bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serotonin‐1A receptor function in the dorsal raphe nucleus following chronic administration of the selective serotonin reuptake inhibitor sertraline
Authors: Rossi Dania V. , Burke Teresa F. , McCasland Melissa , Hensler Julie G. 
Published: January 2008

AbstractSerotonin‐1A (5‐HT1A) receptors in the dorsal raphe nucleus (DRN) function as somatodendritic autoreceptors, and therefore play a critical role in controlling serotonergic cell firing and serotonergic neurotransmission. We hypothesized that a decrease in the capacity of 5‐HT1A receptors to activate G proteins was a general mechanism by which 5‐HT1A receptors in the DRN are desensitized following chronic administration of selective serotonin reuptake inhibitors (SSRIs). Using in vivo microdialysis, we found that the ability of the 5‐HT1A receptor agonist 8‐hydroxydipropylaminotetralin hydrobromide (8‐OH‐DPAT) (0.025 mg/kg, s.c.) to decrease extracellular 5‐HT levels in striatum was attenuated following chronic treatment of rats with the SSRIs sertraline or fluoxetine. This apparent desensitization of somatodendritic 5‐HT1A autoreceptor function was not accompanied by a decrease in 5‐HT1A receptor sites in the coupled, high‐affinity agonist state as measured by the binding of [3H]8‐OH‐DPAT. In marked contrast to what was observed following chronic administration of fluoxetine, 5‐HT1A receptor‐stimulated [35S]GTPγS binding in the DRN was not altered following chronic sertraline treatment. Thus, desensitization of 5‐HT1A somatodendritic autoreceptor function following chronic sertraline administration appears not to be due to a decrease in the capacity 5‐HT1A receptors to activate G proteins in the DRN. Our findings suggest that the SSRIs may not be a homogeneous class of antidepressant drug with regard to the mechanism by which the function of somatodendritic 5‐HT1A autoreceptors is regulated.
Statins reduce neuronal α‐synuclein aggregation in in vitro models of Parkinson’s disease
Authors: Bar‐On Pazit , Crews Leslie , Koob Andrew O. , Mizuno Hideya , Adame Anthony , Spencer Brian , Masliah Eliezer 
Published: January 2008

AbstractAggregation of α‐synuclein (α‐syn) is believed to play a critical role in the pathogenesis of disorders such as dementia with Lewy bodies and Parkinson’s disease. The function of α‐syn remains unclear, although several lines of evidence suggest that α‐syn is involved in synaptic vesicle trafficking probably via lipid binding. Moreover, interactions with cholesterol and lipids have been shown to be involved in α‐syn aggregation. In this context, the main objective of this study was to determine if statins – cholesterol synthesis inhibitors – might interfere with α‐syn accumulation in cellular models. For this purpose, we studied the effects of lovastatin, simvastatin, and pravastatin on the accumulation of α‐syn in a stably transfected neuronal cell line and in primary human neurons. Statins reduced the levels of α‐syn accumulation in the detergent insoluble fraction of the transfected cells. This was accompanied by a redistribution of α‐syn in caveolar fractions, a reduction in oxidized α‐syn, and enhanced neurite outgrowth. In contrast, supplementation of the media with cholesterol increased α‐syn aggregation in detergent insoluble fractions of transfected cells and was accompanied by reduced neurite outgrowth. Taken together, these results suggest that regulation of cholesterol levels with cholesterol inhibitors might be a novel approach for the treatment of Parkinson’s disease.
Brain‐specific carnitine palmitoyl‐transferase‐1c: role in CNS fatty acid metabolism, food intake, and body weight
Authors: Wolfgang Michael J. , Cha Seung Hun , Millington David S. , Cline Gary , Shulman Gerald I. , Suwa Akira , Asaumi Makoto , Kurama Takeshi , Shimokawa Teruhiko , Lane M. Daniel 
Published: January 2008

