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1.
J Clin Invest ; 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38781024

RESUMO

PTEN inactivation is prevalent in human prostate cancer and causes high-grade adenocarcinoma with a long latency. Cancer associated fibroblasts (CAFs) play a pivotal role in tumor progression, but it remains elusive whether and how PTEN-deficient prostate cancers reprogram CAFs to overcome the barriers for tumor progression. Herein, we report that PTEN deficiency induces KLF5 acetylation; and interruption of KLF5 acetylation orchestrates intricate interactions between cancer cells and CAFs that enhance FGFR1 signaling and promote tumor growth. Deacetylated KLF5 promotes tumor cells to secrete TNF-α, which stimulates inflammatory CAFs to release FGF9. CX3CR1 inhibition blocks FGFR1 activation triggered by FGF9 and sensitizes PTEN-deficient prostate cancer to AKT inhibitor capivasertib. This study reveals the role of KLF5 acetylation in reprogramming CAFs and provides a rational for combined therapies using inhibitors of AKT and CX3CR1.

2.
Carbohydr Polym ; 331: 121893, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38388065

RESUMO

The detection of pH and glutathione (GSH) is positively significant for the cell microenvironment imaging. Here, to assess the pH value and the concentration of GSH efficiently and visually, a cellulose-based multi-bands ratiometric fluorescence probe was designed by assembling MnO2-modified cellulose gold nanoclusters, fluorescein isothiocyanate-grafted cellulose nanocrystals (CNCs) and protoporphyrin IX-modified CNCs. The probe exhibits GSH-responsive, pH-sensitive and GSH/pH-independent fluorescent properties at 440 nm, 520 nm, and 633 nm, respectively. Furthermore, the probe identifies GSH within 4 s by degrading MnO2 into Mn2+ in response to GSH. Ingeniously, the green fluorescence of the probe at 520 nm was decreased with pH, and the red fluorescence at 633 nm remained stable. Therefore, the probe displayed distinguishing fluorescence colors from pink to blue and from green to blue for the synchronous detection of pH and GSH concentration within 4 s. The design strategy provides insights to construct multi-bands fluorescence probes for the rapid detection of multiple target analytes.


Assuntos
Corantes Fluorescentes , Compostos de Manganês , Corantes Fluorescentes/química , Fluorescência , Compostos de Manganês/química , Óxidos/química , Espectrometria de Fluorescência , Glutationa , Concentração de Íons de Hidrogênio , Celulose
3.
Int Immunopharmacol ; 128: 111528, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38241845

RESUMO

With the improvement of global dietary conditions, non-alcoholic fatty liver disease (NAFLD) has gradually become prevalent. As the number of NAFLD patients increases, the coexistence of diseases associated with it has come into focus. In this study, based on immune phenotypes, intercellular communication activities, and clinical manifestations of NAFLD patients, IL1RN was identified as a central pro-inflammatory factor. Subsequently, potential downstream biological pathways of IL1RN in liver tissues and various cell types were enriched to describe its functions. Transcription factors Nfkb1, Jun, and Sp1, significantly associated with these functions, were also enriched. Functional studies of IL1RN suggest its potential to trigger autoimmune diseases. Given this, Mendelian randomization analysis was used to explore the causal relationship between NAFLD and various autoimmune diseases, with IL1RN considered as an intermediary introduced into Mendelian randomization studies. The results indicate that IL1RN and its partially related proteins play a certain mediating role in the process of NAFLD inducing rheumatoid arthritis (RA). Finally, additional research results suggest that intrahepatic ALT levels may influence IL1RN levels, possibly through amino acid metabolism.


Assuntos
Artrite Reumatoide , Doenças Autoimunes , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Artrite Reumatoide/genética , Fenótipo , Estudo de Associação Genômica Ampla , Proteína Antagonista do Receptor de Interleucina 1/genética
4.
Small ; 20(13): e2307770, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37963831

