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Abboud J.-L.M.,Kyushu University | Alkorta I.,Institute of Medical Chemistry | Davalos J.Z.,CSIC - Institute of Polymer Science and Technology | Koppel I.A.,CSIC - Institute of Physical Chemistry "Rocasolano" | And 4 more authors.
Bulletin of the Chemical Society of Japan | Year: 2016

We report herein the results of an experimental and computational study of adamantylideneadamantane (1) and a variety of substituted ethylenic hydrocarbons. The standard enthalpy of formation in the gas phase as well as the gas-phase basicity (GA) of 1 were experimentally determined for the first time, respectively by calorimetric techniques and FT-ICR spectrometry. In parallel, computational studies at the MP2/ 6-311+G(d,p), G3(MP2), and G3 levels were performed on the neutral (1) and protonated (1H+ ). The agreement with experimental results was very good. The structures of 1 and1H+ were subject to treatment by "Atoms in Molecules" in order to assess the characteristics of the closest H£H interactions involving both adamantane moieties. Also, the secondorder perturbation analysis within the Natural Bond Orbital Theory methodology shows four degenerate charge-transfer interactions between the ó C?H bond of one of the adamantyl subunits towards the ó∗ C?H of the other adamantyl subunit. The standard enthalpies of formation of new adamantyl compounds were obtained using our experimental data. The computational study of a variety of ethylenic compounds including cyclohexylidenecyclohexane and several alkyl-substituted ethylenes using isodesmic and homodesmotic reactions was carried out. This study was extended to their proton affinities and gas-phase basicities. © 2016 The Chemical Society of Japan.


Serrano A.,Hospital Regional Universitario Carlos Haya | Serrano A.,Institute Salud Carlos III | Pavon F.J.,Hospital Regional Universitario Carlos Haya | Pavon F.J.,Institute Salud Carlos III | And 17 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2012

Enhancement of adi-ponectin level has been shown to have beneficial effects, including antiobesity, antidiabetic, and hepatoprotective effects. This evidence supports the therapeutic utility of adiponectin in complicated obesity. The present study characterized the in vivo effects of sustained adiponectin release by NP-1, a new class of thiazol derivative that increases adiponec-tin levels. Acute administration of NP-1 reduced feeding, increased plasma adiponectin, and improved insulin sensitivity without inducing malaise, as revealed by conditioned taste aversion studies. Short-term (7 days) treatment with NP-1 also reduced feeding and body weight gain and increased phosphorylation of AMPK in muscle, a main intracellular effector of adiponectin. NP-1 was also evaluated in diet-induced obesity, and adult male Wistar rats were fed two different types of diet: a standard high-carbohydrate/low-fat diet (SD) and a high-fat diet (HFD). Once obesity was established, animals were treated daily with NP-1 (5 mg/kg) for 14 consecutive days. Chronic NP-1 induced body weight loss and reduction of food intake and resulted in both a marked decrease in liver steatosis and an improvement of biochemical indexes of liver damage in HFD-fed rats. However, a marked induction of tolerance in adiponectin gene transcription and release was observed after chronic NP-1 with respect to the acute actions of this drug. The present results support the role of adiponectin signaling in diet-induced obesity and set in place a potential use of compounds able to induce adiponectin release for the treatment of obesity and nonalcoholic fatty liver, with the limits imposed by the induction of pharmacological tolerance. © 2012 the American Physiological Society.


Donnelly M.P.,Yale University | Paschou P.,Democritus University of Thrace | Grigorenko E.,Yale University | Gurwitz D.,National Laboratory for the Genetics of Israeli Populations | And 20 more authors.
American Journal of Human Genetics | Year: 2010

The polymorphic inversion on 17q21, sometimes called the microtubular associated protein tau (MAPT) inversion, is an ∼900 kb inversion found primarily in Europeans and Southwest Asians. We have identified 21 SNPs that act as markers of the inverted, i.e., H2, haplotype. The inversion is found at the highest frequencies in Southwest Asia and Southern Europe (frequencies of ∼30%); elsewhere in Europe, frequencies vary from < 5%, in Finns, to 28%, in Orcadians. The H2 inversion haplotype also occurs at low frequencies in Africa, Central Asia, East Asia, and the Americas, though the East Asian and Amerindian alleles may be due to recent gene flow from Europe. Molecular evolution analyses indicate that the H2 haplotype originally arose in Africa or Southwest Asia. Though the H2 inversion has many fixed differences across the ∼900 kb, short tandem repeat polymorphism data indicate a very recent date for the most recent common ancestor, with dates ranging from 13,600 to 108,400 years, depending on assumptions and estimation methods. This estimate range is much more recent than the 3 million year age estimated by Stefansson et al. in 2005.1. © 2010 The American Society of Human Genetics.


