bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aggregates of Small Nuclear Ribonucleic Acids (snRNAs) in Alzheimer's Disease
Authors: Hales Chadwick M. , Dammer Eric B. , Diner Ian , Yi Hong , Seyfried Nicholas T. , Gearing Marla , Glass Jonathan D. , Montine Thomas J. , Levey Allan I. , Lah James J. 
Published: February 2014

AbstractWe recently discovered that protein components of the ribonucleic acid (RNA) spliceosome form cytoplasmic aggregates in Alzheimer's disease (AD) brain, resulting in widespread changes in RNA splicing. However, the involvement of small nuclear RNAs (snRNAs), also key components of the spliceosome complex, in the pathology of AD remains unknown. Using immunohistochemical staining of post‐mortem human brain and spinal cord, we identified cytoplasmic tangle‐shaped aggregates of snRNA in both sporadic and familial AD cases but not in aged controls or other neurodegenerative disorders. Immunofluorescence using antibodies reactive with the 2,2,7‐trimethylguanosine cap of snRNAs and transmission electron microscopy demonstrated snRNA localization with tau and paired helical filaments, the main component of neurofibrillary tangles. Quantitative real‐time polymerase chain reaction (PCR) showed U1 snRNA accumulation in the insoluble fraction of AD brains whereas other U snRNAs were not enriched. In combination with our previous results, these findings demonstrate that aggregates of U1 snRNA and U1 small nuclear ribonucleoproteins represent a new pathological hallmark of AD.
Different Dynamics of Aquaporin 4 and Glutamate Transporter‐1 Distribution in the Perineuronal and Perivascular Compartments during Ischemic Stroke
Authors: Mogoanta Laurentiu , Ciurea Marius , Pirici Ionica , Margaritescu Claudiu , Simionescu Cristiana , Ion Daniela A. , Pirici Daniel 
Published: February 2014

AbstractAquaporin‐4 (AQP4) and glutamate transporter‐1 (GLT‐1) represent the major water and glutamate astrocyte buffering gateways in the brain. Utilizing perilesional ischemic human cortices, we have performed here for the first time an integrative assessment on both AQP4 and GLT‐1, and on their proximity to blood vessels and neurons. Counting the relative number of AQP4±/GLT‐1±/glial fibrillary acidic protein± cells showed that double‐positive variants were overall most frequent, and their number tended to decrease from organized and recent perilesional cortices to controls. AQP4/GLT‐1 colocalization showed higher coefficients for the perilesional cortices compared with controls, suggesting an increased water/glutamate‐buffering capability. Distance frequency analysis of AQP4/GLT‐1 in relationship to neurons showed that both markers were concentrated at 20–40 μm around the perikarya; with AQP4 being more abundant in close proximity, these differences were not being driven by changes in neuropil density alone. Our study suggests a dual, simultaneous astrocytic function depending on the relative distance to neurons and vessels, with increased water and glutamate‐buffering capability in the mid perineuronal space, and an increased water‐buffering capability in the immediate perineuronal space, even higher than around vessels. Thus, adding specific AQP4/GLT‐1 modulator agents selectively depending on the acute/chronic phase of stroke might increase the efficacy of existing treatments.
Opioid receptor trafficking and interaction in nociceptors
Authors: Zhang X , Bao L , Li S 
Published: February 2014

Opiate analgesics such as morphine are often used for pain therapy. However, antinociceptive tolerance and dependence may develop with long‐term use of these drugs. It was found that μ‐opioid receptors can interact with δ‐opioid receptors, and morphine antinociceptive tolerance can be reduced by blocking δ‐opioid receptors. Recent studies have shown that μ‐ and δ‐opioid receptors are co‐expressed in a considerable number of small neurons in the dorsal root ganglion. The interaction of μ‐opioid receptors with δ‐opioid receptors in the nociceptive afferents is facilitated by the stimulus‐induced cell‐surface expression of δ‐opioid receptors, and contributes to morphine tolerance. Further analysis of the molecular, cellular and neural circuit mechanisms that regulate the trafficking and interaction of opioid receptors and related signalling molecules in the pain pathway would help to elucidate the mechanism of opiate analgesia and improve pain therapy.Linked ArticlesThis article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2
Acute metformin preconditioning confers neuroprotection against focal cerebral ischaemia by pre‐activation of AMPK‐dependent autophagy
Authors: Jiang Teng , Yu Jin‐Tai , Zhu Xi‐Chen , Wang Hui‐Fu , Tan Meng‐Shan , Cao Lei , Zhang Qiao‐Quan , Gao Li , Shi Jian‐Quan , Zhang Ying‐Dong , Tan Lan 
Published: February 2014

