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1.
Br J Pharmacol ; 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38710660

RESUMO

BACKGROUND AND PURPOSE: Traumatic brain injury (TBI) remains a major public health concern worldwide with unmet effective treatment. Stimulator of interferon genes (STING) and its downstream type-I interferon (IFN) signalling are now appreciated to be involved in TBI pathogenesis. Compelling evidence have shown that STING and type-I IFNs are key in mediating the detrimental neuroinflammatory response after TBI. Therefore, pharmacological inhibition of STING presents a viable therapeutic opportunity in combating the detrimental neuroinflammatory response after TBI. EXPERIMENTAL APPROACH: This study investigated the neuroprotective effects of the small-molecule STING inhibitor n-(4-iodophenyl)-5-nitrofuran-2-carboxamide (C-176) in the controlled cortical impact mouse model of TBI in 10- to 12-week-old male mice. Thirty minutes post-controlled cortical impact surgery, a single 750-nmol dose of C-176 or saline (vehicle) was administered intravenously. Analysis was conducted 2 h and 24 h post-TBI. KEY RESULTS: Mice administered C-176 had significantly smaller cortical lesion area when compared to vehicle-treated mice 24 h post-TBI. Quantitative temporal gait analysis conducted using DigiGait™ showed C-176 administration attenuated TBI-induced impairments in gait symmetry, stride frequency and forelimb stance width. C-176-treated mice displayed a significant reduction in striatal gene expression of pro-inflammatory cytokines Tnf-α, Il-1ß and Cxcl10 compared to their vehicle-treated counterparts 2 h post-TBI. CONCLUSION AND IMPLICATIONS: This study demonstrates the neuroprotective activity of C-176 in ameliorating acute neuroinflammation and preventing white matter neurodegeneration post-TBI. This study highlights the therapeutic potential of small-molecule inhibitors targeting STING for the treatment of trauma-induced inflammation and neuroprotective potential.

2.
Clin Gastroenterol Hepatol ; 20(9): 2050-2058.e12, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-34274514

RESUMO

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) affects patients' health-related quality of life (HRQoL). Patient-reported outcomes (PROs) evaluating HRQoL were assessed in the RandomizEd Global Phase 3 Study to Evaluate the Impact on NASH with FibRosis of Obeticholic Acid TreatmEnt (REGENERATE) study, which showed that obeticholic acid (OCA) significantly improved fibrosis in patients with NASH. METHODS: Noncirrhotic NASH patients in a phase 3, double-blind, randomized, placebo-controlled, multicenter, international study of OCA were enrolled. The Chronic Liver Disease Questionnaire-NASH and EuroQol EQ-5D-5L were administered at baseline, 6, 12, and 18 months. RESULTS: There were 1218 patients (age, 54.1 ± 11.5 y; 57% women; 43% stage F3) in the expanded intent-to-treat population (stages, F1-F3) assigned randomly to 10 mg (N = 407) or 25 mg (N = 404) OCA or placebo (N = 407). Baseline measurements were balanced across treatment groups for EuroQol EQ-5D-5L and Chronic Liver Disease Questionnaire-NASH, including Itch score: 5.75 ± 1.53 (scale 1-7, with 7 representing no itching). Nineteen (1.6%) patients discontinued therapy (protocol mandated) because of grade 3 pruritus. Patients receiving 25 mg OCA experienced mild worsening of itch scores primarily in the first months of treatment: mean ± SE change from baseline -0.66 ± 0.12, -0.44 ± 0.12, and -0.42 ± 0.13 at 6, 12, and 18 months, respectively (all P < .01). No other PRO worsening was associated with 25 mg OCA. Patients experiencing fibrosis improvement, Nonalcoholic Fatty Liver Disease Activity Score decrease (by ≥2 points), or NASH resolution had greater PRO improvements in some domains. CONCLUSIONS: NASH patients evaluated in REGENERATE had impaired quality of life and underlying pruritus at baseline. Improvement of NASH corresponded with improvement in several HRQoL domains. Generally mild pruritus occurs early after OCA therapy initiation and does not worsen over time. CLINICALTRIALS: gov: NCT02548351.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Adulto , Idoso , Ácido Quenodesoxicólico/análogos & derivados , Método Duplo-Cego , Feminino , Fibrose , Humanos , Cirrose Hepática , Masculino , Pessoa de Meia-Idade , Prurido , Qualidade de Vida
3.
Mol Psychiatry ; 26(10): 5516-5531, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34400772

