Activity

The prevalence of nonsense mutations as a class within genetic diseases such as inherited retinal disorders (IRDs) presents an opportunity to develop a singular, common therapeutic agent for patients whose treatment options are otherwise limited. We propose a novel approach to addressing IRDs utilizing Eukaryotic Ribosome Selective Glycosides, ELX-01 and ELX-06, delivered to the eye by intravitreal (IVT) injection. We assessed read-through activity in vitro using a plasmid-based dual luciferase assay and in vivo in a mouse model of oculocutaneous albinism type 2. These models interrogate a naturally occurring R262X nonsense mutation in the OCA2 gene. ELX-01 and ELX-06 both produced a concentration-dependent increase in read-through of the OCA2 R262X mutation in the dual luciferase assay, with an effect at the top concentration which is superior to both gentamicin and G418. When testing both compounds in vivo, a single IVT injection produced a dose-dependent increase in melanin, consistent with compound read-through activity and functional restoration of the Oca2 protein. These results establish that ELX-01 and ELX-06 produce read-through of a premature stop codon in the OCA2 gene both in vitro and in vivo. 2-MeOE2 clinical trial The in vivo results suggest that these compounds can be dosed IVT to achieve read-through at the back of the eye. These data also suggest that ELX-01 or ELX-06 could serve as a common therapeutic agent across nonsense mutation-mediated IRDs and help to establish a target exposure range for development of a sustained release IVT formulation.Since the COVID-19 outbreak, researchers have tried to characterise the novel coronavirus SARS-CoV-2 to better understand the pathogenic mechanisms of the virus and prevent further dissemination. As a consequence, there has been a bloom in scientific research papers focused on the behaviour of the virus in different environmental contexts. Nevertheless, despite these efforts and due to its novelty, available information about this coronavirus is limited, as several research studies are still ongoing. This review aims to shed light on this issue. To that end, we have examined the scientific literature to date regarding the viability of SARS-CoV-2 on surfaces and fluids or under different environmental conditions (temperature, precipitation and UV radiation). We have also addressed the role of animals in the transmission of this coronavirus.Dietary sugar is an important determinant of the development and progression of nonalcoholic fatty liver disease (NAFLD). However, the molecular mechanisms underlying the deleterious effects of sugar intake on NAFLD under energy-balanced conditions are still poorly understood. Here, we provide a comprehensive analysis of the liver lipidome and mechanistic insights into the pathogenesis of NAFLD induced by the chronic consumption of high-sugar diet (HSD). Newly weaned male Wistar rats were fed either a standard chow diet or an isocaloric HSD for 18 weeks. Livers were harvested for histological, oxidative stress, gene expression, and lipidomic analyses. Intake of HSD increased oxidative stress and induced severe liver injury, microvesicular steatosis, and ballooning degeneration of hepatocytes. Using untargeted lipidomics, we identified and quantified 362 lipid species in the liver. Rats fed with HSD displayed increased hepatic levels of triacylglycerol enriched in saturated and monounsaturated fatty acids, lipids related to mitochondrial function/structure (phosphatidylglycerol, cardiolipin, and ubiquinone), and acylcarnitine (an intermediate lipid of fatty acid beta-oxidation). HSD-fed animals also presented increased levels of some species of membrane lipids and a decreased content of phospholipids containing omega-6 fatty acids. These changes in the lipidome were associated with the downregulation of genes involved in fatty acid oxidation in the liver. In conclusion, our data suggest that the chronic intake of a HSD, even under isocaloric conditions, induces lipid overload, and inefficient/impaired fatty acid oxidation in the liver. Such events lead to marked disturbance in hepatic lipid metabolism and the development of NAFLD.The galloyl moiety is a specific structural feature which dictates, in part, the chemopreventive properties of diet-derived catechins. In ovarian cancer cells, galloylated catechins were recently demonstrated to target the transforming growth factor (TGF)-β-mediated control of the epithelial-mesenchymal transition process. The specific impact of the galloyl moiety on such signaling, however, remains poorly understood. Here, we questioned whether the sole galloyl moiety interacted with TGF-β-receptors to alter signal transduction and chemotactic migratory response in an ES-2 serous carcinoma-derived ovarian cancer cell model. In line with the LogP and LogS values of the tested molecules, we found that TGF-β-induced Smad-3 phosphorylation and cell migration were optimally inhibited, provided that the lateral aliphatic chain of the galloyl moiety reached 8-10 carbons. Functional inhibition of the TGF-β receptor (TGF-βR1) kinase activity was supported by surface plasmon resonance assays showing direct physical interaction between TGF-βR1 and the galloyl moiety. In silico molecular docking analysis predicted a model where galloylated catechins may bind TGF-βR1 within its adenosine triphosphate binding cleft in a site analogous to that of Galunisertib, a selective adenosine triphosphate-mimetic competitive inhibitor of TGF-βR1. In conclusion, our data suggest that the galloyl moiety of the diet-derived catechins provides specificity of action to galloylated catechins by positioning them within the kinase domain of the TGF-βR1 in order to antagonize TGF-β-mediated signaling that is required for ovarian cancer cell invasion and metastasis.This study investigated if the nephroprotective effect of Curcumin in streptozotocin-induced type 1 diabetes mellitus (DM) in rats involves downregulation/inhibition of p66Shc and examined the underlying mechanisms. Rats were divided into 4 groups (n = 12/group) as control, control + Curcumin (100 mg/kg), T1DM, and T1DM + Curcumin. Curcumin was administered orally to control or diabetic rats for 12 weeks daily. As compared to diabetic rats, Curcumin didn’t affect either plasma glucose or insulin levels but significantly reduced serum levels of urea, blood urea nitrogen, and creatinine, and concurrently reduced albumin/protein urea and increased creatinine clearance. It also prevented the damage in renal tubules and mitochondria, mesangial cell expansion, the thickness of the basement membrane. Mechanistically, Curcumin reduced mRNA and protein levels of collagen I/III and transforming growth factor- β-1 (TGF-β1), reduced inflammatory cytokines levels, improved markers of mitochondrial function, and suppressed the release of cytochrome-c and the activation of caspase-3.