bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased L‐DOPA‐derived dopamine following selective MAO‐A or ‐B inhibition in rat striatum depleted of dopaminergic and serotonergic innervation
Authors: Sader‐Mazbar O , Loboda Y , Rabey M J , Finberg J P M 
Published: August 2013

Background and PurposeSelective MAO type B (MAO‐B) inhibitors are effective in potentiation of the clinical effect of L‐DOPA in Parkinson's disease, but dopamine (DA) is deaminated mainly by MAO type A (MAO‐A) in rat brain. We sought to clarify the roles of MAO‐A and MAO‐B in deamination of DA formed from exogenous L‐DOPA in rat striatum depleted of dopaminergic, or both dopaminergic and serotonergic innervations. We also studied the effect of organic cation transporter‐3 (OCT‐3) inhibition by decinium‐22 on extracellular DA levels following L‐DOPA.Experimental ApproachStriatal dopaminergic and/or serotonergic neuronal innervations were lesioned by 6‐hydroxydopamine or 5,7‐dihydroxytryptamine respectively. Microdialysate DA levels after systemic L‐DOPA were measured after inhibition of MAO‐A or MAO‐B by clorgyline or rasagiline respectively. MAO subtype localization in the striatum was determined by immunofluorescence.Key ResultsRasagiline increased DA extracellular levels following L‐DOPA to a greater extent in double‐ than in single‐lesioned rats (2.8‐ and 1.8‐fold increase, respectively, relative to saline treatment); however, clorgyline elevated DA levels in both models over 10‐fold. MAO‐A was strongly expressed in medium spiny neurons (MSNs) in intact and lesioned striata, while MAO‐B was localized in glia and to a small extent in MSNs. Inhibition of OCT‐3 increased DA levels in the double‐ more than the single‐lesion animals.Conclusions and ImplicationsIn striatum devoid of dopaminergic and serotonergic inputs, most deamination of L‐DOPA‐derived DA is mediated by MAO‐A in MSN and a smaller amount by MAO‐B in both MSN and glia. OCT‐3 plays a significant role in uptake of DA from extracellular space. Inhibitors of OCT‐3 are potential future targets for anti‐Parkinsonian treatments.
The serine‐threonine kinase p90RSK is a new target of enzastaurin in follicular lymphoma cells
Authors: Kheirallah S , Fruchon S , Ysebaert L , Blanc A , Capilla F , Marrot A , AlSaati T , Frenois F X , Benhadji K A , Fournié J J , Laurent G , Bezombes C 
Published: August 2013

Background and PurposeFollicular lymphoma is the second most common non‐Hodgkin's lymphoma and, despite the introduction of rituximab for its treatment, this disease is still considered incurable. Besides genetic alterations involving Bcl‐2, Bcl‐6 or c‐Myc, follicular lymphoma cells often display altered B‐cell receptor signalling pathways including overactive PKC and PI3K/Akt systems.Experimental ApproachThe effect of enzastaurin, an inhibitor of PKC, was evaluated both in vitro on follicular lymphoma cell lines and in vivo on a xenograft murine model. Using pharmacological inhibitors and siRNA transfection, we determined the different signalling pathways after enzastaurin treatment.Key ResultsEnzastaurin inhibited the serine‐threonine kinase p90RSK which has downstream effects on GSK3β. Bad and p70S6K. These signalling proteins control follicular lymphoma cell survival and apoptosis; which accounted for the inhibition by enzastaurin of cell survival and its induction of apoptosis of follicular lymphoma cell lines in vitro. Importantly, these results were replicated in vivo where enzastaurin inhibited the growth of follicular lymphoma xenografts in mice.Conclusions and ImplicationsThe targeting of p90RSK by enzastaurin represents a new therapeutic option for the treatment of follicular lymphoma.
Endogenous PYY and GLP‐1 mediate l‐glutamine responses in intestinal mucosa
Authors: Joshi S , Tough I R , Cox H M 
Published: August 2013

