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The endothelium acts as the barrier that prevents circulating lipids such as lipoproteins and fatty acids into the arterial wall; it also regulates normal functioning in the circulatory system by balancing vasodilation and vasoconstriction, modulating the several responses and signals. Plasma lipids can interact with endothelium via different mechanisms and produce different phenotypes. Increased plasma-free fatty acids (FFAs) levels are associated with the pathogenesis of atherosclerosis and cardiovascular diseases (CVD). Because of the multi-dimensional roles of plasma FFAs in mediating endothelial dysfunction, increased FFA level is now considered an essential link in the onset of endothelial dysfunction in CVD. FFA-mediated endothelial dysfunction involves several mechanisms, including dysregulated production of nitric oxide and cytokines, metaflammation, oxidative stress, inflammation, activation of the renin-angiotensin system, and apoptosis. Therefore, modulation of FFA-mediated pathways involved in endothelial dysfunction may prevent the complications associated with CVD risk. This review presents details as to how endothelium is affected by FFAs involving several metabolic pathways.
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Aterosclerose/metabolismo , Endotélio Vascular/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo , Sistema Renina-Angiotensina , Animais , HumanosRESUMO
INTRODUCTION: A recent rapid outbreak of infection around the globe has been caused by a novel coronavirus, now known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was first identified in December 2019 in Wuhan city of Hubei province, People's Republic of China. METHODS: We reviewed the currently available literature on coronaviruses. RESULTS: Coronaviruses are a group of enveloped viruses with non-segmented, single-stranded, and positive-sense RNA genomes. Although 13 variation sites in open reading frames have been identified among SARS-CoV-2 strains, no mutation has been observed so far in envelop protein. The origin and structural biology of SARS-CoV-2 in details are discussed. CONCLUSIONS: Origin and structural biology will help the researchers identify the virus's mechanism in the host and drug design. Currently, no clinical treatments or prevention strategies are available for any human coronavirus.
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COVID-19 , SARS-CoV-2 , Biologia , China , Humanos , Glicoproteína da Espícula de CoronavírusRESUMO
INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated coronavirus pandemic has posed a global health emergency. METHODS: This chapter focuses on the epidemiology and transmission immunopathology of SARS-CoV-2 infection based on the available data on SARS-CoV-2 and other coronaviruses. RESULTS: The virus is transmitted by inhalation or contact with infected droplets, and the incubation period ranges from 2 to 14 days. The case fatality rate is estimated at 6%. Following binding with cell surface angiotensin-converting enzyme 2 (ACE2) receptor, the SARS-CoV-2 enters the host cell and replicates by using host machinery to cause disease. CONCLUSIONS: Cytokine storm due to COVID-19 has challenged the treatment outcome.
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COVID-19 , SARS-CoV-2 , Humanos , Pandemias , Peptidil Dipeptidase A/genética , Glicoproteína da Espícula de CoronavírusRESUMO
INTRODUCTION: Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2)-associated coronavirus pandemic has posed a global health emergency. METHODS: We focused on clinical features, diagnostic evaluation, management, infection prevention, and safe handling of deceased bodies with suspected and confirmed COVID-19. RESULTS: The case fatality rate is estimated at around 3%. Diagnosis is by the demonstration of the virus in respiratory secretions by RT-PCR mainly. Common laboratory findings include average/low white cell counts with elevated C-reactive protein (CRP). The disease is mild in most people; in some (usually the elderly and those with comorbidities), it may progress to pneumonia, acute respiratory distress syndrome (ARDS), and multiple organ dysfunction syndromes (MODS). CONCLUSION: Treatment is primarily supportive; the role of antiviral agents is yet to be established. Prevention entails home isolation of suspected cases and those with mild illnesses and strict infection control measures at hospitals that include contact and droplet precautions.
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COVID-19 , Síndrome do Desconforto Respiratório , Idoso , Antivirais/uso terapêutico , Humanos , Pandemias , SARS-CoV-2RESUMO
BACKGROUND: Brain arteriovenous malformations (bAVM) may rupture causing disability or death. BAVM vessels are characterized by abnormally high flow that in general triggers expansive vessel remodeling mediated by cyclo-oxygenase-2 (COX2), the target of non-steroidal anti-inflammatory drugs. We investigated whether COX2 is expressed in bAVMs and whether it associates with inflammation and haemorrhage in these lesions. METHODS: Tissue was obtained from surgery of 139 bAVMs and 21 normal Circle of Willis samples. The samples were studied with immunohistochemistry and real-time quantitative polymerase chain reaction (RT-PCR). Clinical data was collected from patient records. RESULTS: COX2 expression was found in 78% (109/139) of the bAVMs and localized to the vessels' lumen or medial layer in 70% (95/135) of the bAVMs. Receptors for prostaglandin E2, a COX2-derived mediator of vascular remodeling, were found in the endothelial and smooth muscle cells and perivascular inflammatory cells of bAVMs. COX2 was expressed by infiltrating inflammatory cells and correlated with the extent of inflammation (r = .231, p = .007, Spearman rank correlation). COX2 expression did not associate with haemorrhage. CONCLUSION: COX2 is induced in bAVMs, and possibly participates in the regulation of vessel wall remodelling and ongoing inflammation. Role of COX2 signalling in the pathobiology and clinical course of bAVMs merits further studies.
