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Front Pharmacol [journal]
- lazar: a modular predictive toxicology framework. [Journal Article]
- Front Pharmacol 2013.:38.
lazar (lazy structure-activity relationships) is a modular framework for predictive toxicology. Similar to the read across procedure in toxicological risk assessment, lazar creates local QSAR (quantitative structure-activity relationship) models for each compound to be predicted. Model developers can choose between a large variety of algorithms for descriptor calculation and selection, chemical similarity indices, and model building. This paper presents a high level description of the lazar framework and discusses the performance of example classification and regression models.
- Connexin 43 impacts on mitochondrial potassium uptake. [Journal Article]
- Front Pharmacol 2013.:73.
In cardiomyocytes, connexin 43 (Cx43) forms gap junctions and unopposed hemichannels at the plasma membrane, but the protein is also present at the inner membrane of subsarcolemmal mitochondria (SSM). Both inhibition and genetic ablation of Cx43 reduce ADP-stimulated complex 1 respiration. Since mitochondrial potassium influx impacts on oxygen consumption, we investigated whether or not inhibition or ablation of mitochondrial Cx43 alters mitochondrial potassium uptake. SSM were isolated from rat left ventricular myocardium and loaded with the potassium-sensitive dye PBFI (potassium-binding benzofuran isophthalate). Intramitochondrial potassium was replaced by tetraethylammonium. Mitochondria were incubated under control conditions or treated with 250 μM Gap19, a peptide that specifically inhibits Cx43-based hemichannels at plasma membranes. Subsequently, 140 mM KCl was added and the slope of the increase in PBFI fluorescence over time was calculated. The slope of the PBFI fluorescence of the control mitochondria was set to 100%. In the presence of Gap19, the mitochondrial potassium influx was reduced from 100 ± 11.6% in control mitochondria to 65.5 ± 10.7% (n = 6, p < 0.05). In addition to the pharmacological inhibition of Cx43, potassium influx was studied in mitochondria isolated from conditional Cx43 knockout mice. Here, the ablation of Cx43 was achieved by the injection of 4-hydroxytamoxifen (4-OHT; Cx43(Cre-ER(T)/fl) + 4-OHT). The mitochondria of the Cx43(Cre-ER(T)/fl) + 4-OHT mice contained 3 ± 1% Cx43 (n = 6) of that in control mitochondria (100 ± 11%, n = 8, p < 0.05). The ablation of Cx43 (n = 5) reduced the velocity of the potassium influx from 100 ± 11.2% in control mitochondria (n = 9) to 66.6 ± 5.5% (p < 0.05). Taken together, our data indicate that both pharmacological inhibition and genetic ablation of Cx43 reduce mitochondrial potassium influx.
- Cyclic nucleotide permeability through unopposed connexin hemichannels. [Journal Article]
- Front Pharmacol 2013.:75.
Cyclic adenosine monophosphate (cAMP) is a well-known intracellular and intercellular second messenger. The membrane permeability of such molecules has potential importance for autocrine-like or paracrine-like delivery. Here experiments have been designed to demonstrate whether gap junction hemichannels, composed of connexins, are a possible entrance pathway for cyclic nucleotides into the interior of cells. HeLa cells stably expressing connexin43 (Cx43) and connexin26 (Cx26) were used to study the cyclic nucleotide permeability of gap junction hemichannels. For the detection of cAMP uptake, the cells were transfected using the cyclic nucleotide-modulated channel from sea urchin sperm (SpIH) as the cAMP sensor. SpIH derived currents (I m) were recorded in whole-cell/perforated patch clamp configuration. Perfusion of the cells in an external K(+) aspartate(-) (KAsp) solution containing 500 μM cAMP and no extracellular Ca(2) (+), yielded a five to sevenfold increase in the I m current level. The SpIH current increase was associated with detectable hemichannel current activity. Depolarization of cells in Ca(2) (+)-free NaCl perfusate with 500 μM cAMP also induced a SpIH current increase. Elevating extracellular Ca(2) (+) to mM levels inhibited hemichannel activity. Perfusion with a depolarizing KAsp solution containing 500 μM cAMP and 2 mM Ca(2) (+) did not increase SpIH currents. The addition of the gap junction blocker carbenoxolone to the external solution inhibited cAMP uptake. Both cell depolarization and lowered extracellular Ca(2) (+) increase the open probability of non-junctional hemichannels. Accordingly, the SpIH current augmentation was induced by the uptake of extracellular cAMP via open membrane hemichannels in Cx43 and Cx26 expressing cells. The data presented here show that hemichannels of Cx43 and Cx26 are permeable to cAMP, and further the data suggest that hemichannels are, in fact, a potential pathway for cAMP mediated cell-to-cell signaling.
- Role of connexins in human congenital heart disease: the chicken and egg problem. [Journal Article]
- Front Pharmacol 2013.:70.
