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Age-related endothelial dysfunction is a pivotal factor in the development of cardiovascular diseases, stemming, at least in part, from mitochondrial dysfunction and a consequential increase in oxidative stress. These alterations are central to the decline in vascular health seen with aging, underscoring the urgent need for interventions capable of restoring endothelial function for preventing cardiovascular diseases. Dietary interventions, notably time-restricted feeding (TRF), have been identified for their anti-aging effects on mitochondria, offering protection against age-associated declines in skeletal muscle and other organs. Motivated by these findings, our study aimed to investigate whether TRF could similarly exert protective effects on endothelial health in the vasculature, enhancing mitochondrial function and reducing oxidative stress. To explore this, 12-month-old C57BL/6 mice were placed on a TRF diet, with food access limited to a 6-h window daily for 12 months. For comparison, we included groups of young mice and age-matched controls with unrestricted feeding. We evaluated the impact of TRF on endothelial function by measuring acetylcholine-induced vasorelaxation of the aorta. Mitochondrial health was assessed using fluororespirometry, and vascular reactive oxygen species (ROS) production was quantified with the redox-sensitive dye dihydroethidium. We also quantified 4-hydroxynonenal (4-HNE) levels, a stable marker of lipid peroxidation, in the aorta using ELISA. Our findings demonstrated that aged mice on a standard diet exhibited significant impairments in aortic endothelial relaxation and mitochondrial function, associated with elevated vascular oxidative stress. Remarkably, the TRF regimen led to substantial improvements in these parameters, indicating enhanced endothelial vasorelaxation, better mitochondrial function, and reduced oxidative stress in the aortas of aged mice. This investigation establishes a vital foundation, paving the way for subsequent clinical research aimed at exploring the cardiovascular protective benefits of intermittent fasting.
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Envelhecimento , Aorta , Endotélio Vascular , Mitocôndrias , Estresse Oxidativo , Espécies Reativas de Oxigênio , Vasodilatação , Animais , Camundongos , Mitocôndrias/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Aorta/metabolismo , Aorta/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Envelhecimento/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Aldeídos/metabolismo , Aldeídos/farmacologiaRESUMO
Despite the universal impact of sarcopenia on compromised health and quality of life in the elderly, promising pharmaceutical approaches that can effectively mitigate loss of muscle and function during aging have been limited. Our group and others have reported impairments in peripheral motor neurons and loss of muscle innervation as initiating factors in sarcopenia, contributing to mitochondrial dysfunction and elevated oxidative stress in muscle. We recently reported a reduction in α motor neuron loss in aging mice in response to the compound OKN-007, a proposed antioxidant and anti-inflammatory agent. In the current study, we asked whether OKN-007 treatment in wildtype male mice for 8-9 months beginning at 16 months of age can also protect muscle mass and function. At 25 months of age, we observed a reduction in the loss of whole-body lean mass, a reduced loss of innervation at the neuromuscular junction and well-preserved neuromuscular junction morphology in OKN-007 treated mice versus age matched wildtype untreated mice. The loss in muscle force generation in aging mice (~ 25%) is significantly improved with OKN-007 treatment. In contrast, OKN-007 treatment provided no protection in loss of muscle mass in aging mice. Mitochondrial function was improved by OKN-007 treatment, consistent with its potential antioxidative properties. Together, these exciting findings are the first to demonstrate that interventions through neuroprotection can be an effective therapy to counter aging-related muscle dysfunction.
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Envelhecimento , Debilidade Muscular , Fármacos Neuroprotetores , Sarcopenia , Animais , Masculino , Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Fármacos Neuroprotetores/farmacologia , Debilidade Muscular/tratamento farmacológico , Camundongos , Sarcopenia/tratamento farmacológico , Sarcopenia/prevenção & controle , Músculo Esquelético/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Junção Neuromuscular/efeitos dos fármacos , Antioxidantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Modelos Animais de DoençasRESUMO
Thrombocytopenia, a condition characterized by low platelet counts, can arise from various causes, including autoimmune diseases. Immune thrombocytopenia (ITP), a diagnosis made by excluding other possible causes, is categorized as primary or secondary, with primary ITP being idiopathic and secondary ITP associated with infections or autoimmune conditions. This study highlights a unique instance of severe thrombocytopenia triggered by Helicobacter pylori infection.