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Encéfalo/metabolismo , Ciclo-Oxigenase 2 , Malformações Arteriovenosas Intracranianas , Remodelação Vascular , Encéfalo/patologia , Ciclo-Oxigenase 2/genética , Humanos , Inflamação , Malformações Arteriovenosas Intracranianas/metabolismoRESUMO
To assess the impact of lockdown amidst COVID-19 on undergraduate and postgraduate learners of various colleges and universities of West Bengal. An online survey was conducted from 1 May to 8 May 2020 to collect the information. A structural questionnaire link using 'Google form' was sent to students' through WhatsApp and E-mail. A total of 232 students provided complete information regarding the survey. The simple percentage distribution was used to assess the learning status of the study participants. During the lockdown period, around 70% of learners were involved in e-learning. Most of the learners were used android mobile for attending e-learning. Students have been facing various problems related to depression anxiety, poor internet connectivity, and unfavorable study environment at home. Students from remote areas and marginalized sections mainly face enormous challenges for the study during this pandemic. This study suggests targeted interventions to create a positive space for study among students from the vulnerable section of society. Strategies are urgently needed to build a resilient education system in the state that will ensure to develop the skill for employability and the productivity of the young minds.
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INTRODUCTION: After understanding the genetic basis of cardiovascular disorders, the discovery of prime editing (PE), has opened new horizons for finding their cures. PE strategy is the most versatile editing tool to change cardiac genetic background for therapeutic interventions. The optimization of elements, prediction of efficiency, and discovery of the involved genes regulating the process have not been completed. The large size of the cargo and multi-elementary structure makes the in vivo heart delivery challenging. AREAS COVERED: Updated from recent published studies, the fundamentals of the PEs, their application in cardiology, potentials, shortcomings, and the future perspectives for the treatment of cardiac-related genetic disorders will be discussed. EXPERT OPINION: The ideal PE for the heart should be tissue-specific, regulatable, less immunogenic, high transducing, and safe. However, low efficiency, sup-optimal PE architecture, the large size of required elements, the unclear role of transcriptomics on the process, unpredictable off-target effects, and its context-dependency are subjects that need to be considered. It is also of great importance to see how beneficial or detrimental cell cycle or epigenomic modifier is to bring changes into cardiac cells. The PE delivery is challenging due to the size, multi-component properties of the editors and liver sink.
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Cardiologia , Doenças Cardiovasculares , Sistema Cardiovascular , Cardiopatias , Humanos , CoraçãoRESUMO
As the most versatile and precise gene editing technology, prime editing (PE) can establish a durable cure for most human genetic disorders. Several generations of PE have been developed based on an editor machine or prime editing guide RNA (pegRNA) to achieve any kind of genetic correction. However, due to the early stage of development, PE complex elements need to be optimized for more efficient editing. Smart optimization of editor proteins as well as pegRNA has been contemplated by many researchers, but the universal PE machine's current shortcomings remain to be solved. The modification of PE elements, fine-tuning of the host genes, manipulation of epigenetics, and blockage of immune responses could be used to reach more efficient PE. Moreover, the host factors involved in the PE process, such as repair and innate immune system genes, have not been determined, and PE cell context dependency is still poorly understood. Regarding the large size of the PE elements, delivery is a significant challenge and the development of a universal viral or nonviral platform is still far from complete. PE versions with shortened variants of reverse transcriptase are still too large to fit in common viral vectors. Overall, PE faces challenges in optimization for efficiency, high context dependency during the cell cycling, and delivery due to the large size of elements. In addition, immune responses, unpredictability of outcomes, and off-target effects further limit its application, making it essential to address these issues for broader use in nonpersonalized gene editing. Besides, due to the limited number of suitable animal models and computational modeling, the prediction of the PE process remains challenging. In this review, the fundamentals of PE, including generations, potential, optimization, delivery, in vivo barriers, and the future landscape of the technology are discussed.
