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1.
Artigo em Inglês | MEDLINE | ID: mdl-38445953

RESUMO

RATIONALE: Nitric oxide (NO) is elevated in the airways and serum of allergic asthmatic patients, suggesting an important role in asthma. NO production has been widely attributed to the canonical inducible nitric oxide synthase (iNOS). Much effort has been made to inhibit this enzyme with two outcomes: no asthma improvement; and partial NO reduction, suggesting the involvement of an iNOS-independent source. OBJECTIVES: Neutrophils produce NO under inflammatory conditions and their role in asthma has been overlooked. The present study analyzes their possible role as source of NO. METHODS: Our hypothesis was tested in 99 allergic patients with intermittent bronchial asthma and 26 healthy donors. NO production by blood and sputum neutrophils in response to allergens, anti-IgE, and anti-IgE receptors Abs was assessed by Griess, flow cytometry and confocal microscopy. Extracellular traps (ETs) formation, as a possible consequence of NO production, was quantified by western blot and confocal microscopy, and reactive oxygen species by luminol-enhanced chemiluminescence. RESULTS: Among blood and sputum granulocytes from allergic asthmatic patients, only neutrophils, produce NO by an IgE-dependent mechanism. This production is independent of NOS, but dependent on a reaction between L-arginine and reactive oxygen species from NOX2. NO and ETosis are induced in parallel, and NO amplifies ETs formation, which is a key mediator in asthma. CONCLUSIONS: Our findings reveal a novel role of neutrophils as the unique allergen/IgE-dependent NO source in allergic asthma enhancing ETs formation. These results suggest that NO produced by neutrophils needs further consideration in the treatment of allergic asthma.

2.
Am J Respir Crit Care Med ; 208(8): 879-895, 2023 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-37676930

RESUMO

Rationale: Immune dysregulation is a common feature of pulmonary arterial hypertension (PAH). Histone deacetylase (HDAC)-dependent transcriptional reprogramming epigenetically modulates immune homeostasis and is a novel disease-oriented approach in modern times. Objectives: To identify a novel functional link between HDAC and regulatory T cells (Tregs) in PAH, aiming to establish disease-modified biomarkers and therapeutic targets. Methods: Peripheral blood mononuclear cells were isolated from patients with idiopathic PAH (IPAH) and rodent models of pulmonary hypertension (PH): monocrotaline rats, Sugen5416-hypoxia rats, and Treg-depleted mice. HDAC inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) was used to examine the immune modulatory effects in vivo, ex vivo, and in vitro. Measurements and Main Results: Increased HDAC expression was associated with reduced Foxp3+ Tregs and increased PD-1 (programmed cell death-1) signaling in peripheral blood mononuclear cells from patients with IPAH. SAHA differentially modified a cluster of epigenetic-sensitive genes and induced Foxp3+ Treg conversion in IPAH T cells. Rodent models recapitulated these epigenetic aberrations and T-cell dysfunction. SAHA attenuated PH phenotypes and restored FOXP3 transcription and Tregs in PH rats; interestingly, the effects were more profound in female rats. Selective depletion of CD25+ Tregs in Sugen5416-hypoxia mice neutralized the effects of SAHA. Furthermore, SAHA inhibited endothelial cytokine/chemokine release upon stimulation and subsequent immune chemotaxis. Conclusions: Our results indicated HDAC aberration was associated with Foxp3+ Treg deficiency and demonstrated an epigenetic-mediated mechanism underlying immune dysfunction in PAH. Restoration of Foxp3+ Tregs by HDAC inhibitors is a promising approach to resolve pulmonary vascular pathology, highlighting the potential benefit of developing epigenetic therapies for PAH.

3.
Int J Mol Sci ; 25(2)2024 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-38256268

RESUMO

Cancer is a complex disease that, despite advances in treatment and the greater understanding of the tumor biology until today, continues to be a prevalent and lethal disease. Chemotherapy, radiotherapy, and surgery are the conventional treatments, which have increased the survival for cancer patients. However, the complexity of this disease together with the persistent problems due to tumor progression and recurrence, drug resistance, or side effects of therapy make it necessary to explore new strategies that address the challenges to obtain a positive response. One important point is that tumor cells can interact with the microenvironment, promoting proliferation, dissemination, and immune evasion. Therefore, immunotherapy has emerged as a novel therapy based on the modulation of the immune system for combating cancer, as reflected in the promising results both in preclinical studies and clinical trials obtained. In order to enhance the immune response, the combination of immunotherapy with nanoparticles has been conducted, improving the access of immune cells to the tumor, antigen presentation, as well as the induction of persistent immune responses. Therefore, nanomedicine holds an enormous potential to enhance the efficacy of cancer immunotherapy. Here, we review the most recent advances in specific molecular and cellular immunotherapy and in nano-immunotherapy against cancer in the light of the latest published preclinical studies and clinical trials.