Crespillo A.,Hospital Carlos Haya | Alonso M.,Hospital Carlos Haya | Vida M.,Hospital Carlos Haya | Pavon F.J.,Hospital Carlos Haya | And 12 more authors.
British Journal of Pharmacology | Year: 2011

BACKGROUND AND PURPOSE The lack of safe and effective treatments for obesity has increased interest in natural products that may serve as alternative therapies. From this perspective, we have analysed the effects of daidzein, one of the main soy isoflavones, on diet-induced obesity in rats. EXPERIMENTAL APPROACH Rats made obese after exposure to a very (60%) high fat-content diet were treated with daidzein (50 mg·kg -1) for 14 days. The dose was selected on the basis of the acute effects of this isoflavone on a feeding test. After 14 days, animals were killed and plasma, white and brown adipose tissue, muscle and liver studied for the levels and expression of metabolites, proteins and genes relevant to lipid metabolism. KEY RESULTS A single treatment (acute) with daidzein dose-dependently reduced food intake. Chronic treatment (daily for 14 days) reduced weight gain and fat content in liver, accompanied by high leptin and low adiponectin levels in plasma. While skeletal muscle was weakly affected by treatment, both adipose tissue and liver displayed marked changes after treatment with daidzein, affecting transcription factors and lipogenic enzymes, particularly stearoyl coenzyme A desaturase 1, a pivotal enzyme in obesity. Expression of uncoupling protein 1, an important enzyme for thermogenesis, was increased in brown adipose tissue after daidzein treatment. CONCLUSIONS AND IMPLICATIONS These results support the use of isoflavones in diet-induced obesity, especially when hepatic steatosis is present and open a new field of use for these natural products. © 2011 The British Pharmacological Society.


Temprado M.,CSIC - Institute of Physical Chemistry "Rocasolano" | Temprado M.,University of Alcalá | Roux M.V.,CSIC - Institute of Physical Chemistry "Rocasolano" | Ros F.,Institute of Medical Chemistry | And 3 more authors.
Journal of Chemical and Engineering Data | Year: 2011

The present study reports a differential scanning calorimetry (DSC) study of the barbituric acid derivatives: 1,3-dimethylbarbituric acid [CAS 769-42-6], 5,5-dimethylbarbituric acid [CAS 24448-94-0], 1,3-diethylbarbituric acid [CAS 32479-73-5], 1,3,5-trimethylbarbituric acid [CAS 7358-61-4], 1,5,5-trimethylbarbituric acid [CAS 702-47-6], and tetramethylbarbituric acid [CAS 13566-66-0] in the temperature interval from T = 268 K to their respective melting temperatures. Temperatures, enthalpies and entropies of fusion, and the heat capacities of the solid compounds as a function of temperature are reported. © 2010 American Chemical Society.


Preuner S.,Childrens Cancer Research Institute CCRI | Mitterbauer G.,Institute of Medical Chemistry | Mannhalter C.,Institute of Medical Chemistry | Herndlhofer S.,Medical University of Vienna | And 3 more authors.
European Journal of Cancer | Year: 2012

Background: In chronic myeloid leukaemia (CML), clonal evolution with resistance to tyrosine kinase inhibitors (TKIs) is often triggered by BCR/ABL1 mutations. However, in the context of the complex pro-oncogenic signalling networks which ultimately lead to clonal expansion and disease progression, the exact contribution of BCR/ABL1 mutants remains uncertain. Recent data indicate that detection of BCR/ABL1 mutant subclones does not permit prediction of their expansion dynamics and their potential to become drivers of resistant disease. Methods: To determine the patterns of clonal evolution and the distinct proliferation kinetics of individual BCR/ABL1 mutants during treatment, we employed ligase-dependent polymerase chain reaction (LD-PCR) analysis for quantitative surveillance of CML subclones with various tyrosine kinase domain (TKD) mutations including M244V, L248V, G250E, E255K, T315I, F317L-A/G, M351T and F359V. Findings: Inadequate treatment responses were observed in 27 of 100 patients investigated and 16 were found to bear one or more BCR/ABL1 TKD mutations in separate subclones. Rapid subclone expansion upon onset or switch of TKI treatment was common and sometimes preceded corresponding changes in BCR/ABL1 transcript levels. Mutant subclones were found to respond differentially and sometimes unexpectedly to various treatment modalities. Decline and persistent depletion of specific mutation-bearing subclones in response to treatment could be documented by LD-PCR surveillance. Interpretation: The observations show that quantitative monitoring of mutant BCR/ABL1 subclones by LD-PCR is a powerful tool for detection of clonal evolution, subclone-expansion and subclone-depletion and can contribute to optimised management of patients with CML. © 2011 Elsevier Ltd. All rights reserved.