Background and PurposeRecent clinical trials report that metformin, an activator of AMP‐activated protein kinase (AMPK) used to treat type 2 diabetes, significantly reduces the risk of stroke by actions that are independent of its glucose‐lowering effects. However, the underlying molecular mechanisms are not known. Here, we tested the possibility that acute metformin preconditioning confers neuroprotection by pre‐activation of AMPK‐dependent autophagy in a rat model of permanent middle cerebral artery occlusion (pMCAO).Experimental ApproachMale Sprague‐Dawley rats were pretreated with either vehicle, an AMPK inhibitor, Compound C, or an autophagy inhibitor, 3‐methyladenine, and were injected with a single dose of metformin (10 mg kg−1, i.p.). Then, AMPK activity and autophagy biomarkers in the brain were assessed. At 24 h after metformin treatment, rats were subjected to pMCAO; infarct volume, neurological deficits and cell apoptosis were evaluated 24 and 96 h later.Key ResultsA single dose of metformin significantly activated AMPK and induced autophagy in the brain. The enhanced autophagic activity was inhibited by Compound C pretreatment. Furthermore, acute metformin preconditioning significantly reduced infarct volume, neurological deficits and cell apoptosis during a subsequent focal cerebral ischaemia. The neuroprotection mediated by metformin preconditioning was fully abolished by Compound C and partially inhibited by 3‐methyladenine.Conclusions and ImplicationsThese results provide the first evidence that acute metformin preconditioning induces autophagy by activation of brain AMPK, which confers neuroprotection against subsequent cerebral ischaemia. This suggests that metformin, a well‐known hypoglycaemic drug, may have a practical clinical use for stroke prevention.
Impaired neurogenesis by HIV‐1‐Gp120 is rescued by genetic deletion of fatty acid amide hydrolase enzyme
Authors: Avraham H K , Jiang S , Fu Y , Rockenstein E , Makriyannis A , Wood J , Wang L , Masliah E , Avraham S 
Published: February 2014

Background and PurposeThe HIV‐envelope glycoprotein Gp120 is involved in neuronal injury and is associated with neuro‐AIDS pathogenesis in the brain. Endocannabinoids are important lipid ligands in the CNS regulating neural functions, and their degeneration is controlled by hydrolysing enzymes such as the fatty acid amide hydrolase (FAAH). Here, we examined whether in vivo genetic deletion of Faah gene prevents HIV‐1 Gp120‐mediated effects on neurogenesis.Experimental ApproachWe generated new GFAP/Gp120 transgenic (Tg) mice that have genetic deletion of Faah gene by mating glial fribillary acidic protein (GFAP)/Gp120 Tg mice with Faah−/− mice. Neurogenesis and cell death were assessed by immunocytochemical analysis.Key ResultsEndocannabinoid levels in the brain of the double GFAP/Gp120//Faah−/− mice were similar to those observed in Faah−/− mice. However, unlike the impaired neurogenesis observed in GFAP/Gp120 Tg mice and Faah−/− mice, these GFAP/Gp120//Faah‐/ mice showed significantly improved neurogenesis in the hippocampus, indicated by a significant increase in neuroblasts and neuronal cells, an increase in BrdU+ cells and doublecortin positive cells (DCX+), and an increase in the number of PCNA. Furthermore, a significant decrease in astrogliosis and gliogenesis was observed in GFAP/Gp120//Faah−/−mice and neurogenesis was stimulated by neural progenitor cells (NPCs) and/or the newly formed NPC niches characterized by increased COX‐2 expression and elevated levels of PGE2.Conclusions and ImplicationsIn vivo genetic ablation of Faah, resulted in enhanced neurogenesis through modulation of the newly generated NPC niches in GFAP/Gp120//Faah−/− mice. This suggests a novel approach of using FAAH inhibitors to enhance neurogenesis in HIV‐1 infected brain.
Targeting Rho‐GTPases in immune cell migration and inflammation
Authors: Biro Maté , Munoz Marcia A , Weninger Wolfgang 
Published: February 2014