Assuntos
Imunoterapia , Neoplasias , Humanos , Neoplasias/terapia , Apresentação de Antígeno , Evasão da Resposta Imune , Nanomedicina , Microambiente Tumoral
4.
Int J Mol Sci ; 21(21)2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33114050

RESUMO

Merging targeted systemic gene delivery and systemic chemotherapy against cancer, chemovirotherapy, has the potential to improve chemotherapy and gene therapy treatments and overcome cancer resistance. We introduced a bacteriophage (phage) vector, named human adeno-associated virus (AAV)/phage or AAVP, for the systemic targeting of therapeutic genes to cancer. The vector was designed as a hybrid between a recombinant adeno-associated virus genome (rAAV) and a filamentous phage capsid. To achieve tumor targeting, we displayed on the phage capsid the double-cyclic CDCRGDCFC (RGD4C) ligand that binds the alpha-V/beta-3 (αvß3) integrin receptor. Here, we investigated a combination of doxorubicin chemotherapeutic drug and targeted gene delivery by the RGD4C/AAVP vector. Firstly, we showed that doxorubicin boosts transgene expression from the RGD4C/AAVP in two-dimensional (2D) cell cultures and three-dimensional (3D) tumor spheres established from human and murine cancer cells, while preserving selective gene delivery by RGD4C/AAVP. Next, we confirmed that doxorubicin does not increase vector attachment to cancer cells nor vector cell entry. In contrast, doxorubicin may alter the intracellular trafficking of the vector by facilitating nuclear accumulation of the RGD4C/AAVP genome through destabilization of the nuclear membrane. Finally, a combination of doxorubicin and RGD4C/AAVP-targeted suicide gene therapy exerts a synergistic effect to destroy human and murine tumor cells in 2D and 3D tumor sphere settings.


Assuntos
Doxorrubicina/farmacologia , Vetores Genéticos/farmacologia , Integrinas/metabolismo , Peptídeos/genética , Esferoides Celulares/citologia , Animais , Bacteriófagos/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada , Dependovirus/genética , Terapia Genética , Vetores Genéticos/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Camundongos , Peptídeos/metabolismo , Ratos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Esferoides Celulares/efeitos dos fármacos , Transdução Genética
5.
Nature ; 472(7343): 319-24, 2011 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-21389984

RESUMO

Activation of microglia and inflammation-mediated neurotoxicity are suggested to play a decisive role in the pathogenesis of several neurodegenerative disorders. Activated microglia release pro-inflammatory factors that may be neurotoxic. Here we show that the orderly activation of caspase-8 and caspase-3/7, known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C (PKC)-δ-dependent pathway. We find that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo. Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently reduced neurotoxicity. We observe that these caspases are activated in microglia in the ventral mesencephalon of Parkinson's disease (PD) and the frontal cortex of individuals with Alzheimer's disease (AD). Taken together, we show that caspase-8 and caspase-3/7 are involved in regulating microglia activation. We conclude that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves.


Assuntos
Caspases/metabolismo , Microglia/fisiologia , Síndromes Neurotóxicas/enzimologia , Síndromes Neurotóxicas/patologia , Transdução de Sinais , Doença de Alzheimer/enzimologia , Doença de Alzheimer/patologia , Animais , Caspase 3/deficiência , Caspase 3/metabolismo , Caspase 7/deficiência , Caspase 7/metabolismo , Caspase 8/genética , Caspase 8/metabolismo , Inibidores de Caspase , Caspases/deficiência , Morte Celular/efeitos dos fármacos , Células Cultivadas , Dopamina/metabolismo , Ativação Enzimática , Lobo Frontal/enzimologia , Lobo Frontal/patologia , Técnicas de Silenciamento de Genes , Humanos , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/efeitos dos fármacos , Neostriado/metabolismo , Síndromes Neurotóxicas/metabolismo , Doença de Parkinson/enzimologia , Doença de Parkinson/patologia , Proteína Quinase C-delta/química , Proteína Quinase C-delta/metabolismo , Ratos , Substância Negra/enzimologia , Substância Negra/patologia , Receptor 4 Toll-Like/metabolismo
6.
Artif Intell Med ; 154: 102902, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38852314

