Dietary Fat, Sugar Consumption, and Cardiorespiratory Fitness in Patients With Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is associated with obesity and, indirectly, with unhealthy diet. The role of dietary components in HFpEF is, however, largely unknown. In this study, the authors showed that in obese HFpEF patients, consumption of unsaturated fatty acids (UFA), was associated with better cardiorespiratory fitness, and UFA consumption correlated with better diastolic function and with greater fat-free mass. Similarly, mice fed with a high-fat diet rich in UFA and low in sugars had preserved myocardial function and reduced weight gain. Randomized clinical trials increasing dietary UFA consumption and reducing sugar consumption are warranted to confirm and expand our findings

Telescoped approach to aryl hydroxymethylation in the synthesis of a key pharmaceutical intermediate

An efficient synthetic approach leading to introduction of the hydroxymethyl group to an aryl moiety via combination of the Bouveault formylation and hydride reduction has been optimized using a rational, mechanistic-based approach. This approach enabled telescoping of the two steps into a single efficient process, readily amenable to scaleup

Technology and thermal stability of ALGAN/GAN HFETs

New approaches towards high reliable thermal stable ohmic and Schottky contacts for GaN/AlGaN-HFETs have been developed and implemented in device structures. The contact technology has been systematically optimized towards i) good electrical properties, ii) superior contact morphology and contour definition and Hi) high reliability and thermal stability. HFETs employing source/drain contacts based on WSiN diffusion barriers sandwiched between an Ti/Al/Ti/Au internal layer system and an overlayer metal as well as WSiN/Au and Ir/Au gate contacts have demonstrated long term stability at 400°C, Even after temperature storage tests at 500°C no significant device degradation could be detected. Ir/Au Schottky gates have found to be stable at the rather high level of Schottky barrier height of about 1.1 eV resulting in dramatically reduced leakage currents as compared to standard Pt/Ti/Au gate contacts to GaN-HFETs

Cooperative interactions at M-2 muscarinic acetylcholine receptors: Structure/activity relationships in stepwise shortened bispyridinium- and bis(ammonio)alkane-type allosteric modulators

WOS: 000181555000039PubMed ID: 12675159Muscarinic M-2-receptors allow for divergent modes of allosteric action, depending on the structure of the allosteric modulator. Phthalimido-substituted bis(ammonio)alkane-type modulators belong to the common mode allosteric agents, whereas a physicochemically closely related bispyridinium-oxime with dichlorobenzyl-substituents at both ends is an atypical agent. Here, we compared the actions of stepwise shortened compounds composed of the phthalimido moiety and middle chains of either the bispyridinium- or the bis(ammonio)alkane-type. Allosteric interactions were measured in pig M-2 receptors with the orthosteric probe [H-3]N-methylscopolamine ([H-3]NMS) to label the acetylcholine binding site of the receptors. Dissociation and equilibrium binding experiments revealed parallel structure/activity-relationships in both series of compounds with regard to the cooperativity of interaction with [H-3]NMS and to the underlying binding affinities in radioligand-occupied and free receptors. In conclusion, the findings are in line with the hypothesis that the phthalimido-moiety, but not the middle chain, is pivotal for the topology of interaction with the M-2-receptor protein

Suberoylanilide hydroxamic acid (SAHA) has potent anti-glioma properties in vitro, ex vivo and in vivo

Current treatment modalities for malignant gliomas do not allow long-term survival. Here, we identify suberoylanilide hydroxamic acid (SAHA), an inhibitor of histone deacetylases (HDAC), as an effective experimental anti-glioma agent. Administration of SAHA to various glioma cell lines obtained from human, rat and mouse inhibited tumour cell growth in a range of 1-10 microm. This anti-glioma property is associated with up-regulation of the cell cycle control protein p21/WAF, as well as the induction of apoptosis. A novel tumour invasion model using slice cultures of rat brain corroborated the anti-glioma properties of SAHA in the organotypic brain environment. In this model, glioma invasion compromised adjacent brain parenchyma, and this tumour-associated cytotoxicity could be inhibited by SAHA. In addition, a 10-fold dose escalation experiment did not challenge the viability of cultured brain slices. In vivo, a single intratumoural injection of SAHA 7 days after orthotopic implantation of glioma cells in syngeneic rats doubled their survival time. These observations identify chromatin-modifying enzymes as possible and promising targets for the pharmacotherapy of malignant gliomas

In vitro and ex vivo evaluation of second-generation histone deacetylase inhibitors for the treatment of spinal muscular atrophy

Among a panel of histone deacetylase (HDAC) inhibitors investigated, suberoylanilide hydroxamic acid (SAHA) evolved as a potent and non-toxic candidate drug for the treatment of spinal muscular atrophy (SMA), an alpha-motoneurone disorder caused by insufficient survival motor neuron (SMN) protein levels. SAHA increased SMN levels at low micromolar concentrations in several neuroectodermal tissues, including rat hippocampal brain slices and motoneurone-rich cell fractions, and its therapeutic capacity was confirmed using a novel human brain slice culture assay. SAHA activated survival motor neuron gene 2 (SMN2), the target gene for SMA therapy, and inhibited HDACs at submicromolar doses, providing evidence that SAHA is more efficient than the HDAC inhibitor valproic acid, which is under clinical investigation for SMA treatment. In contrast to SAHA, the compounds m-Carboxycinnamic acid bis-Hydroxamide, suberoyl bishydroxamic acid and M344 displayed unfavourable toxicity profiles, whereas MS-275 failed to increase SMN levels. Clinical trials have revealed that SAHA, which is under investigation for cancer treatment, has a good oral bioavailability and is well tolerated, allowing in vivo concentrations shown to increase SMN levels to be achieved. Because SAHA crosses the blood-brain barrier, oral administration may allow deceleration of progressive alpha-motoneurone degeneration by epigenetic SMN2 gene activation