Project description:Alzheimer’s disease (AD) is a chronic neurodegenerative disease needing effective therapeutics urgently. Sildenafil, one of the approved phosphodiesterase-5 inhibitors, has been implicated as having potential beneficial effect in AD. We showed that sildenafil usage is associated with reduced likelihood of AD across four new drug compactor cohorts, including bumetanide, furosemide, spironolactone, and nifedipine. For instance, sildenafil usage is associated with a 54% reduced prevalence of AD in MarketScan® (hazard ratio [HR] = 0.46, 95% CI 0.32-0.66) and a 30% reduced prevalence of AD in Clinformatics® (HR = 0.70, 95% CI 0.49-1.00) compared to spironolactone. We found that sildenafil treatment significantly reduced tau hyper-phosphorylation (pTau181, pTau205) in a dose-dependent manner in both familial and sporadic AD patient derived neurons. Further RNA-seq data analysis of sildenafil-treated AD patient iPSC-derived neurons revealed that sildenafil specifically targeting AD related genes and molecular pathways involved in axon guidance, AD-presenilin, neurogenesis, neurodegeneration, synaptic dysregulation, vascular smooth muscle contraction (VSMC) and cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling pathway, mechanistically supporting the potential beneficial effect of sildenafil in AD. These real-world patient data validation and mechanistic observations from patient iPSC-derived neurons further suggested that sildenafil is a potential repurposable drug for AD. However, randomized clinical trials are required to validate sildenafil as a potential treatment of AD.
Project description:Recently, it is reported that sildenafil suppresses maturation of PO-induced miRNAs. However, the mechanism of how sildenafil coupled NO-cGMP-PKG signaling affects this maturation was not unraveled. Here, we show that PERK-mediated suppression of miRNAs by sildenafil is vital to keep mitochondrial homeostasis, using cardiac-specific PERK knockout (cko) mice.
Project description:Differential expression in the presence and absence of sildenafil following romidepsin We performed cDNA microarray analysis using an GeneChip® Human Gene 2.0 ST Array to identify cellular genes that may be differentially expressed in the presence and absence of sildenafil following romidepsin treatment in SNK6
Project description:Molecular networking has become a key method to visualize and annotate the chemical space in non-targeted mass spectrometry data. We present feature-based molecular networking (FBMN) as an analysis method in the Global Natural Products Social Molecular Networking (GNPS) infrastructure that builds on chromatographic feature detection and alignment tools. FBMN enables quantitative analysis and resolution of isomers, including from ion mobility spectrometry.
Project description:The only validated treatment to prevent brain damage associated with hypoxia-ischemia (HI) encephalopathy of the newborn is controlled hypothermia with limited benefits. Additional putative neuroprotective drug candidates include sildenafil citrate, a phosphodiesterase-type 5 inhibitor. The main objective of this preclinical study is to assess its ability to reduce HI-induced neuroinflammation, in particular through its potential effect on microglial activation. HI was induced in P10 Sprague–Dawley rats by unilateral carotid permanent artery occlusion and hypoxia (HI), and treated by either hypothermia (HT) alone, Sildenafil (Sild) alone or combined treatment (SildHT). Lesion size, glial activation were analyzed by immunohistochemistry, qRT-PCR and proteomic analyses performed at P13. Exposure to any treatment was not associated with significant reduction in lesions size both in cerebral cortex and hippocampus, 72h after HI. Significant reductions in either Iba1+ (within the ipsilateral hemisphere) or GFAP+ cells (within the ipsilateral hippocampus) were observed in SildHT group, but not in the other treatment groups. In microglia sorted cells, pro-inflammatory markers, ie. Il1b, Il6, Nos2, and CD86 were significantly downregulated in SildHT treatment group only. These changes were restricted to ipsilateral hemisphere, were not evidenced in sorted astrocytes, and were not sex-dependent. Proteomic analyses in sorted microglia refined the pro-inflammatory effect of HI and confirmed a biologically relevant impact of SildHT on specific molecular pathways including notably genes related to neutrophilic functions. Our findings demonstrate that Sildenafil combined with controlled hypothermia confers maximum effect to mitigate microglial activation induced by HI through complex proteomic regulation. The reduction of neuroinflammation induced by Sildenafil may represent an interesting therapeutic strategy for neonatal neuroprotection.
Project description:This paper investigates the utilization of commercial masterbatches of graphene nanoplatelets to improve the properties of neat polymer and wood fiber composites manufactured by conventional processing methods. The effect of aspect ratio of the graphene platelets (represented by the different number of layers in the nanoplatelet) on the properties of high-density polyethylene (HDPE) is discussed. The composites were characterized for their mechanical properties (tensile, flexural, impact) and physical characteristics (morphology, crystallization, and thermal stability). The effect of the addition of nanoplatelets on the thermal conductivity and diffusivity of the reinforced polymer with different contents of reinforcement was also investigated. In general, the mechanical performance of the polymer was enhanced at the presence of either of the reinforcements (graphene or wood fiber). The improvement in mechanical properties of the nanocomposite was notable considering that no compatibilizer was used in the manufacturing. The use of a masterbatch can promote utilization of nano-modified polymer composites on an industrial scale without modification of the currently employed processing methods and facilities.
Project description:Graphene nanoplatelets (GNPs) were prepared using the electrolytic exfoliation method on graphite foil in an ammonium sulfate solution. A series of experiments were conducted in order to optimize the production of the flakes by varying the pH of the solution, applied voltage and current, duration of electrolysis, temperature in the electrolytic system, and type and duration of the ultrasound interaction. The quality of the produced graphene nanoplatelets was analyzed using X-ray diffraction, Raman and IR spectroscopy, and TEM.
Project description:The intermediate filament protein Nestin serves as a biomarker for stem cells and has been used to identify subsets of cancer stem-like cells. However, the mechanistic contributions of Nestin to cancer pathogenesis are not understood. Here we report that Nestin binds the hedgehog pathway transcription factor Gli3 to mediate the development of medulloblastomas of the hedgehog subtype. In a mouse model system, Nestin levels increased progressively during medulloblastoma formation resulting in enhanced tumor growth. Conversely, loss of Nestin dramatically inhibited proliferation and promoted differentiation. Mechanistic investigations revealed that the tumor-promoting effects of Nestin were mediated by binding to Gli3, a zinc finger transcription factor that negatively regulates hedgehog signaling. Nestin binding to Gli3 blocked Gli3 phosphorylation and its subsequent proteolytic processing, thereby abrogating its ability to negatively regulate the hedgehog pathway. Our findings show how Nestin drives hedgehog pathway-driven cancers and uncover in Gli3 a therapeutic target to treat these malignancies.