Background and Purposel‐glutamine (Gln) is an energy source for gastrointestinal (GI) epithelia and can stimulate glucagon‐like peptide 1 (GLP‐1) release from isolated enteroendocrine L‐cells. GLP‐1 and peptide YY (PYY) are co‐secreted postprandially and both peptides have functional roles in glucose homeostasis and energy balance. The primary aim of this project was to establish the endogenous mechanisms underpinning Gln responses within intact GI mucosae using selective receptor antagonists.Experimental ApproachMouse mucosae from different GI regions were voltage‐clamped and short‐circuit current (Isc) was recorded to Gln added to either surface in the absence or presence of antagonists, using wild‐type (WT) or PYY‐/‐ tissues. The glucose sensitivity of Gln responses was also investigated by replacement with mannitol.Key ResultsColonic apical and basolateral Gln responses (at 0.1 and 1 mM) were biphasic; initial increases in Isc were predominantly GLP‐1 mediated. GLP‐1 receptor antagonism significantly reduced the initial Gln response in the PYY‐/‐ colon. The slower reductions in Isc to Gln were PYY‐Y1 mediated as they were absent from the PYY‐/‐ colon and were blocked selectively in WT tissue by a Y1 receptor antagonist. In jejunum mucosa, Gln stimulated monophasic Isc reductions that were PYY‐Y1 receptor mediated. Gln effects were partially glucose sensitive, and Calhex 231 inhibition indicated that the calcium‐sensing receptor (CaSR) was involved.Conclusion and ImplicationsGln stimulates the co‐release of endogenous GLP‐1 and PYY from mucosal L‐cells resulting in paracrine GLP‐1 and Y1 receptor‐mediated electrogenic epithelial responses. This glucose‐sensitive mechanism appears to be CaSR mediated and could provide a significant therapeutic strategy releasing two endogenous peptides better known for their glucose‐lowering and satiating effects.
Structure and function of midkine as the basis of its pharmacological effects
Authors: Muramatsu T 
Published: August 2013

Midkine (MK) is a heparin‐binding growth factor or cytokine and forms a small protein family, the other member of which is pleiotrophin.MKenhances survival, migration, cytokine expression, differentiation and other activities of target cells.MKis involved in various physiological processes, such as development, reproduction and repair, and also plays important roles in the pathogenesis of inflammatory and malignant diseases.MKis largely composed of two domains, namely a moreN‐terminally locatedN‐domain and a moreC‐terminally locatedC‐domain. Both domains are basically composed of three antiparallel β‐sheets. In addition, there are short tails in theN‐terminal andC‐terminal sides and a hinge connecting the two domains. Several membrane proteins have been identified asMKreceptors: receptor protein tyrosine phosphataseZ1 (PTPζ), low‐density lipoprotein receptor‐related protein, integrins, neuroglycanC, anaplastic lymphoma kinase andNotch‐2. Among them, the most established one isPTPζ. It is a transmembrane tyrosine phophatase with chondroitin sulfate, which is essential for high‐affinity binding withMK.PI3KandMAPKplay important roles in the downstream signalling system ofMK, while transcription factors affected byMKsignalling includeNF‐κB,Hes‐1 andSTATs. Because of the involvement ofMKin various physiological and pathological processes,MKitself as well as pharmaceuticals targetingMKand its signalling system are expected to be valuable for the treatment of numerous diseases.Linked ArticlesThis article is part of a themed section on Midkine. To view the other articles in this section visithttp://dx.doi.org/10.1111/bph.2014.171.issue‐4
Bleomycin induces endothelial mesenchymal transition through activation of mTORpathway: a possible mechanism contributing to the sclerotherapy of venous malformations
Authors: Zhang Wei , Chen Gang , Ren Jian‐Gang , Zhao Yi‐Fang 
Published: August 2013

