RESUMO
Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment. ESI1 promotes remyelination in animal models of demyelination and enables de novo myelinogenesis on regenerated CNS axons. ESI1 treatment lengthened myelin sheaths in human iPSC-derived organoids and augmented (re)myelination in aged mice while reversing age-related cognitive decline. Multi-omics revealed that ESI1 induces an active chromatin landscape that activates myelinogenic pathways and reprograms metabolism. Notably, ESI1 triggered nuclear condensate formation of master lipid-metabolic regulators SREBP1/2, concentrating transcriptional co-activators to drive lipid/cholesterol biosynthesis. Our study highlights the potential of targeting epigenetic silencing to enable CNS myelin regeneration in demyelinating diseases and aging.
Assuntos
Epigênese Genética , Bainha de Mielina , Oligodendroglia , Remielinização , Animais , Bainha de Mielina/metabolismo , Humanos , Camundongos , Remielinização/efeitos dos fármacos , Oligodendroglia/metabolismo , Sistema Nervoso Central/metabolismo , Camundongos Endogâmicos C57BL , Rejuvenescimento , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Organoides/metabolismo , Organoides/efeitos dos fármacos , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/genética , Diferenciação Celular/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Masculino , Regeneração/efeitos dos fármacos , Esclerose Múltipla/metabolismo , Esclerose Múltipla/genética , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologiaRESUMO
Oligodendrocyte myelination and remyelination after injury are intricately regulated by various intrinsic and extrinsic factors, including transcriptional regulators. Among these, the zinc-finger protein ZFP488 is an oligodendrocyte-enriched transcriptional regulator that promotes oligodendrocyte differentiation in the developing neural tube and in oligodendroglial cell lines. However, the specific in vivo genetic requirements for ZFP488 during oligodendrocyte development and remyelination have not been defined. To address this gap, we generated a lineage-traceable ZFP488 knock-out mouse line, wherein a H2b-GFP reporter replaces the ZFP488-coding region. Using these mice of either sex, we examined the dynamics of ZFP488 expression from the endogenous promoter in the developing central nervous system (CNS). We observed a unique expression pattern in the oligodendrocyte lineage, with ZFP488 expression particularly enriched in differentiated oligodendrocytes. ZFP488 loss resulted in delayed myelination in the developing CNS and impaired remyelination after demyelinating injury in the brain. Integrated transcriptomic and genomic profiling further revealed that ZFP488 loss decreased expression of myelination-associated genes but not oligodendrocyte progenitor-associated genes, suggesting that ZFP488 serves as a positive regulator of myelination by regulating maturation programs. Thus, our genetic loss-of-function study revealed that ZFP488 regulates a stage-dependent differentiation program that controls the timing of CNS myelination and remyelination.Significance statement Precise timing of myelination is essential for efficient neural communication and is linked to the development of cognitive and motor skills as well as myelin repair after injury. ZFP488 is a transcriptional regulator enriched in oligodendrocytes, however its in vivo functions remain unclear. By generating ZFP488 loss-of-function mice, we demonstrated that ZFP488 is critical for the timing of myelination and remyelination and that its loss impaired the initial differentiation of oligodendrocytes but not their precursor formation and proliferation. Transcriptomic profiling showed that ZFP488 functions as a positive regulator of myelination by modulating oligodendrocyte maturation programs. Thus, our findings underscore the important role of ZFP488 in myelination and the potential of ZFP488 augmentation as an avenue to enhance oligodendrocyte regeneration.