RESUMO

Glioblastoma, characterized as a grade 4 astrocytoma, stands out as the most aggressive brain tumor, often leading to dire outcomes. The challenge of treating glioblastoma is exacerbated by the convergence of genetic mutations and disruptions in gene expression, driven by alterations in epigenetic mechanisms. The integration of artificial intelligence, inclusive of machine learning algorithms, has emerged as an indispensable asset in medical analyses. AI is becoming a necessary tool in medicine and beyond. Current research on Glioblastoma predominantly revolves around non-omics data modalities, prominently including magnetic resonance imaging, computed tomography, and positron emission tomography. Nonetheless, the assimilation of omic data-encompassing gene expression through transcriptomics and epigenomics-offers pivotal insights into patients' conditions. These insights, reciprocally, hold significant value in refining diagnoses, guiding decision- making processes, and devising efficacious treatment strategies. This survey's core objective encompasses a comprehensive exploration of noteworthy applications of machine learning methodologies in the domain of glioblastoma, alongside closely associated research pursuits. The study accentuates the deployment of artificial intelligence techniques for both non-omics and omics data, encompassing a range of tasks. Furthermore, the survey underscores the intricate challenges posed by the inherent heterogeneity of Glioblastoma, delving into strategies aimed at addressing its multifaceted nature.

7.
Circulation ; 126(4): 455-67, 2012 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-22711276

RESUMO

BACKGROUND: Epigenetic programming, dynamically regulated by histone acetylation, is a key mechanism regulating cell proliferation and survival. Little is known about the contribution of histone deacetylase (HDAC) activity to the development of pulmonary arterial hypertension, a condition characterized by profound structural remodeling of pulmonary arteries and arterioles. METHODS AND RESULTS: HDAC1 and HDAC5 protein levels were elevated in lungs from human idiopathic pulmonary arterial hypertension and in lungs and right ventricles from rats exposed to hypoxia. Immunohistochemistry localized increased expression to remodeled vessels in the lung. Both valproic acid, a class I HDAC inhibitor, and suberoylanilide hydroxamic acid (vorinostat), an inhibitor of class I, II, and IV HDACs, mitigated the development of and reduced established hypoxia-induced pulmonary hypertension in the rat. Both valproic acid and suberoylanilide hydroxamic acid inhibited the imprinted highly proliferative phenotype of fibroblasts and R-cells from pulmonary hypertensive bovine vessels and platelet-derived growth factor-stimulated growth of human vascular smooth muscle cells in culture. Exposure to valproic acid and suberoylanilide hydroxamic acid was associated with increased levels of p21 and FOXO3 and reduced expression of survivin. The significantly higher levels of expression of cKIT, monocyte chemoattractant protein-1, interleukin-6, stromal-derived factor-1, platelet-derived growth factor-b, and S100A4 in R-cells were downregulated by valproic acid and suberoylanilide hydroxamic acid treatment. CONCLUSIONS: Increased HDAC activity contributes to the vascular pathology of pulmonary hypertension. The effectiveness of HDAC inhibitors, valproic acid, and suberoylanilide hydroxamic acid, in models of pulmonary arterial hypertension supports a therapeutic strategy based on HDAC inhibition in pulmonary arterial hypertension.


Assuntos
Histona Desacetilases/efeitos dos fármacos , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Ácido Valproico/farmacologia , Ácido Valproico/uso terapêutico , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 1/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Hipóxia/complicações , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Fator de Crescimento Derivado de Plaquetas/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Ratos , Ratos Sprague-Dawley , Vorinostat
8.
Oncogene ; 41(18): 2638-2650, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35354905

