Kynurenic acid amides as novel NR2B selective NMDA receptor antagonists

A novel series of kynurenic acid amides, ring-enlarged derivatives of indole-2-carboxamides, was prepared and identified as in vivo active NR2B subtype selective NMDA receptor antagonists. The synthesis and SAR studies are discussed.     

SAR of a novel 'Anthranilamide Like' series of VEGFR-2, multi protein kinase inhibitors for the treatment of cancer

Novel anthranilamides were surprisingly found to exert additional activity on B-RAF. Corresponding thiophene, pyrazole, and thiazole core analogs were prepared as VEGFR-2 inhibitors with c-KIT, and B-RAF activity. Compounds in the phenyl, thiophene, and thiazole series are in vivo active.     

Dreaming and unilateral brain lesions: A multiple lesion case analysis.

Lesions causing cessation of dreaming are thought to be more frequently left hemispheric than right hemispheric. However, reports of this phenomenon have not excluded epileptic cases and have not reported handedness, etiology of the lesion, lesion location, comorbidity, gender, age, and so forth, on a case-by-case basis. Some authors were also concerned about aphasia being a cause of dream loss and its lateralization, but they never measured its impact statistically. The present investigation reviews cases of post lesion dream cessation that answered to strict criteria for testing hemispheric lateralization and the effect of aphasia on it. In the 31 subjects, left hemisphere lesions were significantly more frequent than right, as predicted, but the left hemisphere lesions were very often associated with aphasia. Nonaphasic cases of total dream loss had lesions equally often in the right and in the left hemisphere. It is proposed that aphasia deprives patients of a second dream-encoding system, which is important enough to induce amnesia of dream occurrence. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Toward Clinically Compatible Phase-Contrast Mammography

Phase-contrast mammography using laboratory X-ray sources is a promising approach to overcome the relatively low sensitivity and specificity of clinical, absorption-based screening. Current research is mostly centered on identifying potential diagnostic benefits arising from phase-contrast and dark-field mammography and benchmarking the latter with conventional state-of-the-art imaging methods. So far, little effort has been made to adjust this novel imaging technique to clinical needs. In this article, we address the key points for a successful implementation to a clinical routine in the near future and present the very first dose-compatible and rapid scan-time phase-contrast mammograms of both a freshly dissected, cancer-bearing mastectomy specimen and a mammographic accreditation phantom.     

Expression of soluble Saccharomyces cerevisiae alcohol dehydrogenase in Escherichia coli applicable to oxido-reduction bioconversions

Six-carbon aldehydes and alcohols belong to flavours and fragrances with wide application in the food, feed, cosmetic, chemical and pharmaceutical sectors. In the present study, we prepared the expression system for production of recombinant yeast alcohol dehydrogenase 1 (YADH1) from Saccharomyces cerevisiae which is suitable also for catalysis of the interconversion of C-6 aldehydes and alcohols. We have demonstrated that an effective three-step strategy can overcome the insolubility problems during YADH1 production in Escherichia coli. We used trxB and gor deficient expression strain, decreased concentration of isopropyl β-D-1-thiogalactopyranoside and lowered temperature to 20°C during induction. Finally, kinetic parameters of recombinant YADH1 were determined and we concluded it is a promising enzyme also for the interconversion of C-6 alcohols/aldehydes in green note volatile production.     

Relationship of Circulating Hyaluronic Acid Levels to Disease Control in Asthma and Asthmatic Pregnancy

Uncontrolled asthma is a risk factor for pregnancy-related complications. Hyaluronic acid (HA), a potential peripheral blood marker of tissue fibrosis in various diseases, promotes eosinophil survival and plays a role in asthmatic airway inflammation as well as in physiological processes necessary to maintain normal pregnancy; however the level of circulating HA in asthma and asthmatic pregnancy is unknown. We investigated HA levels in asthmatic patients (N = 52; asthmatic pregnant (AP) N = 16; asthmatic non-pregnant (ANP) N = 36) and tested their relationship to asthma control. Serum HA level was lower in AP than in ANP patients (27 [24.7–31.55] vs. 37.4 [30.1–66.55] ng/mL, p = 0.006); the difference attenuated to a trend after its adjustment for patients’ age (p = 0.056). HA levels and airway resistance were positively (r = 0.467, p = 0.004), HA levels and Asthma Control Test (ACT) total score inversely (r = −0.437, p = 0.01) associated in ANP patients; these relationships remained significant even after their adjustments for age. The potential value of HA in the determination of asthma control was analyzed using ROC analysis which revealed that HA values discriminate patients with ACT total score ≥20 (controlled patients) and <20 (uncontrolled patients) with a 0.826 efficacy (AUC, 95% CI: 0.69–0.97, p = 0.001) when 37.4 ng/mL is used as cut-off value in ANP group, and with 0.78 efficacy (AUC, 95% CI: 0.65–0.92, p = 0.0009) in the whole asthmatic cohort. In conclusion circulating HA might be a marker of asthma control, as it correlates with airway resistance and has good sensitivity in the detection of impaired asthma control. Decrease of HA level in pregnancy may be the consequence of pregnancy induced immune tolerance.     