AbstractWhile the brain does not utilize fatty acids as a primary energy source, recent evidence shows that intermediates of fatty acid metabolism serve as hypothalamic sensors of energy status. Increased hypothalamic malonyl‐CoA, an intermediate in fatty acid synthesis, is indicative of energy surplus and leads to the suppression of food intake and increased energy expenditure. Malonyl‐CoA functions as an inhibitor of carnitine palmitoyl‐transferase 1 (CPT1), a mitochondrial outer membrane enzyme that initiates translocation of fatty acids into mitochondria for oxidation. The mammalian brain expresses a unique homologous CPT1, CPT1c, that binds malonyl‐CoA tightly but does not support fatty acid oxidation in vivo, in hypothalamic explants or in heterologous cell culture systems. CPT1c knockout (KO) mice under fasted or refed conditions do not exhibit an altered CNS transcriptome of genes known to be involved in fatty acid metabolism. CPT1c KO mice exhibit normal levels of metabolites and of hypothalamic malonyl‐CoA and fatty acyl‐CoA levels either in the fasted or refed states. However, CPT1c KO mice exhibit decreased food intake and lower body weight than wild‐type littermates. In contrast, CPT1c KO mice gain excessive body weight and body fat when fed a high‐fat diet while maintaining lower or equivalent food intake. Heterozygous mice display an intermediate phenotype. These findings provide further evidence that CPT1c plays a role in maintaining energy homeostasis, but not through altered fatty acid oxidation.
Relaxation induced by red wine polyphenolic compounds in rat pulmonary arteries: lack of inhibition by NO‐synthase inhibitor
Authors: Leblais Véronique , Krisa Stéphanie , Valls Josep , Courtois Arnaud , Abdelouhab Sabrina , Vila Alicia Martin , Mérillon Jean‐Michel , Muller Bernard 
Published: January 2008

AbstractSome red wine polyphenols exert nitric oxide (NO)‐dependent relaxation in systemic arteries, following activation of endothelial NO synthase (eNOS). In this study, the effect of red wine polyphenols was determined in rat intrapulmonary arteries, and the effect of some of these compounds was compared with the responses obtained in rat aorta. In pulmonary arteries, red wine polyphenolic extract (> 300 μg/mL) exerted relaxation that was not inhibited by the NOS inhibitor Nω‐nitro‐l‐arginine methylester (l‐NAME) or endothelium removal. Among the several fractions obtained from the extract, the one enriched with anthocyanins was less active than fractions containing non‐anthocyanins. Among the latter, the most active for relaxing pulmonary arteries was the one enriched in the stilbene derivative trans‐resveratrol (relaxation for concentration >10 μg/mL). Trans‐piceid, the glucoside derivative of trans‐resveratrol, was almost inactive. Trans‐resveratrol‐induced relaxation, as well as relaxation to the anthocyanin delphinidin, was l‐NAME‐insensitive in pulmonary arteries. In aorta, trans‐resveratrol and trans‐piceid exerted similar effects to those in pulmonary arteries that were also not inhibited by l‐NAME. However, red wine polyphenolic extract and delphinidin induced relaxation of aorta at much lower concentrations (about 10 μg/mL) than in pulmonary arteries, and their effects were inhibited by l‐NAME. These data show differences between small intrapulmonary arteries and systemic conductance arteries in their responses to red wine polyphenols, the major difference being that the relaxant effect of these compounds is not blunted by NOS inhibitor in pulmonary arteries. They suggest that red wine polyphenols act directly on smooth muscle to promote pulmonary artery relaxation.
Drugs and their molecular targets: an updated overview
Authors: Landry Yves , Gies Jean‐Pierre 
Published: January 2008

AbstractAbout 330 targets bind approved drugs, 270 encoded by the human genome and 60 belonging to pathogenic organisms. A large number of druggable targets have been recently proposed from preclinical and first clinical data, but a huge reservoir of putative drug targets, possibly several thousands, remains to be explored. This overview considers the different types of ligands and their selectivity in the main superfamilies of drug targets, enzymes, membrane transporters and ion channels, and the various classes of membrane and nuclear receptors with their signalling pathway. Recently approved drugs such as monoclonal antibodies, tyrosine kinase and proteasome inhibitors, and major drugs under clinical studies are reviewed with their molecular target and therapeutic interest. The druggability of emerging targets is discussed, such as multidrug resistance transporters and cystic fibrosis transmembrane conductance regulator (CFTR), hyperpolarization‐activated cyclic nucleotides‐gated (HCN), cyclic nucleotide‐gated (CNG) and transient receptor potential (TRP) ion channels, tumour necrosis factor (TNF) and receptor activator of NFκB (RANK) receptors, integrins, and orphan or recently deorphanized G‐protein‐coupled and nuclear receptors. Large advances have been made in the therapeutical use of recombinant cytokines and growth factors (i.e. tasonermin, TNFα‐1a; becaplermin, platelet‐derived growth factor (PDGF); dibotermin‐alpha, bone morphogenetic proteins (BMP)2; anakinra, interleukin‐1 receptor antagonist protein (IRAP), and in enzyme replacement therapy, i.e. algasidase (alpha‐galactosidase) and laronidase (alpha‐l‐iduronidase). New receptor classes are emerging, e.g. membrane aminopeptidases, and novel concepts are stimulating drug research, e.g. epigenetic therapy, but the molecular target of some approved drugs, such as paracetamol and imidazolines, still need to be identified.
Impact of nevirapine or efavirenz co‐administration on ritonavir‐boosted amprenavir pharmacokinetics in HIV‐infected patients
Authors: Dailly Eric , Raffi François , Biron Charlotte , Allavena C. , Jolliet P. 
Published: January 2008

