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We performed an integrative transcriptomic in silico analysis using lung adenocarcinoma A549 cells treated with the neddylation inhibitor MLN4924 and the gefitinib-resistant PC9 cell line (PC9GR). We focused on the transcriptional effects of the top differentially expressed ncRNA biotypes and their correlating stemness factors. Interestingly, MLN4924-treated cells showed a significant upregulation of mRNAs involved in carcinogenesis, cell attachment, and differentiation pathways, as well as a parallel downregulation of stemness maintenance and survival signaling pathways, an effect that was inversely observed in PC9GR cells. Moreover, we found that stemness factor expression could be contrasted by selected up-regulated ncRNAs upon MLN4924 treatment in a dose and time-independent manner. Furthermore, upregulated miRNAs and lncRNA-targeted mRNAs showed an evident enrichment of proliferation, differentiation, and apoptosis pathways, while downregulated ncRNA-targeted mRNAs were implicated in stem cell maintenance. Finally, our results proved that stemness (KLF4 and FGFR2) and epithelial-mesenchymal transition (ZEB2, TWIST2, SNAI2, CDH2, and VIM) factors, which are highly expressed in PC9GR cells compared to gefitinib-sensitive PC9 cells, could be abrogated with the neddylation inhibitor MLN4924 mainly through activation of epithelial differentiation pathways, thus exerting a protective role in lung cancer cells and chemosensitivity against lung tumorigenic transformation.
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RESUMEN Las redes de tráfico humano para la prostitución captan a menores vulnerables, en especial, a quienes consideran no les queda otra opción que emigrar al norte para hacer frente a problemas económicos graves. El objetivo del presente trabajo fue establecer si el orden de nacimiento representó un factor de riesgo, asociado a la vulnerabilidad para la trata sexual de menores centroamericanas, traficadas a Estados Unidos. Las entrevistadas mostraban vulnerabilidades vinculadas con estructuras sociales y conductas individuales. Por una parte, todas crecieron en hogares caracterizados por la pobreza extrema. Por otra parte, también presentaban vulnerabilidades relacionadas con el embarazo adolescente, la falta de educación, la disfuncionalidad familiar y la participación en mercados ilegales. Ocupar el primer lugar en orden de nacimiento eleva la vulnerabilidad de las menores a ser traficadas a Estados Unidos para el comercio sexual. Por el contrario, ocupar el último lugar disminuye este riesgo.
ABSTRACT Human trafficking networks for prostitution recruit vulnerable underage girls, especially those who are considered with no choice but to migrate north to cope with serious economic problems. The aim of this work was to determine if birth order represented a risk factor associated to the vulnerability for sex trafficking of Central American female minors. The interviewees presented vulnerabilities associated to social structures and individual behaviors. On the one hand, all of them grew up in house holds characterized by extreme poverty. On the other hand, they also had vulnerabilities related to teenage pregnancy, lack of education, family dysfunction and participation in illegal markets. Findings suggest that occupying the first place in the order of birth raises the vulnerability of minors to being trafficked to the United States for sex trade. On the contrary, occupying the last place decreases this risk.
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Fibrosis is a condition characterized by the excessive accumulation of extracellular matrix proteins in tissues, leading to organ dysfunction and failure. Recent studies have identified EP300, a histone acetyltransferase, as a crucial regulator of the epigenetic changes that contribute to fibrosis. In fact, EP300-mediated acetylation of histones alters global chromatin structure and gene expression, promoting the development and progression of fibrosis. Here, we review the role of EP300-mediated epigenetic regulation in multi-organ fibrosis and its potential as a therapeutic target. We discuss the preclinical evidence that suggests that EP300 inhibition can attenuate fibrosis-related molecular processes, including extracellular matrix deposition, inflammation, and epithelial-to-mesenchymal transition. We also highlight the contributions of small molecule inhibitors and gene therapy approaches targeting EP300 as novel therapies against fibrosis.
