RESUMO
Tumor microenvironment (TME) plays an important role in tumor progression, metastasis and therapy resistance. Remodeling the TME has recently been deemed an attractive tumor therapeutic strategy. Due to its complexity and heterogeneity, remodeling the TME still faces great challenges. With the great advantage of drug loading ability, tumor accumulation, multifactor controllability, and persistent guest molecule release ability, mesoporous nanodrug delivery systems (MNDDSs) have been widely used as effective antitumor drug delivery tools as well as remolding TME. This review summarizes the components and characteristics of the TME, as well as the crosstalk between the TME and cancer cells and focuses on the important role of drug delivery strategies based on MNDDSs in targeted remodeling TME metabolic and synergistic anticancer therapy.
Assuntos
Antineoplásicos , Nanopartículas , Neoplasias , Humanos , Microambiente Tumoral , Nanopartículas/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias/patologia , Sistemas de Liberação de MedicamentosRESUMO
Generation of induced pluripotent stem cells typically requires the ectopic expression of transcription factors to reactivate the pluripotency network. However, it remains largely unclear what remodeling events on endogenous chromatin trigger reprogramming toward induced pluripotent stem cells (iPSCs). Toward this end, we employed CRISPR activation to precisely target and remodel endogenous gene loci of Oct4 and Sox2. Interestingly, we found that single-locus targeting of Sox2 was sufficient to remodel and activate Sox2, which was followed by the induction of other pluripotent genes and establishment of the pluripotency network. Simultaneous remodeling of the Oct4 promoter and enhancer also triggered reprogramming. Authentic pluripotent cell lines were established in both cases. Finally, we showed that targeted manipulation of histone acetylation at the Oct4 gene locus could also initiate reprogramming. Our study generated authentic iPSCs with CRISPR activation through precise epigenetic remodeling of endogenous loci and shed light on how targeted chromatin remodeling triggers pluripotency induction.
Assuntos
Montagem e Desmontagem da Cromatina/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Loci Gênicos , Células-Tronco Pluripotentes Induzidas/metabolismo , Fator 3 de Transcrição de Octâmero/genética , Fatores de Transcrição SOXB1/genética , Animais , Reprogramação Celular , Elementos Facilitadores Genéticos/genética , Fibroblastos/metabolismo , Células HEK293 , Humanos , Camundongos , Fator 3 de Transcrição de Octâmero/metabolismo , Regiões Promotoras Genéticas , Fatores de Transcrição SOXB1/metabolismoRESUMO
Bone, acting as the main load-bearing organ in human body, is of mechanical adaptability. It is prevalent but perilous that under fatigue loading, bone suffers from fatigue damage characterized as the initiation, propagation of micro-cracks, deterioration of bone mechanical properties or even stress fracture, which is commonly seen in long distance running of athletes, fitness training of military recruits and daily activities of the elderly. Bone fatigue damages exist in multi-levels of ultra-micro structure, microstructure and macrostructure. The anti-fatigue units in cortical bone (osteons) and cellular components (osteocytes) inside have been proved to play important roles in fatigue damage prevention, micro-cracks recognition and bone-targeted remodeling activation. Therefore, a general review and summing-up of relative research findings can help to provide a systematic understanding of fatigue behavior and corresponding repair process, and to give some useful references and insights for subsequent clinical researches aiming at prevention and treatment for bone fatigue damage.
RESUMO
Bone growth, development and maintenance, which become multidisciplinary with the rapid development of biomechanics, tissue engineering and cell biology, are intimately linked with bone remodeling. Mechanobiology has become an important method to study bone remodeling. This article summarizes related skeletal mechanobiology researches in recent years to provide theoretical basis for bone remodeling, bone tissue engineering and clinical treatments of related orthopedic disorders.