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Extracellular vesicles (EVs) are produced, secreted, and targeted by most human cells, including cells that compose nervous system tissues. EVs carry several types of biomolecules, such as lipids, proteins and microRNA, and can function as signaling agents in physiological and pathological processes. In this chapter, we will focus on EVs and their cargo secreted by brain cells, especially neurons and glia, and how these aspects are affected in pathological conditions. The chapter covers neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, as well as several psychiatric disorders, namely schizophrenia, autism spectrum disorder and major depressive disorder. This chapter also addresses other types of neurological dysfunctions, epilepsy and traumatic brain injury. EVs can cross the blood brain barrier, and thus brain EVs may be detected in more accessible peripheral tissue, such as circulating blood. Alterations in EV composition and contents can therefore impart valuable clues into the molecular etiology of these disorders, and serve biomarkers regarding disease prevalence, progression and treatment. EVs can also be used to carry drugs and biomolecules into brain tissue, considered as a promising drug delivery agent for neurological diseases. Therefore, although this area of research is still in its early development, it offers great potential in further elucidating and in treating neurological disorders.
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Biomarcadores , Vesículas Extracelulares , Enfermedades Neurodegenerativas , Humanos , Vesículas Extracelulares/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Enfermedades Neurodegenerativas/terapia , Biomarcadores/metabolismo , Trastornos Mentales/metabolismo , Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/terapia , Animales , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/patologíaRESUMEN
Aim: Childhood maltreatment (CM) may affect not only directly exposed individuals but also their offspring. However, the underlying biological mechanisms remain unclear. microRNAs (miRNAs) may play a regulatory role in this process. This study investigates the relationship between maternal exposure to CM and miRNA expression in maternal and perinatal tissues.Methods: We enrolled 43 pregnant women and assessed their CM exposure. We collected maternal blood, cord blood and placental tissue samples during childbirth and performed miRNA profiling using next generation sequencing.Results: Maternal CM was inversely associated with hsa-miR-582-3p levels in cord blood. Pathway analysis revealed that this miRNA regulates genes involved in intrauterine development.Conclusion: Our findings highlight the potential impact of maternal CM exposure on offspring epigenetic mechanisms.
Child maltreatment (CM) includes physical, sexual and emotional abuse, as well as physical and emotional neglect. CM not only harms those directly exposed but can also negatively impact their offspring. However, the biological reasons behind this are not well understood. To explore this further, our study investigates how CM affects the biology of pregnant women and their newborns through changes in small regulatory molecules called microRNAs (miRNAs). We recruited 43 pregnant women and assessed their exposure to CM. During childbirth, we collected blood samples from the mothers, blood from the umbilical cord and placental samples. We then analyzed the levels of miRNAs in these samples using advanced sequencing technology. We observed that more severe maternal exposure to CM was associated with lower levels of a miRNA named hsa-miR-582-3p in umbilical cord blood. This miRNA regulates genes involved in fetal development in utero and has been linked to spontaneous preterm birth. It may also influence immunologic and stress-related processes. Thus, newborns of mothers who had been exposed to CM may be more vulnerable to adverse effects on their brain development and overall health. Despite our small sample size, our study highlights the importance of addressing CM as an intergenerational concern and provides new insights into the biological mechanisms through which maternal CM can affect offspring.
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Sangre Fetal , Exposición Materna , MicroARNs , Humanos , Femenino , Sangre Fetal/metabolismo , MicroARNs/genética , MicroARNs/sangre , Embarazo , Adulto , Exposición Materna/efectos adversos , Maltrato a los Niños , Placenta/metabolismo , Epigénesis Genética , NiñoRESUMEN
Traumatic brain injury (TBI) is a prevalent and debilitating condition, which often leads to the development of post-traumatic epilepsy (PTE), a condition that yet lacks preventive strategies. Biperiden, an anticholinergic drug, is a promising candidate that has shown efficacy in murine models of PTE. MicroRNAs (miRNAs), small regulatory RNAs, can help in understanding the biological basis of PTE and act as TBI- and PTE-relevant biomarkers that can be detected peripherally, as they are present in extracellular vesicles (EVs) that cross the blood-brain barrier. This study aimed to investigate miRNAs in serum EVs from patients with TBI, and their association with biperiden treatment and PTE. Blood samples of 37 TBI patients were collected 10 days after trauma and treatment initiation in a double-blind clinical trial. A total of 18 patients received biperiden, with three subjects developing PTE, and 19 received placebo, with two developing PTE. Serum EVs were characterized by size distribution and protein profiling, followed by high-throughput sequencing of the EV miRNome. Differential expression analysis revealed no significant differences in miRNA expression between TBI patients with and without PTE. Interestingly, miR-9-5p displayed decreased expression in biperiden-treated patients compared to the placebo group. This miRNA regulates genes enriched in stress response pathways, including axonogenesis and neuronal death, relevant to both PTE and TBI. These findings indicate that biperiden may alter miR-9-5p expression in serum EVs, which may play a role in TBI resolution.