RESUMO
Oligodendrocyte differentiation and myelination in the central nervous system are controlled and coordinated by a complex gene regulatory network that contains several transcription factors, including Zfp488 and Nkx2.2. Despite the proven role in oligodendrocyte differentiation little is known about the exact mode of Zfp488 and Nkx2.2 action, including their target genes. Here, we used overexpression of Zfp488 and Nkx2.2 in differentiating CG4 cells to identify aspects of the oligodendroglial expression profile that depend on these transcription factors. Although both transcription factors are primarily described as repressors, the detected changes argue for an additional function as activators. Among the genes activated by both Zfp488 and Nkx2.2 was the G protein-coupled receptor Gpr37 that is important during myelination. In agreement with a positive effect on Gpr37 expression, downregulation of the G protein-coupled receptor was observed in Zfp488- and in Nkx2.2-deficient oligodendrocytes in the mouse. We also identified several potential regulatory regions of the Gpr37 gene. Although Zfp488 and Nkx2.2 both bind to one of the regulatory regions downstream of the Gpr37 gene in vivo, none of the regulatory regions was activated by either transcription factor alone. Increased activation by Zfp488 or Nkx2.2 was only observed in the presence of Sox10, a transcription factor continuously present in oligodendroglial cells. Our results argue that both Zfp488 and Nkx2.2 also act as transcriptional activators during oligodendrocyte differentiation and cooperate with Sox10 to allow the expression of Gpr37 as a modulator of the myelination process.
Assuntos
Diferenciação Celular , Proteína Homeobox Nkx-2.2 , Proteínas de Homeodomínio , Oligodendroglia , Receptores Acoplados a Proteínas G , Fatores de Transcrição SOXE , Fatores de Transcrição , Animais , Feminino , Masculino , Camundongos , Diferenciação Celular/fisiologia , Proteínas de Homeodomínio/metabolismo , Proteínas de Homeodomínio/genética , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Fatores de Transcrição SOXE/metabolismo , Fatores de Transcrição SOXE/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genéticaRESUMO
The hypoimmunogenicity of tumors is one of the main bottlenecks of cancer immunotherapy. Enhancing tumor immunogenicity can improve the efficacy of tumor immunotherapy by increasing antigen exposure and presentation, and establishing an inflammatory microenvironment. Here, a multifunctional antigen trapping nanoparticle with indocyanine green (ICG), aluminum hydroxide (Al(OH)3) and oxaliplatin (OXA) (PPIAO) has been developed for tumor photoacoustic/ultrasound dual-modality imaging and therapy. The combination of photothermal/photodynamic therapy and chemotherapy induced tumor antigen exposure and release through immunogenic death of tumor cells. A timely capture and storage of antigens by aluminum hydroxide enabled dendritic cells to recognize and present those antigens spatiotemporally. In an ovarian tumor model, the photoacoustic-mediated PPIAO NPs combination therapy achieved a transition from "cold tumor" to "hot tumor" that promoted more CD8+ T lymphocytes activation in vivo and intratumoral infiltration, and successfully inhibited the growth of primary and metastatic tumors. An in situ tumor vaccine effect was produced from the treated tumor tissue, assisting mice against the recurrence of tumor cells. This study provided a simple and effective personalized tumor vaccine strategy for better treatment of metastatic and recurrent tumors. The developed multifunctional tumor antigen trapping nanoparticles may be a promising nanoplatform for integrating multimodal imaging monitoring, tumor treatment, and tumor vaccine immunotherapy.
Assuntos
Vacinas Anticâncer , Nanopartículas , Neoplasias Ovarianas , Humanos , Feminino , Camundongos , Animais , Fototerapia/métodos , Nanopartículas/uso terapêutico , Hidróxido de Alumínio , Linhagem Celular Tumoral , Verde de Indocianina , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/tratamento farmacológico , Imunoterapia , Antígenos de Neoplasias , Microambiente TumoralRESUMO
In evolutionary dynamics, the population structure and multiplayer interactions significantly impact the evolution of cooperation levels. Previous works mainly focus on the theoretical analysis of multiplayer games on regular networks or pairwise games on complex networks. Combining these two factors, complex networks and multiplayer games, we obtain the fixation probability and fixation time of the evolutionary public goods game in a structured population represented by a signed network. We devise a stochastic framework for estimating fixation probability with weak mistrust or strong mistrust mechanisms and develop a deterministic replicator equation to predict the expected density of cooperators when the system evolves to the equilibrium on a signed network. Specifically, the most interesting result is that negative edges diversify the cooperation steady state, evolving in three different patterns of fixed probability in Erdös-Rényi signed and Watts-Strogatz signed networks with the new "strong mistrust" mechanism.
