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Copy number variations (CNVs) are an important class of variations contributing to the pathogenesis of many disease phenotypes. Detecting CNVs from genomic data remains difficult, and the most currently applied methods suffer from an unacceptably high false positive rate. A common practice is to have human experts manually review original CNV calls for filtering false positives before further downstream analysis or experimental validation. Here, we propose DeepCNV, a deep learning-based tool, intended to replace human experts when validating CNV calls, focusing on the calls made by one of the most accurate CNV callers, PennCNV. The sophistication of the deep neural network algorithm is enriched with over 10 000 expert-scored samples that are split into training and testing sets. Variant confidence, especially for CNVs, is a main roadblock impeding the progress of linking CNVs with the disease. We show that DeepCNV adds to the confidence of the CNV calls with an optimal area under the receiver operating characteristic curve of 0.909, exceeding other machine learning methods. The superiority of DeepCNV was also benchmarked and confirmed using an experimental wet-lab validation dataset. We conclude that the improvement obtained by DeepCNV results in significantly fewer false positive results and failures to replicate the CNV association results.
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Variações do Número de Cópias de DNA , Aprendizado Profundo , Doença/genética , Genoma Humano , Área Sob a Curva , Benchmarking , Conjuntos de Dados como Assunto , Doença/classificação , Reações Falso-Positivas , Humanos , Curva ROCRESUMO
INTRODUCTION: The World Health Organization recommends regular monitoring of the efficacy of nationally recommended antimalarial drugs. We present the results of studies on the efficacy of recommended antimalarials and molecular markers of artemisinin and partner resistance in Afghanistan, Pakistan, Somalia, Sudan and Yemen. METHODS: Single-arm prospective studies were conducted to evaluate the efficacy of artesunate-sulfadoxine-pyrimethamine (ASSP) in Afghanistan and Pakistan, artemether-lumefantrine (AL) in all countries, or dihydroartemisinin-piperaquine (DP) in Sudan for the treatment of Plasmodium falciparum. The efficacy of chloroquine (CQ) and AL for the treatment of Plasmodium vivax was evaluated in Afghanistan and Somalia, respectively. Patients were treated and monitored for 28 (CQ, ASSP and AL) or 42 (DP) days. Polymerase chain reaction (PCR)-corrected cure rate and parasite positivity rate at Day 3 were estimated. Mutations in the P. falciparum kelch 13 (Pfk13) gene and amplifications of plasmepsin (Pfpm2) and multidrug resistance-1 (Pfmdr-1) genes were also studied. RESULTS: A total of 1680 (249 for ASSP, 1079 for AL and 352 for DP) falciparum cases were successfully assessed. A PCR-adjusted ASSP cure rate of 100% was observed in Afghanistan and Pakistan. For AL, the cure rate was 100% in all but four sites in Sudan, where cure rates ranged from 92.1% to 98.8%. All but one patient were parasite-free at Day 3. For P. vivax, cure rates were 98.2% for CQ and 100% for AL. None of the samples from Afghanistan, Pakistan and Yemen had a Pfk13 mutation known to be associated with artemisinin resistance. In Sudan, the validated Pfk13 R622I mutation accounted for 53.8% (14/26) of the detected non-synonymous Pfk13 mutations, most of which were repeatedly detected in Gadaref. A prevalence of 2.7% and 9.3% of Pfmdr1 amplification was observed in Pakistan and Yemen, respectively. CONCLUSION: High efficacy of ASSP, AL and DP in the treatment of uncomplicated falciparum infection and of CQ and AL in the treatment of P. vivax was observed in the respective countries. The repeated detection of a relatively high rate of Pfk13 R622I mutation in Sudan underscores the need for close monitoring of the efficacy of recommended ACTs, parasite clearance rates and Pfk13 mutations in Sudan and beyond. Registration numbers of the trials: ACTRN12622000944730 and ACTRN12622000873729 for Afghanistan, ACTRN12620000426987 and ACTRN12617001025325 for Pakistan, ACTRN12618001224213 for Somalia, ACTRN12617000276358, ACTRN12622000930785 and ACTRN12618001800213 for Sudan and ACTRN12617000283370 for Yemen.