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The primary goal is to examine the association between women's decision-making autonomy and utilization of antenatal care services among ever-married women in India. The entire study has been accomplished with the help of secondary data composed from the latest round of the National Family Health Survey (NFHS-5) conducted during 2019-21. A total of 34,618 ever-married women aged 15-49 with at least one live birth preceding five years of the survey have been taken into consideration in this study. Bivariate and multivariate analyses were conducted for proper illustration of the outcome. A sizable proportion of women did not fulfill the WHO-recommended criterion of obtaining ANC services. Utilization of full ANC services is found in some regions of southern, eastern, northern, and northeastern states, and in some districts of Gujarat. After adjusting the other explanatory variables, the result of multivariate analysis indicates that women's autonomy is significantly and positively associated with the utilization of full antenatal care services. Women who participate actively in decision-making are more likely to use full ANC services (AOR: 1.316, 95% CI: 1.197-1.446, p<0.05). Additionally, likelihood of utilization of full ANC services is high among women aged 25-34 years, are educated, have access to the media, come from richest wealth quintile, and are from southern, western, and eastern regions. Therefore, appropriate measures should be adopted to eliminate gender bias and promote women's empowerment for the overall improvement of maternal health as well as societal health.
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Tomada de Decisões , Autonomia Pessoal , Cuidado Pré-Natal , Humanos , Feminino , Adulto , Cuidado Pré-Natal/estatística & dados numéricos , Índia , Adolescente , Gravidez , Pessoa de Meia-Idade , Adulto Jovem , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Fatores SocioeconômicosRESUMO
Evidence is emerging on the role of maternal diet, gut microbiota, and other lifestyle factors in establishing lifelong health and disease, which are determined by transgenerationally inherited epigenetic modifications. Understanding epigenetic mechanisms may help identify novel biomarkers for gestation-related exposure, burden, or disease risk. Such biomarkers are essential for developing tools for the early detection of risk factors and exposure levels. It is necessary to establish an exposure threshold due to nutrient deficiencies or other environmental factors that can result in clinically relevant epigenetic alterations that modulate disease risks in the fetus. This narrative review summarizes the latest updates on the roles of maternal nutrients (n-3 fatty acids, polyphenols, vitamins) and gut microbiota on the placental epigenome and its impacts on fetal brain development. This review unravels the potential roles of the functional epigenome for targeted intervention to ensure optimal fetal brain development and its performance in later life.
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Epigenoma , Desenvolvimento Fetal , Microbioma Gastrointestinal , Fenômenos Fisiológicos da Nutrição Materna , Placenta , Humanos , Gravidez , Feminino , Placenta/metabolismo , Epigênese Genética , Nutrientes , Polifenóis , Encéfalo/metabolismo , Encéfalo/embriologia , Dieta , Ácidos Graxos Ômega-3RESUMO
Chronic low-grade adipose tissue inflammation is associated with metabolic disorders. Inflammation results from the intertwined cross-talks of pro-inflammatory and anti-inflammatory pathways in the immune response of adipose tissue. In addition, adipose FABP4 levels and lipid droplet proteins are involved in systemic and tissue inflammation. Dysregulated adipocytes help infiltrate immune cells derived from bone marrow responsible for producing cytokines and chemokines. When adipose tissue expands in excess, adipocyte exhibits increased secretion of adipokines and is implicated in metabolic disturbances due to the release of free fatty acids. This review presents an emerging concept in adipose tissue fat metabolism, fatty acid handling and binding proteins, and lipid droplet proteins and their involvement in inflammatory disorders.
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Tecido Adiposo , Ácidos Graxos , Humanos , Ácidos Graxos/metabolismo , Adipócitos , Inflamação/metabolismo , Proteínas Associadas a Gotículas Lipídicas/metabolismoRESUMO
Changes in gene expression are involved in many brain functions. Epigenetic processes modulate gene expression by histone modification and DNA methylation or RNA-mediated processes, which is important for brain function. Consequently, epigenetic changes are also a part of brain diseases such as mental illness and addiction. Understanding the role of different factors on the brain epigenome may help us understand the function of the brain. This review discussed the effects of caffeine, lipids, addictive substances, physical activity, and pollutants on the epigenetic changes in the brain and their modulatory effects on brain function.