RESUMO

Amyloidogenic processing of the amyloid precursor protein (APP) forms the amyloid-ß peptide (Aß) component of pathognomonic extracellular plaques of AD. Additional early cortical changes in AD include neuroinflammation and elevated iron levels. Activation of the innate immune system in the brain is a neuroprotective response to infection; however, persistent neuroinflammation is linked to AD neuropathology by uncertain mechanisms. Non-parametric machine learning analysis on transcriptomic data from a large neuropathologically characterised patient cohort revealed the acute phase protein lactoferrin (Lf) as the key predictor of amyloid pathology. In vitro studies showed that an interaction between APP and the iron-bound form of Lf secreted from activated microglia diverted neuronal APP endocytosis from the canonical clathrin-dependent pathway to one requiring ADP ribosylation factor 6 trafficking. By rerouting APP recycling to the Rab11-positive compartment for amyloidogenic processing, Lf dramatically increased neuronal Aß production. Lf emerges as a novel pharmacological target for AD that not only modulates APP processing but provides a link between Aß production, neuroinflammation and iron dysregulation.


Assuntos
Doença de Alzheimer , Lactoferrina , Proteínas de Fase Aguda , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Humanos
4.
J Neurochem ; 156(6): 979-987, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32614980

RESUMO

Glutaminyl cyclases (QC) catalyze the formation of neurotoxic pGlu-modified amyloid-ß peptides found in the brains of people with Alzheimer's disease (AD). Reports of several-fold increases in soluble QC (sQC) expression in the brain and peripheral circulation of AD individuals has prompted the development of QC inhibitors as potential AD therapeutics. There is, however, a lack of standardized quantitative data on QC expression in human tissues, precluding inter-laboratory comparison and validation. We tested the hypothesis that QC is elevated in AD tissues by quantifying levels of sQC protein and activity in post-mortem brain tissues from AD and age-matched control individuals. We found a modest but statistically significant increase in sQC protein, which paralleled a similar increase in enzyme activity. In plasma samples sourced from the Australian Imaging, Biomarker and Lifestyle study we determined that QC activity was not different between the AD and control group, though a modest increase was observed in female AD individuals compared to controls. Plasma QC activity was further correlated with levels of circulating monocytes in AD individuals. These data provide quantitative evidence that alterations in QC expression are associated with AD pathology.


Assuntos
Doença de Alzheimer/enzimologia , Aminoaciltransferases/metabolismo , Encéfalo/enzimologia , Idoso , Idoso de 80 Anos ou mais , Aminoaciltransferases/antagonistas & inibidores , Aminoaciltransferases/sangue , Austrália , Autopsia , Biomarcadores , Bases de Dados Factuais , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Valores de Referência , Caracteres Sexuais
5.
Mol Psychiatry ; 25(9): 1958-1966, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32444869

RESUMO

The proteolytic cleavage of ß-amyloid precursor protein (APP) to form the amyloid beta (Aß) peptide is related to the pathogenesis of Alzheimer's disease (AD) because APP mutations that influence this processing either induce familial AD or mitigate the risk of AD. Yet Aß formation itself may not be pathogenic. APP promotes neuronal iron efflux by stabilizing the cell-surface presentation of ferroportin, the only iron export channel of cells. Mislocalization of APP can promote iron retention, thus we hypothesized that changes in endocytotic trafficking associated with altered APP processing could contribute to the neuronal iron elevation and oxidative burden that feature in AD pathology. Here, we demonstrate, using genetic and pharmacological approaches, that endocytotic amyloidogenic processing of APP impairs iron export by destabilizing ferroportin on the cell surface. Conversely, preferential non-amyloidogenic processing of APP at the cell surface promotes ferroportin stabilization to decrease intraneuronal iron. A new Aß-independent hypothesis emerges where the amyloidogenic processing of APP, combined with age-dependent iron elevation in the tissue, increases pro-oxidant iron burden in AD.