Background and PurposeBleomycin (BLM), one of the most common sclerosants, is often used to treat venous malformations (VMs). The present study was designed to investigate whether endothelial mesenchymal transition (EndoMT) contributes to the therapeutic effects ofBLM.Experimental ApproachEndothelial and mesenchymal markers of HUVECs were measured by immunofluorescence, real‐time quantitative PCR and Western blot analysis. Cell migration and tube formation assays were performed to evaluate endothelial cell function. Slug small‐interferingRNAand specific inhibitors [Z‐VAD‐FMK for pan caspases, rapamycin for mammalian target of rapamycin (mTOR)] were used to investigate the mechanism.Key ResultsLong term (48 h or longer) treatment withBLM(0.1 mU·mL−1) inducedEndoMTinHUVECs, as manifested by a reduction in the expression of vascular endothelial‐cadherin and an up‐regulation in the expression of α‐smooth muscle actin and fibroblast specific protein‐1, as well as activation of the transcription factor Slug. The size and protein content of the transformed cells were increased. BLM also enhanced the migration of HUVECs but diminished their tube formation. By employing rapamycin, we demonstrated that activation of the mTORpathway is involved inBLM‐inducedEndoMTinHUVECs.Conclusions and ImplicationsOur results show that a Slug‐dependentEndoMTprocess is involved inBLM‐induced therapeutic effects on endothelial cells and, more importantly, indicate the potential role of this process in the sclerotherapy ofVMs.
Novel roles for β‐arrestins in the regulation of pharmacological sequestration to predict agonist‐induced desensitization of dopamine D3 receptors
Authors: Min C , Zheng M , Zhang X , Caron M G , Kim K M 
Published: August 2013

Background and PurposeIn addition to typical GPCR kinase (GRK)‐/β‐arrestin‐dependent internalization, dopamine D3 receptor employed an additional GRK‐independent sequestration pathway. In this study, we investigated the molecular mechanism of this novel sequestration pathway.Experimental ApproachRadioligand binding, flow cytometry and cell surface biotinylation assay were used to characterize trafficking properties of D2 and D3 receptors. Serine/threonine and N‐linked glycosylation mutants of the D3 receptor were utilized to locate receptor regions involved in pharmacological sequestration and desensitization. Various point mutants of the D2 and D3 receptors, whose sequestration and desensitization properties were altered, were combined with knockdown cells of GRKs or β‐arrestins to functionally correlate pharmacological sequestration and desensitization.Key ResultsThe D3 receptor, but not the D2 receptor, showed characteristic trafficking behaviour in which receptors were shifted towards the more hydrophobic domains within the plasma membrane without translocation into other intracellular compartments. Among various amino acid residues tested, S145/S146, C147 and N12/19 were involved in pharmacological sequestration and receptor desensitization. Both pharmacological sequestration and desensitization of D3 receptor required β‐arrestins, and functional relationship was observed between two processes when it was tested for D3 receptor variants and agonists.Conclusions and ImplicationsPharmacological sequestration of D3 receptor accompanies movement of cell surface receptors into a more hydrophobic fraction within the plasma membrane and renders D3 receptor inaccessible to hydrophilic ligands. Pharmacological sequestration is correlated with desensitization of the D3 receptor in a Gβγ‐ and β‐arrestin‐dependent manner. This study provides new insights into molecular mechanism governing GPCR trafficking and desensitization.
Anandamide transport inhibition by ARN272 attenuates nausea‐induced behaviour in rats, and vomiting in shrews (Suncus murinus)
Authors: O'Brien L D , Limebeer C L , Rock E M , Bottegoni G , Piomelli D , Parker L A 
Published: August 2013

Background and PurposeTo understand how anandamide transport inhibition impacts the regulation of nausea and vomiting and the receptor level mechanism of action involved. In light of recent characterization of an anandamide transporter, fatty acid amide hydrolase‐1‐like anandamide transporter, to provide behavioural support for anandamide cellular reuptake as a facilitated transport process.Experimental ApproachThe systemic administration of the anandamide transport inhibitor ARN272 ([(4‐(5‐(4‐hydroxy‐phenyl)‐3,4‐diaza‐bicyclo[4.4.0]deca‐1(6),2,4,7,9‐pentaen‐2‐ylamino)‐phenyl)‐phenylamino‐methanone]) was used to evaluate the prevention of LiCl‐induced nausea‐induced behaviour (conditioned gaping) in rats, and LiCl‐induced emesis in shrews (Suncus murinus). The mechanism of how prolonging anandamide availability acts to regulate nausea in rats was explored by the antagonism of cannabinoid 1 (CB1) receptors with the systemic co‐administration of SR141716.Key ResultsThe systemic administration of ARN272 produced a dose‐dependent suppression of nausea‐induced conditioned gaping in rats, and produced a dose‐dependent reduction of vomiting in shrews. The systemic co‐administration of SR141716 with ARN272 (at 3.0 mg·kg−1) in rats produced a complete reversal of ARN272‐suppressed gaping at 1.0 mg·kg−1. SR141716 alone did not differ from the vehicle solution.Conclusions and ImplicationsThese results suggest that anandamide transport inhibition by the compound ARN272 tonically activates CB1 receptors and as such produces a type of indirect agonism to regulate toxin‐induced nausea and vomiting. The results also provide behavioural evidence in support of a facilitated transport mechanism used in the cellular reuptake of anandamide.
Calcified neurocysticercosis lesions and antiepileptic drug–resistant epilepsy: A surgically remediable syndrome?
Authors: Rathore Chaturbhuj , Thomas Bejoy , Kesavadas Chandrasekharan , Abraham Mathew , Radhakrishnan Kurupath 
Published: August 2013