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With the recent increase in deforestation, forest fires, and regional temperatures, the concerns around the rapid and complete collapse of the Amazon rainforest ecosystem have heightened. The thresholds of deforestation and the temperature increase required for such a catastrophic event are still uncertain. However, our analysis presented here shows that signatures of changing Amazon are already apparent in historical climate data sets. Here, we extend the methods of climate network analysis and apply them to study the temporal evolution of the connectivity between the Amazon rainforest and the global climate system. We observe that the Amazon rainforest is losing short-range connectivity and gaining more long-range connections, indicating shifts in regional-scale processes. Using embeddings inspired by manifold learning, we show that the Amazon connectivity patterns have undergone a fundamental shift in the 21st century. By investigating edge-based network metrics on similar regions to the Amazon, we see the changing properties of the Amazon are noticeable in comparison. Furthermore, we simulate diffusion and random walks on these networks and observe a faster spread of perturbations from the Amazon in recent decades. Our methodology innovations can act as a template for examining the spatiotemporal patterns of regional climate change and its impact on global climate using the toolbox of climate network analysis.
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Oxidative stress is associated with tissue dysfunctions that can lead to reduced health. Prior work has shown that oxidative stress contributes to both muscle atrophy and cellular senescence, which is a hallmark of aging that may drive in muscle atrophy and muscle contractile dysfunction. The purpose of the study was to test the hypothesis that cellular senescence contributes to muscle atrophy or weakness. To increase potential senescence in skeletal muscle, we used a model of oxidative stress-induced muscle frailty, the CuZn superoxide dismutase knockout (Sod1KO) mouse. We treated 6-month-old wildtype (WT) and Sod1KO mice with either vehicle or a senolytic treatment of combined dasatinib (5 mg/kg) + quercetin (50 mg/kg) (D + Q) for 3 consecutive days every 15 days. We continued treatment for 7 months and sacrificed the mice at 13 months of age. Treatment with D + Q did not preserve muscle mass, reduce NMJ fragmentation, or alter muscle protein synthesis in Sod1KO mice when compared to the vehicle-treated group. However, we observed an improvement in muscle-specific force generation in Sod1KO mice treated with D + Q when compared to Sod1KO-vehicle mice. Overall, these data suggest that reducing cellular senescence via D + Q is not sufficient to mitigate loss of muscle mass in a mouse model of oxidative stress-induced muscle frailty but may mitigate some aspects of oxidative stress-induced muscle dysfunction.
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Fragilidade , Senoterapia , Camundongos , Animais , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Camundongos Knockout , Estresse Oxidativo , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Músculo Esquelético/metabolismo , Superóxido Dismutase/metabolismoRESUMO
Atomoxetine (ATX) is a non-stimulant used to treat attention-deficit/hyperactivity disorder (ADHD) and systemic exposure is highly variable due to polymorphic cytochrome P450 2D6 (CYP2D6) activity. The objective of this study was to characterize the time course of ATX and metabolites (4-hydroxyatomoxetine (4-OH); N-desmethylatomoxetine (NDA); and 2-carboxymethylatomoxetine (2-COOH)) exposure following oral ATX dosing in children with ADHD to support individualized dosing. A nonlinear mixed-effect modeling approach was used to analyze ATX, 4-OH, and NDA plasma and urine, and 2-COOH urine profiles obtained over 24-72 hours from children with ADHD (n = 23) following a single oral ATX dose. Demographics and CYP2D6 activity score (AS) were evaluated as covariates. Simulations were performed to explore the ATX dosing in subjects with various CYP2D6 AS. A simultaneous pharmacokinetic modeling approach was used in which a model for ATX, 4-OH, and NDA in plasma and urine, and 2-COOH in urine was developed. Plasma ATX, 4-OH, and NDA were modeled using two-compartment models with first-order elimination. CYP2D6 AS was a significant determinant of ATX apparent oral clearance (CL/F), fraction metabolized to 4-OH, and systemic exposure of NDA. CL/F of ATX varied almost 7-fold across the CYP2D6 AS groups: AS 2: 20.02 L/hour; AS 1: 19.00 L/hour; AS 0.5: 7.47 L/hour; and AS 0: 3.10 L/hour. The developed model closely captures observed ATX, 4-OH, and NDA plasma and urine, and 2-COOH urine profiles. Application of the model shows the potential for AS-based dosing recommendations for improved individualized dosing.
