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1.
Mol Cell Biochem ; 478(6): 1245-1250, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36282351

RESUMO

The loss of cardiomyocytes after myocardial infarction (MI) leads to heart failure. Recently, we demonstrated that transient overexpression of 4 cell cycle factors (4F), using a polycistronic non-integrating lentivirus (TNNT2-4F-NIL) resulted in significant improvement in cardiac function in a rat model of MI. Yet, it is crucial to demonstrate the reversal of the heart failure-related pathophysiological manifestations, such as renin-angiotensin-aldosterone system activation (RAAS). To assess that, Fisher 344 rats were randomized to receive TNNT2-4F-NIL or control virus seven days after coronary occlusion for 2 h followed by reperfusion. 4 months after treatment, N-terminal pro-brain natriuretic peptide, plasma renin activity, and aldosterone levels returned to the normal levels in rats treated with TNNT2-4F-NIL but not in vehicle-treated rats. Furthermore, the TNNT2-4F-NIL-treated group showed significantly less liver and kidney congestion than vehicle-treated rats. Thus, we conclude that in rat models of MI, TNNT2-4F-NIL reverses RAAS activation and subsequent systemic congestion.


Assuntos
Insuficiência Cardíaca , Infarto do Miocárdio , Animais , Ratos , Aldosterona/metabolismo , Ciclo Celular , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/terapia , Insuficiência Cardíaca/metabolismo , Rim/metabolismo , Infarto do Miocárdio/metabolismo , Renina/genética , Renina/metabolismo , Sistema Renina-Angiotensina
2.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299340

RESUMO

Unlike some lower vertebrates which can completely regenerate their heart, the human heart is a terminally differentiated organ. Cardiomyocytes lost during cardiac injury and heart failure cannot be replaced due to their limited proliferative capacity. Therefore, cardiac injury generally leads to progressive failure. Here, we summarize the latest progress in research on methods to induce cardiomyocyte cell cycle entry and heart repair through the alteration of cardiomyocyte plasticity, which is emerging as an effective strategy to compensate for the loss of functional cardiomyocytes and improve the impaired heart functions.


Assuntos
Proliferação de Células/fisiologia , Insuficiência Cardíaca/terapia , Miócitos Cardíacos/metabolismo , Animais , Ciclo Celular , Plasticidade Celular/genética , Plasticidade Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Coração/fisiologia , Insuficiência Cardíaca/fisiopatologia , Traumatismos Cardíacos/terapia , Humanos , Miócitos Cardíacos/fisiologia , Regeneração/fisiologia , Transdução de Sinais
3.
Biomedicines ; 12(7)2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-39062028

RESUMO

Wilms tumor (WT), or nephroblastoma, is the predominant renal malignancy in the pediatric population. This narrative review explores the evolution of personalized care strategies for WT, synthesizing critical developments in molecular diagnostics and treatment approaches to enhance patient-specific outcomes. We surveyed recent literature from the last five years, focusing on high-impact research across major databases such as PubMed, Scopus, and Web of Science. Diagnostic advancements, including liquid biopsies and diffusion-weighted MRI, have improved early detection precision. The prognostic significance of genetic markers, particularly WT1 mutations and miRNA profiles, is discussed. Novel predictive tools integrating genetic and clinical data to anticipate disease trajectory and therapy response are explored. Progressive treatment strategies, particularly immunotherapy and targeted agents such as HIF-2α inhibitors and GD2-targeted immunotherapy, are highlighted for their role in personalized treatment protocols, especially for refractory or recurrent WT. This review underscores the necessity for personalized management supported by genetic insights, with improved survival rates for localized disease exceeding 90%. However, knowledge gaps persist in therapies for high-risk patients and strategies to reduce long-term treatment-related morbidity. In conclusion, this narrative review highlights the need for ongoing research, particularly on the long-term outcomes of emerging therapies and integrating multi-omic data to inform clinical decision-making, paving the way for more individualized treatment pathways.

4.
Br J Radiol ; 97(1154): 283-291, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38308033

RESUMO

Rapid advancements in the critical care management of acute brain injuries have facilitated the survival of numerous patients who may have otherwise succumbed to their injuries. The probability of conscious recovery hinges on the extent of structural brain damage and the level of metabolic and functional cerebral impairment, which remain challenging to assess via laboratory, clinical, or functional tests. Current research settings and guidelines highlight the potential value of fluorodeoxyglucose-PET (FDG-PET) for diagnostic and prognostic purposes, emphasizing its capacity to consistently illustrate a metabolic reduction in cerebral glucose uptake across various disorders of consciousness. Crucially, FDG-PET might be a pivotal tool for differentiating between patients in the minimally conscious state and those in the unresponsive wakefulness syndrome, a persistent clinical challenge. In patients with disorders of consciousness, PET offers utility in evaluating the degree and spread of functional disruption, as well as identifying irreversible neural damage. Further, studies that capture responses to external stimuli can shed light on residual or revived brain functioning. Nevertheless, the validity of these findings in predicting clinical outcomes calls for additional long-term studies with larger patient cohorts suffering from consciousness impairment. Misdiagnosis of conscious illnesses during bedside clinical assessments remains a significant concern. Based on the clinical research settings, current clinical guidelines recommend PET for diagnostic and/or prognostic purposes. This review article discusses the clinical categories of conscious disorders and the diagnostic and prognostic value of PET imaging in clinically unresponsive patients, considering the known limitations of PET imaging in such contexts.