SummaryPurposeIn contrast to the well‐recognized association between acute symptomatic seizures and neurocysticercosis, the association between antiepileptic drug (AED)–resistant epilepsy and calcified neurocysticercosis lesions (CNLs) is poorly understood. We studied the association between AED‐resistant epilepsy and CNLs, including the feasibility and outcome of resective surgery.MethodsFrom the prospective database maintained at our epilepsy center, we reviewed the data of all patients with AED‐resistant epilepsy who underwent presurgical evaluation from January 2001 to July 2010 and had CNL on imaging. We used clinical, neuroimaging, and interictal, ictal, and intracranial electroencephalography (EEG) findings to determine the association between CNL and epilepsy. Suitable candidates underwent resective surgery.Key FindingsForty‐five patients fulfilled the inclusion criteria. In 17 patients, CNL was proven to be the causative lesion for AED‐resistant epilepsy (group 1); in 18 patients, CNL was associated with unilateral hippocampal sclerosis (HS; group 2); and in 10 patients, CNLs were considered as incidental lesions (group 3). In group 1 patients, CNLs were more common in frontal lobes (12/17), whereas in group 2 patients, CNLs were more commonly located in temporal lobes (11/18; p = 0.002). Group 2 patients were of a younger age at epilepsy onset than those in group 1 (8.9 ± 7.3 vs. 12.6 ± 6.8 years, p = 0.003). Perilesional gliosis was more common among patients in group 1 when compared to group 3 patients (12/17 vs. 1/10; p = 0.006). Fifteen patients underwent resective surgery. Among group 1 patients, four of five became seizure‐free following lesionectomy alone. In group 2, four patients underwent anterior temporal lobectomy (ATL) alone, of whom one became seizure‐free; five underwent ATL combined with removal of CNL (two of them after intracranial EEG and all of them became seizure‐free, whereas one patient underwent lesionectomy alone and did not become seizure‐free.SignificanceIn endemic regions, although rare, CNLs are potential cause for AED‐resistant and surgically remediable epilepsy, as well as dual pathology. Presence of perilesional gliosis contributes to epileptogenicity of these lesions. For those patients with CNL and HS, resection of both lesions favors better chance of seizure‐free outcome.
Reassessing regime shifts in the North Pacific: incremental climate change and commercial fishing are necessary for explaining decadal‐scale biological variability
Authors: Litzow Michael A. , Mueter Franz J. , Hobday Alistair J. 
Published: August 2013