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Transtorno do Deficit de Atenção com Hiperatividade , Propilaminas , Criança , Adolescente , Humanos , Cloridrato de Atomoxetina/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Citocromo P-450 CYP2D6 , Éteres Fenílicos/uso terapêutico , Inibidores da Captação AdrenérgicaRESUMO
Multiple sclerosis (MS) is a chronic demyelinating disorder resulting in demyelination, neuroaxonal degeneration, and sclerosis. This often-debilitating disease affects young females mainly. Literature describing the pathology and phenotypic features is vast. Although there are extensive descriptions of new-onset MS presentations, few document the initial presentation as a transient ischemic attack or ischemic stroke. The case we present highlights the rarity of such presentation. In the literature, we found scarce reports about MS as presenting as a stroke mimicker with some studies quoting from 2.2% to 4.4% of the cases having MS. Our case serves as a reminder that MS can mimic acute ischemic strokes and the importance of maintaining MS apart of the differential in a young female with no significant history present with acute neurological deficits to reduce the complications of MS and the healthcare-associated costs.
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Our laboratory previously showed lipid hydroperoxides and oxylipin levels are elevated in response to loss of skeletal muscle innervation and are associated with muscle pathologies. To elucidate the pathological impact of lipid hydroperoxides, we overexpressed glutathione peroxidase 4 (GPx4), an enzyme that targets reduction of lipid hydroperoxides in membranes, in adult CuZn superoxide dismutase knockout (Sod1KO) mice that show accelerated muscle atrophy associated with loss of innervation. The gastrocnemius muscle from Sod1KO mice shows reduced mitochondrial respiration and elevated oxidative stress (F2 -isoprostanes and hydroperoxides) compared to wild-type (WT) mice. Overexpression of GPx4 improved mitochondrial respiration and reduced hydroperoxide generation in Sod1KO mice, but did not attenuate the muscle loss that occurs in Sod1KO mice. In contrast, contractile force generation is reduced in EDL muscle in Sod1KO mice relative to WT mice, and overexpression of GPx4 restored force generation to WT levels in Sod1KO mice. GPx4 overexpression also prevented loss of muscle contractility at the single fibre level in fast-twitch fibres from Sod1KO mice. Muscle fibres from Sod1KO mice were less sensitive to both depolarization and calcium at the single fibre level and exhibited a reduced activation by S-glutathionylation. GPx4 overexpression in Sod1KO mice rescued the deficits in both membrane excitability and calcium sensitivity of fast-twitch muscle fibres. Overexpression of GPx4 also restored the sarco/endoplasmic reticulum Ca2+ -ATPase activity in Sod1KO gastrocnemius muscles. These data suggest that GPx4 plays an important role in preserving excitation-contraction coupling function and Ca2+ homeostasis, and in maintaining muscle and mitochondrial function in oxidative stress-induced sarcopenia. KEY POINTS: Knockout of CuZn superoxide dismutase (Sod1KO) induces elevated oxidative stress with accelerated muscle atrophy and weakness. Glutathione peroxidase 4 (GPx4) plays a fundamental role in the reduction of lipid hydroperoxides in membranes, and overexpression of GPx4 improves mitochondrial respiration and reduces hydroperoxide generation in Sod1KO mice. Muscle contractile function deficits in Sod1KO mice are alleviated by the overexpression of GPx4. GPx4 overexpression in Sod1KO mice rescues the impaired muscle membrane excitability of fast-twitch muscle fibres and improves their calcium sensitivity. Sarco/endoplasmic reticulum Ca2+ -ATPase activity in Sod1KO muscles is decreased, and it is restored by the overexpression of GPx4. Our results confirm that GPx4 plays an important role in preserving excitation-contraction coupling function and Ca2+ homeostasis, and maintaining muscle and mitochondrial function in oxidative stress-induced sarcopenia.