RESUMO

Ewing sarcoma (EWS) is an aggressive bone and soft tissue tumor with high susceptibility to metastasize. The underlying molecular mechanisms leading to EWS metastases remain poorly understood. Epigenetic changes have been implicated in EWS tumor growth and progression. Linking epigenetics and metastases may provide insight into novel molecular targets in EWS and improve its treatment. Here, we evaluated the effects of a selective G9a histone methyltransferase inhibitor (BIX01294) on EWS metastatic process. Our results showed that overexpression of G9a in tumors from EWS patients correlates with poor prognosis. Moreover, we observe a significantly higher expression of G9a in metastatic EWS tumor as compared to either primary or recurrent tumor. Using functional assays, we demonstrate that pharmacological G9a inhibition using BIX01294 disrupts several metastatic steps in vitro, such as migration, invasion, adhesion, colony formation and vasculogenic mimicry. Moreover, BIX01294 reduces tumor growth and metastases in two spontaneous metastases mouse models. We further identified the sialidase NEU1 as a direct target and effector of G9a in the metastatic process in EWS. NEU1 overexpression impairs migration, invasion and clonogenic capacity of EWS cell lines. Overall, G9a inhibition impairs metastases in vitro and in vivo through the overexpression of NEU1. G9a has strong potential as a prognostic marker and may be a promising therapeutic target for EWS patients.


Assuntos
Sarcoma de Ewing , Animais , Linhagem Celular Tumoral , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Histona Metiltransferases/metabolismo , Humanos , Camundongos , Recidiva Local de Neoplasia , Neuraminidase/metabolismo , Neuraminidase/uso terapêutico , Proteínas de Fusão Oncogênica/genética , Proteína Proto-Oncogênica c-fli-1/genética , Proteína Proto-Oncogênica c-fli-1/metabolismo , Proteína EWS de Ligação a RNA/genética , Sarcoma de Ewing/tratamento farmacológico , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia
9.
J Clin Invest ; 132(6)2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35113813

RESUMO

New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine-depleting agent ADI-PEG20 in a non-arginine-auxotrophic cellular background (argininosuccinate synthetase 1 positive). Moreover, this combination led to durable and complete radiological and pathological response, with extended disease-free survival in an orthotopic immune-competent model of GBM, with no significant toxicity. ADI-PEG20 not only enhanced the cellular sensitivity of argininosuccinate synthetase 1-positive GBM to ionizing radiation by elevated production of nitric oxide (˙NO) and hence generation of cytotoxic peroxynitrites, but also promoted glioma-associated macrophage/microglial infiltration into tumors and turned their classical antiinflammatory (protumor) phenotype into a proinflammatory (antitumor) phenotype. Our results provide an effective, well-tolerated, and simple strategy to improve GBM treatment that merits consideration for early evaluation in clinical trials.


Assuntos
Antineoplásicos , Glioblastoma , Antineoplásicos/uso terapêutico , Arginina , Argininossuccinato Sintase/genética , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Humanos , Hidrolases , Microglia , Polietilenoglicóis
10.
Epigenomics ; 13(5): 397-403, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-29932342

RESUMO

One of the major obstacles to the development of effective new cancer treatments and the main factor for the increasing number of clinical trial failures appears to be the paucity of accurate, reproducible and robust drug resistance testing methods. Most research assessing the resistance of cancers to chemotherapy has concentrated on genetic-based molecular mechanisms, while the role of epigenetics in drug resistance has been generally overlooked. This is rather surprising given that an increasing body of evidence pointing to the fact that epigenetic mechanism alterations appear to play a pivotal role in cancer initiation, progression and development of chemoresistance. This resulted in a series of clinical trials involving epi-drug as single treatment or combined with cancer conventional drugs. In this review, we provided the main mechanisms by which the epigenetic regulators control the resistance to cancer drugs.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Metilação de DNA , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , MicroRNAs , Neoplasias/metabolismo
11.
Mol Ther Nucleic Acids ; 26: 401-416, 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34552821

RESUMO

MicroRNAs (miRNAs) are promising drug targets for obesity and metabolic disorders. Recently, miRNA mimics are providing a unique mechanism of action that guides the process for drug development and sets out the context of their therapeutic application. miRNA (miR)-21 expression in white adipose tissue (WAT) has been associated with obesity. We aimed to analyze miR-21 expression levels in relation to diabetes and obesity to determine the effect that miR-21 mimic has on processes involved in WAT functionality, to dissect the underlying molecular mechanisms, and to study the potential therapeutic application of the miR-21 mimic against obesity. We found higher miR-21 levels in WAT from non-diabetic obese compared to normoweight humans and mice. Moreover, in 3T3-L1 adipocytes, miR-21 mimic affect genes involved in WAT functionality regulation and significantly increase the expression of genes involved in browning and thermogenesis. Interestingly, in vivo treatment with the miR-21 mimic blocked weight gain induced by a high-fat diet in obese mice, without modifying food intake or physical activity. This was associated with metabolic enhancement, WAT browning, and brown adipose tissue (AT) thermogenic programming through vascular endothelial growth factor A (VEGF-A), p53, and transforming growth factor ß1 (TGF-ß1) signaling pathways. Our findings suggest that miR-21 mimic-based therapy may provide a new opportunity to therapeutically manage obesity and consequently, its associated alterations.