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Antimaláricos , Artemisininas , Malária Falciparum , Malária Vivax , Malária , Humanos , Antimaláricos/uso terapêutico , Antimaláricos/farmacologia , Estudos Prospectivos , Combinação Arteméter e Lumefantrina/uso terapêutico , Artemeter/uso terapêutico , Artemisininas/uso terapêutico , Malária/tratamento farmacológico , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Malária Falciparum/parasitologia , Cloroquina/uso terapêutico , Artesunato/uso terapêutico , Plasmodium falciparum/genética , Combinação de Medicamentos , Malária Vivax/tratamento farmacológico , Malária Vivax/epidemiologia , Resistência a Medicamentos/genéticaRESUMO
Histones are important component of eukaryotic cells chromatin and consist of arginine and lysine residues. Histones play an important role in the protection of DNA. Their contents significantly affect high-level chromatin structure formation, gene expression, DNA replication, and other important life activities. Protein degradation is an important regulatory mechanism of histone content. Recent studies have revealed that modification of amino acid sequence is directly related to histone breakdown. In addition, histone degradation is closely related to covalent modifications, such as ubiquitination and acetylation, which are considered to be driving factors in gene regulation. Gene regulation is an important mechanism in adaptation to the environment and survival of species. With the introduction of highly efficient technology, various mutations in histones have been identified in yeast. In the field of epigenetics and the transmission of chromatin states, two widely used model organisms are the budding yeast Saccharomyces cerevisiae and Schizosaccharomyces pombe. Higher eukaryotes can use their silent loci to maintain their epigenetic states and providing the base to investigate mechanisms underlying development. Therfore, both species have contributed a plethora of information on these mechanisms in both yeast and higher eukaryotes. This study focuses on the role of histone modifications in controlling telomeric silencing in Saccharomyces cerevisiae and centromeric silencing in S. pombe as examples of genetic loci that demonstrate epigenetic inheritance. In view of recent advances, this review focuses on the post-translational modification of histone amino acid residues and reviews the relationship between histone degradation and amino acid residue modification.
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Histonas , Saccharomyces cerevisiae , Aminoácidos/metabolismo , Cromatina/metabolismo , Histonas/química , Histonas/genética , Histonas/metabolismo , Processamento de Proteína Pós-Traducional , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismoRESUMO
BACKGROUND: Not all cells in a given individual are identical in their genomic makeup. Mosaicism describes such a phenomenon where a mixture of genotypic states in certain genomic segments exists within the same individual. Mosaicism is a prevalent and impactful class of non-integer state copy number variation (CNV). Mosaicism implies that certain cell types or subset of cells contain a CNV in a segment of the genome while other cells in the same individual do not. Several studies have investigated the impact of mosaicism in single patients or small cohorts but no comprehensive scan of mosaic CNVs has been undertaken to accurately detect such variants and interpret their impact on human health and disease. RESULTS: We developed a tool called Montage to improve the accuracy of detection of mosaic copy number variants in a high throughput fashion. Montage directly interfaces with ParseCNV2 algorithm to establish disease phenotype genome-wide association and determine which genomic ranges had more or less than expected frequency of mosaic events. We screened for mosaic events in over 350,000 samples using 1% allele frequency as the detection limit. Additionally, we uncovered disease associations of multiple phenotypes with mosaic CNVs at several genomic loci. We additionally investigated the allele imbalance observations genome-wide to define non-diploid and non-integer copy number states. CONCLUSIONS: Our novel algorithm presents an efficient tool with fast computational runtime and high levels of accuracy of mosaic CNV detection. A curated mosaic CNV callset of 3716 events in 2269 samples is presented with comparability to previous reports and disease phenotype associations. The new algorithm can be freely accessed via: https://github.com/CAG-CNV/MONTAGE .
