (OR = 2.46; P = 0.004). The presence of the IL-8 (-251) AA genotype was highly associated with elevated NPC risk for male patients. A significant association was demonstrated between the IL-8 (-251) AA genotype and the aggressive forms of NPC as defined by large tumor size, lymph node metastasis, and advanced stages. Moreover, the presence of the IL-8 (-251) AA genotype indicated a significant association with decreased overall survival. Our findings suggest that the IL-8 promoter polymorphism is associated with increased nasopharyngeal carcinoma risk, particularly in males, as well as disease progress, supporting our hypothesis for IL-8 involvement in NPC pathogenesis.     

Skin involvement in Susac's syndrome

Susac's syndrome (SS) is a rare microangiopathy affecting the precapillary arterioles of the brain, retina and inner ear, presumably resulting from an autoimmune endotheliopathy. We report the first case of SS with histologically proven skin involvement, in a 24-year-old male who presented a subacute encephalopathy, branch retinal artery occlusions and bilateral hearing loss, two weeks after the onset of a livedo racemosa of the flanks and feet. Skin biopsies revealed a thrombus in several dermal arterioles, endothelial cells swelling and a mild perivascular lymphocytic infiltrate, which correspond to the same histological findings as previously observed in brain but also in muscle biopsies of patients with SS. A complete recovery was achieved in 4 months with corticosteroids. Follow-up MRI showed centro-callosal "holes". Skin involvement in SS has pathological plausibility since serum antibodies directly binding to central nervous system but also to generic endothelium cells have been reported. Our report supports that SS is a systemic disease that could affect other organs in addition to the brain, retina and inner ear. We suggest careful skin examination should be considered in patients with a suspicion of SS.     

Leptin and leptin receptor polymorphisms are associated with increased risk and poor prognosis of breast carcinoma

Background  

Leptin (LEP) has been consistently associated with angiogenesis and tumor growth. Leptin exerts its physiological action through its specific receptor (LEPR). We have investigated whether genetic variations in LEP and LEPR have implications for susceptibility to and prognosis in breast carcinoma.     

Rhombencephalosynapsis diagnosed in childhood: clinical and MRI findings.

Rhombencephalosynapsis (RES) is a rare cerebellar malformation of unknown etiology characterized by vermal agenesis or hypogenesis, fusion of hemispheres and the dentate nuclei. Clinical presentation and prognosis are extremely variable and generally depends one the associated supratentorial anomalies. We report the first Tunisian case of RES diagnosed by magnetic resonance imaging (MRI) in a 3.5-year-old boy born to consanguineous parents. The child had spastic diplegia, facial dysmorphia, skeletal anomalies and normal intellectual development. Additional supratentorial anomalies were agenesis of septum pellucidum, moderate hydrocephalus and hypogenesis of corpus callosum. In this paper, the clinical and MRI findings and possible pathogenesis of this disorder are discussed.