Substituted anilides from chitin-based 3-acetamido-furfural

The synthesis of aromatic compounds from biomass-derived furans is a key strategy in the pursuit of a sustainable economy. Within this field, a Diels-Alder/aromatization cascade reaction with chitin-based furans is emerging as a powerful tool for the synthesis of nitrogen-containing aromatics. In this study we present the conversion of chitin-based 3-acetamido-furfural (3A5F) into an array of di- and tri-substituted anilides in good to high yields (62-90%) via a hydrazone mediated Diels-Alder/aromatization sequence. The addition of acetic anhydride expands the dienophile scope and improves yields. Moreover, replacing the typically used dimethyl hydrazone with its pyrrolidine analogue, shortens reaction times and further increases yields. The hydrazone auxiliary is readily converted into either an aldehyde or a nitrile group, thereby providing a plethora of functionalized anilides. The developed procedure was also applied to 3-acetamido-5-acetylfuran (3A5AF) to successfully prepare a phthalimide. </p

Pharmacokinetic Modeling of [11C]GSK-189254, PET Tracer Targeting H3 Receptors, in Rat Brain

[Image: see text] The histamine H(3) receptor has been considered as a target for the treatment of various central nervous system diseases. Positron emission tomography (PET) studies with the radiolabeled potent and selective histamine H(3) receptor antagonist [(11)C]GSK-189254 in rodents could be used to examine the mechanisms of action of novel therapeutic drugs or to assess changes of regional H(3) receptor density in animal models of neurodegenerative disease. [(11)C]GSK-189254 was intravenously administered to healthy Wistar rats (n = 10), and a 60 min dynamic PET scan was carried out. Arterial blood samples were obtained during the scan to generate a metabolite-corrected plasma input function. PET data were analyzed using a one-tissue compartment model (1T2k), irreversible (2T3k) or reversible two-tissue compartment models (2T4k), graphical analysis (Logan and Patlak), reference tissue models (SRTM and SRTM2), and standard uptake values (SUVs). The Akaike information criterion and the standard error of the estimated parameters were used to select the most optimal quantification method. This study demonstrated that the 2T4k model with a fixed blood volume fraction and Logan graphical analysis can best describe the kinetics of [(11)C]GSK-189254 in the rat brain. SUV(40–60) and the reference tissue-based measurements DVR(2T4k), BP(ND)(SRTM), and SUV ratio could also be used as a simplified method to estimate H(3) receptor availability in case blood sampling is not feasible

Binding of the Dual-Action Anti-Parkinsonian Drug AG-0029 to Dopamine D-2 and Histamine H-3 Receptors:A PET Study in Healthy Rats

Introduction: Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor dysfunction and a diverse range of nonmotor symptoms. Functional relationships between the dopaminergic and histaminergic systems suggest that dual-action pharmaceuticals like AG-0029 (D-2/D-3 agonist/H-3 antagonist) could ameliorate both the motor and cognitive symptoms of PD. The current study aimed to demonstrate the interaction of AG-0029 with its intended targets in the mammalian brain using positron emission tomography (PET). Methods: Healthy male Wistar rats were scanned with a small-animal PET camera, using either the dopamine D-2/D-3 receptor ligand [C-11]raclopride or the histamine H-3 receptor ligand [C-11]GSK-189254, before and after treatment with an intravenous, acute, single dose of AG-0029. Dynamic [C-11]raclopride PET data (60 min duration) were analyzed using the simplified reference tissue model 2 (SRTM2) with cerebellum as reference tissue and the nondisplaceable binding potential as the outcome parameter. Data from dynamic [C-11]GSK-189254 scans (60 min duration) with arterial blood sampling were analyzed using Logan graphical analysis with the volume of distribution (V-T) as the outcome parameter. Receptor occupancy was estimated using a Lassen plot. Results: Dopamine D-2/3 receptor occupancies in the striatum were 22.6 +/- 18.0 and 84.0 +/- 3.5% (mean +/- SD) after administration of 0.1 and 1 mg/kg AG-0029, respectively. In several brain regions, the V-T values of [C-11]GSK-189254 were significantly reduced after pretreatment of rats with 1 or 10 mg/kg AG-0029. The H-3 receptor occupancies were 11.9 +/- 8.5 and 40.3 +/- 11.3% for the 1 and 10 mg/kg doses of AG-0029, respectively. Conclusions: Target engagement of AG-0029 as an agonist at dopamine D-2/D-3 receptors and an antagonist at histamine H-3 receptors could be demonstrated in the rat brain with [C-11]raclopride and [C-11]GSK-189254 PET, respectively. The measured occupancy values reflect the previously reported high (subnanomolar) affinity of AG-0029 to D-2/D-3 and moderate (submicromolar) affinity to H-3 receptors