Soluble semicarbazide-sensitive amine oxidase (SSAO) activity is related to oxidative stress and subchronic inflammation in streptozotocin-induced diabetic rats

Diabetes is known to increase the risk of Alzheimer's disease (AD) and vascular dementia via oxidative stress and inflammation. There are speculations that SSAO activity might be related to the development of AD. Our aim was to investigate whether changes of soluble SSAO activity, oxidative stress and inflammation markers are related to each other in diabetes. Soluble and tissue-bound SSAO activities (from serum and aorta, respectively) were determined in streptozotocin (STZ)-induced diabetic rats without insulin treatment, receiving insulin once, or twice daily compared to control animals. After three weeks of treatment soluble and tissue-bound SSAO activities (seSSAO and aoSSAO, respectively), serum total antioxidant status (TAS), high sensitivity C-reactive protein (hsCRP), fructose amine levels and routine laboratory parameters were determined. SeSSAO activity significantly increased in the diabetic groups without treatment and receiving insulin once daily, and a marked decrease in aoSSAO activity was seen in all diabetic groups. Increased oxidative stress was correlated with hsCRP elevation, while hsCRP and seSSAO activity were also significantly correlated. In all groups seSSAO and aoSSAO activities were in negative correlation with each other. Our results support the view that poor metabolic control leads to increased oxidative stress, which in turn may cause the elevation of hsCRP levels. Soluble SSAO on the one hand acts as an adhesion molecule - thus possibly being a factor responsible for the late complications of diabetes - and on the other hand, it may contribute to oxidative stress. Our parsimonious conclusion is that there is a relation between the risk factors of AD and vascular dementia (diabetes, oxidative stress and chronic inflammation) and SSAO activity, which may originate from the vessel wall.     

Regulation of ENaC and CFTR expression with K+ channel modulators and effect on fluid absorption across alveolar epithelial cells

In a recent study (Leroy C, Dagenais A, Berthiaume Y, and Brochiero E. Am J Physiol Lung Cell Mol Physiol 286: L1027-L1037, 2004), we identified an ATP-sensitive K(+) (K(ATP)) channel in alveolar epithelial cells, formed by inwardly rectifying K(+) channel Kir6.1/sulfonylurea receptor (SUR)2B subunits. We found that short applications of K(ATP), voltage-dependent K(+) channel KvLQT1, and calcium-activated K(+) (K(Ca)) channel modulators modified Na(+) and Cl(-) currents in alveolar monolayers. In addition, it was shown previously that a K(ATP) opener increased alveolar liquid clearance in human lungs by a mechanism possibly related to epithelial sodium channels (ENaC). We therefore hypothesized that prolonged treatment with K(+) channel modulators could induce a sustained regulation of ENaC activity and/or expression. Alveolar monolayers were treated for 24 h with inhibitors of K(ATP), KvLQT1, and K(Ca) channels identified by PCR. Glibenclamide and clofilium (K(ATP) and KvLQT1 inhibitors) strongly reduced basal transepithelial current, amiloride-sensitive Na(+) current, and forskolin-activated Cl(-) currents, whereas pinacidil, a K(ATP) activator, increased them. Interestingly, K(+) inhibitors or membrane depolarization (induced by valinomycin in high-K(+) medium) decreased alpha-, beta-, and gamma-ENaC and CFTR mRNA. alpha-ENaC and CFTR proteins also declined after glibenclamide or clofilium treatment. Conversely, pinacidil augmented ENaC and CFTR mRNAs and proteins. Since alveolar fluid transport was found to be driven, at least in part, by Na(+) transport through ENaC, we tested the impact of K(+) channel modulators on fluid absorption across alveolar monolayers. We found that glibenclamide and clofilium reduced fluid absorption to a level similar to that seen in the presence of amiloride, whereas pinacidil slightly enhanced it. Long-term regulation of ENaC and CFTR expression by K(+) channel activity could benefit patients with pulmonary diseases affecting ion transport and fluid clearance.