Assuntos
Doença de Alzheimer , Precursor de Proteína beta-Amiloide , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Humanos , Ferro , Neurônios
6.
Neurochem Res ; 44(6): 1367-1374, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30796750

RESUMO

Cell surface ß-Amyloid precursor protein (APP) is known to have a functional role in iron homeostasis through stabilising the iron export protein ferroportin (FPN). Mechanistic evidence of this role has previously only been provided through transcriptional or translational depletion of total APP levels. However, numerous post-translational modifications of APP are reported to regulate the location and trafficking of this protein to the cell surface. Stable overexpressing cell lines were generated that overexpressed APP with disrupted N-glycosylation (APPN467K and APPN496K) or ectodomain phosphorylation (APPS206A); sites selected for their proximity to the FPN binding site on the E2 domain of APP. We hypothesise that impaired N-glycosylation or phosphorylation of APP disrupts the functional location on the cell surface or binding to FPN to consequentially alter intracellular iron levels through impaired cell surface FPN stability. Outcomes confirm that these post-translational modifications are essential for the correct location of APP on the cell surface and highlight a novel mechanism by which the cell can modulate iron homeostasis. Further interrogation of other post-translational processes to APP is warranted in order to fully understand how each modification plays a role on regulating intracellular iron levels in health and disease.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Homeostase/fisiologia , Ferro/metabolismo , Neurônios/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Linhagem Celular Tumoral , Glicosilação , Camundongos , Fosforilação/genética , Mutação Puntual , Processamento de Proteína Pós-Traducional/genética , Transporte Proteico/genética
7.
Neurotherapeutics ; 15(4): 1055-1062, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30112699

RESUMO

Proteolytic cleavage of the amyloid precursor protein (APP) into the Aß peptide has been an extensively researched mechanism for Alzheimer's disease, but the normal function of the protein is less understood. APP functions to regulate neuronal iron content by stabilizing the surface presentation of ferroportin-the only iron exporter channel of cells. The present study aims to quantify the contribution of APP to brain and peripheral iron by examining the lifetime impact on brain and liver iron levels in APP knockout mice. Consistent with previous reports, we found that wild-type mice exhibited an age-dependent increase in iron and ferritin in the brain, while no age-dependent changes were observed in the liver. APP ablation resulted in an exaggeration of age-dependent iron accumulation in the brain and liver in mice that was assessed at 8, 12, 18, and 22 months of age. Brain ferroportin levels were decreased in APP knockout mice, consistent with a mechanistic role for APP in stabilizing this iron export protein in the brain. Iron elevation in the brain and liver of APP knockout mice correlated with decreased transferrin receptor 1 and increased ferritin protein levels. However, no age-dependent increase in brain ferritin iron saturation was observed in APP-KO mice despite similar protein expression levels potentially explaining the vulnerability of APP-KO mice to parkinsonism and traumatic brain sequelae. Our results support a crucial role of APP in regulating brain and peripheral iron, and show that APP may act to oppose brain iron elevation during aging.


Assuntos
Envelhecimento/patologia , Precursor de Proteína beta-Amiloide/deficiência , Encéfalo/metabolismo , Ferro/metabolismo , Fígado/metabolismo , Fatores Etários , Precursor de Proteína beta-Amiloide/genética , Animais , Ferritinas/metabolismo , Camundongos , Camundongos Knockout
8.
Eur Heart J Qual Care Clin Outcomes ; 3(4): 274-280, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29044394

RESUMO

Aims: Patients with familial hypercholesterolaemia (FH) have an elevated cardiovascular (CV) risk. The objective of this analysis was to adjust CV risk equations derived in non-FH populations with hyperlipidaemia to predict CV risk in FH patients, and then to use these adjusted CV risk equations in a decision analytic model in order to predict lifetime CV risk in FH patients. Methods and results: A literature search of publications reporting CV risk in FH patients identified the publication with the most credible estimate of CV risk increase. A CV event rate ratio (RR) (FH vs. non-FH) was derived from reported odds ratios by pooling treated and untreated patients. Predicted CV event risks based on non-FH risk equations were adjusted with the RR to reflect CV risk in FH patients. A decision analytic model incorporating these adjusted risk equations was used to predict 10-year and lifetime CV risk in FH patients. Combining the derived RR of 7.1 (95% CI: 5.7-8.7) with the predicted CV risks in a decision analytic model yielded 10-year and lifetime risk estimates of 45% and 88% in FH patients based on the RUTHERFORD-2 trial population. Based on the initial (cross-sectional) RR of 7.1, FH patients were predicted to have 3.9 times more events over their lifetime than non-FH patients with a similar risk profile. Conclusion: The CV risk in FH is high and represents an unmet medical need for patients. Increased efforts for better diagnosis and management of FH should be employed to improve patient outcomes.