Lipoxygenases and Poly(ADP-Ribose) Polymerase in Amyloid Beta Cytotoxicity

The 12/15-lipoxygenase(s) (LOX), poly(ADP-ribose) polymerase (PARP-1) activity and mitochondrial apoptosis inducing factor (AIF) protein in the amyloid β (Aβ) toxicity were investigated in PC12 cells that express either wild-type (APPwt) or double Swedish mutation (APPsw) forms of human Aβ precursor protein. Different levels of Aβ secretion and free radicals formation characterize these cells. The results demonstrated a relationship between the Aβ levels and LOX protein expression and activity. High Aβ concentration in APPsw cells correlated with a significant increase in free radicals and LOX activation, which leads to translocation of p65/NF-κB into the nucleus. An increase in AIF expression in mitochondria was observed concurrently with inhibition of PARP-1 activity in the nuclear fraction of APPsw cells. We suggested that AIF accumulation in mitochondria may be involved in adaptive/protective processes. However, inhibition of PARP-1 may be responsible for the disturbances in transcription and DNA repair as well as the degeneration of APP cells. Under conditions of increased nitrosative stress, evoked by the nitric oxide donor, sodium nitroprusside (SNP, 0.5 mM), 70–80% of all cells types died after 24 h, significantly more in APPsw cells. There was no further significant change in mitochondrial AIF level and PARP-1 activity compared to corresponding non-treated cells. Only one exception was observed in PC12 control, where SNP significantly inhibits PARP-1 activity. Moreover, SNP significantly activated gene expression for 12/15-LOX in all types of investigated cells. Inhibitors of all LOX isoforms and specific inhibitor of 12-LOX enhanced the survival of cells that were subjected to SNP. We conclude that the LOX pathways may play a role in Aβ toxicity and in nitrosative-stress-induced cell death and that inhibition of these pathways offers novel protective strategies

Superconducting nanowire single-photon detectors: physics and applications

Single-photon detectors based on superconducting nanowires (SSPDs or SNSPDs) have rapidly emerged as a highly promising photon-counting technology for infrared wavelengths. These devices offer high efficiency, low dark counts and excellent timing resolution. In this review, we consider the basic SNSPD operating principle and models of device behaviour. We give an overview of the evolution of SNSPD device design and the improvements in performance which have been achieved. We also evaluate device limitations and noise mechanisms. We survey practical refrigeration technologies and optical coupling schemes for SNSPDs. Finally we summarize promising application areas, ranging from quantum cryptography to remote sensing. Our goal is to capture a detailed snapshot of an emerging superconducting detector technology on the threshold of maturity.Comment: 27 pages, 5 figures, Review article preprint versio

Activation and modulation of antiviral and apoptotic genes in pigs infected with classical swine fever viruses of high, moderate or low virulence

The immune response to CSFV and the strategies of this virus to evade and suppress the pigs’ immune system are still poorly understood. Therefore, we investigated the transcriptional response in the tonsils, median retropharyngeal lymph node (MRLN), and spleen of pigs infected with CSFV strains of similar origin with high, moderate, and low virulence. Using a porcine spleen/intestinal cDNA microarray, expression levels in RNA pools prepared from infected tissue at 3 dpi (three pigs per virus strain) were compared to levels in pools prepared from uninfected homologue tissues (nine pigs). A total of 44 genes were found to be differentially expressed. The genes were functionally clustered in six groups: innate and adaptive immune response, interferon-regulated genes, apoptosis, ubiquitin-mediated proteolysis, oxidative phosphorylation and cytoskeleton. Significant up-regulation of three IFN-γ-induced genes in the MRLNs of pigs infected with the low virulence strain was the only clear qualitative difference in gene expression observed between the strains with high, moderate and low virulence. Real-time PCR analysis of four response genes in all individual samples largely confirmed the microarray data at 3 dpi. Additional PCR analysis of infected tonsil, MRLN, and spleen samples collected at 7 and 10 dpi indicated that the strong induction of expression of the antiviral response genes chemokine CXCL10 and 2′–5′ oligoadenylate synthetase 2, and of the TNF-related apoptosis-inducing ligand (TRAIL) gene at 3 dpi, decreased to lower levels at 7 and 10 dpi. For the highly and moderately virulent strains, this decrease in antiviral and apoptotic gene expression coincided with higher levels of virus in these immune tissues

Potential biological role of poly (ADP-ribose) polymerase (PARP) in male gametes

Maintaining the integrity of sperm DNA is vital to reproduction and male fertility. Sperm contain a number of molecules and pathways for the repair of base excision, base mismatches and DNA strand breaks. The presence of Poly (ADP-ribose) polymerase (PARP), a DNA repair enzyme, and its homologues has recently been shown in male germ cells, specifically during stage VII of spermatogenesis. High PARP expression has been reported in mature spermatozoa and in proven fertile men. Whenever there are strand breaks in sperm DNA due to oxidative stress, chromatin remodeling or cell death, PARP is activated. However, the cleavage of PARP by caspase-3 inactivates it and inhibits PARP's DNA-repairing abilities. Therefore, cleaved PARP (cPARP) may be considered a marker of apoptosis. The presence of higher levels of cPARP in sperm of infertile men adds a new proof for the correlation between apoptosis and male infertility. This review describes the possible biological significance of PARP in mammalian cells with the focus on male reproduction. The review elaborates on the role played by PARP during spermatogenesis, sperm maturation in ejaculated spermatozoa and the potential role of PARP as new marker of sperm damage. PARP could provide new strategies to preserve fertility in cancer patients subjected to genotoxic stresses and may be a key to better male reproductive health