AbstractThe influence of nevirapine or efavirenz co‐administration on ritonavir‐boosted amprenavir pharmacokinetics was investigated in HIV‐infected patients with a population pharmacokinetic approach. The analysis was performed with a population of 61 patients treated with fosamprenavir/ritonavir (700 mg/100 mg twice daily) combined with nucleoside/nucleotide reverse transcriptase inhibitors ± enfuvirtide and no other antiretroviral drugs (group A, n = 46) or nevirapine (group B, n = 10) or efavirenz (group C, n = 5). No significant increase in amprenavir clearance [mean ± standard deviation: 22.49 ± 10.32 (group A) vs. 21.57 ± 9.62 (group B) vs. 20.15 ± 5.18 (group C) L/h] and no significant decrease in trough amprenavir plasma concentrations [1.75 ± 0.95 (group A) vs. 1.82 ± 0.72 (group B) vs. 1.55 ± 0.66 (group C) mg/L] were found in groups B and C in comparison with group A, although nevirapine and efavirenz are inductors of protease inhibitors metabolism. These results suggest that fosamprenavir/ritonavir should be used at standard doses of 700 mg/100 mg twice daily when combined with efavirenz or nevirapine.
The effects of NG‐nitro‐l‐arginine methyl ester on systolic pressure, diastolic pressure and pulse pressure according to the initial level of blood pressure
Authors: Ruiz Antonio , López Ruth M. , Pérez Teresa , Castillo Carlos , Castillo Enrique F. 
Published: January 2008

AbstractThe objective of this study was to re‐examine whether the effect of the nitric oxide synthesis inhibitor, NG‐nitro‐l‐arginine methyl ester (l‐NAME), on blood pressure depends on peripheral vascular tone. The effects of l‐NAME (10 mg/kg, i.v.) on diastolic blood pressure (DBP), systolic blood pressure (SBP), pulse pressure (PP) and heart rate (HR) were studied in pithed rats. Sal‐pithed rats received 0.9% NaCl, 10 μl/kg/min. Vascular tone was step‐wise increased with 3, 10 and 30 μg/kg/min intravenous phenylephrine infusion (LPhe‐pithed, MPhe‐pithed and HPhe‐pithed rats respectively). l‐NAME elicited vasopressor responses in all the animals studied. l‐NAME increases in SBP and DBP in Sal‐pithed rats were significantly smaller than the ones obtained in phenylephrine infused rats. The increases in DBP elicited by l‐NAME were greater in LPhe‐pithed rats compared with those of MPhe‐pithed and HPhe‐pithed rats (i.e. the step‐wise rises in DBP obtained with phenylephrine were inversely related to the increases in DBP produced by l‐NAME); however, the increases in SBP were similar between these experimental groups. The PP increased during l‐NAME‐induced pressor responses in phenylephrine‐infused rats. l‐NAME increases in PP showed the following order: Sal‐pithed < LPhe‐pithed < MPhe‐pithed ≤ HPhe‐pithed rats. HR was not modified by l‐NAME. In conclusion, the vasopressor responses produced by l‐NAME in pithed rats are influenced by the pre‐existing vasomotor tone in complex form. We did not find a simple positive correlation between the vascular tone or level of arterial pressure, and the magnitude of the diastolic and systolic pressor responses elicited by l‐NAME. Interestingly, the increase in PP induced by l‐NAME was greater in accordance with the increasing value of baseline arterial pressure. NO synthesis inhibition in the arterial endothelium may possibly explain the increase in PP caused by l‐NAME, as resulting from the reduction in proximal conduit artery compliance.
Effects of cooling and warming on 5‐hydroxytryptamine‐ and acetylcholine‐induced contractions of human umbilical vessels: role of nitric oxide
Authors: Atalık K.E. , Kılıç M. , Nurullahoğlu Z.Ü. , Doğan N. 
Published: January 2008