Inborn cardiac diseases are among the most frequent congenital anomalies and are the main cause of death in infants within the first year of age in industrialized countries when not adequately treated. They can be divided into simple and complex cardiac malformations. The former ones, for instance atrial and ventricular septal defects, valvular or subvalvular stenosis or insufficiency account for up to 80% of cardiac abnormalities. The latter ones, for example transposition of the great vessels, Tetralogy of Fallot or Shone's anomaly often do not involve only the heart, but also the great vessels and although occurring less frequently, these severe cardiac malformations will become symptomatic within the first months of age and have a high risk of mortality if the patients remain untreated. In the last decade, there is increasing evidence that cardiac gap junction proteins, the connexins (Cx), might have an impact on cardiac anomalies. In the heart, mainly three of them (Cx40, Cx43, and Cx45) are differentially expressed with regard to temporal organogenesis and to their spatial distribution in the heart. These proteins, forming gap junction channels, are most important for a normal electrical conduction and coordinated synchronous heart muscle contraction and also for the normal embryonic development of the heart. Animal and also some human studies revealed that at least in some cardiac malformations alterations in certain gap junction proteins are present but until today no particular gap junction mutation could be assigned to a specific cardiac anomaly. As gap junctions have often been supposed to transmit growth and differentiation signals from cell to cell it is reasonable to assume that they are somehow involved in misdirected growth present in many inborn heart diseases playing a primary or contributory role. This review addresses the potentional role of gap junctions in the development of inborn heart anomalies like the conotruncal heart defects.
- The effects of cocoa on the immune system. [Journal Article]
- Front Pharmacol 2013.:71.
Cocoa is a food relatively rich in polyphenols, which makes it a potent antioxidant. Due to its activity as an antioxidant, as well as through other mechanisms, cocoa consumption has been reported to be beneficial for cardiovascular health, brain functions, and cancer prevention. Furthermore, cocoa influences the immune system, in particular the inflammatory innate response and the systemic and intestinal adaptive immune response. Preclinical studies have demonstrated that a cocoa-enriched diet modifies T cell functions that conduce to a modulation of the synthesis of systemic and gut antibodies. In this regard, it seems that a cocoa diet in rats produces changes in the lymphocyte composition of secondary lymphoid tissues and the cytokines secreted by T cells. These results suggest that it is possible that cocoa could inhibit the function of T helper type 2 cells, and in line with this, the preventive effect of cocoa on IgE synthesis in a rat allergy model has been reported, which opens up new perspectives when considering the beneficial effects of cocoa compounds. On the other hand, cocoa intake modifies the functionality of gut-associated lymphoid tissue by means of modulating IgA secretion and intestinal microbiota. The mechanisms involved in these influences are discussed here. Further research may elucidate the cocoa compounds involved in such an effect and also the possible medical approaches to these repercussions.
- Does the use of an electronic reminder device with or without counseling improve adherence to lipid-lowering treatment? The results of a randomized controlled trial. [Journal Article]
- Front Pharmacol 2013.:69.
Background:Lipid-lowering treatment with statins has proven to be effective in reducing cardiovascular events and mortality. In daily practice, however, adherence to medication is often low and this compromises the therapeutic effect. The aim of this study was to assess the effectiveness of an electronic reminder device (ERD) with or without counseling to improve refill adherence and persistence for statin treatment in non-adherent patients.
Methods:A multicenter, community pharmacy-based, randomized controlled trial was conducted in 24 pharmacies in the Netherlands among patients with pre-baseline refill adherence rates between 50 and 80%. Eligible patients aged 65 years or older were randomly assigned to 1 of 3 groups: (1) counseling with an ERD (n = 134), (2) ERD with a written instruction (n = 131), and a (3) control group that received the usual treatment (n = 134). Main outcome measure: refill adherence to statin treatment for a 360-day period after inclusion (PDC360). Patients with a refill rate ≥80% were considered adherent. The effect among subgroups was also assessed.
Results:There were no relevant differences at baseline. In the counseling with ERD group 54 of 130 eligible patients received the counseling with ERD. In the ERD group, 117 of 123 eligible patients received the ERD. The proportions of adherent patients in the counseling with ERD-group (69.2%) and in the ERD group (72.4%) were not higher than in the control group (64.8%). Among women using statins for secondary prevention, more patients were adherent in the ERD group (86.1%) than in the control group (52.6%) (p < 0.005). In men using statins for secondary prevention the ERD was found to have no effect.
Conclusion:In this randomized controlled trial, no statistically significant improvement of refill adherence was found if an ERD was used with or without counseling. However, in a subgroup of women using statins for secondary prevention the ERD did improve adherence significantly.
- Targeting potassium channels for increasing delivery of imaging agents and therapeutics to brain tumors. [Journal Article]
- Front Pharmacol 2013.:62.
