bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular analysis of ATP‐sensitive K+ channel subunits expressed in mouse vas deferens myocytes
Authors: Iwasa Kazuomi , Zhu Hai‐Lei , Shibata Atsushi , Maehara Yoshihiko , Teramoto Noriyoshi 
Published: October 2013

Background and PurposeATP‐sensitive K+ (KATP) channels, which are composed of KIR6.x associated with sulphonylurea receptor (SUR) subunits, have been detected in native smooth muscle cells, but it is currently not known which of these is expressed in mouse vas deferens myocytes.Experimental ApproachPharmacological and electrophysiological properties of KATP channels in mouse vas deferens myocytes were investigated using patch clamp techniques. Molecular biological analyses were performed to examine the properties of these KATP channels.Key ResultsDuring conventional whole‐cell recording, pinacidil elicited an inward current that was suppressed by glibenclamide, a sulfonylurea agent, and by U‐37883A, a selective KIR6.1 blocker. When 0.3 mM ATP was added to the pipette solution, the peak amplitude of the pinacidil‐induced current was much smaller than that recorded in its absence. When 3 mM UDP, GDP or ADP was included in the pipette solution, an inward current was elicited after establishment of the conventional whole‐cell configuration, with potency order being UDP > GDP > ADP. These nucleoside diphosphate‐induced inward currents were suppressed by glibenclamide. MCC‐134, a SUR modulator, induced glibenclamide‐sensitive KATP currents that were similar to those induced by 100 μM pinacidil. In the cell‐attached configuration, pinacidil activated channels with a conductance similar to that of KIR6.1. Reverse transcription PCR analysis revealed the expression of KIR6.1 and SUR2B transcripts and immunohistochemical studies indicated the presence of KIR6.1 and SUR2B proteins in the myocytes.Conclusions and ImplicationsOur results indicate that native KATP channels in mouse vas deferens myocytes are a heterocomplex of KIR6.1 channels and SUR2B subunits.
Naringenin inhibits the growth of Dictyostelium and MDCK‐derived cysts in a TRPP2 (polycystin‐2)‐dependent manner
Authors: Waheed A , Ludtmann M H R , Pakes N , Robery S , Kuspa A , Dinh C , Baines D , Williams R S B , Carew M A 
Published: October 2013

Background and PurposeIdentifying and characterizing potential new therapeutic agents to target cell proliferation may provide improved treatments for neoplastic disorders such as cancer and polycystic diseases.Experimental ApproachWe used the simple, tractable biomedical model Dictyostelium to investigate the molecular mechanism of naringenin, a dietary flavonoid with antiproliferative and chemopreventive actions in vitro and in animal models of carcinogenesis. We then translated these results to a mammalian kidney model, Madin‐Darby canine kidney (MDCK) tubule cells, grown in culture and as cysts in a collagen matrix.Key ResultsNaringenin inhibited Dictyostelium growth, but not development. Screening of a library of random gene knockout mutants identified a mutant lacking TRPP2 (polycystin‐2) that was resistant to the effect of naringenin on growth and random cell movement. TRPP2 is a divalent transient receptor potential cation channel, where mutations in the protein give rise to type 2 autosomal dominant polycystic kidney disease (ADPKD). Naringenin inhibited MDCK cell growth and inhibited cyst growth. Knockdown of TRPP2 levels by siRNA in this model conferred partial resistance to naringenin such that cysts treated with 3 and 10 μM naringenin were larger following TRPP2 knockdown compared with controls. Naringenin did not affect chloride secretion.Conclusions and ImplicationsThe action of naringenin on cell growth in the phylogenetically diverse systems of Dictyostelium and mammalian kidney cells, suggests a conserved effect mediated by TRPP2 (polycystin‐2). Further studies will investigate naringenin as a potential new therapeutic agent in ADPKD.Linked ArticlesThis article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue‐10
Quality control gone wrong: mitochondria, lysosomal storage disorders and neurodegeneration
Authors: Osellame L D , Duchen M R 
Published: October 2013