Chiba P.,Institute of Medical Chemistry | Freissmuth M.,Medical University of Vienna | Stockner T.,Medical University of Vienna
Pharmacological Research | Year: 2014

SLC6 family members and ABC transporters represent two extremes: SLC6 transporters are confined to the membrane proper and only expose small segments to the hydrophilic milieu. In ABC transporters the hydrophobic core is connected to a large intracellular (eponymous) ATP binding domain that is comprised of two discontiguous repeats. Accordingly, their folding problem is fundamentally different. This can be gauged from mutations that impair the folding of the encoded protein and give rise to clinically relevant disease phenotypes: in SLC6 transporters, these cluster at the protein-lipid interface on the membrane exposed surface. Mutations in ABC-transporters map to the interface between nucleotide binding domains and the coupling helices, which provide the connection to the hydrophobic core. Folding of these mutated ABC-transporters can be corrected with ligands/substrates that bind to the hydrophobic core. This highlights a pivotal role of the coupling helices in the folding trajectory. In contrast, insights into pharmacochaperoning of SLC6 transporters are limited to monoamine transporters - in particular the serotonin transporter (SERT) - because of their rich pharmacology. Only ligands that stabilize the inward facing conformation act as effective pharmacochaperones. This indicates that the folding trajectory of SERT proceeds via the inward facing conformation. Mutations that impair folding of SLC6 family members can be transmitted as dominant or recessive alleles. The dominant phenotype of the mutation can be rationalized, because SLC6 transporters are exported in oligomeric form from the endoplasmic reticulum (ER). Recessive transmission requires shielding of the unaffected gene product from the mutated transporter in the ER. This can be accounted for by a chaperone-COPII (coatomer protein II) exchange model, where proteinaceous ER-resident chaperones engage various intermediates prior to formation of the oligomeric state and subsequent export from the ER. It is likely that the action of pharmacochaperones is contingent on and modulated by these chaperones. © 2013 The Authors.


PubMed | Institute of Medical Chemistry and Medical University of Vienna
Type: | Journal: Pharmacological research | Year: 2014

SLC6 family members and ABC transporters represent two extremes: SLC6 transporters are confined to the membrane proper and only expose small segments to the hydrophilic milieu. In ABC transporters the hydrophobic core is connected to a large intracellular (eponymous) ATP binding domain that is comprised of two discontiguous repeats. Accordingly, their folding problem is fundamentally different. This can be gauged from mutations that impair the folding of the encoded protein and give rise to clinically relevant disease phenotypes: in SLC6 transporters, these cluster at the protein-lipid interface on the membrane exposed surface. Mutations in ABC-transporters map to the interface between nucleotide binding domains and the coupling helices, which provide the connection to the hydrophobic core. Folding of these mutated ABC-transporters can be corrected with ligands/substrates that bind to the hydrophobic core. This highlights a pivotal role of the coupling helices in the folding trajectory. In contrast, insights into pharmacochaperoning of SLC6 transporters are limited to monoamine transporters - in particular the serotonin transporter (SERT) - because of their rich pharmacology. Only ligands that stabilize the inward facing conformation act as effective pharmacochaperones. This indicates that the folding trajectory of SERT proceeds via the inward facing conformation. Mutations that impair folding of SLC6 family members can be transmitted as dominant or recessive alleles. The dominant phenotype of the mutation can be rationalized, because SLC6 transporters are exported in oligomeric form from the endoplasmic reticulum (ER). Recessive transmission requires shielding of the unaffected gene product from the mutated transporter in the ER. This can be accounted for by a chaperone-COPII (coatomer protein II) exchange model, where proteinaceous ER-resident chaperones engage various intermediates prior to formation of the oligomeric state and subsequent export from the ER. It is likely that the action of pharmacochaperones is contingent on and modulated by these chaperones.

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