Every year in the US, 20,000 new primary and nearly 200,000 metastatic brain tumor cases are reported. The cerebral microvessels/capillaries that form the blood-brain barrier not only protect the brain from toxic agents in the blood but also pose a significant hindrance to the delivery of small and large therapeutic molecules. Different strategies have been employed to circumvent the physiological barrier posed by blood-brain tumor barrier (BTB). Studies in our laboratory have identified significant differences in the expression levels of certain genes and proteins between normal and brain tumor capillary endothelial cells (ECs). In this study, we validated the non-invasive and clinically relevant dynamic contrast enhancing-magnetic resonance imaging (DCE-MRI) method with invasive, clinically irrelevant but highly accurate quantitative autoradiography method using rat glioma model. We also showed that DCE-MRI metric of tissue vessel perfusion-permeability is sensitive to changes in blood vessel permeability following administration of calcium-activated potassium (BKCa) channel activator NS-1619. Our results show that human gliomas and brain tumor ECs that overexpress BKCa channels can be targeted for increased BTB permeability for MRI enhancing agents to brain tumors. We conclude that monitoring the outcome of increased MRI enhancing agents' delivery to microsatellites and leading tumor edges in glioma patients would lead to beneficial clinical outcome.
- Interfering amino terminal peptides and functional implications for heteromeric gap junction formation. [Journal Article]
- Front Pharmacol 2013.:67.
Connexin43 (Cx43) is widely expressed in many different tissues of the human body. In cells of some organs, Cx43 is co-expressed with other connexins (Cx), including Cx46 and Cx50 in lens, Cx40 in atrium, Purkinje fibers, and the blood vessel wall, Cx45 in heart, and Cx37 in the ovary. Interactions with the co-expressed connexins may have profound functional implications. The abilities of Cx37, Cx45, Cx46, and Cx50 to function in heteromeric gap junction combinations with Cx43 are well documented. Different studies disagree regarding the ability of Cx43 and Cx40 to produce functional heteromeric gap junctions with each other. We review previous studies regarding the heteromeric interactions of Cx43. The possibility of negative functional interactions between the cytoplasmic pore-forming amino-terminal (NT) domains of these connexins was assessed using pentameric connexin sequence-specific NT domain [interfering NT (iNT)] peptides applied to cells expressing homomeric Cx40, Cx37, Cx45, Cx46, and Cx50 gap junctions. A Cx43 iNT peptide corresponding to amino acids 9-13 (Ac-KLLDK-NH2) specifically inhibited the electrical coupling of Cx40 gap junctions in a transjunctional voltage (V j)-dependent manner without affecting the function of homologous Cx37, Cx46, Cx50, and Cx45 gap junctions. A Cx40 iNT (Ac-EFLEE-OH) peptide counteracted the V j-dependent block of Cx40 gap junctions, whereas a similarly charged Cx50 iNT (Ac-EEVNE-OH) peptide did not, suggesting that these NT domain interactions are not solely based on electrostatics. These data are consistent with functional Cx43 heteromeric gap junction formation with Cx37, Cx45, Cx46, and Cx50 and suggest that Cx40 uniquely experiences functional suppressive interactions with a Cx43 NT domain sequence. These findings present unique functional implications about the heteromeric interactions between Cx43 and Cx40 that may influence cardiac conduction in atrial myocardium and the specialized conduction system.
- Burden of Friedreich's Ataxia to the Patients and Healthcare Systems in the United States and Canada. [Journal Article]
- Front Pharmacol 2013.:66.
Objective:The study intended to substantiate healthcare resource utilization, costs, and funding patterns of US and Canadian Friedreich's Ataxia (FRDA) populations, to assess compliance with treatment guidance and to identify areas where novel healthcare measures or improved access to existing care may improve patients' functional and social capabilities and reduce the financial impact on the healthcare systems.
Methods:Healthcare resource utilization and costs were collected in a cross-sectional study in the US (N = 197) and Canada (N = 43) and analyzed across severity of disease categories. Descriptive statistics, correlation analysis, and hypothesis testing were applied.
Results:In the US, healthcare costs of FRDA patients were higher than those of "adults with two and more chronic conditions." Significantly higher costs were incurred in advanced stages of the disease, with paid homecare being the main driver. This pattern was also observed in Canada. Compliance with the recommended annual neurological and cardiological follow-up was high, but was low for the recommended regular speech therapy. In the US public and private funding ratios were similar for the FRDA and the general populations. In Canada the private funding ratio for FRDA was higher than average.
Conclusion:The variety of healthcare measures addressing the broad range of symptoms of FRDA, and the increasing use of paid home care as disease progresses made total US healthcare costs of FRDA exceed the costs of US adults with two and more chronic conditions. Therefore, measures delaying disease progression will allow patients to maintain their independence longer and may reduce costs to the healthcare system. Novel measures to address dysarthria and to ensure access to them should be further investigated. The higher than average private funding ratio in Canada was due to the relatively high cost of the pharmacological treatment of FRDA.
- Editorial on research topic: aldo-keto reductases and role in human disease. [Journal Article]
- Front Pharmacol 2013.:65.