Assuntos
Doenças Cardiovasculares , Colesterol/sangue , Hiperlipoproteinemia Tipo II , Medição de Risco , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Saúde Global , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/epidemiologia , Incidência , Fatores de Risco
9.
Sci Rep ; 7(1): 9835, 2017 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-28852095

RESUMO

Amyloid precursor protein (APP) and its extracellular domain, soluble APP alpha (sAPPα) play important physiological and neuroprotective roles. However, rare forms of familial Alzheimer's disease are associated with mutations in APP that increase toxic amyloidogenic cleavage of APP and produce amyloid beta (Aß) at the expense of sAPPα and other non-amyloidogenic fragments. Although mitochondrial dysfunction has become an established hallmark of neurotoxicity, the link between Aß and mitochondrial function is unclear. In this study we investigated the effects of increased levels of neuronal APP or Aß on mitochondrial metabolism and gene expression, in human SH-SY5Y neuroblastoma cells. Increased non-amyloidogenic processing of APP, but not Aß, profoundly decreased respiration and enhanced glycolysis, while mitochondrial DNA (mtDNA) transcripts were decreased, without detrimental effects to cell growth. These effects cannot be ascribed to Aß toxicity, since higher levels of endogenous Aß in our models do not cause oxidative phosphorylation (OXPHOS) perturbations. Similarly, chemical inhibition of ß-secretase decreased mitochondrial respiration, suggesting that non-amyloidogenic processing of APP may be responsible for mitochondrial changes. Our results have two important implications, the need for caution in the interpretation of mitochondrial perturbations in models where APP is overexpressed, and a potential role of sAPPα or other non-amyloid APP fragments as acute modulators of mitochondrial metabolism.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Mitocôndrias/metabolismo , Fosforilação Oxidativa , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Linhagem Celular , Respiração Celular/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Ativação Enzimática , Dosagem de Genes , Genes Mitocondriais , Glicólise , Humanos , Mitocôndrias/genética , Mutação , Neurônios/metabolismo , Transcrição Gênica
10.
Mol Neurodegener ; 12(1): 45, 2017 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-28592304

RESUMO

Parkinson's disease is a multifactorial neurodegenerative disorder, the aetiology of which remains elusive. The primary clinical feature of progressively impaired motor control is caused by a loss of midbrain substantia nigra dopamine neurons that have a high α-synuclein (α-syn) and iron content. α-Syn is a neuronal protein that is highly modified post-translationally and central to the Lewy body neuropathology of the disease. This review provides an overview of findings on the role post translational modifications to α-syn have in membrane binding and intracellular vesicle trafficking. Furthermore, we propose a concept in which acetylation and phosphorylation of α-syn modulate endocytic import of iron and vesicle transport of dopamine during normal physiology. Disregulated phosphorylation and oxidation of α-syn mediate iron and dopamine dependent oxidative stress through impaired cellular location and increase propensity for α-syn aggregation. The proposition highlights a connection between α-syn, iron and dopamine, three pathological components associated with disease progression in sporadic Parkinson's disease.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Ferro/metabolismo , Doença de Parkinson/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , alfa-Sinucleína/metabolismo , Animais , Dopamina/metabolismo , Humanos
12.
ACS Chem Neurosci ; 8(4): 731-736, 2017 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-28029772

RESUMO

Ferroxidase activity has been reported to be altered in various biological fluids in neurodegenerative disease, but the sources contributing to the altered activity are uncertain. Here we assay fractions of serum and cerebrospinal fluid with a newly validated triplex ferroxidase assay. Our data indicate that while ceruloplasmin, a multicopper ferroxidase, is the predominant source of serum activity, activity in CSF predominantly derives from a <10 kDa component, specifically from polyanions such as citrate and phosphate. We confirm that in human biological samples, ceruloplasmin activity in serum is decreased in Alzheimer's disease, but in CSF a reduction of activity in Alzheimer's disease originates from the polyanion component.