Leukocytes are unmatched migrators capable of traversing barriers and tissues of remarkably varied structural composition. An effective immune response relies on the ability of its constituent cells to infiltrate target sites. Yet, unwarranted mobilization of immune cells can lead to inflammatory diseases and tissue damage ranging in severity from mild to life‐threatening. The efficacy and plasticity of leukocyte migration is driven by the precise spatiotemporal regulation of the actin cytoskeleton. The small GTPases of the Rho family (Rho‐GTPases), and their immediate downstream effector kinases, are key regulators of cellular actomyosin dynamics and are therefore considered prime pharmacological targets for stemming leukocyte motility in inflammatory disorders. This review describes advances in the development of small‐molecule inhibitors aimed at modulating the Rho‐GTPase‐centric regulatory pathways governing motility, many of which stem from studies of cancer invasiveness. These inhibitors promise the advent of novel treatment options with high selectivity and potency against immune‐mediated pathologies.Linked ArticlesThis article is part of a themed section on Cytoskeleton, Extracellular Matrix, Cell Migration, Wound Healing and Related Topics. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue‐24
ABT‐263 enhances sorafenib‐induced apoptosis associated with Akt activity and the expression of Bax and p21(CIP1/WAF1) in human cancer cells
Authors: Li Jingru , Chen Yicheng , Wan Jiali , Liu Xin , Yu Chunrong , Li Wenhua 
Published: February 2014

Background and purposeSorafenib, a potent inhibitor that targets several kinases associated with tumourigenesis and cell survival, has been approved for clinical treatment as a single agent. However, combining sorafenib with other agents improves its anti‐tumour efficacy in various preclinical tumour models. ABT‐263, a second‐generation BH3 mimic, binds to the anti‐apoptotic family members Bcl‐2, Bcl‐xL and Bcl‐w, and has been demonstrated to enhance TNFSF10 (TRAIL)‐induced apoptosis in human hepatocarcinoma cells. Hence, we investigated the effects of ABT‐263 treatment combined with sorafenib.Experimental ApproachThe effects of ABT‐263 combined with sorafenib were investigated in vitro, on cell viability, clone formation and apoptosis, and the mechanism examined using western blot and flow cytometry. This combination was also evaluated in vivo, in a mouse xenograft model; tumour growth, volume and weights were measured and a TUNEL assay performed.Key ResultsABT‐263 enhanced sorafenib‐induced apoptosis while sparing non‐tumourigenic cells. Although ABT‐263 plus sorafenib significantly stimulated intracellular reactive oxygen species production and subsequent mitochondrial depolarization, this was not sufficient to trigger cell apoptosis. ABT‐263 plus sorafenib significantly decreased Akt activity, which was, at least partly, involved in its effect on apoptosis. Bax and p21 (CIP1/WAF1) were shown to play a critical role in ABT‐263 plus sorafenib‐induced apoptosis. Combining sorafenib with ABT‐263 dramatically increased its efficacy in vivo.Conclusion and ImplicationsThe anti‐tumour activity of ABT‐263 plus sorafenib may involve the induction of intrinsic cell apoptosis via inhibition of Akt, and reduced Bax and p21 expression. Our findings offer a novel effective therapeutic strategy for tumour treatment.
Using viruses as nanomedicines
Authors: van Kan‐Davelaar H E , van Hest J C M , Cornelissen J J L M , Koay M S T 
Published: February 2014

The field of nanomedicine involves the design and fabrication of novel nanocarriers for the intracellular delivery of therapeutic cargo or for use in molecular diagnostics. Although traditionally recognized for their ability to invade and infect host cells, viruses and bacteriophages have been engineered over the past decade as highly promising molecular platforms for the targeted delivery and treatment of many human diseases. Inherently biodegradable, the outer capsids of viruses are composed entirely of protein building blocks, which can be genetically or chemically engineered with molecular imaging reagents, targeting ligands and therapeutic molecules. While there are several examples of viruses as in vitro molecular cargo carriers, their potential for applications in nanomedicine has only recently emerged. Here we highlight recent developments towards the design and engineering of viruses for the treatment of cancer, bacterial infections and immune system‐related diseases.Linked ArticlesThis article is part of a themed section on Nanomedicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue‐17
Peptide Inhibitors Against Dengue Virus Infection
Authors: Panya Aussara , Bangphoomi Kunan , Choowongkomon Kiattawee , Yenchitsomanus Pa‐thai 
Published: February 2014

