75 research outputs found
Glycine propionyl-L-carnitine increases plasma nitrate/nitrite in resistance trained men
We have recently demonstrated that oral intake of glycine propionyl-L-carnitine (GPLC) increases plasma nitrate/nitrite (NOx), a surrogate measure of nitric oxide production. However, these findings were observed at rest, and in previously sedentary subjects
PDE 7 Inhibitors: New Potential Drugs for the Therapy of Spinal Cord Injury
BACKGROUND: Primary traumatic mechanical injury to the spinal cord (SCI) causes the death of a number of neurons that to date can neither be recovered nor regenerated. During the last years our group has been involved in the design, synthesis and evaluation of PDE7 inhibitors as new innovative drugs for several neurological disorders. Our working hypothesis is based on two different facts. Firstly, neuroinflammation is modulated by cAMP levels, thus the key role for phosphodiesterases (PDEs), which hydrolyze cAMP, is undoubtedly demonstrated. On the other hand, PDE7 is expressed simultaneously on leukocytes and on the brain, highlighting the potential crucial role of PDE7 as drug target for neuroinflammation. METHODOLOGY/PRINCIPAL FINDINGS: Here we present two chemically diverse families of PDE7 inhibitors, designed using computational techniques such as virtual screening and neuronal networks. We report their biological profile and their efficacy in an experimental SCI model induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. We have selected two candidates, namely S14 and VP1.15, as PDE7 inhibitors. These compounds increase cAMP production both in macrophage and neuronal cell lines. Regarding drug-like properties, compounds were able to cross the blood brain barrier using parallel artificial membranes (PAMPA) methodology. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and production of a range of inflammatory mediators, tissue damage, and apoptosis. Treatment of the mice with S14 and VP1.15, two PDE7 inhibitors, significantly reduced the degree of spinal cord inflammation, tissue injury (histological score), and TNF-α, IL-6, COX-2 and iNOS expression. CONCLUSIONS/SIGNIFICANCE: All these data together led us to propose PDE7 inhibitors, and specifically S14 and VP1.15, as potential drug candidates to be further studied for the treatment of SCI
CRISPR-mediated direct mutation of cancer genes in the mouse liver
The study of cancer genes in mouse models has traditionally relied on genetically-engineered strains made via transgenesis or gene targeting in embryonic stem (ES) cells1. Here we describe a new method of cancer model generation using the CRISPR/Cas system in vivo in wild-type mice. We have used hydrodynamic injection to deliver a CRISPR plasmid DNA expressing Cas9 and single guide RNAs (sgRNAs)2–4 to the liver and directly target the tumor suppressor genes Pten5 and p536, alone and in combination. CRISPR-mediated Pten mutation led to elevated Akt phosphorylation and lipid accumulation in hepatocytes, phenocopying the effects of deletion of the gene using Cre-LoxP technology7, 8. Simultaneous targeting of Pten and p53 induced liver tumors that mimicked those caused by Cre-loxP-mediated deletion of Pten and p53. DNA sequencing of liver and tumor tissue revealed insertion or deletion (indel) mutations of the tumor suppressor genes, including bi-allelic mutations of both Pten and p53 in tumors. Furthermore, co-injection of Cas9 plasmids harboring sgRNAs targeting the β-Catenin gene (Ctnnb1) and a single-stranded DNA (ssDNA) oligonucleotide donor carrying activating point mutations led to the generation of hepatocytes with nuclear localization of β-Catenin. This study demonstrates the feasibility of direct mutation of tumor suppressor genes and oncogenes in the liver using the CRISPR/Cas system, which presents a new avenue for rapid development of liver cancer models and functional genomics
Effective behaviour change techniques for physical activity and healthy eating in overweight and obese adults; systematic review and meta-regression analyses
Use of the REG1 anticoagulation system in patients with acute coronary syndromes undergoing percutaneous coronary intervention: results from the phase II RADAR-PCI study
We sought to determine the feasibility of conducting percutaneous coronary intervention (PCI) in high-risk acute coronary syndrome (ACS) patients utilising the REG1 system consisting of pegnivacogin, an aptameric factor IXa inhibitor, and its controlling agent anivamersen.
In RADAR, ACS patients were randomised to pegnivacogin 1 mg/kg with 25%, 50%, 75%, or 100% anivamersen reversal or unfractionated heparin. Of the 640 patients randomised, 388 (61%) underwent PCI. Major modified ACUITY 30-day bleeding rates were 18% (25% reversal), 12% (50% reversal), 9% (75% reversal), and 7% (100% reversal), compared with 11% with heparin. The corresponding total bleeding rates were 68%, 39%, 35%, 34%, and 38% (heparin). Ischaemic events were less frequent in those receiving pegnivacogin versus heparin (4.4% vs. 7.3%, p=0.3). Thirty-day urgent TVR (1.1% vs. 0.9%, p=1.0), myocardial infarction (4.0% vs. 6.4%, p=0.3), and angiographic complication (11.2% and 10.8%, p=0.9) rates were similar with pegnivacogin and heparin. There were no incidences of clot formation on guidewires or catheters.
High-level factor IXa inhibition in ACS patients undergoing PCI, with at least 50% reversal, has a favourable bleeding profile and appears effective at suppressing ischaemic events and thrombotic complications. Larger phase trials in PCI are warranted.
ClinicalTrials.gov NCT00932100
Fatal pneumococcal septicemia in a girl with visceral heterotaxy and polysplenia: a case report
An in vivo strategy to counteract post-administration anticoagulant activity of azido-Warfarin
Drugs, usually long acting and metabolically stable molecules, might be the source of adverse effects triggered by complex drug interactions, anaphylaxis and drug-induced coagulopathy. To circumvent this growing drug safety issue, we herein investigate the opportunity offered by bio-orthogonal chemistry for in vivo drug neutralization. We design a small-molecule anticoagulant drug (Warfarin) containing an azide group that acts as a safety pin. It allows drug deactivation and restoration of physiological coagulation via in vivo click reaction with a suitable cyclooctyne-based neutralizing agent. In this strategy, the new molecule formed by reaction of the drug and the antidote is deprived of biological activity and prone to fast renal clearance. This 'Click &Clear' approach lays ground for new strategies in designing drugs with switchable biophysical properties
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