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Sarcopenia , Animais , Camundongos , Adenosina Trifosfatases/genética , Cálcio , Glutationa , Glutationa Peroxidase/genética , Peróxido de Hidrogênio , Lipídeos , Camundongos Knockout , Músculo Esquelético/fisiologia , Fenótipo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Superóxido Dismutase , Superóxido Dismutase-1/genéticaRESUMO
Graphene and related two-dimensional materials (2DMs) have shown promise across numerous technology areas including flexible electronics, energy storage and pollution remediation. Research into novel applications of these atomically thin materials relies on access to synthesis techniques for producing 2DMs with suitable quality and quantity. Liquid-phase exfoliation is a mechanochemical approach that can achieve this and produce defect-free nanomaterial dispersions which are compatible for downstream use (e.g. inkjet printing, coatings). Here, using kitchen blenders to deliver shear-driven exfoliation, we develop a range of inexpensive hardware solutions that can allow researchers to synthesise 2DMs using a controllable, sustainable and scalable process. Extensive modifications were necessary as the onboard electronics lack the experimental controls (temperature, speed, characterisation) for scientific research and precision synthesis. The technical aspects (including the many lessons learned) of the modifications are discussed and a simple selection process is proposed for creating bespoke mechanochemical processors for any application in the hope that this encourages experimentation. Specific builds with detailed notes, cost breakdown and associated files are provided in the Open Science Framework (OSF) repository, OpenLPE associated with this article.
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Our previous studies support a key role for mitochondrial lipid hydroperoxides as important contributors to denervation-related muscle atrophy, including muscle atrophy associated with aging. Phospholipid hydroperoxide glutathione peroxidase 4 (GPX4) is an essential antioxidant enzyme that directly reduces phospholipid hydroperoxides and we previously reported that denervation-induced muscle atrophy is blunted in a mouse model of GPX4 overexpression. Therefore, the goal of the present study was to determine whether GPX4 overexpression can reduce the age-related increase in mitochondrial hydroperoxides in skeletal muscle and ameliorate age-related muscle atrophy and weakness (sarcopenia). Male C57Bl6 WT and GPX4 transgenic (GPX4Tg) mice were studied at 3 to 5 and 23-29 months of age. Basal mitochondrial peroxide generation was reduced by 34% in muscle fibers from aged GPX4Tg compared to old WT mice. GPX4 overexpression also reduced levels of lipid peroxidation products: 4-HNE, MDA, and LOOHs by 38%, 32%, and 84% respectively in aged GPX4Tg mice compared to aged WT mice. Muscle mass was preserved in old GPX4 Tg mice by 11% and specific force generation was 21% higher in old GPX4Tg versus age matched male WT mice. Oxylipins from lipoxygenases (LOX) and cyclooxygenase (COX), as well as less abundant non-enzymatically generated isomers, were significantly reduced by GPX4 overexpression. The expression of cPLA2, 12/15-LOX and COX-2 were 1.9-, 10.5- and 3.4-fold greater in old versus young WT muscle respectively, and 12/15-LOX and COX-2 levels were reduced by 37% and 35%, respectively in muscle from old GPX4Tg mice. Our study suggests that lipid peroxidation products may play an important role in the development of sarcopenia, and their detoxification might be an effective intervention in preventing muscle atrophy.