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Variações do Número de Cópias de DNA , Estudo de Associação Genômica Ampla , Genômica , Humanos , Polimorfismo de Nucleotídeo Único , SoftwareRESUMO
BACKGROUND AND PURPOSE: We reviewed our experience of synovial sarcoma to identify factors predictive of local recurrence and overall survival, the impact of chemotherapy and outcomes after surgical excision alone. MATERIALS AND METHODS: 81 patients were treated between 1997 and 2014 of mean age 39 years (8-78). Tumours were in the extremity in 55 (67%). 9 patients presented with metastases and 10 with unresectable disease. Mean follow-up was 3.7 years (SD 3.8). Treatment groups were palliative, surgery only, surgery and radiotherapy, or surgery with chemotherapy (with or without radiotherapy). RESULTS: Local recurrence-free survival (LRFS) was 73% at 5 years, and 68% at 10 and 15 years. In multivariate analysis, positive surgical margins were an independent predictor of LRFS. Overall survival (OS) was 50% at 5 years for all patients, and 62% at 5 years for those treated with curative intent. Larger tumour size and non-extremity locations were predictors of poorer OS. Patients who had chemotherapy did not have significantly better OS or LRS than others. INTERPRETATION: These results show that where feasible, curative resection should not be delayed for chemotherapy. Treatment with surgery only can be associated with good outcomes in selected patients with smaller extremity tumours; although our series is small.
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Sarcoma Sinovial , Adolescente , Adulto , Idoso , Antineoplásicos/uso terapêutico , Criança , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estudos Retrospectivos , Sarcoma Sinovial/tratamento farmacológico , Sarcoma Sinovial/mortalidade , Sarcoma Sinovial/cirurgia , Resultado do Tratamento , Reino Unido , Adulto JovemRESUMO
AIMS: This paper investigates the distributional implications for eight population groups of using six different instruments to measure wellbeing and to prioritise access to health services. Specifically, it examines the importance of different physical and psycho-social problems for the scores obtained using each instrument and whether scores differ because of differences in the concept measured by the instrument or because of the instrument's construction. METHODS: Patients with seven chronic conditions and a sample of the 'healthy' public were administered six instruments: two utility instruments; two self-rating scales; a subjective wellbeing instrument and the ICECAP measure of capability. Scores were regressed upon the subscales of the SF-36 and the AQoL-8D. Each instrument's 'problem mix' was measured by the numerical importance of the subscales for the instrument's score and compared with the problem mix of patients constructed from all of the instruments. RESULTS: The apparent importance of different problems varied significantly with the instrument used to assess welfare but not with the chronic conditions. The correspondence between an instrument's problem mix and the patients' problem mix was highly variable. CONCLUSION: Different instruments give prominence to different physical and psycho-social problems and consequently favour different groups of patients. Budgetary decisions which appear to be based on efficiency criteria such as the cost per quality-adjusted life year (QALY) conceal distributive effects attributable to the instrument used in the analysis. The effects are additional to the ethical questions considered in making an equity-efficiency trade-off as they arise from the measurement of efficiency.
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Qualidade de Vida/psicologia , Anos de Vida Ajustados por Qualidade de Vida , Seguridade Social/psicologia , Feminino , Humanos , Masculino , Inquéritos e QuestionáriosRESUMO
The d-band center and surface negative charge density generally determine the adsorption and activation of CO2, thus serving as important descriptors of the catalytic activity toward CO2 hydrogenation. Herein, we engineered the d-band center and negative charge density of Rh-based catalysts by tuning their dimensions and introducing non-noble metals to form an alloy. During the hydrogenation of CO2 into methanol, the catalytic activity of Rh75W25 nanosheets was 5.9, 4.0, and 1.7 times as high as that of Rh nanoparticles, Rh nanosheets, and Rh73W27 nanoparticles, respectively. Mechanistic studies reveal that the remarkable activity of Rh75W25 nanosheets is owing to the integration of quantum confinement and alloy effect. Specifically, the quantum confinement in one dimension shifts up the d-band center of Rh75W25 nanosheets, strengthening the adsorption of CO2. Moreover, the alloy effect not only promotes the activation of CO2 to form CO2δ- but also enhances the adsorption of intermediates to facilitate further hydrogenation of the intermediates into methanol.