RESUMO

Understanding the gold core-ligand interaction in gold nanoclusters (GNCs) is essential for the on-demand tailoring of their photoluminescence properties and long-term stability. Here, inspired by the suckers arranged directionally on the tentacles of octopus, a series of GNCs with regulating ligand structures are grown and stabilized on the cellulose nanocrystals (CNCs). The carboxylated CNCs providing an electron-rich environment to promote the luminescence of GNCs and stabilize it within a long-term of 1 year through anchoring and diluting effects, and the highest quantum yields reaches 31.02% in ultrapure water. Interestingly, this bionic preparation strategy is generally applicable to various ligands for tailoring on-demand hROS-responsive and nonresponsive GNCs to construct tunable-emission wavelength dual GNCs ratiometric probes. The results show that designing a specific ligand structure to inhibit the transformation of Au-Au to Au (I)-ligand in GNCs is crucial to regulate the hROS-responsive characteristics. As expected, the interfacial compatible dual GNCs ratiometric probe with a hROS limit of detection of 0.74 µmol L-1 can diagnose certain diseases through intracellular hROS imaging. This work provides important insights for understanding the gold core-ligand interaction in GNCs during the oxidation process triggered by intracellular hROS.


Assuntos
Ouro , Nanopartículas Metálicas , Ouro/química , Ligantes , Luminescência , Diagnóstico por Imagem , Nanopartículas Metálicas/química
5.
J Colloid Interface Sci ; 659: 127-138, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38159489

RESUMO

The progressive presentation of multilevel information enhances the security level of information storage and transmission. Here, a time-multiplexed self-erasing nanopaper was developed by integrating cellulose nanofiber (CNF)-stabilized gold nanoclusters and CNF-modified long afterglow materials. The orange fluorescence of gold nanoclusters on nanopaper was regulated by the reversible swelling and shrinking of CNF induced by water solution, while the cyan fluorescence of micron-long afterglow remained stable and acted as the background signal. It was noteworthy that the fluorescence colour and intensity of the nanopaper could be freely adjusted between orange and cyan on the time scale. Therefore, the array information on the nanopaper could be encoded by a water solution, iterated variation as the step-by-step solvent volatilized on the time scale measured by the time of the afterglow duration. This work provides a new approach for constructing time-multiplexed self-erasing nanopaper for confidential information storage and transmission.

6.
Nature ; 623(7989): 1034-1043, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37993715

RESUMO

Diet-derived nutrients are inextricably linked to human physiology by providing energy and biosynthetic building blocks and by functioning as regulatory molecules. However, the mechanisms by which circulating nutrients in the human body influence specific physiological processes remain largely unknown. Here we use a blood nutrient compound library-based screening approach to demonstrate that dietary trans-vaccenic acid (TVA) directly promotes effector CD8+ T cell function and anti-tumour immunity in vivo. TVA is the predominant form of trans-fatty acids enriched in human milk, but the human body cannot produce TVA endogenously1. Circulating TVA in humans is mainly from ruminant-derived foods including beef, lamb and dairy products such as milk and butter2,3, but only around 19% or 12% of dietary TVA is converted to rumenic acid by humans or mice, respectively4,5. Mechanistically, TVA inactivates the cell-surface receptor GPR43, an immunomodulatory G protein-coupled receptor activated by its short-chain fatty acid ligands6-8. TVA thus antagonizes the short-chain fatty acid agonists of GPR43, leading to activation of the cAMP-PKA-CREB axis for enhanced CD8+ T cell function. These findings reveal that diet-derived TVA represents a mechanism for host-extrinsic reprogramming of CD8+ T cells as opposed to the intrahost gut microbiota-derived short-chain fatty acids. TVA thus has translational potential for the treatment of tumours.


Assuntos
Linfócitos T CD8-Positivos , Neoplasias , Ácidos Oleicos , Animais , Bovinos , Humanos , Camundongos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Laticínios , Ácidos Graxos Voláteis/farmacologia , Ácidos Graxos Voláteis/uso terapêutico , Leite/química , Neoplasias/dietoterapia , Neoplasias/imunologia , Ácidos Oleicos/farmacologia , Ácidos Oleicos/uso terapêutico , Carne Vermelha , Ovinos
7.
Surg Endosc ; 37(3): 2163-2172, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36326932