Dengue virus (DENV) infection has become a public health problem worldwide. The development of anti‐DENV drug is urgently needed because neither licensed vaccine nor specific drug is currently available. Inhibition of DENV attachment and entry to host cells by blocking DENV envelope (E) protein is an attractive strategy for anti‐DENV drug development. A hydrophobic pocket on the DENV E protein is essential for structural transition in the membrane fusion, and inhibition of this process is able to inhibit DENV infection. To search for a safe anti‐DENV drug, we identified short peptides targeting the hydrophobic pocket by molecular docking. In addition, the information of predicted ligand‐binding site of reported active compounds of DENV2 hydrophobic pocket was also used for peptide inhibitors selection. The di‐peptide, EF, was the most effective on DENV2 infection inhibition in vitro with a half maximal inhibition concentration (IC50) of 96 μm. Treatment of DENV2 with EF at the concentration of 200 μm resulted in 83.47% and 84.15% reduction in viral genome and intracellular E protein, respectively. Among four DENV serotypes, DENV2 was the most effective for the inhibition. Our results provide the proof of concept for the development of therapeutic peptide inhibitors against DENV infection by the computer‐aided molecular design.
Synthesis and Anticonvulsant Activity of Ethyl 2,2‐dimethyl‐1‐(2‐substitutedhydrazinecarboxamido) Cyclopropanecarboxylate Derivatives
Authors: Zhong Min , Zhang Yongmin , He Xianran 
Published: February 2014

In this study on the development of new anticonvulsants, fourteen ethyl 2,2‐dimethyl‐1‐(2‐substitutedhydrazinecarboxamido) cyclopropanecarboxylate derivatives were synthesized and tested for anticonvulsant activity using the maximal electroshock, subcutaneous pentylenetetrazole screens, which are the most widely employed seizure models for early identification of candidate anticonvulsants. Their neurotoxicity was determined applying the rotorod test. Two compounds 6f and 6k showed promising anticonvulsant activities in both models employed for anticonvulsant evaluation. The most active compound 6k showed the maximal electroshock‐induced seizures with ED50 value of 9.2 mg/kg and TD50 value of 387.5 mg/kg after intraperitoneally injection to mice, which provided compound 6k with a protective index (TD50/ED50) of 42.1 in the maximal electroshock test.
Prevalence and risk factors of tinnitus: the Korean National Health and Nutrition Examination Survey 2010–2011, a cross‐sectional study
Authors: Park R.J. , Moon J.D. 
Published: February 2014

ObjectivesThe aim of this study was to examine the association between tinnitus and several potential risk factors in Korean population.DesignA cross‐sectional study.SettingBased on data from the fifth Korean National Health and Nutrition Examination Survey.ParticipantsThe study included 10 061 Korean individuals.Main outcome measuresTinnitus was assessed by using a questionnaire, and otorhinolaryngologic examination was conducted. Risk factors associated with tinnitus were evaluated using a multiple logistic regression analysis.ResultsOf the 10 061 participants ranging from 20 to 97 years old, the overall prevalence of any tinnitus was 21.4% and annoying tinnitus was 7.3%. In a multivariable logistic regression model, the following factors were associated with having tinnitus: occupational noise exposure [any tinnitus, odd ratio (OR) = 1.34; annoying tinnitus, OR = 1.47], non‐occupational noise exposure (any tinnitus, OR = 1.48; annoying tinnitus, OR = 2.02), hearing impairment (any tinnitus, OR = 2.27; annoying tinnitus, OR = 3.61), chronic otitis media (any tinnitus, OR = 1.53; annoying tinnitus, OR = 1.36), chronic rhinosinusitis (any tinnitus, OR = 1.38; annoying tinnitus, OR = 1.38), temporomandibular disorder (any tinnitus, OR = 1.69; annoying tinnitus, OR = 1.90), depression (any tinnitus, OR = 1.44; annoying tinnitus, OR = 1.70), and higher stress level (any tinnitus, OR = 1.28; annoying tinnitus, OR = 1.76).ConclusionsThese results suggest that tinnitus is common in Korea and may be associated with some avoidable risk factors.
Limonene hydroperoxide analogues show specific patch test reactions
Authors: Bråred Christensson Johanna , Hellsén Staffan , Börje Anna , Karlberg Ann‐Therese 
Published: February 2014