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Oxilipinas , Sarcopenia , Animais , Masculino , Camundongos , Ciclo-Oxigenase 2 , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Sarcopenia/genéticaRESUMO
The Hierarchical Taxonomy of Psychopathology (HiTOP; Kotov et al., 2017, 2021) is offered as a dimensional alternative to traditional categorical diagnostic nosologies such as the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD). HiTOP researchers have recently published an open-source assessment system for clinical implementation, the HiTOP Digital Assessment and Tracker (Jonas et al., 2021). Here, we argue that the Minnesota Multiphasic Personality Inventory-3 (MMPI-3; Ben-Porath & Tellegen 2020a), given its structural similarities to HiTOP, can augment these efforts to shift the diagnostic paradigm, with the additional strength of being comprehensively validated, standardized, and normed. Sellbom et al. (2021) examined the factor structure of the MMPI-3 Specific Problems Scales (plus RC6 and RC8), finding a pattern of latent factors much like those proposed by HiTOP in both a general mental health sample and a prisoner sample. The present study is a partial replication of Sellbom et al. (2021) with a primary medical care outpatient sample (n = 164) and a college student sample (n = 529). A sequential factoring approach yielded emergent structures that are comparable to the HiTOP model. These findings with different and important samples support the generalizability of the MMPI-3 in assessing HiTOP constructs. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
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MMPI , Psicopatologia , Humanos , Saúde Mental , Manual Diagnóstico e Estatístico de Transtornos Mentais , Classificação Internacional de DoençasRESUMO
Cachexia is characterized by losses in lean body mass and its progression results in worsened quality of life and exacerbated outcomes in cancer patients. However, the role and impact of fibrosis during the early stages and development of cachexia in under-investigated. The purpose of this study was to determine if fibrosis occurs during cachexia development, and to evaluate this in both sexes. Female and male C57BL6/J mice were injected with phosphate-buffered saline or Lewis Lung Carcinoma (LLC) at 8-week of age, and tumors were allowed to develop for 1, 2, 3, or 4 weeks. 3wk and 4wk female tumor-bearing mice displayed a dichotomy in tumor growth and were reassigned to high tumor (HT) and low tumor (LT) groups. In vitro analyses were also performed on cocultured C2C12 and 3T3 cells exposed to LLC conditioned media. Immunohistochemistry and quantitative polymerase chain reaction (qPCR) analysis were used to investigate fibrosis and fibrosis-related signaling in skeletal muscle. Collagen deposition in skeletal muscle was increased in the 1wk, LT, and HT groups in female mice. However, collagen deposition was only increased in the 4wk group in male mice. In general, female mice displayed earlier alterations in extracellular matrix (ECM)-related genes beginning at 1wk post-LLC injection. Whereas this was not seen in males. While overall tumor burden is tightly correlated to cachexia development in both sexes, fibrotic development is not. Male mice did not exhibit early-stage alterations in ECM-related genes contrary to what was noted in female mice.
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Caquexia , Carcinoma Pulmonar de Lewis , Masculino , Feminino , Animais , Camundongos , Caquexia/etiologia , Caquexia/patologia , Qualidade de Vida , Músculo Esquelético/patologia , Carcinoma Pulmonar de Lewis/complicações , Carcinoma Pulmonar de Lewis/patologia , Camundongos Endogâmicos C57BLRESUMO
Serotonin reuptake inhibitor antidepressants, including selective serotonin reuptake inhibitors (SSRIs; i.e., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline), serotonin and norepinephrine reuptake inhibitors (i.e., desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine), and serotonin modulators with SSRI-like properties (i.e., vilazodone and vortioxetine) are primary pharmacologic treatments for major depressive and anxiety disorders. Genetic variation in CYP2D6, CYP2C19, and CYP2B6 influences the metabolism of many of these antidepressants, which may potentially affect dosing, efficacy, and tolerability. In addition, the pharmacodynamic genes SLC6A4 (serotonin transporter) and HTR2A (serotonin-2A receptor) have been examined in relation to efficacy and side effect profiles of these drugs. This guideline updates and expands the 2015 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and SSRI dosing and summarizes the impact of CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A genotypes on antidepressant dosing, efficacy, and tolerability. We provide recommendations for using CYP2D6, CYP2C19, and CYP2B6 genotype results to help inform prescribing these antidepressants and describe the existing data for SLC6A4 and HTR2A, which do not support their clinical use in antidepressant prescribing.