RESUMO

BACKGROUND: Currently, endoscopic submucosal dissection (ESD) is widely used as therapeutic methods for superficial esophageal neoplasms (SENs). However, patients are likely to develop esophageal strictures after ESD. Our study aims to explore the possible risk factors for esophageal strictures after ESD and develop and validate a risk model for predicting the progression of postoperative esophageal strictures. METHODS: Clinical data of patients who underwent ESD in our hospital for suspected early esophageal squamous cell carcinoma were collected from January 2014 to March 2020. The possible risk factors for postoperative esophageal strictures were analyzed by univariate and multivariate logistic regression analysis. Eventually, a risk-scoring model was built, in which 70% of patients were used to develop the model and the remaining 30% were used for validation. RESULTS: A total of 553 patients who received ESD were involved, and the incidence of esophageal strictures after ESD was 16.6% (92/553). In our study, the operating time, circumferential range, lesion location, depth of infiltration, and R0 resection were independent risk factors for esophageal strictures after ESD. According to the risk of postoperative esophageal stenosis, a risk-scoring model for esophageal strictures prediction was developed. The risk score ranged from 0 to 11 points, and the risk scores were divided into low risk (0-3 points), intermediate risk (4-7 points), and high risk (8-11 points). The proportions of esophageal stenosis progression in the corresponding risk categories were 6.33%, 29.14%, and 100%. CONCLUSIONS: We developed a risk-scoring model based on factors including circumferential range, lesion location, depth of infiltration, and R0 resection. It stratified patients into low-, intermediate-, and high-risk groups for postoperative esophageal strictures development. This scoring model may have the potential to guide the management of patients after ESD in the future.


Assuntos
Ressecção Endoscópica de Mucosa , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Estenose Esofágica , Humanos , Neoplasias Esofágicas/patologia , Estenose Esofágica/epidemiologia , Estenose Esofágica/etiologia , Ressecção Endoscópica de Mucosa/efeitos adversos , Ressecção Endoscópica de Mucosa/métodos , Constrição Patológica/etiologia , Estudos Retrospectivos , Resultado do Tratamento
8.
Front Oncol ; 12: 1006340, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36300093

RESUMO

Prostate cancer (PCa) is the most common cancer in men in the United States. About 10 - 20% of PCa progress to castration-resistant PCa (CRPC), which is accompanied by metastasis and therapeutic resistance. Aldehyde dehydrogenase (ALDH) is famous as a marker of cancer stem-like cells in different cancer types, including PCa. Generally, ALDHs catalyze aldehyde oxidation into less toxic carboxylic acids and give cancers a survival advantage by reducing oxidative stress caused by aldehyde accumulation. In PCa, the expression of ALDHs is associated with a higher tumor stage and more lymph node metastasis. Functionally, increased ALDH activity makes PCa cells gain more capabilities in self-renewal and metastasis and reduces the sensitivity to castration and radiotherapy. Therefore, it is promising to target ALDH or ALDHhigh cells to eradicate PCa. However, challenges remain in moving the ALDH inhibitors to PCa therapy, potentially due to the toxicity of pan-ALDH inhibitors, the redundancy of ALDH isoforms, and the lack of explicit understanding of the metabolic signaling transduction details. For targeting PCa stem-like cells (PCSCs), different regulators have been revealed in ALDHhigh cells to control cell proliferation and tumorigenicity. ALDH rewires essential signaling transduction in PCa cells. It has been shown that ALDHs produce retinoic acid (RA), bind with androgen, and modulate diverse signaling. This review summarizes and discusses the pathways directly modulated by ALDHs, the crucial regulators that control the activities of ALDHhigh PCSCs, and the recent progress of ALDH targeted therapies in PCa. These efforts will provide insight into improving ALDH-targeted treatment.

9.
Front Genet ; 13: 914404, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35812743

RESUMO

DNA methylation is treated as an important epigenetic mark in various biological activities. In the past, a large number of articles focused on 5 mC while lacking attention to N6-methyladenine (6 mA). The presence of 6 mA modification was previously discovered only in prokaryotes. Recently, with the development of detection technologies, 6 mA has been found in several eukaryotes, including protozoans, metazoans, plants, and fungi. The importance of 6 mA in prokaryotes and single-celled eukaryotes has been widely accepted. However, due to the incredibly low density of 6 mA and restrictions on detection technologies, the prevalence of 6 mA and its role in biological processes in eukaryotic organisms are highly debated. In this review, we first summarize the advantages and disadvantages of 6 mA detection methods. Then, we conclude existing reports on the prevalence of 6 mA in eukaryotic organisms. Next, we highlight possible methyltransferases, demethylases, and the recognition proteins of 6 mA. In addition, we summarize the functions of 6 mA in eukaryotes. Last but not least, we summarize our point of view and put forward the problems that need further research.