Assuntos
Evolução Biológica , Teoria dos Jogos , Comportamento Cooperativo , Dinâmica Populacional , ProbabilidadeRESUMO
The development of productive and durable non-precious metal catalysts for the sluggish oxygen evolution reaction (OER) is critical for water splitting. Herein, a novel NiSe-FeOx heterojunction encapsulated in lignin-derived carbon layer (NiSe-FeOx@LC) was synthesized via hydrothermal self-assembly and in-situ pyrolysis. NiSe-FeOx@LC exhibited excellent OER performance with an overpotential of 265 mV at 50 mA·cm-2, a Tafel slope of 83 mV·dec-1, as well as long-term stability. Both experimental and DFT calculation results indicated that the doping of FeOx into NiSe@LC successfully optimized the dual interface structure between NiSe and FeOx, thereby promoted the d-bands orbital hybridization, that facilitated electron transfer. Besides, the carbon coating effectively protected the NiSe-FeOx components from leaching and agglomerating during the reaction. This study provides insight into the significance of lignin-derived carbon-encapsulated metallic catalyst for electrocatalytic OER process.
Assuntos
Lignina , Oxigênio , Oxigênio/química , Catálise , Lignina/química , Compostos Férricos/química , Técnicas Eletroquímicas , Carbono/química , OxirreduçãoRESUMO
Biomolecular condensates, the membraneless cellular compartments formed by liquid-liquid phase separation (LLPS), represent an important mechanism for physiological and tumorigenic processes. Recent studies have advanced our understanding of how these condensates formed in the cytoplasm or nucleus regulate Hippo signaling, a central player in organogenesis and tumorigenesis. Here, we review recent findings on the dynamic formation and function of biomolecular condensates in regulating the Hippo-yes-associated protein (YAP)/transcription coactivator with PDZ-binding motif (TAZ) signaling pathway under physiological and pathological processes. We further discuss how the nuclear condensates of YAP- or TAZ-fusion oncoproteins compartmentalize crucial transcriptional co-activators and alter chromatin architecture to promote oncogenic programs. Finally, we highlight key questions regarding how these findings may pave the way for novel therapeutics to target cancer.
Assuntos
Via de Sinalização Hippo , Neoplasias , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Fatores de Transcrição , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/química , Animais , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas de Sinalização YAP/metabolismo , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional/metabolismoRESUMO
Cervical carcinoma is the fourth most common gynecological cancer. Here we reported the synthesis of oxygen-carried and lipopolysaccharide (LPS)/ indocyanine green (ICG)-loaded nanoparticles (OLI_NPs) for photo-sonodynamic therapy (PSDT) mediated combination therapy to induce systemic antitumor immune responses. We effectively built a new nanoparticle system, a multifunctional nanoagent that integrated the ability of dual-model imaging and therapy for tumors. In this study, we confirmed that OLI_NPs can act as a multifunctional platform that enables not only to diagnose tumors conveniently but also to efficiently provide treatment of in situ tumors, permitting simultaneous dual-mode imaging and localization of the therapy in combination with PSDT-mediated drug release. Furthermore, our combined strategy could effectively depress the tumor development and extend mouse life by the combination of inducing immunogenic cell death (ICD) with encapsulated LPS. In conclusion, combining therapy of OLI_NPs plus PSDT can induce anti-tumor immune responses and tumor antigen-specific immunity in a common TC-1 graft tumor model. Therefore, this combination therapy is a viable technique for cervical cancer treatment.
