RESUMEN
Human life expectancy has been significantly extended, which poses major challenges to our healthcare and social systems. Aging-associated cognitive impairment is attributed to endothelial dysfunction in the cardiovascular system and neurological dysfunction in the central nervous system. The central nervous system is considered an immune-privileged tissue due to the exquisite protection provided by the blood-brain barrier. The present review provides an overview of the structure and function of blood-brain barrier, extending the cell components of blood-brain barrier from endothelial cells and pericytes to astrocytes, perivascular macrophages and oligodendrocyte progenitor cells. In particular, the pathological changes in the blood-brain barrier in aging, with special focus on the underlying mechanisms and molecular changes, are presented. Furthermore, the potential preventive/therapeutic strategies against aging-associated blood-brain barrier disruption are discussed.
RESUMEN
The master DNA damage repair histone protein, H2AX, is essential for orchestrating the recruitment of downstream mediator and effector proteins at damaged chromatin. The phosphorylation of H2AX at S139, γH2AX, is well-studied for its DNA repair function. However, the extended C-terminal tail is not characterized. Here, we define the minimal motif on H2AX for the canonical function in activating the MDC1-RNF8-RNF168 phosphorylation-ubiquitination pathway that is important for recruiting repair proteins, such as 53BP1 and BRCA1. Interestingly, H2AX recruits 53BP1 independently from the MDC1-RNF8-RNF168 pathway through its evolved C-terminal linker region with S139 phosphorylation. Mechanistically, 53BP1 recruitment to damaged chromatin is mediated by the interaction between the H2AX C-terminal tail and the 53BP1 Oligomerization-Tudor domains. Moreover, γH2AX-linker mediated 53BP1 recruitment leads to camptothecin resistance in H2AX knockout cells. Overall, our study uncovers an evolved mechanism within the H2AX C-terminal tail for regulating DNA repair proteins at damaged chromatin.
Asunto(s)
Cromatina , Daño del ADN , Histonas , Proteína 1 de Unión al Supresor Tumoral P53 , Ubiquitinación , Humanos , Proteínas Adaptadoras Transductoras de Señales , Proteína BRCA1/metabolismo , Proteína BRCA1/genética , Camptotecina/farmacología , Proteínas de Ciclo Celular , Cromatina/metabolismo , Reparación del ADN , Células HEK293 , Histonas/metabolismo , Histonas/genética , Fosforilación , Proteína 1 de Unión al Supresor Tumoral P53/metabolismo , Proteína 1 de Unión al Supresor Tumoral P53/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
This research presents a new approach to facilely fabricating a multifunctional film using polyvinyl alcohol (PVA) as the base material. The film is modified chemically to incorporate various desirable properties such as high transparency, UV-shielding, antibacterial activity, and fluorescence. The fabrication process of this film is straightforward and efficient. The modified film showed exceptional UV-blocking capability, effectively blocking 100% of UV radiation. It also exhibits strong antibacterial properties. Additionally, the film emitted bright blue fluorescence, which can be useful in various optical and sensing applications. Despite the chemical modification, the film retained the excellent properties of PVA, including high transparency (90%) at 550 nm and good mechanical strength. Furthermore, it demonstrated remarkable stability even under harsh conditions such as exposure to long-term UV radiation, extreme temperatures (-40 or 120 °C), or immersion in different solvents. Overall, this work showcases a promising strategy to develop versatile, structurally stable, transparent, and flexible polymer films with multiple functionalities. These films have potential applications in various fields that require protection, such as packaging materials, biomedical devices, and optical components.