10.
Angew Chem Int Ed Engl ; 61(35): e202207108, 2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-35789523

RESUMO

Production of more than 20 million tons of epoxides per year from olefins suffers from low atom economy due to the use of oxidants and complex catalysts with unsatisfactory selectivity, leading to huge environmental and economic costs. We present a proof-of-concept application of electron-rich RuO2 nanocrystals to boost the highly selective epoxidation of cyclooctene via direct oxygen transfer from water as the sole oxygen source under mild conditions. The enhanced electron enrichment of RuO2 nanocrystals via the Schottky effect with nitrogen-doped carbons largely promotes the capture and activation of cyclooctene to give a high turnover frequency (260 h-1 ) of cyclooctene oxide, far surpassing the reported values (<20 h-1 ) of benchmarked catalysts at room temperature with oxidants. Our electron-rich RuO2 electrocatalysts enable efficient and durable hydrogen production (Faradaic efficiency >90 %) on the cathode without impacting on the selectivity to epoxide (>99 %) on the anode.

11.
Mol Cell ; 82(11): 1992-2005.e9, 2022 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-35417664

RESUMO

Phospholipase A2, group VII (PLA2G7) is widely recognized as a secreted, lipoprotein-associated PLA2 in plasma that converts phospholipid platelet-activating factor (PAF) to a biologically inactive product Lyso-PAF during inflammatory response. We report that intracellular PLA2G7 is selectively important for cell proliferation and tumor growth potential of melanoma cells expressing mutant NRAS, but not cells expressing BRAF V600E. Mechanistically, PLA2G7 signals through its product Lyso-PAF to contribute to RAF1 activation by mutant NRAS, which is bypassed by BRAF V600E. Intracellular Lyso-PAF promotes p21-activated kinase 2 (PAK2) activation by binding to its catalytic domain and altering ATP kinetics, while PAK2 significantly contributes to S338-phosphorylation of RAF1 in addition to PAK1. Furthermore, the PLA2G7-PAK2 axis is also required for full activation of RAF1 in cells stimulated by epidermal growth factor (EGF) or cancer cells expressing mutant KRAS. Thus, PLA2G7 and Lyso-PAF exhibit intracellular signaling functions as key elements of RAS-RAF1 signaling.


Assuntos
Fosfolipídeos , Proteínas Proto-Oncogênicas B-raf , Fosfolipases A2 , Fator de Ativação de Plaquetas/análogos & derivados , Fator de Ativação de Plaquetas/metabolismo
12.
J Am Chem Soc ; 144(12): 5418-5423, 2022 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-35230846

RESUMO

Merging existing catalysts together as a cascade catalyst may achieve "one-pot" synthesis of complex but functional molecules by simplifying multistep reactions, which is the blueprint of sustainable chemistry with low pollutant emission and consumption of energy and materials only when the smooth mass exchange between different catalysts is ensured. Effective strategies to facilitate the mass exchange between different active centers, which may dominate the final activity of various cascade catalysts, have not been reached until now, even though charged interfaces due to work function driven electron exchange have been widely observed. Here, we successfully constructed mass (reactants and intermediates) exchange paths between Pd/N-doped carbon and MoC/N-doped carbon induced by interfacial electron exchange to trigger the mild and cascade methylation of amines using CO2 and H2. Theoretical and experimental results have demonstrated that the mass exchange between electron-rich MoC and electron-deficient Pd could prominently improve the production of N,N-dimethyl tertiary amine, which results in a remarkably high turnover frequency value under mild conditions, outperforming the state-of-the-art catalysts in the literature by a factor of 5.9.


Assuntos
Dióxido de Carbono , Elétrons , Aminas/química , Carbono/química , Dióxido de Carbono/química , Catálise
13.
Front Cell Dev Biol ; 10: 866820, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35356276

RESUMO

Ribonucleic acid (RNA) and proteins play critical roles in gene expression and regulation. The relevant study increases the understanding of various life processes and contributes to the diagnosis and treatment of different diseases. RNA imaging and mapping RNA-protein interactions expand the understanding of RNA biology. However, the existing methods have some limitations. Recently, precise RNA targeting of CRISPR-Cas13 in cells has been reported, which is considered a new promising platform for RNA imaging in living cells and recognition of RNA-protein interactions. In this review, we first described the current findings on Cas13. Furthermore, we introduced current tools of RNA real-time imaging and mapping RNA-protein interactions and highlighted the latest advances in Cas13-mediated tools. Finally, we discussed the advantages and disadvantages of Cas13-based methods, providing a set of new ideas for the optimization of Cas13-mediated methods.