Assuntos
Nanopartículas , Neoplasias do Colo do Útero , Humanos , Feminino , Animais , Camundongos , Neoplasias do Colo do Útero/terapia , Modelos Animais de Doenças , Lipopolissacarídeos/farmacologia , Linhagem Celular Tumoral , Verde de Indocianina/farmacologia , ImunidadeRESUMO
PURPOSE: Tumor metastasis and drug resistance have always been vital aspects to cancer mortality and prognosis. To compromise metastasis and drug resistance, a nanoparticle IPPD-PHF2 (IR780/PLGA-PEI(Dox)-PHF2) has been engineered to accomplish efficient targeted epigenotherapy forced by PHF2-induced MET (mesenchymal to epithelial transition). MATERIALS AND METHODS: IPPD-PHF2 nanoparticle was synthesized and characterized by several analytical techniques. The transfection efficiency of IPP-PHF2 (IR780/PLGA-PEI-PHF2) was compared with PP-PHF2 (PLGA-PEI-PHF2) in vitro by WB and in vivo by IHC, and the cytotoxicity of IPP was compared with Lipo2000 in vitro by CCK8 assay. The inhibition of cancer cell migration caused by PHF2-upregulation was tested by wound healing assay, and the enhanced chemotherapeutic sensitivity was detected by flow cytometry. Tumor-targeting property of IPPD-PHF2 was proved by fluorescent imaging in vivo with MDA-MB-231 tumor-bearing nude mice. Except for fluorescent imaging ability, considerable photoacoustic signals of IPPD-PHF2 at tumor sites were verified. The anti-tumor activity of IPPD-PHF2 was investigated using in vivo human breast cancer MDA-MB-231 cell models. RESULTS: Tumor-targeting nanoparticle IPPD-PHF2 had an average size of about 319.2 nm, a stable zeta potential at about 38 mV. The encapsulation efficiency of doxorubicin was around 39.28%, and the adsorption capacity of plasmids was about 64.804 µg/mg. Significant up-regulation of PHF2 induced MET and caused reduced migration as well as enhanced chemotherapeutic sensitivity. Either IPPD (IR780/PLGA-PEI(Dox)) or IPP-PHF2 (IR780/PLGA-PEI-PHF2) presented minor therapeutic effects, whereas IPPD-PHF2 specifically accumulated within tumors, showed extraordinary transfection efficiency specifically in tumor sites, acted as inhibitors of metastasis and proliferation, and presented good multimodality imaging potentials in vivo. CONCLUSION: IPPD-PHF2 NPs is a promising tool to bring epigenotherapy into a more practical era, and the potential application of harm-free multimodality imaging guidance is of great value.
Assuntos
Antineoplásicos/uso terapêutico , Epigênese Genética , Nanopartículas/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Transfecção , Animais , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Feminino , Proteínas de Homeodomínio/metabolismo , Humanos , Indóis/química , Camundongos Nus , Nanopartículas/ultraestrutura , Metástase Neoplásica , Técnicas Fotoacústicas , Polietilenoimina/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/químicaRESUMO
High-intensity focused ultrasound (HIFU) is a representative non-invasive method of cancer therapy, but its low therapeutic efficacy and risk of damage to surrounding normal tissue hinder its further clinical development and application. Sonodynamic therapy (SDT) kills tumor cells through reactive oxygen molecules produced by sonosensitizers during ultrasound treatment. SDT can enhance HIFU efficacy like microbubbles. In this work, we developed nanoscale N2O microbubbles (N2O-mbs) by an improved mechanical oscillation method. These microbubbles showed good biocompatibility and tumor cell binding. The sonosensitivity of the N2O-mbs was detected both extracellularly and intracellularly through the detection of reactive oxygen species generation. The toxic effects of these sonodynamic microbubbles on tumor cells and the synergistic effect on HIFU treatment were evaluated. Significant apoptosis was caused by reactive oxygen species produced by N2O-mbs under ultrasound irradiation. N2O-mbs combined with HIFU increased tumor cell necrosis and apoptosis in vitro and the coagulative necrotic volume and echo intensity in the bovine liver target area ex vivo. These sonodynamic microbubbles have been also demonstrated to efficiently inhibit tumor growth in vivo. N2O-mbs have a significant impact on the treatment and ablation effect of HIFU due to the advantages of microbubble and extraordinary sonosensitivity. This finding suggests that N2O-mbs may be a novel auxiliary agent for ultrasound that can be used to promote HIFU tumor thermal ablation.