AbstractThe effects of cooling (to 28 °C) and warming (to 41 °C) on the vasoconstrictions induced by 5‐hydroxytryptamine (5‐HT) and acetylcholine (ACh) and the role of nitric oxide in these effects were analyzed in human umbilical artery and vein. 5‐HT (10−9–10−4 m) and ACh (10−9–10−4 m) induced concentration‐dependent contractions at 37, 28 and 41 °C. During cooling, the sensitivity, but not the maximal response, of 5‐HT and ACh was significantly higher than at 37 °C; and during warming, again the sensitivity, but not the maximal response, of both contractile agents was significantly lower than at 37 °C. Neither cooling to 28 °C nor warming to 41 °C, after treatment with NG‐nitro‐l‐arginine methyl esther (l‐NAME, 10−4 m), modify the effect of temperature in both vessels. These results suggest that cooling‐ and warming‐induced responses in human umbilical artery and vein are independent of nitric oxide.
Evidence that age‐related changes in p38 MAP kinase contribute to the decreased steroid production by the adrenocortical cells from old rats
Authors: Abidi Parveen , Leers‐Sucheta Susan , Cortez Yuan , Han Jiahuai , Azhar Salman 
Published: January 2008

SummaryThe current studies were initiated to investigate whether excessive oxidative stress exerts its antisteroidogenic action through modulation of oxidant‐sensitive mitogen‐activated protein kinase (MAPK) signaling pathways. Western blot analysis indicated that aging caused increased phosphorylation and activation of rat adrenal p38 MAPK, but not the ERK1/2 or JNK1/2. Lipid peroxidation measurements (an index of cellular oxidative stress) indicated that adrenal membranes from young animals contained only minimal levels of endogenous thiobarbituric acid‐reactive substances (TBARS), and exposure of membranes to enzymatic and non‐enzymatic pro‐oxidants enhanced TBARS formation approximately 12‐ and 20‐fold, respectively. The adrenal membranes from old animals showed much more susceptibility to lipid peroxidation and exhibited roughly 4‐ to 6‐fold higher TBARS formation than young controls both under basal conditions and in response to pro‐oxidants. Qualitatively similar results were obtained when lipid peroxide formation was measured using a sensitive FOXRS (ferrous oxidation‐xylenol orange‐reactive substances) technique. We next tested whether aging‐induced excessive oxidative insult alters steroidogenesis through modulation of MAPK signaling pathway. Treatment of adrenocortical cells from old rats with specific p38 MAPK inhibitors restored Bt2cAMP‐stimulated steroidogenesis ~60–70% of the value seen in cells of young animals. Likewise, pretreatment of cells with reactive oxygen species (ROS) scavengers MnTMPyP and N‐acetyl cysteine also partially rescued age‐induced loss of steroid production. In contrast, simultaneous treatment of cells with ROS scavengers and p38 MAPK inhibitor did not produce any additional effect suggesting that both types of inhibitors exert their stimulatory action through inhibition of p38 MAPK activation. Collectively, these results indicate that p38 MAPK functions as a signaling effector in oxidative stress‐induced inhibition of steroidogenesis during aging.
Architectural changes in the thymus of aging mice
Authors: Aw Danielle , Silva Alberto B. , Maddick Mandy , Von Zglinicki Thomas , Palmer Donald B. 
Published: January 2008

SummaryAge‐associated thymic involution is one of the most dramatic and ubiquitous changes in the immune system, although the precise mechanisms involved still remain obscured. Several hypotheses have been proposed incorporating extrinsic and intrinsic factors, however, changes in the thymic microenvironment itself is one of the least investigated. We therefore decided to undertake a detailed histological examination of the aging thymus in order to elucidate possible mechanisms of thymic atrophy. This investigation provides insight into the changes within the murine thymus with age, demonstrating a new approach to quantify protein expressional differences while preserving the thymic architecture. There is a decline in expression of thymic epithelial cell‐specific makers and an increase in fibroblast content in the aging mouse thymus. This is concurrent with a disorganization of the thymic compartments, a morphological transformation within the epithelial cells and alterations of their archetypal staining patterns. Furthermore, this is linked to a rise in apoptotic cells and the novel finding of increased senescence in the thymus of older mice that appears to be colocalized in the epithelial compartment. These changes within the thymic epithelial cells may be in part accountable for thymic atrophy and responsible for the decline in T‐cell output.
Valproic acid extendsCaenorhabditis eleganslifespan
Authors: Evason Kimberley , Collins James J. , Huang Cheng , Hughes Stacie , Kornfeld Kerry 
Published: January 2008