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Transtorno Depressivo Maior , Inibidores Seletivos de Recaptação de Serotonina , Humanos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP2B6/genética , Farmacogenética , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Serotonina , Antidepressivos/uso terapêutico , Citalopram/uso terapêutico , GenótipoRESUMO
Neuronal oxidative stress has been implicated in aging and neurodegenerative disease. Here we investigated the impact of elevated oxidative stress induced in mouse spinal cord by deletion of Mn-Superoxide dismutase (MnSOD) using a neuron specific Cre recombinase in Sod2 floxed mice (i-mn-Sod2 KO). Sod2 deletion in spinal cord neurons was associated with mitochondrial alterations and peroxide generation. Phenotypically, i-mn-Sod2 KO mice experienced hindlimb paralysis and clasping behavior associated with extensive demyelination and reduced nerve conduction velocity, axonal degeneration, enhanced blood brain barrier permeability, elevated inflammatory cytokines, microglia activation, infiltration of neutrophils and necroptosis in spinal cord. In contrast, spinal cord motor neuron number, innervation of neuromuscular junctions, muscle mass, and contractile function were not altered. Overall, our findings show that loss of MnSOD in spinal cord promotes a phenotype of demyelination, inflammation and progressive paralysis that mimics phenotypes associated with progressive multiple sclerosis.
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Esclerose Múltipla , Doenças Neurodegenerativas , Camundongos , Animais , Mitocôndrias , Superóxido Dismutase/genética , Neurônios Motores , Superóxido Dismutase-1/genética , Fenótipo , Paralisia/genética , Inflamação/genéticaRESUMO
In Australia, 13% of women are diagnosed with breast cancer (BC) in their lifetime with approximately 20,000 women diagnosed with the disease in 2021. BC is characterised by complex histological and genomic influences with recent advances in cancer biology improving early diagnosis and personalised treatment interventions. The Phosphatidyl-inositol-3-kinase/Protein kinase B (PI3K/AKT) pathway is essential in apoptosis resistance, cell survival, activation of cellular responses to DNA damage and DNA repair. Heparan sulfate proteoglycans (HSPGs) are ubiquitous molecules found on the cell surface and in the extracellular matrix with essential functions in regulating cell survival, growth, adhesion and as mediators of cell differentiation and migration. HSPGs, particularly the syndecans (SDCs), have been linked to cancers, making them an exciting target for anticancer treatments. In the PI3K/AKT pathway, syndecan-4 (SDC4) has been shown to downregulate AKT Serine/Threonine Kinase (AKT1) gene expression, while the ATM Serine/Threonine Kinase (ATM) gene has been found to inhibit this pathway upstream of AKT. We investigated single-nucleotide polymorphisms (SNPs) in HSPG and related genes SDC4, AKT1 and ATM and their influence on the prevalence of BC. SNPs were genotyped in the Australian Caucasian Genomics Research Centre Breast Cancer (GRC-BC) population and in the Griffith University-Cancer Council Queensland Breast Cancer Biobank (GU-CCQ BB) population. We identified that SDC4-rs1981429 and ATM-rs228590 may influence the development and progression of BC, having the potential to become biomarkers in early BC diagnosis and personalised treatment.
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Neoplasias da Mama , Feminino , Humanos , Neoplasias da Mama/patologia , Sindecana-4/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Austrália , Proteoglicanas de Heparan Sulfato/metabolismo , Biomarcadores , Serina , Proteínas Mutadas de Ataxia Telangiectasia/metabolismoRESUMO
Objective: Pharmacogenomics (PGx) is increasingly being used for creating individualized treatments for patient care. Healthcare professionals, especially pharmacists, need to understand how genetic variation impacts the efficacy and toxicity of medications. Due to the breadth and complexity of PGx-related information, it has been challenging to determine what information should be included in pharmacy curricula and how best to educate students. Methods: The University of Minnesota College of Pharmacy recently began the process of incorporating into the curriculum expanded competencies for PGx from the American Association of Colleges of Pharmacy (AACP) Pharmacogenomics Special Interest Group (PGx-SIG). We evaluated our curriculum for PGx content, determined what was currently being taught and identified educational gaps. Results: A review of our Doctor of Pharmacy curriculum showed substantial PGx content, although it was inconsistently taught throughout the required courses and in some courses absent. We revised the content of existing courses incorporating content that meet most of the PGx-SIG recommended competencies. Conclusion: There are and will be major changes in our understanding of the influences of PGx on individualized medical treatment. As our understanding grows, information on PGx in pharmacy curriculums will need to keep pace with these changes. We have begun this process at the University of Minnesota by doing a full review of PGx related information and making appropriate revisions in the pharmacy curriculum.