Assuntos
Doença de Alzheimer/metabolismo , Líquido Cefalorraquidiano/enzimologia , Ceruloplasmina/metabolismo , Ferro/metabolismo , Soro/enzimologia , Ceruloplasmina/análise , Humanos , Oxirredução
13.
Clin Ther ; 38(7): 1696-709, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27261205

RESUMO

PURPOSE: The goal of this study was to determine cardiovascular disease (CVD) risk associated with familial hypercholesterolemia (FH). METHODS: A systematic review of the published literature was conducted. All publications describing FH risk from PubMed ("cardiovascular disease risk + familial hypercholesterolaemia," 2004-2015), Internet and Medline search of FH registries, and associated references were screened for FH-related CVD risk in titles, abstracts, and study methods. CVD risk expressed as rates, odds, or ratios of mortality and morbidity were extracted. Each article was reviewed for bias by 2 reviewers within 17 items in 7 categories; a modified Newcastle-Ottawa assessment scale was used for nonrandomized studies. FINDINGS: The complete literature search identified 712 potential publications: 549 from PubMed (Medline), 150 from registries, and 13 from references. Fourteen articles met the inclusion criteria: 8 from registries in the United Kingdom, the Netherlands, Norway, and Spain; 5 from single hospitals or families in Japan, Denmark, the Netherlands, and the United Kingdom; and a population survey in Denmark. Across studies, attrition bias was low in 22 (80%) of 28 items. Risk of selection bias was high in 35 (63%) of 56 items. Selection bias risk was due to low representativeness and lack of a non-FH comparator group within the same study; detection bias risk was due to variable definitions of CVD outcomes/measurement; and performance bias risk was due to long-term, intensive treatment, the most common limitations for registries. Studies from single hospitals and families lacked generalizability. In contrast, the Danish study revealed a low bias in each of the 4 selection bias criteria and 2 attrition risk criteria. Fatal and nonfatal CVD events were collected in the study. Comparing patients with FH versus non-FH patients, the odds ratios for coronary artery disease were 10.3 (95% CI, 7.8-13.8) and 13.2 (95% CI, 10.0-17.4) in subjects treated and not treated with lipid-lowering therapy, respectively. These ratios fall within the ranges of ratios reported in other studies but are generally higher than the ratios from registries and clinics, in which intensive specialized management is available. IMPLICATIONS: There is a lack of available data describing CVD risk in patients with FH, and many of the existing studies have biases in their design that could affect their risk estimates. A Danish study had the highest quality based on a predefined quality check list, providing the most credible estimates of the increase in CVD risk in patients with FH. The CVD risk due to FH is high and represents unmet medical need for patients with FH. Further research is warranted to validate the magnitude of risk.


Assuntos
Doenças Cardiovasculares/etiologia , Hiperlipoproteinemia Tipo II/complicações , Doença da Artéria Coronariana/etiologia , Humanos , Risco
14.
J Biol Chem ; 291(12): 6134-45, 2016 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-26697885

RESUMO

Pyroglutamate-modified amyloid-ß (pE-Aß) is a highly neurotoxic amyloid-ß (Aß) isoform and is enriched in the brains of individuals with Alzheimer disease compared with healthy aged controls. Pyroglutamate formation increases the rate of Aß oligomerization and alters the interactions of Aß with Cu(2+) and lipids; however, a link between these properties and the toxicity of pE-Aß peptides has not been established. We report here that Aß3pE-42 has an enhanced capacity to cause lipid peroxidation in primary cortical mouse neurons compared with the full-length isoform (Aß(1-42)). In contrast, Aß(1-42) caused a significant elevation in cytosolic reactive oxygen species, whereas Aß3pE-42 did not. We also report that Aß3pE-42 preferentially associates with neuronal membranes and triggers Ca(2+) influx that can be partially blocked by the N-methyl-d-aspartate receptor antagonist MK-801. Aß3pE-42 further caused a loss of plasma membrane integrity and remained bound to neurons at significantly higher levels than Aß(1-42) over extended incubations. Pyroglutamate formation was additionally found to increase the relative efficiency of Aß-dityrosine oligomer formation mediated by copper-redox cycling.


Assuntos
Peptídeos beta-Amiloides/farmacologia , Sinalização do Cálcio , Neurônios/metabolismo , Fragmentos de Peptídeos/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Ascórbico/química , Permeabilidade da Membrana Celular , Células Cultivadas , Cobre/química , Humanos , Peroxidação de Lipídeos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos , Ácido Pirrolidonocarboxílico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo
15.
Pharmacoeconomics ; 33(10): 1049-67, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25963579

