RESUMO
Although nanomaterials have shown promising biomedical application potential, incomplete understanding of their molecular interactions with biological systems prevents their inclusion into mainstream clinical applications. Here we show that black phosphorus (BP) nanomaterials directly affect the cell cycle's centrosome machinery. BP destabilizes mitotic centrosomes by attenuating the cohesion of pericentriolar material and consequently leads to centrosome fragmentation within mitosis. As a result, BP-treated cells exhibit multipolar spindles and mitotic delay, and ultimately undergo apoptosis. Mechanistically, BP compromises centrosome integrity by deactivating the centrosome kinase polo-like kinase 1 (PLK1). BP directly binds to PLK1, inducing its aggregation, decreasing its cytosolic mobility and eventually restricting its recruitment to centrosomes for activation. With this mechanism, BP nanomaterials show great anticancer potential in tumour xenografted mice. Together, our study reveals a molecular mechanism for the tumoricidal properties of BP and proposes a direction for biomedical application of nanomaterials by exploring their intrinsic bioactivities.
Assuntos
Proteínas de Ciclo Celular/genética , Centrossomo/efeitos dos fármacos , Nanoestruturas/química , Neoplasias/tratamento farmacológico , Fósforo/farmacologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Animais , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular/antagonistas & inibidores , Células HeLa , Xenoenxertos , Humanos , Camundongos , Mitose/efeitos dos fármacos , Neoplasias/genética , Neoplasias/patologia , Fósforo/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Quinase 1 Polo-LikeRESUMO
Although immuno-oncotherapy in clinic has gained great success, the immunosuppressive tumor microenvironment (TME) existing in the "cold" tumor with insufficient and exhausted lymphocytes may result in a lower-than-expected therapeutic efficiency. Therefore, a properly designed synergistic strategy that can effectively turn the "cold" tumor to "hot" should be considered to improve the therapeutic effects of immuno-oncotherapy. Herein, TME-responsive penetrating nanogels (NGs) were developed, which can improve the delivery and penetration of the co-loaded resiquimod (R848) and green tea catechin (EGCG) in tumors by a nano-sized controlled releasing system of the soluble cyclodextrin-drug inclusion complex. Consequently, the NGs effectively promoted the maturation of dendritic cells, stimulated the cytotoxic T lymphocytes (CTLs), and decreased the PD-L1 expression in tumors. The combination of NGs with the OX40 agonist (αOX40) further synergistically enhanced the activation and infiltration of CTLs into the deep tumor and inhibited the suppression effects from the regulatory T cells (Tregs). As a result, an increased ratio of active CTLs to Tregs in tumors (20.66-fold) was achieved with a 91.56% tumor suppression effect, indicating a successful switch of "cold" tumors to "hot" for an immunologically beneficial TME with significantly improved anti-tumor immune therapeutics. This strategy could be tailored to other immuno-oncotherapeutic approaches to solve the urgent efficiency concerns of the checkpoint-based treatment in clinic.
Assuntos
Antineoplásicos/uso terapêutico , Catequina/uso terapêutico , Portadores de Fármacos/química , Imidazóis/uso terapêutico , Nanogéis/química , Neoplasias/tratamento farmacológico , 2-Hidroxipropil-beta-Ciclodextrina/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antígeno B7-H1/metabolismo , Catequina/química , Catequina/farmacocinética , Linhagem Celular Tumoral , Células Dendríticas/efeitos dos fármacos , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Feminino , Ácido Hialurônico/análogos & derivados , Imidazóis/química , Imidazóis/farmacocinética , Imunomodulação , Camundongos Endogâmicos C57BL , Neoplasias/metabolismo , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacosRESUMO
The transcription factor NF-E2-related factor 2 (Nrf2) is a central regulator of cellular antioxidant and detoxification response. The association between Nrf2 activity and iron-related oxidative stress in neurodegenerative diseases has been studied, and Nrf2 was found to transcriptionally regulate the expression of iron transporters and ferroptosis-related factors. However, the role of Nrf2 in age-related motor dysfunction and its link to iron metabolism dysregulation in brain have not been fully elucidated. In this study, with different ages of Nrf2 knockout (KO) and wild type (WT) mice, we investigated the effects of Nrf2 deficiency on brain oxidative stress, iron metabolism and the motor coordination ability of mice. In contrast to the predicted neuroprotective role of Nrf2 in oxidative stress-related diseases, we found that Nrf2 KO remarkably improved the motor coordination of aged mice, which was associated with the reduced ROS level and decreased apoptosis of dopaminergic neurons in substantia nigra (SN) of 18-month-old Nrf2 KO mice. With high-iron and Parkinson's disease (PD) mouse models, we revealed that Nrf2 KO prevented the deposition of brain iron, particularly in SN and striatum, which may subsequently delay motor dysfunction in aged mice. The regulation of Nrf2 KO on brain iron metabolism was likely mediated by decreasing the ferroportin 1 (FPN1) level on brain microvascular endothelial cells, thus hindering the process of iron entry into the brain. Nrf2 may be a potential therapeutic target in age-related motor dysfunction diseases for its role in regulating brain iron homeostasis.
Assuntos
Envelhecimento , Células Endoteliais , Transtornos Motores , Fator 2 Relacionado a NF-E2 , Envelhecimento/genética , Animais , Células Endoteliais/metabolismo , Ferro , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Substância Negra/metabolismoRESUMO
The human insulin-like growth factor-II (IGF-II) gene transcribes four mRNAs (P1 mRNA-P4 mRNA), and P3 mRNA overexpression contributes to hepatocarcinogenesis. IGF-II-derived miR-483-5p is implicated in the development of cancers. Here, we investigated the involvement of miR-483-5p in P3 mRNA overexpression regulation and its role in hepatocellular carcinoma. Our results showed that miR-483-5p up-regulated P3 mRNA transcription by targeting the 5'-untranslated region (5'UTR) of P3 mRNA in hepatocellular carcinoma. The mechanism was involved in recruiting of an argonaute 1(Ago1)-argonaute 2 (Ago2) complex to the P3 mRNA 5'UTR and the P3 promoter of IGF-II gene by miR-483-5p, accompanied by increased enrichment of RNA polymerase II and activating histone marks histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 27 acetylation (H3K27ac), and histone 4 lysine 5/8/12/16 acetylation (H4Kac) at the P3 promoter. High miR-483-5p expression was an independent predictor for shorter survival of HCC patients. The findings suggest that miR-483-5p promotes P3 mRNA transcription by recruiting the Ago1-Ago2 complex to the P3 mRNA 5'UTR and is associated with poor prognosis of HCC. Our results display a potential new model for miRNAs to up-regulate gene expression.