15.
Mol Cell ; 81(18): 3833-3847.e11, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34289383

RESUMO

Mutant isocitrate dehydrogenase (IDH) 1 and 2 play a pathogenic role in cancers, including acute myeloid leukemia (AML), by producing oncometabolite 2-hydroxyglutarate (2-HG). We recently reported that tyrosine phosphorylation activates IDH1 R132H mutant in AML cells. Here, we show that mutant IDH2 (mIDH2) R140Q commonly has K413 acetylation, which negatively regulates mIDH2 activity in human AML cells by attenuating dimerization and blocking binding of substrate (α-ketoglutarate) and cofactor (NADPH). Mechanistically, K413 acetylation of mitochondrial mIDH2 is achieved through a series of hierarchical phosphorylation events mediated by tyrosine kinase FLT3, which phosphorylates mIDH2 to recruit upstream mitochondrial acetyltransferase ACAT1 and simultaneously activates ACAT1 and inhibits upstream mitochondrial deacetylase SIRT3 through tyrosine phosphorylation. Moreover, we found that the intrinsic enzyme activity of mIDH2 is much higher than mIDH1, thus the inhibitory K413 acetylation optimizes leukemogenic ability of mIDH2 in AML cells by both producing sufficient 2-HG for transformation and avoiding cytotoxic accumulation of intracellular 2-HG.


Assuntos
Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/metabolismo , Acetil-CoA C-Acetiltransferase/metabolismo , Acetilação , Animais , Antineoplásicos/farmacologia , Feminino , Humanos , Isocitrato Desidrogenase/metabolismo , Ácidos Cetoglutáricos/metabolismo , Leucemia Mieloide Aguda/genética , Lisina/genética , Lisina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Mutação/genética , NADP/metabolismo , Proteínas Nucleares/metabolismo , Fosforilação , Polimorfismo de Nucleotídeo Único/genética , Cultura Primária de Células , Ligação Proteica , Processamento de Proteína Pós-Traducional , Proteínas Tirosina Quinases/metabolismo
17.
Nat Commun ; 12(1): 1714, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33731701

RESUMO

Advanced prostate cancer (PCa) often develops bone metastasis, for which therapies are very limited and the underlying mechanisms are poorly understood. We report that bone-borne TGF-ß induces the acetylation of transcription factor KLF5 in PCa bone metastases, and acetylated KLF5 (Ac-KLF5) causes osteoclastogenesis and bone metastatic lesions by activating CXCR4, which leads to IL-11 secretion, and stimulating SHH/IL-6 paracrine signaling. While essential for maintaining the mesenchymal phenotype and tumorigenicity, Ac-KLF5 also causes resistance to docetaxel in tumors and bone metastases, which is overcome by targeting CXCR4 with FDA-approved plerixafor. Establishing a mechanism for bone metastasis and chemoresistance in PCa, these findings provide a rationale for treating chemoresistant bone metastasis of PCa with inhibitors of Ac-KLF5/CXCR4 signaling.


Assuntos
Neoplasias Ósseas/secundário , Carcinogênese , Transição Epitelial-Mesenquimal , Fatores de Transcrição Kruppel-Like/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Acetilação , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzilaminas/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Ciclamos/uso terapêutico , Docetaxel/uso terapêutico , Humanos , Interleucina-11/genética , Interleucina-11/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Masculino , Camundongos , Mutação , Osteogênese , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo
18.
Theranostics ; 10(17): 7656-7670, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32685011

RESUMO

Prostate cancer is the second leading cause of cancer-related death in the United States. As a first line treatment for hormone-refractory prostate cancer, docetaxel (DTX) treatment leads to suboptimal effect since almost all patients eventually develop DTX resistance. In this study, we investigated whether and how TGF-ß affects DTX resistance of prostate cancer. Methods: Cytotoxicity of DTX in DU 145 and PC-3 cells was measured by CCK-8 and Matrigel colony formation assays. Resistance to DTX in DU 145 cells was examined in a xenograft tumorigenesis model. A luciferase reporter system was used to determine transcriptional activities. Gene expression was analyzed by RT-qPCR and Western blotting. Results: We found that KLF5 is indispensable in TGF-ß-induced DTX resistance. Moreover, KLF5 acetylation at lysine 369 mediates DTX resistance in vitro and in vivo. We showed that the TGF-ß/acetylated KLF5 signaling axis activates Bcl-2 expression transcriptionally. Furthermore, DTX-induced Bcl-2 degradation depends on a proteasome pathway, and TGF-ß inhibits DTX-induced Bcl-2 ubiquitination. Conclusion: Our study demonstrated that the TGF-ß-acetylated KLF5-Bcl-2 signaling axis mediates DTX resistance in prostate cancer and blockade of this pathway could provide clinical insights into chemoresistance of prostate cancer.