AbstractIn areas of the North Pacific that are largely free of overfishing, climate regime shifts – abrupt changes in modes of low‐frequency climate variability – are seen as the dominant drivers of decadal‐scale ecological variability. We assessed the ability of leading modes of climate variability [Pacific Decadal Oscillation (PDO), North Pacific Gyre Oscillation (NPGO), Arctic Oscillation (AO), Pacific‐North American Pattern (PNA), North Pacific Index (NPI), El Niño‐Southern Oscillation (ENSO)] to explain decadal‐scale (1965–2008) patterns of climatic and biological variability across two North Pacific ecosystems (Gulf of Alaska and Bering Sea). Our response variables were the first principle component (PC1) of four regional climate parameters [sea surface temperature (SST), sea level pressure (SLP), freshwater input, ice cover], and PCs 1–2 of 36 biological time series [production or abundance for populations of salmon (Oncorhynchus spp.), groundfish, herring (Clupea pallasii), shrimp, and jellyfish]. We found that the climate modes alone could not explain ecological variability in the study region. Both linear models (for climate PC1) and generalized additive models (for biology PC1–2) invoking only the climate modes produced residuals with significant temporal trends, indicating that the models failed to capture coherent patterns of ecological variability. However, when the residual climate trend and a time series of commercial fishery catches were used as additional candidate variables, resulting models of biology PC1–2 satisfied assumptions of independent residuals and out‐performed models constructed from the climate modes alone in terms of predictive power. As measured by effect size and Akaike weights, the residual climate trend was the most important variable for explaining biology PC1 variability, and commercial catch the most important variable for biology PC2. Patterns of climate sensitivity and exploitation history for taxa strongly associated with biology PC1–2 suggest plausible mechanistic explanations for these modeling results. Our findings suggest that, even in the absence of overfishing and in areas strongly influenced by internal climate variability, climate regime shift effects can only be understood in the context of other ecosystem perturbations.
Nitrogen deposition promotes the production of new fungal residues but retards the decomposition of old residues in forest soil fractions
Authors: Griepentrog Marco , Bodé Samuel , Boeckx Pascal , Hagedorn Frank , Heim Alexander , Schmidt Michael W. I. 
Published: August 2013

AbstractAtmospheric nitrogen (N) deposition has frequently been observed to increase soil carbon (C) storage in forests, but the underlying mechanisms still remain unclear. Changes in microbial community composition and substrate use are hypothesized to be one of the key mechanisms affected by N inputs. Here, we investigated the effects of N deposition on amino sugars, which are used as biomarkers for fungal‐ and bacterial‐derived microbial residues in soil. We made use of a 4‐year combined CO2 enrichment and N deposition experiment in model forest ecosystems, providing a distinct 13C signal for ‘new’ and ‘old’ C in soil organic matter and microbial residues measured in density and particle‐size fractions of soils. Our hypothesis was that N deposition decreases the amount of fungal residues in soils, with the new microbial residues being more strongly affected than old residues. The soil fractionation showed that organic matter and microbial residues are mainly stabilized by association with soil minerals in the heavy and fine fractions. Moreover, the bacterial residues are relatively enriched at mineral surfaces compared to fungal residues. The 13C tracing indicated a greater formation of fungal residues compared to bacterial residues after 4 years of experiment. In contradiction to our hypotheses, N deposition significantly increased the amount of new fungal residues in bulk soil and decreased the decomposition of old microbial residues associated with soil minerals. The preservation of old microbial residues could be due to decreased N limitation of microorganisms and therefore a reduced dependence on organic N sources. This mechanism might be especially important in fine heavy fractions with low C/N ratios, where microbial residues are effectively protected from decomposition by association with soil minerals.
Evidence for strong seasonality in the carbon storage and carbon use efficiency of an Amazonian forest
Authors: Rowland Lucy , Hill Timothy Charles , Stahl Clement , Siebicke Lukas , Burban Benoit , Zaragoza‐Castells Joana , Ponton Stephane , Bonal Damien , Meir Patrick , Williams Mathew 
Published: August 2013

AbstractThe relative contribution of gross primary production and ecosystem respiration to seasonal changes in the net carbon flux of tropical forests remains poorly quantified by both modelling and field studies. We use data assimilation to combine nine ecological time series from an eastern Amazonian forest, with mass balance constraints from an ecosystem carbon cycle model. The resulting analysis quantifies, with uncertainty estimates, the seasonal changes in the net carbon flux of a tropical rainforest which experiences a pronounced dry season. We show that the carbon accumulation in this forest was four times greater in the dry season than in the wet season and that this was accompanied by a 5% increase in the carbon use efficiency. This seasonal response was caused by a dry season increase in gross primary productivity, in response to radiation and a similar magnitude decrease in heterotrophic respiration, in response to drying soils. The analysis also predicts increased carbon allocation to leaves and wood in the wet season, and greater allocation to fine roots in the dry season. This study demonstrates implementation of seasonal variations in parameters better enables models to simulate observed patterns in data. In particular, we highlight the necessity to simulate the seasonal patterns of heterotrophic respiration to accurately simulate the net carbon flux seasonal tropical forest.