RESUMO

BACKGROUND: The challenges of comparative effectiveness to support health technology assessment (HTA) agencies are important considerations in the choices of antipsychotic medications for the treatment of schizophrenia. OBJECTIVES: Our aim was to assess the study methods used and outcomes reported in the published literature to address the question of comparative effectiveness of newer antipsychotic agents and the adequacy and availability of evidence to support HTA agencies. DATA SOURCE: A systematic search of the PubMed database from 1 January 2009 to 30 September 2013 was conducted to identify studies evaluating new atypical antipsychotics reporting on comparative effectiveness. STUDY SELECTION: The systematic review comprised of studies on schizophrenia patients where at least two drugs were being compared and at least one treatment group received one of the following second-generation antipsychotics: risperidone, olanzapine, aripiprazole, paliperidone, asenapine, iloperidone, lurasidone, and quetiapine. The included studies were also required to have an efficacy, safety or economic outcome, such as Positive and Negative Syndrome Scale (PANSS) score, weight gain, resource utilization, or costs. STUDY APPRAISAL AND SYNTHESIS METHODS: Two reviewers (BW and GK) independently applied the inclusion criteria. Disagreements between reviewers were resolved by consensus, referring to the original sources. Information on the methodology and outcomes was collected for each included study. This included study description, head-to-head drug comparison, patient population, study methodology, statistical methods, reported outcomes, study support, and journal type. RESULTS: A total of 198 studies were identified from electronic search methods. The largest category of studies was randomized controlled trials [RCTs] (N = 73; 36.9%), which were largely directed at the regulatory endpoint. Fewer studies were undertaken for HTA-purposes cohort studies (N = 53; 26.8%), meta-analyses (N = 32; 16.2%), economic studies (N = 14; 7.1%), and cross-sectional studies (N = 13; 6.6%). Direct head-to-head comparisons preferred by HTA were dominated by the comparison involving olanzapine and risperidone, representing 149 (75.3%) and 119 (60.1%) studies, respectively. RCTs, which are the primary study type for regulatory submissions, showed a lack of bias. Studies aimed at HTA were not as well performed. Cohort studies suffered from bias in the selection of comparison groups, lack of control for confounders, and differential dropout rates. As a group, cross-sectional studies scored poorly for bias, with a primary failure to identify a representative sample. Economic studies showed highly variable bias, with bias in the representation of effectiveness data, model assumptions without validation, and lack of sensitivity analyses. LIMITATIONS: One limitation of this systematic review is that it only included studies from 2009 to 2013, potentially excluding some earlier comparator studies, particularly those involving first-generation antipsychotics. CONCLUSIONS: This review of comparative effectiveness studies of second-generation antipsychotic agents for schizophrenic patients revealed a wide range of study types, study methodologies, and outcomes. For traditional efficacy outcomes and select safety outcomes, there is strong evidence from many well-conducted studies; however, there are fewer studies of types preferred by HTA with limited head-to-head comparisons and a higher risk of bias in the execution of these studies.


Assuntos
Antipsicóticos/uso terapêutico , Pesquisa Comparativa da Efetividade/métodos , Esquizofrenia/tratamento farmacológico , Avaliação da Tecnologia Biomédica , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Antipsicóticos/economia , Análise Custo-Benefício , Humanos , Esquizofrenia/economia , Resultado do Tratamento
16.
Clin Genitourin Cancer ; 13(2): 101-12, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25262852

RESUMO

INTRODUCTION: This study aimed to examine the impact of advanced prostate cancer and its treatments on patients' perceptions of their health and to better understand concerns not captured by currently available health-related quality of life (HRQL) instruments. PATIENTS AND METHODS: Open ended one-on-one interviews were conducted with patients with prostate cancer who had biochemical failure or metastatic cancer to understand the impacts of disease and treatments on patients' perceptions of their lives. Interviews with 25 patients (7 biochemical failure and 18 metastatic) and 6 clinicians were conducted. Patient responses were analyzed to assess whether information saturation (ie, the point at which no new information is collected) was attained and compared with currently available HRQL instruments. The data informed the development of a comprehensive conceptual model illustrating the impacts of advanced disease and treatments. Clinical expert interviews also informed the conceptual model. RESULTS: Patients with prostate cancer reported many of the key symptoms already captured by current measures, such as bone pain, urinary functioning, bowel functioning, and fatigue. However, a number of impacts reported as bothersome by patients were identified that are not fully captured by existing HRQL measures. Specific examples include genital atrophy, muscle atrophy, stamina, body image, and emotional well-being. CONCLUSION: The conceptual model identified herein describes the impacts of prostate cancer and its treatments from the patient's perspective. The model can be useful in identifying key concepts important to patients that should be measured in trials to capture treatment benefits. The model also can help inform the selection of patient-reported outcomes to assess these benefits.