The eukaryotic cell possesses specialized pathways to turn over and degrade redundant proteins and organelles. Each pathway is unique and responsible for degradation of distinctive cytosolic material. The ubiquitin‐proteasome system and autophagy (chaperone‐mediated, macro, micro and organelle specific) act synergistically to maintain proteostasis. Defects in this equilibrium can be deleterious at cellular and organism level, giving rise to various disease states. Dysfunction of quality control pathways are implicated in neurodegenerative diseases and appear particularly important in Parkinson's disease and the lysosomal storage disorders. Neurodegeneration resulting from impaired degradation of ubiquitinated proteins and α‐synuclein is often accompanied by mitochondrial dysfunction. Mitochondria have evolved to control a diverse number of processes, including cellular energy production, calcium signalling and apoptosis, and like every other organelle within the cell, they must be ‘recycled.’ Failure to do so is potentially lethal as these once indispensible organelles become destructive, leaking reactive oxygen species and activating the intrinsic cell death pathway. This process is paramount in neurons which have an absolute dependence on mitochondrial oxidative phosphorylation as they cannot up‐regulate glycolysis. As such, mitochondrial bioenergetic failure can underpin neural death and neurodegenerative disease. In this review, we discuss the links between cellular quality control and neurodegenerative diseases associated with mitochondrial dysfunction, with particular attention to the emerging links between Parkinson's and Gaucher diseases in which defective quality control is a defining factor.Linked ArticlesThis article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue‐8
Development of pharmacological strategies for mitochondrial disorders
Authors: Kanabus M , Heales S J , Rahman S 
Published: October 2013

Mitochondrial diseases are an unusually genetically and phenotypically heterogeneous group of disorders, which are extremely challenging to treat. Currently, apart from supportive therapy, there are no effective treatments for the vast majority of mitochondrial diseases. Huge scientific effort, however, is being put into understanding the mechanisms underlying mitochondrial disease pathology and developing potential treatments. To date, a variety of treatments have been evaluated by randomized clinical trials, but unfortunately, none of these has delivered breakthrough results. Increased understanding of mitochondrial pathways and the development of many animal models, some of which are accurate phenocopies of human diseases, are facilitating the discovery and evaluation of novel prospective treatments. Targeting reactive oxygen species has been a treatment of interest for many years; however, only in recent years has it been possible to direct antioxidant delivery specifically into the mitochondria. Increasing mitochondrial biogenesis, whether by pharmacological approaches, dietary manipulation or exercise therapy, is also currently an active area of research. Modulating mitochondrial dynamics and mitophagy and the mitochondrial membrane lipid milieu have also emerged as possible treatment strategies. Recent technological advances in gene therapy, including allotopic and transkingdom gene expression and mitochondrially targeted transcription activator‐like nucleases, have led to promising results in cell and animal models of mitochondrial diseases, but most of these techniques are still far from clinical application.Linked ArticlesThis article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue‐8
First‐in‐class cardiolipin‐protective compound as a therapeutic agent to restore mitochondrial bioenergetics
Authors: Szeto Hazel H 
Published: October 2013

A decline in energy is common in aging, and the restoration of mitochondrial bioenergetics may offer a common approach for the treatment of numerous age‐associated diseases. Cardiolipin is a unique phospholipid that is exclusively expressed on the inner mitochondrial membrane where it plays an important structural role in cristae formation and the organization of the respiratory complexes into supercomplexes for optimal oxidative phosphorylation. The interaction between cardiolipin and cytochrome c determines whether cytochrome c acts as an electron carrier or peroxidase. Cardiolipin peroxidation and depletion have been reported in a variety of pathological conditions associated with energy deficiency, and cardiolipin has been identified as a target for drug development. This review focuses on the discovery and development of the first cardiolipin‐protective compound as a therapeutic agent. SS‐31 is a member of the Szeto‐Schiller (SS) peptides known to selectively target the inner mitochondrial membrane. SS‐31 binds selectively to cardiolipin via electrostatic and hydrophobic interactions. By interacting with cardiolipin, SS‐31 prevents cardiolipin from converting cytochrome c into a peroxidase while protecting its electron carrying function. As a result, SS‐31 protects the structure of mitochondrial cristae and promotes oxidative phosphorylation. SS‐31 represents a new class of compounds that can recharge the cellular powerhouse and restore bioenergetics. Extensive animal studies have shown that targeting such a fundamental mechanism can benefit highly complex diseases that share a common pathogenesis of bioenergetics failure. This review summarizes the mechanisms of action and therapeutic potential of SS‐31 and provides an update of its clinical development programme.Linked ArticlesThis article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue‐8
Genetic regulation of immunoglobulin E level in different pathological states: integration of mouse and human genetics
Authors: Gusareva Elena S. , Kurey Iryna , Grekov Igor , Lipoldová Marie 
Published: October 2013

ABSTRACTImmunoglobulin E (IgE) first evolved in mammals. It plays an important role in defence against helminths and parasitic infection and in pathological states including allergic reactions, anti‐tumour defence and autoimmune diseases. Elucidation of genetic control of IgE level could help us to understand regulation of the humoral immune response in health and disease, the etiology and pathogenesis of many human diseases, and to facilitate discovery of more effective methods for their prevention and cure. Herein we summarise progress in the genetics of regulation of IgE level in human diseases and show that integration of different approaches and use of animal models have synergistic effects in gaining new knowledge about both protective and pathological roles of this important antibody.
Dental visiting history between ages 13 and 30 years and oral health‐related impact
Authors: Brennan David S. , Spencer A. John 
Published: October 2013