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Both pharmacogenomics (PGx) and the medication experience (MedXp) share a common purpose for their use, which is to optimally tailor medications to each unique individual. The former pursues this aim by using an individual's genetic makeup, while the latter considers the subjective experience of medication-taking in one's life. The different ways by which these fields of study pursue their shared aim have resulted in relatively little understanding of their relationship when utilized in care processes to produce health outcomes. This commentary explores this gap and identifies implications for future research that can help close it to improve person-centered care.
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Aims: To assess knowledge and attitudes toward pharmacogenomics (PGx) of incoming doctoral pharmacy students, to evaluate the internal structure and reliability of the PGx survey and to identify variables associated with the different responses. Methods: A PGx survey based on the core pharmacist competencies in PGx was created. Results: Of 83.2% analyzable responses, 91% believed PGx is a useful tool and relevant to future practice but over 70% stated they lack confidence in clinical PGx knowledge. This 38-item PGx survey included three factors showing high reliability. Prior genetic/PGx testing and unsatisfactory medication experiences were associated with a more positive attitude toward PGx. Conclusion: The majority of students have positive attitudes toward PGx, but lack knowledge in genetic concepts and clinical PGx.
A pharmacogenomics (PGx) survey with high reliability showed that incoming doctoral pharmacy students have positive attitudes toward PGx, but lack knowledge of genetic concepts and clinical PGx.
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Estudantes de Farmácia , Humanos , Farmacogenética/educação , Reprodutibilidade dos Testes , Farmacêuticos , AtitudeRESUMO
Loss of innervation is a key driver of age associated muscle atrophy and weakness (sarcopenia). Our laboratory has previously shown that denervation induced atrophy is associated with the generation of mitochondrial hydroperoxides and lipid mediators produced downstream of cPLA2 and 12/15 lipoxygenase (12/15-LOX). To define the pathological impact of lipid hydroperoxides generated in denervation-induced atrophy in vivo, we treated mice with liproxstatin-1, a lipid hydroperoxide scavenger. We treated adult male mice with 5 mg/kg liproxstain-1 or vehicle one day prior to sciatic nerve transection and daily for 7 days post-denervation before tissue analysis. Liproxstatin-1 treatment protected gastrocnemius mass and fiber cross sectional area (â¼40% less atrophy post-denervation in treated versus untreated mice). Mitochondrial hydroperoxide generation was reduced 80% in vitro and by over 65% in vivo by liproxstatin-1 treatment in denervated permeabilized muscle fibers and decreased the content of 4-HNE by â¼25% post-denervation. Lipidomic analysis revealed detectable levels of 25 oxylipins in denervated gastrocnemius muscle and significantly increased levels for eight oxylipins that are generated by metabolism of fatty acids through 12/15-LOX. Liproxstatin-1 treatment reduced the level of three of the eight denervation-induced oxylipins, specifically 15-HEPE, 13-HOTrE and 17-HDOHE. Denervation elevated protein degradation rates in muscle and treatment with liproxstatin-1 reduced rates of protein breakdown in denervated muscle. In contrast, protein synthesis rates were unchanged by denervation. Targeted proteomics revealed a number of proteins with altered expression after denervation but no effect of liproxstain-1. Transcriptomic analysis revealed 203 differentially expressed genes in denervated muscle from vehicle or liproxstatin-1 treated mice, including ER stress, nitric oxide signaling, Gαi signaling, glucocorticoid receptor signaling, and other pathways. Overall, these data suggest lipid hydroperoxides and oxylipins are key drivers of increased protein breakdown and muscle loss associated with denervation induced atrophy and a potential target for sarcopenia intervention.