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Lesiones Traumáticas del Encéfalo , Regulación hacia Abajo , Vesículas Extracelulares , MicroARNs , Humanos , MicroARNs/genética , MicroARNs/sangre , MicroARNs/metabolismo , Lesiones Traumáticas del Encéfalo/sangre , Lesiones Traumáticas del Encéfalo/genética , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Vesículas Extracelulares/metabolismo , Masculino , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Femenino , Adulto , Persona de Mediana Edad , Método Doble Ciego , Epilepsia Postraumática/sangre , Adulto JovenRESUMEN
The striking and complex phenotype of Cockayne syndrome (CS) patients combines progeria-like features with developmental deficits. Since the establishment of the in vitro culture of skin fibroblasts derived from patients with CS in the 1970s, significant progress has been made in the understanding of the genetic alterations associated with the disease and their impact on molecular, cellular, and organismal functions. In this review, we provide a historic perspective on the research into CS by revisiting seminal papers in this field. We highlighted the great contributions of several researchers in the last decades, ranging from the cloning and characterization of CS genes to the molecular dissection of their roles in DNA repair, transcription, redox processes and metabolism control. We also provide a detailed description of all pathological mutations in genes ERCC6 and ERCC8 reported to date and their impact on CS-related proteins. Finally, we review the contributions (and limitations) of many genetic animal models to the study of CS and how cutting-edge technologies, such as cell reprogramming and state-of-the-art genome editing, are helping us to address unanswered questions.
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Most of the studies on air pollution focus on emissions from fossil fuel burning in urban centers. However, approximately half of the world's population is exposed to air pollution caused by biomass burning emissions. In the Brazilian Amazon population, over 10 million people are directly exposed to high levels of pollutants resulting from deforestation and agricultural fires. This work is the first study to present an integrated view of the effects of inhalable particles present in emissions of biomass burning. Exposing human lung cells to particulate matter smaller than 10 µm (PM10), significantly increased the level of reactive oxygen species (ROS), inflammatory cytokines, autophagy, and DNA damage. Continued PM10 exposure activated apoptosis and necrosis. Interestingly, retene, a polycyclic aromatic hydrocarbon present in PM10, is a potential compound for the effects of PM10, causing DNA damage and cell death. The PM10 concentrations observed during Amazon biomass burning were sufficient to induce severe adverse effects in human lung cells. Our study provides new data that will help elucidate the mechanism of PM10-mediated lung cancer development. In addition, the results of this study support the establishment of new guidelines for human health protection in regions strongly impacted by biomass burning.
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Contaminantes Atmosféricos/toxicidad , Contaminación del Aire , Muerte Celular , Daño del ADN , Células Epiteliales/efectos de los fármacos , Exposición por Inhalación , Pulmón/efectos de los fármacos , Células A549 , Agricultura/métodos , Brasil , Conservación de los Recursos Naturales , Células Epiteliales/patología , Humanos , Pulmón/patología , Modelos BiológicosRESUMEN
Cancer is a leading cause of death worldwide, and while great advances have been made particularly in chemotherapy, many types of cancer still present a dismal prognosis. In the case of glioma, temozolomide (TMZ) is the main option for treatment, but it has limited success due to drug resistance. While this resistance is usually associated to DNA repair mechanisms, in this work we demonstrate that oxidative stress plays an important role. We showed that upon TMZ treatment there is an induction of the nuclear factor erythroid 2-related factor 2 (NRF2), which is the main antioxidant transcription factor regulator in human cells. This is accompanied by an enhancement of glutathione (GSH) concentration in the tumor cells. The effectiveness of this pathway was proven by silencing NFR2, which greatly enhanced cell death upon TMZ treatment both in vitro and in vivo. Also, higher DNA damage and induced cell death was observed by combining BSO - a GSH inhibitor - with TMZ. Similar effects were also observed using in vitro and in vivo models of melanoma, thus possibly indicating that GSH has a decisive role in TMZ resistance in a wider range of tumors. Thus, a combined regimen of BSO and TMZ configures an interesting therapeutic alternative for fighting both glioma and melanoma.