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Ligas/química , Dióxido de Carbono/química , Nanopartículas/química , Ródio/química , Tungstênio/química , Adsorção , Catálise , Eletrônica , Hidrogênio/química , Hidrogenação , Metanol/química , Modelos Teóricos , Tamanho da Partícula , Propriedades de SuperfícieRESUMO
The photothermal effect is applied in CO2 hydrogenation to reduce the reaction temperature under illumination by encapsulating Pt nanocubes and Au nanocages into a zeolitic imidazolate framework (ZIF-8). Under illumination, the heat generated by the photothermal effect of Au nanocages is mainly insulated in the ZIF-8 to form a localized high-temperature region, thereby improving the catalytic activity of Pt nanocubes.
RESUMO
As the electron transfer to CO2 is a critical step in the activation of CO2 , it is of significant importance to engineer the electronic properties of CO2 hydrogenation catalysts to enhance their activity. Herein, we prepared Pt3 Co nanocrystals with improved catalytic performance towards CO2 hydrogenation to methanol. Pt3 Co octapods, Pt3 Co nanocubes, Pt octapods, and Pt nanocubes were tested, and the Pt3 Co octapods achieved the best catalytic activity. Both the presence of multiple sharp tips and charge transfer between Pt and Co enabled the accumulation of negative charges on the Pt atoms in the vertices of the Pt3 Co octapods. Moreover, infrared reflection absorption spectroscopy confirmed that the high negative charge density at the Pt atoms in the vertices of the Pt3 Co octapods promotes the activation of CO2 and accordingly enhances the catalytic activity.
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Non-noble bimetallic nanocrystals (NCs) have been widely explored due to not only their low cost and abundant content in the Earth's crust but also their outstanding performance in catalytic reactions. However, controllable synthesis of non-noble alloys remains a significant challenge. Here we report a facile synthesis of CuNi octahedra and nanocubes with controllable shapes and tunable compositions. Its success relies on the use of borane morpholine as a reducing agent, which upon decomposition generates a burst of H2 molecules to induce rapid formation of the nuclei. Specifically, octahedra switched to nanocubes with an increased amount of borane morpholine. In addition, the ratio of CuNi NCs could be facilely tuned by changing the molar ratio of both precursors. The obtained CuNi NCs exhibited high activity in aldehyde-alkyne-amine coupling reactions, and their performance is strongly facet- and composition-dependent due to the competition of the surface energy (enhanced by increasing the percent of Ni) and active sites (derived from Cu atoms).
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PURPOSE: Health state utilities measured by the major multi-attribute utility instruments differ. Understanding the reasons for this is important for the choice of instrument and for research designed to reconcile these differences. This paper investigates these reasons by explaining pairwise differences between utilities derived from six multi-attribute utility instruments in terms of (1) their implicit measurement scales; (2) the structure of their descriptive systems; and (3) 'micro-utility effects', scale-adjusted differences attributable to their utility formula. METHODS: The EQ-5D-5L, SF-6D, HUI 3, 15D and AQoL-8D were administered to 8,019 individuals. Utilities and unweighted values were calculated using each instrument. Scale effects were determined by the linear relationship between utilities, the effect of the descriptive system by comparison of scale-adjusted values and 'micro-utility effects' by the unexplained difference between utilities and values. RESULTS: Overall, 66 % of the differences between utilities was attributable to the descriptive systems, 30.3 % to scale effects and 3.7 % to micro-utility effects. DISCUSSION: Results imply that the revision of utility algorithms will not reconcile differences between instruments. The dominating importance of the descriptive system highlights the need for researchers to select the instrument most capable of describing the health states relevant for a study. CONCLUSIONS: Reconciliation of inconsistent utilities produced by different instruments must focus primarily upon the content of the descriptive system. Utility weights primarily determine the measurement scale. Other differences, attributable to utility formula, are comparatively unimportant.