12.
Oncogene ; 40(39): 5843-5853, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34345016

RESUMO

Ewing sarcoma (EWS) is an aggressive bone and soft tissue tumor of children and young adults in which the principal driver is a fusion gene, EWSR1-FLI1. Although the essential role of EWSR1-FLI1 protein in the regulation of oncogenesis, survival, and tumor progression processes has been described in-depth, little is known about the regulation of chimeric fusion-gene expression. Here, we demonstrate that the active nuclear HDAC6 in EWS modulates the acetylation status of specificity protein 1 (SP1), consequently regulating the SP1/P300 activator complex binding to EWSR1 and EWSR1-FLI1 promoters. Selective inhibition of HDAC6 impairs binding of the activator complex SP1/P300, thereby inducing EWSR1-FLI1 downregulation and significantly reducing its oncogenic functions. In addition, sensitivity of EWS cell lines to HDAC6 inhibition is higher than other tumor or non-tumor cell lines. High expression of HDAC6 in primary EWS tumor samples from patients correlates with a poor prognosis in two independent series accounting 279 patients. Notably, a combination treatment of a selective HDAC6 and doxorubicin (a DNA damage agent used as a standard therapy of EWS patients) dramatically inhibits tumor growth in two EWS murine xenograft models. These results could lead to suitable and promising therapeutic alternatives for patients with EWS.


Assuntos
Proteína Proto-Oncogênica c-fli-1 , Sarcoma de Ewing , Acetilação , Carcinogênese , Desacetilase 6 de Histona , Humanos , Regiões Promotoras Genéticas
13.
Metabolites ; 10(9)2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32859120

RESUMO

Metabolic regulation of immune cells has arisen as a critical set of processes required for appropriate response to immunological signals. While our knowledge in this area has rapidly expanded in leukocytes, much less is known about the metabolic regulation of brain-resident microglia. In particular, the role of alternative nutrients to glucose remains poorly understood. Here, we use stable-isotope (13C) tracing strategies and metabolomics to characterize the oxidative metabolism of ß-hydroxybutyrate (BHB) in human (HMC3) and murine (BV2) microglia cells and the interplay with glucose in resting and LPS-activated BV2 cells. We found that BHB is imported and oxidised in the TCA cycle in both cell lines with a subsequent increase in the cytosolic NADH:NAD+ ratio. In BV2 cells, stimulation with LPS upregulated the glycolytic flux, increased the cytosolic NADH:NAD+ ratio and promoted the accumulation of the glycolytic intermediate dihydroxyacetone phosphate (DHAP). The addition of BHB enhanced LPS-induced accumulation of DHAP and promoted glucose-derived lactate export. BHB also synergistically increased LPS-induced accumulation of succinate and other key immunometabolites, such as α-ketoglutarate and fumarate generated by the TCA cycle. Finally, BHB upregulated the expression of a key pro-inflammatory (M1 polarisation) marker gene, NOS2, in BV2 cells activated with LPS. In conclusion, we identify BHB as a potentially immunomodulatory metabolic substrate for microglia that promotes metabolic reprogramming during pro-inflammatory response.

14.
Front Genet ; 11: 578011, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33024443

RESUMO

Chemotherapy is one of the most established and effective treatments for almost all types of cancer. However, the elevated toxicity due to the non-tumor-associated effects, development of secondary malignancies, infertility, radiation-induced fibrosis and resistance to treatment limit the effectiveness and safety of treatment. In addition, these multiple factors significantly impact quality of life. Over the last decades, our increased understanding of cancer epigenetics has led to new therapeutic approaches and the promise of improved patient outcomes. Epigenetic alterations are commonly found in cancer, especially the increased expression and activity of histone deacetylases (HDACs). Dysregulation of HDACs are critical to the development and progression of the majority of tumors. Hence, HDACs inhibitors (HDACis) were developed and now represent a very promising treatment strategy. The use of HDACis as monotherapy has shown very positive pre-clinical results, but clinical trials have had only limited success. However, combinatorial regimens with other cancer drugs have shown synergistic effects both in pre-clinical and clinical studies. At the same time, these combinations have enhanced the efficacy, reduced the toxicity and tumor resistance to therapy. In this review, we will examine examples of HDACis used in combination with other cancer drugs and highlight the synergistic effects observed in recent preclinical and clinical studies.