Assuntos
Docetaxel/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Fator de Crescimento Transformador beta1/metabolismo , Acetilação , Animais , Apoptose/genética , Linhagem Celular Tumoral , Docetaxel/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Fatores de Transcrição Kruppel-Like/genética , Masculino , Camundongos , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Estabilidade Proteica , Proteólise/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Recombinantes/metabolismo , Ativação Transcricional , Ubiquitinação/efeitos dos fármacos , Ubiquitinação/genética , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Nat Commun ; 11(1): 997, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32081850

RESUMO

Prostate development depends on balanced cell proliferation and differentiation, and acetylated KLF5 is known to alter epithelial proliferation. It remains elusive whether post-translational modifications of transcription factors can differentially determine adult stem/progenitor cell fate. Here we report that, in human and mouse prostates, Klf5 is expressed in both basal and luminal cells, with basal cells preferentially expressing acetylated Klf5. Functionally, Klf5 is indispensable for maintaining basal progenitors, their luminal differentiation, and the proliferation of their basal and luminal progenies. Acetylated Klf5 is also essential for basal progenitors' maintenance and proper luminal differentiation, as deacetylation of Klf5 causes excess basal-to-luminal differentiation; attenuates androgen-mediated organoid organization; and retards postnatal prostate development. In basal progenitor-derived luminal cells, Klf5 deacetylation increases their proliferation and attenuates their survival and regeneration following castration and subsequent androgen restoration. Mechanistically, Klf5 deacetylation activates Notch signaling. Klf5 and its acetylation thus contribute to postnatal prostate development and regeneration by controlling basal progenitor cell fate.


Assuntos
Fatores de Transcrição Kruppel-Like/metabolismo , Próstata/crescimento & desenvolvimento , Próstata/metabolismo , Acetilação , Androgênios/metabolismo , Animais , Diferenciação Celular , Proliferação de Células , Humanos , Fatores de Transcrição Kruppel-Like/deficiência , Fatores de Transcrição Kruppel-Like/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Orquiectomia , Organoides/citologia , Organoides/metabolismo , Próstata/citologia , Regeneração , Transdução de Sinais , Células-Tronco/citologia , Células-Tronco/metabolismo
20.
ACS Appl Bio Mater ; 3(7): 4335-4347, 2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34841220

RESUMO

Although tumor-associated macrophages (TAMs) have been shown to promote cancer progression, their roles in tumor development and resistance to therapy remain to be fully understood, mainly because of the lack of a good approach to evaluate the dynamic changes of heterogeneous macrophages in their residing microenvironment. Here, we report an approach of using antibiofouling PEG-b-AGE polymer-coated iron oxide nanoparticles (IONPs) for targeted imaging of mannose receptor (CD206)-expressing M2-like TAMs. Antibiofouling polymer coatings block non-specific phagocytosis of IONPs by different cells but enable ligand-mediated CD206+ M2-like macrophage targeting after surface functionalizing with mannose (Man-IONP). Costaining tissue sections of the 4T1 mouse mammary tumors using an anti-CD206 antibody and fluorescent dye (TRITC)-labeled Man-IONP showed 94.7 ± 4.5% colocalization of TRITC-Man-IONPs with the anti-CD206 antibody. At 48 h after intravenous (i.v.) injection of Man-IONPs, magnetic resonance imaging of mice bearing orthotopic 4T1 mammary tumors showed a significantly larger IONP-induced decrease of the transverse relaxation time (T 2) in tumors with 29.4 ± 1.5 ms compared to 12.3 ± 3.6 ms in tumors that received non-targeted IONP probes (P < 0.001). Immunofluorescence-stained tumor tissue sections collected at 6, 18, and 24 h after i.v. administration of the nanoprobes revealed that Man-IONPs specifically targeted CD206+ M2-like macrophages in various tumor areas at all time points, while nonconjugated IONPs were absent in the tumor after 18 h. Thus, antibiofouling Man-IONPs demonstrated the capability of explicitly imaging CD206+ M2-like macrophages in vivo and potentials for investigating the dynamics of macrophages in the tumor microenvironment and delivering therapeutics targeting M2-like TAMs.

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