Assuntos
Análise Custo-Benefício , Qualidade de Vida , Inquéritos e Questionários , Adolescente , Adulto , Idoso , Algoritmos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Many mental health surveys and clinical studies do not include a multi-attribute utility instrument (MAUI) that produces quality-adjusted life-years (QALYs). There is also some question about the sensitivity of the existing utility instruments to mental health. AIMS: To compare the sensitivity of five commonly used MAUIs (Assessment of Quality of Life - Eight Dimension Scale (AQoL-8D), EuroQoL-five dimension (EQ-5D-5L), Short Form 6D (SF-6D), Health Utilities Index Mark 3 (HUI3), 15D) with that of disease-specific depression outcome measures (Depression Anxiety Stress Scales (DASS-21) and the Kessler Psychological Distress Scale (K10)) and develop 'crosswalk' transformation algorithms between the measures. METHOD: Individual data from 917 people with self-report depression collected as part of the International Multi-Instrument Comparison Survey. RESULTS: All the MAUIs discriminated between the levels of severity measured by the K10 and the DASS-21. The AQoL-8D had the highest correlation with the disease-specific measures and the best goodness-of-fit transformation properties. CONCLUSIONS: The algorithms developed in this study can be used to determine cost-effectiveness of services or interventions where utility measures are not collected.
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Depressão/diagnóstico , Depressão/terapia , Avaliação de Resultados em Cuidados de Saúde/métodos , Qualidade de Vida , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Custo-Benefício , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Anos de Vida Ajustados por Qualidade de Vida , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Inquéritos e Questionários , Adulto JovemRESUMO
This paper describes an instrument for measuring the social value of changes in health status, the Relative Social Willingness to Pay. It is a unique combination of measurement attributes designed to minimise cognitive complexity and provide an additional option for measuring 'social value'. Similar to the person trade-off (PTO), it adopts a social perspective and asks respondents to evaluate programmes on behalf of society. Unlike the PTO, trade-offs between the options use dollars, not numbers of patients. Respondents are not, however, asked for their personal willingness to pay. Rather, the opportunity cost of funds spent on one service is as an offsetting reduction in funds for a second service. The amount spent on each service therefore indicates relative, not absolute, value. However, the two services combine to produce one Quality adjusted life year which allows the calculation of a Quality adjusted life year-like unit of social value on a 0-1 scale. A three-stage survey was used to test the instrument's reliability, validity and sensitivity to the framing of the main question. Results indicate that the Relative Social Willingness to Pay produces values similar to but less than the PTO and time trade-off techniques.
Assuntos
Financiamento Pessoal/economia , Nível de Saúde , Modelos Econômicos , Anos de Vida Ajustados por Qualidade de Vida , Adolescente , Adulto , Análise Custo-Benefício , Coleta de Dados/métodos , Honorários e Preços , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos TestesRESUMO
PURPOSE: The objective of this paper is to describe the four-stage methodology used to obtain utility scores for the Assessment of Quality of Life (AQoL)-8D, a 35-item 8 dimension multi-attribute utility instrument, which was created to achieve a high degree of sensitivity to psycho-social health. METHODS: Data for the analyses were obtained from a representative group of 347 members of the Australian public and from 323 mental health patients each of whom provided VAS and time trade-off valuations of multiple health states. Data were used initially to create multiplicative scoring algorithms for each of the instrument's 8 dimensions and for the overall instrument. Each of the algorithms was then subject to a second-stage econometric 'correction'. RESULTS: Algorithms were successfully created for each of the AQoL-8D's dimensions, for physical and mental 'super-dimensions' and for the overall AQoL-8D instrument. The final AQoL-8D algorithm has good predictive power with respect to the TTO valuations. CONCLUSIONS: The AQoL-8D is a suitable instrument for researchers conducting cost utility analyses generally but, in particular, for the analysis of services affecting psycho-social health.