Assuntos
Lesões Encefálicas , Transtornos da Consciência , Humanos , Transtornos da Consciência/diagnóstico , Transtornos da Consciência/metabolismo , Fluordesoxiglucose F18/metabolismo , Encéfalo/metabolismo , Estado Vegetativo Persistente/diagnóstico por imagem , Estado Vegetativo Persistente/metabolismo , Tomografia por Emissão de Pósitrons/métodos
5.
Sci Rep ; 13(1): 17048, 2023 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-37813914

RESUMO

Autism Spectrum Disorder (ASD) is characterized as a neurodevelopmental disorder with a heterogeneous nature, influenced by genetics and exhibiting diverse clinical presentations. In this study, we dissect Autism Spectrum Disorder (ASD) into its behavioral components, mirroring the diagnostic process used in clinical settings. Morphological features are extracted from magnetic resonance imaging (MRI) scans, found in the publicly available dataset ABIDE II, identifying the most discriminative features that differentiate ASD within various behavioral domains. Then, each subject is categorized as having severe, moderate, or mild ASD, or typical neurodevelopment (TD), based on the behavioral domains of the Social Responsiveness Scale (SRS). Through this study, multiple artificial intelligence (AI) models are utilized for feature selection and classifying each ASD severity and behavioural group. A multivariate feature selection algorithm, investigating four different classifiers with linear and non-linear hypotheses, is applied iteratively while shuffling the training-validation subjects to find the set of cortical regions with statistically significant association with ASD. A set of six classifiers are optimized and trained on the selected set of features using 5-fold cross-validation for the purpose of severity classification for each behavioural group. Our AI-based model achieved an average accuracy of 96%, computed as the mean accuracy across the top-performing AI models for feature selection and severity classification across the different behavioral groups. The proposed AI model has the ability to accurately differentiate between the functionalities of specific brain regions, such as the left and right caudal middle frontal regions. We propose an AI-based model that dissects ASD into behavioral components. For each behavioral component, the AI-based model is capable of identifying the brain regions which are associated with ASD as well as utilizing those regions for diagnosis. The proposed system can increase the speed and accuracy of the diagnostic process and result in improved outcomes for individuals with ASD, highlighting the potential of AI in this area.


Assuntos
Transtorno do Espectro Autista , Humanos , Transtorno do Espectro Autista/diagnóstico por imagem , Transtorno do Espectro Autista/patologia , Inteligência Artificial , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos , Aprendizado de Máquina
6.
Br J Pharmacol ; 180(24): 3271-3289, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37547998

RESUMO

BACKGROUND AND PURPOSE: Myocardial infarction (MI) is the leading cause of mortality globally due in part to the limited ability of cardiomyocytes (CMs) to regenerate. Recently, we demonstrated that overexpression of four-cell cycle factors, CDK1, CDK4, cyclin B1 and cyclin D1 (4F), induced cell division in ~20% of the post-mitotic CMs overexpressed 4F. The current study aims to identify a small molecule that augments 4F-induced CM cycle induction. EXPERIMENTAL APPROACH, KEY RESULTS: Screening of small molecules with a potential to augment 4F-induced cell-cycle induction in 60-day-old mature human induced pluripotent cardiomyocytes (hiPS-CMs) revealed N-(4,6-Dimethylpyridin-2-yl)-4-(pyridine-4-yl)piperazine-1-carbothioamide (NDPPC), which activates cell cycle progression in 4F-transduced hiPS-CMs. Autodock tool and Autodock vina computational methods showed that NDPPC has a potential interaction with the binding site at the human p38⍺ mitogen-activated protein kinase (p38⍺ MAP kinase), a critical negative regulator of the mammalian cell cycle. A p38 MAP kinase activity assay showed that NDPPC inhibits p38⍺ with 5-10 times lower IC50 compared to the other P38 isoforms in a dose-dependent manner. Overexpression of p38⍺ MAP kinase in CMs inhibited 4F cell cycle induction, and treatment with NDPPC reversed the cell cycle inhibitory effect. CONCLUSION AND IMPLICATIONS: NDPPC is a novel inhibitor for p38 MAP kinase and is a promising drug to augment CM cell cycle response to the 4F. NDPPC could become an adjunct treatment with other cell cycle activators for heart failure treatment.


Assuntos
Inibidores Enzimáticos , Miócitos Cardíacos , Animais , Humanos , Miócitos Cardíacos/metabolismo , Inibidores Enzimáticos/farmacologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Ciclo Celular , Divisão Celular , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Mamíferos/metabolismo
7.
Commun Biol ; 5(1): 934, 2022 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-36085302

RESUMO

There is need for a reliable in vitro system that can accurately replicate the cardiac physiological environment for drug testing. The limited availability of human heart tissue culture systems has led to inaccurate interpretations of cardiac-related drug effects. Here, we developed a cardiac tissue culture model (CTCM) that can electro-mechanically stimulate heart slices with physiological stretches in systole and diastole during the cardiac cycle. After 12 days in culture, this approach partially improved the viability of heart slices but did not completely maintain their structural integrity. Therefore, following small molecule screening, we found that the incorporation of 100 nM tri-iodothyronine (T3) and 1 µM dexamethasone (Dex) into our culture media preserved the microscopic structure of the slices for 12 days. When combined with T3/Dex treatment, the CTCM system maintained the transcriptional profile, viability, metabolic activity, and structural integrity for 12 days at the same levels as the fresh heart tissue. Furthermore, overstretching the cardiac tissue induced cardiac hypertrophic signaling in culture, which provides a proof of concept for the ability of the CTCM to emulate cardiac stretch-induced hypertrophic conditions. In conclusion, CTCM can emulate cardiac physiology and pathophysiology in culture for an extended time, thereby enabling reliable drug screening.


Assuntos
Biomimética , Coração , Cardiomegalia , Meios de Cultura , Humanos , Sístole
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