Assuntos
Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Qualidade de Vida/psicologia , Idoso , Idoso de 80 Anos ou mais , Coleta de Dados , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Metástase Neoplásica , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/psicologia
17.
PLoS One ; 9(12): e114174, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25464026

RESUMO

Ceruloplasmin is a ferroxidase that interacts with ferroportin to export cellular iron, but is not expressed in neurons. We recently reported that the amyloid precursor protein (APP) is the analogous iron-exporting chaperone for neurons and other cells. The ferroxidase activity of APP has since been called into question. Using a triplex Fe2+ oxidation assay, we analyzed the activity of a soluble form of APP (sAPPα) within a buffer of physiological pH and anionic charge, and determined that iron oxidation originated from phosphate. Using various techniques such as flow-cytometry to measure surface presented proteins, we confirmed that endogenous APP is essential for ferroportin persistence on the neuronal surface. Therefore, despite lacking ferroxidase activity, APP still supports iron export from neurons.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Ceruloplasmina/metabolismo , Animais , Células HEK293 , Humanos , Camundongos , Oxirredução
18.
Biochim Biophys Acta ; 1840(12): 3299-310, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25152357

RESUMO

BACKGROUND: Iron oxidation is thought to be predominantly handled enzymatically in the body, to minimize spontaneous combustion with oxygen and to facilitate cellular iron export by loading transferrin. This process may be impaired in disease, and requires more accurate analytical assays to interrogate enzymatic- and auto-oxidation within a physiologically relevant environment. METHOD: A new triplex ferroxidase activity assay has been developed that overcomes the previous assay limitations of measuring iron oxidation at a physiologically relevant pH and salinity. RESULTS: Revised enzymatic kinetics for ceruloplasmin (Vmax≈35µMFe(3+)/min/µM; Km≈15µM) are provided under physiological conditions, and inhibition by sodium azide (Ki for Ferric Gain 78.3µM, Ki for transferrin loading 8.1×10(4)µM) is quantified. We also used this assay to characterize the non-enzymatic oxidation of iron that proceeded linearly under physiological conditions. CONCLUSIONS AND GENERAL SIGNIFICANCE: These findings indicate that the requirement of an enzyme to oxidize iron may only be necessary under conditions of adverse pH or anionic strength, for example from hypoxia. In a normal physiological environment, Fe(3+) incorporation into transferrin would be sufficiently enabled by the biological polyanions that are prevalent within extracellular fluids.

19.
Front Aging Neurosci ; 6: 91, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24860500

RESUMO

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease. It begins years prior to the onset of clinical symptoms, such as memory loss and cognitive decline. Pathological hallmarks of AD include the accumulation of ß-amyloid in plaques and hyperphosphorylated tau in neurofibrillary tangles. Copper, iron, and zinc are abnormally accumulated and distributed in the aging brain. These metal ions can adversely contribute to the progression of AD. Dysregulation of cholesterol metabolism has also been implicated in the development of AD pathology. To date, large bodies of research have been carried out independently to elucidate the role of metals or cholesterol on AD pathology. Interestingly, metals and cholesterol affect parallel molecular and biochemical pathways involved in AD pathology. The possible links between metal dyshomeostasis and altered brain cholesterol metabolism in AD are reviewed.

20.
Front Pharmacol ; 5: 81, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24795635

RESUMO

As with most bioavailable transition metals, iron is essential for many metabolic processes required by the cell but when left unregulated is implicated as a potent source of reactive oxygen species. It is uncertain whether the brain's evident vulnerability to reactive species-induced oxidative stress is caused by a reduced capability in cellular response or an increased metabolic activity. Either way, dys-regulated iron levels appear to be involved in oxidative stress provoked neurodegeneration. As in peripheral iron management, cells within the central nervous system tightly regulate iron homeostasis via responsive expression of select proteins required for iron flux, transport and storage. Recently proteins directly implicated in the most prevalent neurodegenerative diseases, such as amyloid-ß precursor protein, tau, α-synuclein, prion protein and huntingtin, have been connected to neuronal iron homeostatic control. This suggests that disrupted expression, processing, or location of these proteins may result in a failure of their cellular iron homeostatic roles and augment the common underlying susceptibility to neuronal oxidative damage that is triggered in neurodegenerative disease.

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