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Cafeína , Transtornos Relacionados ao Uso de Substâncias , Humanos , Micronutrientes , Epigênese Genética , Metilação de DNA , Transtornos Relacionados ao Uso de Substâncias/genética , Encéfalo , Exercício FísicoRESUMO
Despite scientific development, cancer is still a fatal disease. The development of cancer is thought to be significantly influenced by fatty acids. Several mechanisms that control fatty acid absorption and metabolism are reported to be altered in cancer cells to support their survival. Cancer cells can use de novo synthesis or uptake of extracellular fatty acid if one method is restricted. This factor makes it more difficult to target one pathway while failing to treat the disease properly. Side effects may also arise if several inhibitors simultaneously target many targets. If a viable inhibitor could work on several routes, the number of negative effects might be reduced. Comparative investigations against cell viability have found several potent natural and manmade substances. In this review, we discuss the complex roles that fatty acids play in the development of tumors and the progression of cancer, newly discovered and potentially effective natural and synthetic compounds that block the uptake and metabolism of fatty acids, the adverse side effects that can occur when multiple inhibitors are used to treat cancer, and emerging therapeutic approaches.
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Coronary heart disease (CHD) is the leading cause of death around the world. Based on the roles of vascular endothelial growth factor (VEGF) family members to regulate blood and lymphatic vessels and metabolic functions, several therapeutic approaches have been attempted during the last decade. However proangiogenic therapies based on classical VEGF-A have been disappointing. Therefore, it has become important to focus on other VEGFs such as VEGF-B, which is a novel member of the VEGF family. Recent studies have shown the very promising potential of the VEGF-B to treat CHD and heart failure. The aim of this review article is to present the role of VEGF-B in endothelial biology and as a potential therapeutic agent for CHD and heart failure. In addition, key differences between the VEGF-A and VEGF-B effects on endothelial functions are demonstrated.
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Doença das Coronárias , Insuficiência Cardíaca , Humanos , Fator A de Crescimento do Endotélio Vascular , Fator B de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular , Insuficiência Cardíaca/tratamento farmacológico , Doença das Coronárias/tratamento farmacológicoRESUMO
Cytoplasmic fatty acid-binding proteins (FABPs) are multipurpose proteins that can modulate lipid fluxes, trafficking, signaling, and metabolism. FABPs regulate metabolic and inflammatory pathways, its inhibition can improve type 2 diabetes mellitus and atherosclerosis. In addition, FABPs are involved in obesity, metabolic disease, cardiac dysfunction, and cancers. FABPs are promising tissue biomarkers in solid tumors for diagnostic and/or prognostic targets for novel therapeutic strategies. The signaling responsive elements of FABPs and determinants of FABP-mediated functions may be exploited in preventing or treating these diseases.
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Diabetes Mellitus Tipo 2 , Doenças Metabólicas , Neoplasias , Citosol/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Humanos , Doenças Metabólicas/metabolismo , Neoplasias/metabolismoRESUMO
Background: Previous studies have indicated that vascular endothelial growth factor B186 (VEGF-B186) supports coronary vascular growth in normal and ischemic myocardium. However, previous studies also indicated that induction of ventricular arrhythmias is a severe side effect preventing the use of VEGF-B186 in cardiac gene therapy, possibly mediated by binding to neuropilin 1 (NRP1). We have designed a novel VEGF-B186 variant, VEGF-B186R127S, which is resistant to proteolytic processing and unable to bind to NRP1. Here, we studied its effects on mouse heart to explore the mechanism of VEGF-B186-induced vascular growth along with its effects on cardiac performance. Methods: Following the characterization of VEGF-B186R127S, we performed ultrasound-guided adenoviral VEGF-B186R127S gene transfers into the murine heart. Vascular growth and heart functions were analyzed using immunohistochemistry, RT-PCR, electrocardiogram and ultrasound examinations. Endothelial progenitor cells (EPCs) were isolated from the circulating blood and characterized. Also, in vitro experiments were carried out in cardiac endothelial cells with adenoviral vectors. Results: The proteolytically resistant VEGF-B186R127S significantly induced vascular growth in mouse heart. Interestingly, VEGF-B186R127S gene transfer increased the number of circulating EPCs that secreted VEGF-A. Other proangiogenic factors were also present in plasma and heart tissue after the VEGF-B186R127S gene transfer. Importantly, VEGF-B186R127S gene transfer did not cause any side effects, such as arrhythmias. Conclusion: VEGF-B186R127S induces vascular growth in mouse heart by recruiting EPCs. VEGF-B186R127S is a novel therapeutic agent for cardiac therapeutic angiogenesis to rescue myocardial tissue after an ischemic insult.