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Saúde Mental , Modelos Psicológicos , Psicometria/métodos , Qualidade de Vida/psicologia , Adolescente , Adulto , Idoso , Algoritmos , Austrália , Estudos de Casos e Controles , Custos e Análise de Custo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria/economia , Inquéritos e Questionários , Adulto JovemRESUMO
Gene therapy for hemophilia has advanced tremendously after thirty years of continual study and development. Advancements in medical science have facilitated attaining normal levels of Factor VIII (FVIII) or Factor IX (FIX) in individuals with haemophilia, thereby offering the potential for their complete recovery. Despite the notable advancements in various countries, there is significant scope for further enhancement in haemophilia gene therapy. Adeno-associated virus (AAV) currently serves as the primary vehicle for gene therapy in clinical trials targeting haemophilia. Subsequent investigations will prioritize enhancing viral capsid structures, transgene compositions, and promoters to achieve heightened transduction efficacy, diminished immunogenicity, and more predictable therapeutic results. The present study indicates that whereas animal models have transduction efficiency that is over 100% high, human hepatocytes are unable to express clotting factors and transduction efficiency to comparable levels. According to the current study, achieving high transduction efficiency and high levels of clotting factor expression in human hepatocytes is still insufficient. It is also crucial to reduce the risk of cellular stress caused by protein overload. Despite encountering various hurdles, the field of haemophilia gene therapy holds promise for the future. As technology continues to advance and mature, it is anticipated that a personalized therapeutic approach will be developed to cure haemophilia effectively.
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Dependovirus , Fator IX , Terapia Genética , Vetores Genéticos , Hemofilia A , Humanos , Hemofilia A/terapia , Hemofilia A/genética , Dependovirus/genética , Terapia Genética/métodos , Vetores Genéticos/genética , Animais , Fator IX/genética , Fator VIII/genética , Hepatócitos/metabolismo , Transdução GenéticaRESUMO
Pathological fractures commonly occur in patients with metastatic bone diseases, particularly multiple myeloma. The current optimal management for metastatic pathological lesions affecting the proximal femur is surgical intervention. Surgical planning and appropriate use of imaging modalities are pivotal in the appropriate treatment of pathological fractures. Impending fractures create added layers of complexity in the decision-making process. The appropriateness of different surgical interventions involves a multi-disciplinary approach and the importance of holistic healthcare is paramount in these circumstances.
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Investigating therapeutic miRNAs is a rewarding endeavour for pharmaceutical companies. Since its discovery in 1993, our understanding of miRNA biology has advanced significantly. Numerous studies have emphasised the disruption of miRNA expression in various diseases, making them appealing candidates for innovative therapeutic approaches. Hepatocellular carcinoma (HCC) is a significant malignancy that poses a severe threat to human health, accounting for approximately 70%-85% of all malignant tumours. Currently, the efficacy of several HCC therapies is limited. Alterations in various biomacromolecules during HCC progression and their underlying mechanisms provide a basis for the investigation of novel and effective therapeutic approaches. MicroRNAs, also known as miRNAs, have been identified in the last 20 years and significantly impact gene expression and protein translation. This atypical expression pattern is strongly associated with the onset and progression of various malignancies. Gene therapy, a novel form of biological therapy, is a prominent research area. Therefore, miRNAs have been used in the investigation of tumour gene therapy. This review examines the mechanisms of action of miRNAs, explores the correlation between miRNAs and HCC, and investigates the use of miRNAs in HCC gene therapy.