SummaryBackgroundThe fragrance terpene R‐limonene is a very weak sensitizer, but forms allergenic oxidation products upon contact with air. The primary oxidation products of oxidized limonene, the hydroperoxides, have an important impact on the sensitizing potency of the oxidation mixture. One analogue, limonene‐1‐hydroperoxide, was experimentally shown to be a significantly more potent sensitizer than limonene‐2‐hydroperoxide in the local lymph node assay with non‐pooled lymph nodes.ObjectivesTo investigate the pattern of reactivity among consecutive dermatitis patients to two structurally closely related limonene hydroperoxides, limonene‐1‐hydroperoxide and limonene‐2‐hydroperoxide.MethodsLimonene‐1‐hydroperoxide, limonene‐2‐hydroperoxide, at 0.5% in petrolatum, and oxidized limonene 3.0% pet. were tested in 763 consecutive dermatitis patients.ResultsOf the tested materials, limonene‐1‐hydroperoxide gave most reactions, with 2.4% of the patients showing positive patch test reactions. Limonene‐2‐hydroperoxide and oxidized R‐limonene gave 1.7% and 1.2% positive patch test reactions, respectively. Concomitant positive patch test reactions to other fragrance markers in the baseline series were frequently noted.ConclusionsThe results are in accordance with the experimental studies, as limonene‐1‐hydroperoxide gave more positive patch test reactions in the tested patients than limonene‐2‐hydroperoxide. Furthermore, the results support the specificity of the allergenic activity of the limonene hydroperoxide analogues and the importance of oxidized limonene as a cause of contact allergy.
Expression of HMGA2 in bladder cancer and its association with epithelial‐to‐mesenchymal transition
Authors: Ding X. , Wang Y. , Ma X. , Guo H. , Yan X. , Chi Q. , Li J. , Hou Y. , Wang C. 
Published: February 2014

AbstractObjectivesHigh mobility group protein2 (HMGA2) and epithelial‐to‐mesenchymal transition are both related to progress of bladder cancer, however, the relationship between HMGA2, E‐cadherin and vimentin in bladder cancer is not yet known. Thus, this study has examined expression of HMGA2, E‐cadherin and vimentin in bladder cancer and investigated their relationship.Materials and methodsThe 5637 bladder cancer cell line and SV‐HUC‐1 normal uroepithelial cells were used to study expression of HMGA2, E‐cadherin and vimentin using RT‐PCR and western blotting. Paraffin wax‐embedded bladder cancer tissues were used to study protein expression using immunohistochemistry and χ2 analysis and Kendall's correlation were utilized statistical methods.ResultsOverexpression of HMGA2 was associated with down‐regulation of E‐cadherin and up‐regulation of vimentin in the 5637 bladder cancer line. A total of 49 paraffin wax‐embedded tissues of transitional cell bladder cancer were used. Positive expression levels of HMGA2 protein and vimentin were 41 and 43% in bladder tissues, respectively. No expression of E‐cadherin was found in 43%. Expression of HMGA2, loss of E‐cadherin and expression of vimentin are all significantly correlated with bladder cancer grade and stage. Loss of E‐cadherin and expression of vimentin both correlated with recurrence of the bladder cancer.ConclusionsExpression of HMGA2 was closely associated with occurrence of epithelial‐to‐mesenchymal transition. Expression of HMGA2, loss of E‐cadherin and expression of vimentin may indicate high degree malignancy of bladder cancer. Loss of E‐cadherin expression and positive expression of vimentin may predict recurrence of bladder cancer.
Myasthenia and risk of cancer: a population‐based case–control study
Authors: Pedersen E. G. , Pottegård A. , Hallas J. , Friis S. , Hansen K. , Jensen P. E. H. , Gaist D. 
Published: February 2014

Background and purposeTo evaluate the association between having non‐thymoma myasthenia and the risk of extra‐thymic cancer in a population‐based setting.MethodsA nationwide case–control study was conducted in Denmark based on medical registries. The study included all cases with a first time diagnosis of cancer during 2000–2009. Each case was matched by birth year and gender with eight population controls using risk set sampling. Subjects with myasthenia were identified through a validated register‐based algorithm. Conditional logistic regression was used to compute crude and adjusted odds ratios (ORs), with 95% confidence intervals (CIs), for cancer associated with a prior diagnosis of myasthenia.ResultsIn all, 233 437 cases and 1 867 009 controls were identified. A total of 80 cases and 518 controls had a prior diagnosis of myasthenia. Myasthenia was not associated with an increased risk of overall cancer (OR 1.1; 95% CI 0.9–1.4). Adjusted ORs for major cancer sites were also close to unity, whereas an elevated risk of lymphomas was observed (OR 2.0; 95% CI 0.8–5.5). Early‐onset myasthenia was associated with a slightly increased OR for overall cancer (1.5; 95% CI 1.0–2.3); however, this estimate was based on small numbers.ConclusionsNon‐thymoma myasthenia was not associated with an increased risk of overall cancer. Larger studies are necessary to evaluate the association between myasthenia and risk of lymphoma and the potential effect modification by age of myasthenia onset in relation to cancer risk.