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Cancer cells survive and grow despite various advanced anti-cancer therapy. To overcome this antineoplastic resistance, adjuvant therapy is often required to prevent cancer cells' immunoescape capacity. Established tumors build a stressful and hostile microenvironment in order to escape protective innate and adaptive immune responses. Specific conditions and factors within tumors, including hypoxia, nutrient starvation, acidic pH, and increased levels of free radicals, provoke a state of "endoplasmic reticulum stress" in both malignant cells and infiltrating myeloid cells. The stimulated endoplasmic reticulum stress can affect cancer progression via cross-talks with the innate immune system. Recently, the immunosuppressive activities of myeloid cells in the development of antineoplastic resistance are gaining more attention. Based on all these available data, we hypothesize that interruption of innate-immune recognition-mediated emergency myelopoiesis may be beneficial in halting cancer progression.
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Mielopoese , Neoplasias , Estresse do Retículo Endoplasmático , Humanos , Imunidade Inata , Células Mieloides , Microambiente TumoralRESUMO
The dysregulation of fat metabolism is involved in various disorders, including neurodegenerative, cardiovascular, and cancers. The uptake of long-chain fatty acids (LCFAs) with 14 or more carbons plays a pivotal role in cellular metabolic homeostasis. Therefore, the uptake and metabolism of LCFAs must constantly be in tune with the cellular, metabolic, and structural requirements of cells. Many metabolic diseases are thought to be driven by the abnormal flow of fatty acids either from the dietary origin and/or released from adipose stores. Cellular uptake and intracellular trafficking of fatty acids are facilitated ubiquitously with unique combinations of fatty acid transport proteins and cytoplasmic fatty acid-binding proteins in every tissue. Extensive data are emerging on the defective transporters and metabolism of LCFAs and their clinical implications. Uptake and metabolism of LCFAs are crucial for the brain's functional development and cardiovascular health and maintenance. In addition, data suggest fatty acid metabolic transporter can normalize activated inflammatory response by reprogramming lipid metabolism in cancers. Here we review the current understanding of how LCFAs and their proteins contribute to the pathophysiology of three crucial diseases and the mechanisms involved in the processes.
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Ácidos Graxos , Neoplasias , Transporte Biológico , Antígenos CD36/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Humanos , Metabolismo dos LipídeosRESUMO
During the last trimester of gestation and for the first 18 months after birth, both docosahexaenoic acid,22:6n-3 (DHA) and arachidonic acid,20:4n-6 (ARA) are preferentially deposited within the cerebral cortex at a rapid rate. Although the structural and functional roles of DHA in brain development are well investigated, similar roles of ARA are not well documented. The mode of action of these two fatty acids and their derivatives at different structural-functional roles and their levels in the gene expression and signaling pathways of the brain have been continuously emanating. In addition to DHA, the importance of ARA has been much discussed in recent years for fetal and postnatal brain development and the maternal supply of ARA and DHA. These fatty acids are also involved in various brain developmental processes; however, their mechanistic cross talks are not clearly known yet. This review describes the importance of ARA, in addition to DHA, in supporting the optimal brain development and growth and functional roles in the brain.
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Ácido Araquidônico/fisiologia , Encéfalo/crescimento & desenvolvimento , Ácidos Docosa-Hexaenoicos/fisiologia , Fenômenos Fisiológicos da Nutrição Materna , Animais , Ácido Araquidônico/deficiência , Encéfalo/embriologia , Encéfalo/metabolismo , Desenvolvimento Infantil , Ácidos Docosa-Hexaenoicos/deficiência , Feminino , Humanos , Lactente , Fenômenos Fisiológicos da Nutrição Materna/fisiologiaRESUMO
Atherosclerosis is a chronic inflammatory disease characterized by extensive remodeling of medium and large-sized arteries. Inward remodeling (=lumen shrinkage) of the vascular walls is the underlying cause for ischemia in target organs. Therefore, inward remodeling can be considered the predominant feature of atherosclerotic pathology. Outward remodeling (=lumen enlargement) is a physiological response compensating for lumen shrinkage caused by neointimal hyperplasia, but as a pathological response to changes in blood flow, outward remodeling leads to substantial arterial wall thinning. Thinned vascular walls are prone to rupture, and subsequent thrombus formation accounts for the majority of acute cardiovascular events. Pathological remodeling is driven by inflammatory cells which induce vascular smooth muscle cells to switch from quiescent to a proliferative and migratory phenotype. After decades of intensive research, the molecular mechanisms of arterial remodeling are starting to unfold. In this mini-review, we summarize the current knowledge of the epigenetic and transcriptional regulation of vascular smooth muscle cell phenotype switching from the contractile to the synthetic phenotype involved in arterial remodeling and discuss potential therapeutic options.