15.
PLoS One ; 15(6): e0234243, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32502203

RESUMO

The presence of the chimeric EWSR1-FLI1 oncoprotein is the main and initiating event defining Ewing sarcoma (ES). The dysregulation of epigenomic and proteomic homeostasis induced by the oncoprotein contributes to a wide variety of events involved in oncogenesis and tumor progression. Attempts at studying the effects of EWSR1-FLI1 in non-tumor cells to understand the mechanisms underlying sarcomagenesis have been unsuccessful to date, as ectopic expression of EWSR1-FLI1 blocks cell cycle progression and induces apoptosis in the tested cell lines. Therefore, it is essential to find a permissive cell type for EWSR1-FLI1 expression that allows its endogenous molecular functions to be studied. Here we have demonstrated that HeLa cell lines are permissive to EWSR1-FLI1 ectopic expression, and that our model substantially recapitulates the endogenous activity of the EWSR1-FLI1 fusion protein. This model could contribute to better understanding ES sarcomagenesis by helping to understand the molecular mechanisms induced by the EWSR1-FLI1 oncoprotein.


Assuntos
Carcinogênese/genética , Expressão Ectópica do Gene , Proteínas de Fusão Oncogênica/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Sítios de Ligação , DNA/metabolismo , Células HeLa , Humanos , Proteínas de Fusão Oncogênica/metabolismo
16.
Cells ; 9(7)2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32709045

RESUMO

The pro-inflammatory immune response driven by microglia is a key contributor to the pathogenesis of several neurodegenerative diseases. Though the research of microglia spans over a century, the last two decades have increased our understanding exponentially. Here, we discuss the phenotypic transformation from homeostatic microglia towards reactive microglia, initiated by specific ligand binding to pattern recognition receptors including toll-like receptor-4 (TLR4) or triggering receptors expressed on myeloid cells-2 (TREM2), as well as pro-inflammatory signaling pathways triggered such as the caspase-mediated immune response. Additionally, new research disciplines such as epigenetics and immunometabolism have provided us with a more holistic view of how changes in DNA methylation, microRNAs, and the metabolome may influence the pro-inflammatory response. This review aimed to discuss our current knowledge of pro-inflammatory microglia from different angles, including recent research highlights such as the role of exosomes in spreading neuroinflammation and emerging techniques in microglia research including positron emission tomography (PET) scanning and the use of human microglia generated from induced pluripotent stem cells (iPSCs). Finally, we also discuss current thoughts on the impact of pro-inflammatory microglia in neurodegenerative diseases.


Assuntos
Sistema Nervoso Central/patologia , Inflamação/patologia , Microglia/patologia , Animais , Caspases/metabolismo , Epigênese Genética , Humanos , Microglia/enzimologia , Modelos Biológicos
18.
Oncogene ; 38(13): 2320-2336, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30478450

RESUMO

Despite emergence of new systemic therapies, metastatic melanoma remains a challenging and often fatal form of skin cancer. The renin-angiotensin system (RAS) is a major physiological regulatory pathway controlling salt-water equilibrium, intravascular volume and blood pressure. Biological effects of the RAS are mediated by the vasoactive hormone angiotensin II (AngII) via two receptor subtypes, AT1R (encoded by AGTR1) and AT2R (encoded by AGTR2). We report decreasing expression and increasing CpG island methylation of AGTR1 in metastatic versus primary melanoma and detection in serum of methylated genomic DNA from the AGTR1 CpG island in metastatic melanoma implying that AGTR1 encodes a tumour suppressor function in melanoma. Consistent with this hypothesis, antagonism of AT1R using losartan or shRNA-mediated knockdown in melanoma cell lines expressing AGTR1 resulted in acquisition of the ability to proliferate in serum-free conditions. Conversely, ectopic expression of AGTR1 in cell lines lacking endogenous expression inhibits proliferation irrespective of the presence of AngII implying a ligand-independent suppressor function for AT1R. Treatment of melanoma cell lines expressing endogenous AT2R with either AngII or the AT2R-selective agonist Y6AII induces proliferation in serum-free conditions whereas the AT2R-specific antagonists PD123319 and EMA401 inhibit melanoma growth and angiogenesis and potentiate inhibitors of BRAF and MEK in cells with BRAF V600 mutations. Our results demonstrate that the RAS has both oncogenic and tumour suppressor functions in melanoma. Pharmacological inhibition of AT2R may provide therapeutic opportunities in melanomas expressing this receptor and AGTR1 CpG island methylation in serum may serve as a novel biomarker of metastatic melanoma.