AbstractBackgroundThe aim was to assess the role of visit history factors between the age of 13 and 30 years on oral health‐related impact.Materials and MethodsIn 1988‐89, n = 7 673 South Australian school children aged 13 years were sampled with n = 4 604 children (60.0%) and n = 4 476 parents (58.3%) returning questionnaires. In 2005‐06, n = 632 baseline study participants responded (43.0% response of those traced and living in Adelaide). Oral health impact was measured at age 30 years using OHIP‐14.ResultsMultivariate regression showed that OHIP scores were significantly higher (P < 0.05) for those with episodes of relief of pain visits once (β = 1.487) or two or more times (β = 2.883), and episodes of extraction once (β = 1.301) or two or more times (β = 3.172). Higher positive dental visit attitude scores were associated with lower OHIP scores (β = −1.265), as were being male (β = −0.637), having a job (β = −1.555) and being tertiary educated (β = −0.632).ConclusionsHistory of adverse dental events between the age of 13 and 30 years such as episodes of relief of pain visits and episodes of extraction was associated with higher impact of oral health problems at age 30 suggesting a cumulative effect.
The NLRP3 inflammasome: role in airway inflammation
Authors: Im H. , Ammit A. J. 
Published: October 2013

SummaryAsthma is characterized by airway inflammation, airway hyperresponsiveness and airway remodelling. Uncontrolled airway inflammation or repeated asthma exacerbations can lead to airway remodelling, which cannot be reversed by current pharmacological treatment, and consequently lead to decline in lung function. Thus, it is critical to understand airway inflammation in asthma and infectious exacerbation. The inflammasome has emerged as playing a key role in innate immunity and inflammation. Upon ligand sensing, inflammasome components assemble and self‐oligomerize, leading to caspase‐1 activation and maturation of pro‐IL‐1β and pro‐IL‐18 into bioactive cytokines. These bioactive cytokines then play a pivotal role in the initiation and amplification of inflammatory processes. In addition to facilitating the proteolytic activation of IL‐1β and IL‐18, inflammasomes also participate in cell death through caspase‐1‐mediated pyroptosis. In this review, we describe the structure and function of the inflammasome and provide an overview of our current understanding of role of the inflammasome in airway inflammation. We focus on nucleotide‐binding domain and leucine‐rich repeat protein 3 (NLRP3) inflammasome as it is the best‐characterized subtype shown expressed in airway and considered to play a key role in chronic airway diseases such as asthma.
Developments in the field of allergy in 2012 through the eyes of Clinical & Experimental Allergy
Authors: Mari A. , Antonietta Ciardiello M. , Passalacqua G. , Vliagoftis H. , Wardlaw A. J. , Wickman M 
Published: October 2013

SummaryIn 2012, we received 683 submissions and published 20 editorials, 38 reviews, 11 letters and 128 original articles. This represents an acceptance rate for original papers in the range of 20%. About 30% of original papers were triaged not to go out to review, either because the editors did not feel they had sufficient priority for publication or because the topic did not feel right for the readers of the journal. We place great emphasis on obtaining sufficient high‐quality reviews to make our decisions on publication fair and consistent. Inevitably, however, there is a degree of luck about what gets published and which papers miss out, and we are always happy to receive an appeal on our decisions either at the triage stage or after review. This gives us the opportunity to revisit the decision and revise it or explain in more detail to the authors the basis for the decision. Once again in 2012, we were delighted by the quality of the papers submitted and the breadth and depth of research into allergic disease that it revealed. The pattern of papers submitted was similar in previous years with considerable emphasis on all aspects of asthma and rhinitis. We were particularly pleased with our special issue on severe asthma. Elucidating mechanisms using either animal models or patients has always been a major theme of the journal, and the excellent work in these areas has been summarized by Harissios Vliagoftis with a particularly interesting section on early‐life events guiding the development of allergic disease, which understandably continue to be a major theme of research. Magnus Wickman summarized the papers looking at the epidemiology of allergic disease including work from birth cohorts, which are an increasingly rich source of data on risk factors for allergic disease, and two papers on the epidemiology of anaphylaxis. Giovanni Passalacqua discussed the papers in the clinical allergy section of the journal, and Adriano Mari who runs the excellent Allergome website discussed the papers looking at allergens including characterization and the relative usefulness of allergen arrays versus single extracts in diagnosis and management.
Understanding the causation of primary angle closure disease using the sufficient component cause model
Authors: Thomas Ravi , Mengersen Kerrie , Thomas Aleysha , Walland Mark J 
Published: October 2013