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The term "cardiovascular diseases" (CVD) refers to various ailments that affect the heart and blood vessels, including myocardial ischemia, congenital heart defects, heart failure, rheumatic heart disease, hypertension, peripheral artery disease, atherosclerosis, and cardiomyopathies. Despite significant breakthroughs in preventative measures and treatment choices, CVDs significantly contribute to morbidity and mortality, imposing a considerable financial burden. Oxidative stress (OS) is a fundamental contributor to the development and progression of CVDs, resulting from an inherent disparity in generating reactive oxygen species. The disparity above significantly contributes to the aberrant operation of the cardiovascular system. To tackle this issue, therapeutic intervention primarily emphasizes the nuclear erythroid 2-related factor 2 (Nrf2), a transcription factor crucial in regulating endogenous antioxidant defense systems against OS. The Nrf2 exhibits potential as a promising target for effectively managing CVDs. Significantly, an emerging field of study is around the utilization of natural substances to stimulate the activation of Nrf2, hence facilitating the promotion of cardioprotection. This technique introduces a new pathway for treating CVD. The substances above elicit their advantageous effects by mitigating the impact of OS via initiating Nrf2 signaling. The primary objective of our study is to provide significant insights that can contribute to advancing treatment methods, including natural products. These strategies aim to tackle the obstacles associated with CVDs.
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Doenças Cardiovasculares , Humanos , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Antioxidantes/uso terapêutico , Antioxidantes/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Cardiovascular disease is the leading cause of death, medical complications, and healthcare costs. Although recent advances have been in treating cardiovascular disorders linked with a reduced ejection fraction, acutely decompensate cardiac failure remains a significant medical problem. The transient receptor potential cation channel (TRPC6) family responds to neurohormonal and mechanical stress, playing critical roles in cardiovascular diseases. Therefore, TRP C6 channels have great promise as therapeutic targets. Numerous studies have investigated the roles of TRP C6 channels in pain neurons, highlighting their significance in cardiovascular research. The TRPC6 protein exhibits a broad distribution in various organs and tissues, including the brain, nerves, heart, blood vessels, lungs, kidneys, gastrointestinal tract, and other bodily structures. Its activation can be triggered by alterations in osmotic pressure, mechanical stimulation, and diacylglycerol. Consequently, TRPC6 plays a significant role in the pathophysiological mechanisms underlying diverse diseases within living organisms. A recent study has indicated a strong correlation between the disorder known as TRPC6 and the development of cardiovascular diseases. Consequently, investigations into the association between TRPC6 and cardiovascular diseases have gained significant attention in the scientific community. This review explores the most recent developments in the recognition and characterization of TRPC6. Additionally, it considers the field's prospects while examining how TRPC6 might be altered and its clinical applications.
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Doenças Cardiovasculares , Canal de Cátion TRPC6 , Humanos , Pulmão/metabolismo , Canais de Cátion TRPC/metabolismo , Canal de Cátion TRPC6/metabolismoRESUMO
Patients with preexisting cardiovascular disease or those at high risk for developing the condition are often offered exercise as a form of therapy. Patients with cancer who are at an increased risk for cardiovascular issues are increasingly encouraged to participate in exercise-based, interdisciplinary programs due to the positive correlation between these interventions and clinical outcomes following myocardial infarction. Diabetic cardiomyopathy (DC) is a cardiac disorder that arises due to disruptions in the homeostasis of individuals with diabetes. One of the primary reasons for mortality in individuals with diabetes is the presence of cardiac structural damage and functional abnormalities, which are the primary pathological features of DC. The aetiology of dilated cardiomyopathy is multifaceted and encompasses a range of processes, including metabolic abnormalities, impaired mitochondrial function, dysregulation of calcium ion homeostasis, excessive cardiomyocyte death, and fibrosis. In recent years, many empirical investigations have demonstrated that exercise training substantially impacts the prevention and management of diabetes. Exercise has been found to positively impact the recovery of diabetes and improve several metabolic problem characteristics associated with DC. One potential benefit of exercise is its ability to increase systolic activity, which can enhance cardiometabolic and facilitate the repair of structural damage to the heart caused by DC, leading to a direct improvement in cardiac health. In contrast, exercise has the potential to indirectly mitigate the pathological progression of DC through its ability to decrease circulating levels of sugar and fat while concurrently enhancing insulin sensitivity. A more comprehensive understanding of the molecular mechanism via exercise facilitates the restoration of DC disease must be understood. Our goal in this review was to provide helpful information and clues for developing new therapeutic techniques for motion alleviation DC by examining the molecular mechanisms involved.