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Epigênese Genética , Histonas , Humanos , Fibrose , Histonas/metabolismo , Matriz Extracelular/metabolismo , Histona Acetiltransferases/metabolismo , Proteína p300 Associada a E1A/genética , Proteína p300 Associada a E1A/metabolismoRESUMO
Complex molecular mechanisms define our responses to environmental stimuli. Beyond the DNA sequence itself, epigenetic machinery orchestrates changes in gene expression induced by diet, physical activity, stress and pollution, among others. Importantly, nutrition has a strong impact on epigenetic players and, consequently, sustains a promising role in the regulation of cellular responses such as oxidative stress. As oxidative stress is a natural physiological process where the presence of reactive oxygen-derived species and nitrogen-derived species overcomes the uptake strategy of antioxidant defenses, it plays an essential role in epigenetic changes induced by environmental pollutants and culminates in signaling the disruption of redox control. In this review, we present an update on epigenetic mechanisms induced by environmental factors that lead to oxidative stress and potentially to pathogenesis and disease progression in humans. In addition, we introduce the microenvironment factors (physical contacts, nutrients, extracellular vesicle-mediated communication) that influence the epigenetic regulation of cellular responses. Understanding the mechanisms by which nutrients influence the epigenome, and thus global transcription, is crucial for future early diagnostic and therapeutic efforts in the field of environmental medicine.
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Environmental pollution nowadays has not only a direct correlation with human health changes but a direct social impact. Epidemiological studies have evidenced the increased damage to human health on a daily basis because of damage to the ecological niche. Rapid urban growth and industrialized societies importantly compromise air quality, which can be assessed by a notable accumulation of air pollutants in both the gas and the particle phases. Of them, particulate matter (PM) represents a highly complex mixture of organic and inorganic compounds of the most variable size, composition, and origin. PM being one of the most complex environmental pollutants, its accumulation also varies in a temporal and spatial manner, which challenges current analytical techniques used to investigate PM interactions. Nevertheless, the characterization of the chemical composition of PM is a reliable indicator of the composition of the atmosphere, the quality of breathed air in urbanized societies, industrial zones and consequently gives support for pertinent measures to avoid serious health damage. Epigenomic damage is one of the most promising biological mechanisms of air pollution-derived carcinogenesis. Therefore, this review aims to highlight the implication of PM exposure in diverse molecular mechanisms driving human diseases by altered epigenetic regulation. The presented findings in the context of pan-organic cancer, fibrosis, neurodegeneration and metabolic diseases may provide valuable insights into the toxicity effects of PM components at the epigenomic level and may serve as biomarkers of early detection for novel targeted therapies.
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Double-stranded RNA adenosine deaminase 1 (ADAR1) is significantly down-regulated in fibroblasts derived from Idiopathic Pulmonary Fibrosis (IPF) patients, and its overexpression restored levels of miRNA-21, PELI1, and SPRY2. There are two ADAR1 isoforms in humans, ADAR1-p110 and ADAR1-p150, generated by an alternative promoter. Let-7d is considered an essential microRNA in Pulmonary Fibrosis (PF). In silico analysis revealed COL3A1 and SMAD2, proteins involved in the development of IPF, as Let-7d targets. We analyzed the role of ADAR1-p110 and ADAR1-p150 isoforms in the regulation of Let-7d maturation and the effect of this regulation on the expression of COL3A1 and SMAD2 in IPF fibroblast. We demonstrated that differential expression and subcellular distribution of ADAR1 isoforms in fibroblasts contribute to the up-regulation of pri-miR-Let-7d and down-regulation of mature Let-7d. Induction of overexpression of ADAR1 reestablishes the expression of pri-miR-Let-7d and Let-7d in lung fibroblasts. The reduction of mature Let-7d upregulates the expression of COL3A1 and SMAD2. Thus, ADAR1 isoforms and Let-7d could have a synergistic role in IPF, which is a promising explanation in the mechanisms of fibrosis development, and the regulation of both molecules could be used as a therapeutic approach in IPF.
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Adenosina Desaminase , Fibrose Pulmonar Idiopática , MicroRNAs , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Pulmão/metabolismo , Proteínas de Membrana/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas de Ligação a RNARESUMO
Environmental factors, including pollutants and lifestyle, constitute a significant role in severe, chronic pathologies with an essential societal, economic burden. The measurement of all environmental exposures and assessing their correlation with effects on individual health is defined as the exposome, which interacts with our unique characteristics such as genetics, physiology, and epigenetics. Epigenetics investigates modifications in the expression of genes that do not depend on the underlying DNA sequence. Some studies have confirmed that environmental factors may promote disease in individuals or subsequent progeny through epigenetic alterations. Variations in the epigenetic machinery cause a spectrum of different disorders since these mechanisms are more sensitive to the environment than the genome, due to the inherent reversible nature of the epigenetic landscape. Several epigenetic mechanisms, including modifications in DNA (e.g., methylation), histones, and noncoding RNAs can change genome expression under the exogenous influence. Notably, the role of long noncoding RNAs in epigenetic processes has not been well explored in the context of exposome-induced tumorigenesis. In the present review, our scope is to provide relevant evidence indicating that epigenetic alterations mediate those detrimental effects caused by exposure to environmental toxicants, focusing mainly on a multi-step regulation by diverse noncoding RNAs subtypes.