AbstractBackgroundSeveral risk factors have been associated with primary angle closure disease, but their actual role in causation of an individual case is not clear.DesignConcept paper.Participants/SamplesNo patient participation.MethodsThe sufficient component cause model is briefly explained in the context of primary angle closure disease. The framework is used to conceptualize the role of individual mechanisms of disease. The possibility of personalized treatment for primary angle closure disease is discussed in this context.Main Outcome MeasuresQualitative concepts in disease causality may refine research and treatment in primary angle closure disease.ResultsThe minimum set of conditions that are sufficient for primary angle closure disease to occur is considered the sufficient component cause model for that individual case. Described risk factors (including genes) as well as currently unknown influences play a role in the model. There may be many such models and all complementary components in any sufficient‐cause model must be present for disease to occur. Interruption of any one component in that model can be used for treatment. Pupillary block is likely a component of most such models and may currently be considered a universally necessary component of these models.ConclusionsThe sufficient component cause model can be used as a framework to explain the role of individual mechanisms of causation and treatment of primary angle closure disease. It also aids understanding of the proportion of disease due to specific causes.
Nanosecond‐laser application in intermediate AMD: 12‐month results of fundus appearance and macular function
Authors: Guymer Robyn H , Brassington Kate H , Dimitrov Peter , Makeyeva Galina , Plunkett Malcolm , Xia Wie , Chauhan Devinder , Vingrys Algis , Luu Chi D 
Published: October 2013

AbstractBackgroundA novel, ultra‐low energy nanosecond laser (retinal rejuvenation therapy) has been developed with the aim to slow progression of early age‐related macular degeneration (AMD). The safety, changes in fundus characteristics and macular function in a cohort of participants with bilateral intermediate AMD are reported.DesignProspective non‐randomised, pilot intervention study.Participants or SamplesSubjects with bilateral intermediate AMD (n = 50, aged 50–75 years).MethodsUltra‐low energy laser pulses applied in 12 spots around the macula of one eye (0.15–0.45 mJ), using 400 μm diameter spot, 3 nanosecond pulse length, 532 nm wavelength and energy titrated to each patient.Main Outcome MeasuresBest corrected visual acuity, drusen area and macular sensitivity (flicker perimetry) at baseline and at 3, 6 and 12 months post‐laser.ResultsTreatment was painless with no clinically visible lesions. No participant developed choroidal neovascularization, while two with thin central retinal thickness at baseline developed atrophy at 12‐month follow up. Drusen area was reduced in 44% of treated eyes and 22% of untreated fellow eyes, with changes in drusen and function not being coincident. Improvement in flicker threshold within the central 3° was observed in both the treated and untreated fellow eyes at 3 months post‐laser. Of the 11 eyes at greatest risk of progression (flicker defect >15 dB), seven improved sufficiently to be taken out of this high‐risk category.ConclusionsA single unilateral application of nanosecond laser to the macula produced bilateral improvements in macula appearance and function. The nanosecond retinal rejuvenation therapy laser warrants ongoing evaluation as an early intervention for AMD.
Immediate Occlusal versus Non‐Occlusal Loading of Implants: A Randomized Clinical Pilot Study
Authors: Vogl Susanne , Stopper Marlene , Hof Markus , Wegscheider Walther A. , Lorenzoni Martin 
Published: October 2013

AbstractBackgroundImmediate occlusal and non‐occlusal loading protocols have been discussed and, despite varying success rates, are considered viable in selected cases. Preoperative implant planning and intraoperative transfer are essential to the success of implant‐supported reconstructions in partially or completely edentulous jaws.PurposeThis study was performed to compare clinical outcomes of immediate occlusal versus non‐occlusal loading of posterior implants.Materials and MethodsOf 19 patients with 52 screw‐type implants replacing mandibular molars or premolars, nine patients with 21 implants were randomized to a study group that received immediate restorations with occlusal loading, whereas 10 patients with 31 implants were randomized to a control group that received provisional restorations without occlusal loading. Occlusal loading was defined as full loading in maximum intercuspidation. Single‐tooth or splinted multiunit restorations were incorporated by screw retention or cementation. Marginal bone defects (MBD), implant survival, and implant success were evaluated 12 months after insertion.ResultsBoth groups revealed similar MBD levels consistent with previous reports. No implants were lost (overall survival: 100%) or found to fail (overall success: 100%). No significant intergroup differences were noted for any of the evaluated parameters.ConclusionsImmediate restorations in partially edentulous mandibles demonstrated successful clinical and radiographic 12‐month results. Larger long‐term prospective studies are needed to confirm the final evidence and predictability of immediate functional loading as a standard treatment concept for partially edentulous jaws.