SummaryAging is an important biological phenomenon and a major contributor to human disease and disability, but no drugs have been demonstrated to delay human aging.Caenorhabditis elegansis a valuable model for studies of animal aging, and the analysis of drugs that extend the lifespan of this animal can elucidate mechanisms of aging and might lead to treatments for age‐related disease. By testing drugs that are Food and Drug Administration approved for human use, we discovered that the mood stabilizer and anticonvulsant valproic acid (VA) extendedC. eleganslifespan. VA also delayed age‐related declines of body movement, indicating that VA delays aging. Valproic acid is a small carboxylic acid that is the most frequently prescribed anticonvulsant drug in humans. A structure–activity analysis demonstrated that the related compound valpromide also extends lifespan. Valproic acid treatment may modulate the insulin/IGF‐1 growth factor signaling pathway, because VA promoted dauer larvae formation and DAF‐16 nuclear localization. To investigate the mechanism of action of VA in delaying aging, we analyzed the effects of combining VA with other compounds that extend the lifespan ofC. elegans. Combined treatment of animals with VA and the heterocyclic anticonvulsant trimethadione caused a lifespan extension that was significantly greater than treatment with either of these drugs alone. These data suggest that the mechanism of action of VA is distinct from that of trimethadione, and demonstrate that lifespan‐extending drugs can be combined to produce additive effects.
Percutaneous Treatment for Mitral Regurgitation: The QuantumCor System
Authors: HEUSER RICHARD R. , WITZEL THOMAS , DICKENS DUANE , TAKEDA PATRICIA A. 
Published: January 2008

Aims:

Percutaneous edge‐to‐edge techniques and annuloplasty have been used to treat mitral regurgitation (MR). However, neither intervention can be performed reliably a second time and, with annuloplasty, a foreign body is left behind. The mitral and tricuspid annuli are areas of dense collagen (

Fig. 1

); treatment with radiofrequency (RF) energy in sheep reduces their size, and can be repeated without affecting the coronary sinus. RF energy may also be used in leaflet procedures. Our aim was to improve mitral valve competence using techniques that can be incorporated into a minimally invasive approach. This trichrome stain slide shows the amount of collagen present in the mitral annulus (in green).image
Methods:

In open‐heart procedures in 16 healthy sheep (6 with naturally occurring MR), we used a malleable probe (QuantumCor, Inc., Lake Forest, CA) that conforms to the annular shape to deliver RF energy via a standard generator to replicate a surgical mitral annular ring. Four segments of the posterior mitral valve annulus were treated while on cardiopulmonary support via a left thoracotomy with access via the atrial appendage. Seven sheep were followed chronically.
Results:

All sheep underwent intracardiac echocardiography (ICE) or direct circumferential measurement of the mitral annulus before and after RF therapy. RF therapy was administered in less than 4 minutes in each case, and the mean anteroposterior (AP) annular distance was reduced by a mean of 5.75 ± 0.86 mm (23.8% reduction, P< 0.001). In the 6 sheep with nonischemic MR, regurgitation was eliminated. Acute histopathology (HP) demonstrated no damage to the leaflets, coronary sinuses, or coronary arteries. At 30 days, the AP distance continued to be reduced in the 7 surviving sheep (mean 5.0 ± .6 mm, 21.4% reduction, P< 0.001).
Conclusions:

In a sheep model, RF energy applied for less than 4 minutes per case at subablative temperatures in four quadrants of the posterior mitral valve annulus reduced the AP and circumferential annular distances significantly, and eliminated nonischemic MR. Results will need to be confirmed in follow‐up studies to determine safety and efficacy. RF energy administered as a novel, percutaneous method of mitral valve annuloplasty may have the potential to reduce morbidity and mortality associated with current surgical techniques.