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Epigênese Genética , Expossoma , Carcinogênese/genética , Metilação de DNA , Humanos , RNA não Traduzido/genéticaRESUMO
Resumen El comercio sexual de jóvenes, que son llevadas desde Centroamérica y México hacia Estados Unidos, ha sido ampliamente documentado, y sin embargo, sigue siendo un problema grave, del que se desconocen sus cambiantes dinámicas y estrategias de reclutamiento, ya sean voluntarias o forzadas. El objetivo de este trabajo fue examinar los mecanismos utilizados por las redes de traficantes para reclutar mujeres migrantes, para ser prostituidas en Nevada, Estados Unidos. Este trabajo está fundamentado en una metodología cualitativa, que incluye entrevistas a 3 reclutadores centroamericanos y 12 mujeres de México y Centroamérica. Los principales resultados encontrados indican que estas redes reclutan preferentemente a menores de edad, vulnerables, con un pasado relacionado con la prostitución y necesidades económicas apremiantes. Los mecanismos de reclutamiento utilizados por estas redes no se basan en el uso de la violencia, sino en el abuso de una situación de vulnerabilidad. En conclusión, el hecho de no recurrir a estrategias de reclutamiento violentas disminuye el riesgo de esta actividad, ya que las mujeres no les denuncian, porque no se consideran víctimas.
Abstract The international sex trade, involving young people who are taken from Central America and Mexico to the United States, has been widely documented. However, it remains a serious problem, from which its changing dynamics and recruitment strategies, whether voluntary or forced, are unknown. The objective of this paper was to examine the mechanisms used by sex smuggling networks to recruit migrant women to be prostituted in Nevada, USA. This research is based on a qualitative methodology that includes interviews with 3 Central American recruiters and 12 women from Mexico and Central America. The main results indicate that these networks recruit predominantly vulnerable underage girls with a past associated with prostitution and towering economic necessities. Recruitment mechanisms used by these networks are not based on the use of violence, but on the abuse of a position of vulnerability. In conclusion, not resorting to violent recruitment strategies reduces the risk of this activity, since women do not report them because they do not consider themselves victims.
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Neurodegenerative diseases are among the leading causes of disability and death worldwide. The disease-related socioeconomic burden is expected to increase with the steadily increasing life expectancy. In spite of decades of clinical and basic research, most strategies designed to manage degenerative brain diseases are palliative. This is not surprising as neurodegeneration progresses "silently" for decades before symptoms are noticed. Importantly, conceptual models with heuristic value used to study neurodegeneration have been constructed retrospectively, based on signs and symptoms already present in affected patients; a circumstance that may confound causes and consequences. Hence, innovative, paradigm-shifting views of the etiology of these diseases are necessary to enable their timely prevention and treatment. Here, we outline four alternative views, not mutually exclusive, on different etiological paths toward neurodegeneration. First, we propose neurodegeneration as being a secondary outcome of a primary cardiovascular cause with vascular pathology disrupting the vital homeostatic interactions between the vasculature and the brain, resulting in cognitive impairment, dementia, and cerebrovascular events such as stroke. Second, we suggest that the persistence of senescent cells in neuronal circuits may favor, together with systemic metabolic diseases, neurodegeneration to occur. Third, we argue that neurodegeneration may start in response to altered body and brain trophic interactions established via the hardwire that connects peripheral targets with central neuronal structures or by means of extracellular vesicle (EV)-mediated communication. Lastly, we elaborate on how lifespan body dysbiosis may be linked to the origin of neurodegeneration. We highlight the existence of bacterial products that modulate the gut-brain axis causing neuroinflammation and neuronal dysfunction. As a concluding section, we end by recommending research avenues to investigate these etiological paths in the future. We think that this requires an integrated, interdisciplinary conceptual research approach based on the investigation of the multimodal aspects of physiology and pathophysiology. It involves utilizing proper conceptual models, experimental animal units, and identifying currently unused opportunities derived from human data. Overall, the proposed etiological paths and experimental recommendations will be important guidelines for future cross-discipline research to overcome the translational roadblock and to develop causative treatments for neurodegenerative diseases.