Assuntos
Proliferação de Células , Melanoma/patologia , Melanoma/terapia , Terapia de Alvo Molecular , Sistema Renina-Angiotensina/fisiologia , Amidas/farmacologia , Amidas/uso terapêutico , Angiotensina II/farmacologia , Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Células Cultivadas , Metilação de DNA/efeitos dos fármacos , Embrião não Mamífero , Fumaratos/farmacologia , Fumaratos/uso terapêutico , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Melanoma/genética , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Metástase Neoplásica , Piridinas/farmacologia , Piridinas/uso terapêutico , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
19.
J Periodontol ; 89(2): 228-234, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29520824

RESUMO

BACKGROUND: Periodontitis develops through an inflammatory process caused by an infection at the microbial biofilm, followed by tissue destruction mediated by leukocytes, which cause clinically significant destruction of connective tissue and bone. Several elements derived from the bacteria cause the inflammatory response and the release of mediators involved in destruction of the periodontium. There are number of inflammatory mediators released by leukocytes, mainly neutrophils, upon bacterial challenge. Neutrophils produce and release eosinophil cationic protein (ECP) and histamine, two important inflammatory mediators; however, their role has not been characterized in periodontal inflammation. Thus, the purpose of this study is to investigate whether neutrophils from patients with periodontitis can produce ECP and histamine in response to lipopolysaccharides (LPSs). METHODS: ECP and histamine production in response to LPSs was analyzed by enzyme-linked immunosorbent assay. Expression of the histidine decarboxylase and ECP was also analyzed by flow cytometry and fluorescence microscopy in neutrophils from patients with periodontitis in response to LPS. RESULTS: It was found that neutrophils from patients with periodontitis express higher levels of histidine decarboxylase and ECP than those from healthy volunteers, and they also release higher levels of histamine. CONCLUSION: Findings described could represent new knowledge indicating neutrophils as a source of histamine and ECP in the progression of periodontitis.


Assuntos
Proteína Catiônica de Eosinófilo , Periodontite , Histamina , Humanos , Leucócitos , Neutrófilos
20.
Cell Death Dis ; 9(12): 1192, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30546006

RESUMO

Glioblastoma multiforme (GBM) remains a cancer with a poor prognosis and few effective therapeutic options. Successful medical management of GBM is limited by the restricted access of drugs to the central nervous system (CNS) caused by the blood brain barrier (BBB). We previously showed that a subset of GBM are arginine auxotrophic because of transcriptional silencing of ASS1 and/or ASL and are sensitive to pegylated arginine deiminase (ADI-PEG20). However, it is unknown whether depletion of arginine in peripheral blood in vivo has therapeutic activity against intracranial disease. In the present work, we describe the efficacy of ADI-PEG20 in an intracranial model of human GBM in which tumour growth and regression are assessed in real time by measurement of luciferase activity. Animals bearing intracranial human GBM tumours of varying ASS status were treated with ADI-PEG20 alone or in combination with temozolomide and monitored for tumour growth and regression. Monotherapy ADI-PEG20 significantly reduces the intracranial growth of ASS1 negative GBM and extends survival of mice carrying ASS1 negative GBM without obvious toxicity. The combination of ADI-PEG20 with temozolomide (TMZ) demonstrates enhanced effects in both ASS1 negative and ASS1 positive backgrounds.Our data provide proof of principle for a therapeutic strategy for GBM using peripheral blood arginine depletion that does not require BBB passage of drug and is well tolerated. The ability of ADI-PEG20 to cytoreduce GBM and enhance the effects of temozolomide argues strongly for its early clinical evaluation in the treatment of GBM.


Assuntos
Argininossuccinato Sintase/genética , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Hidrolases/farmacologia , Polietilenoglicóis/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Arginina/metabolismo , Argininossuccinato Sintase/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Camundongos , Temozolomida/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
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