Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.595
Filtrar
1.
Molecules ; 26(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34443600

RESUMO

Organotin(IV) compounds are a class of non-platinum metallo-conjugates exhibiting antitumor activity. The effects of different organotin types has been related to several mechanisms, including their ability to modify acetylation protein status and to promote apoptosis. Here, we focus on triorganotin(IV) complexes of butyric acid, a well-known HDAC inhibitor with antitumor properties. The conjugated compounds were synthesized and characterised by FTIR spectroscopy, multi-nuclear (1H, 13C and 119Sn) NMR, and mass spectrometry (ESI-MS). In the triorganotin(IV) complexes, an anionic monodentate butyrate ligand was observed, which coordinated the tin atom on a tetra-coordinated, monomeric environment similar to ester. FTIR and NMR findings confirm this structure both in solid state and solution. The antitumor efficacy of the triorganotin(IV) butyrates was tested in colon cancer cells and, among them, tributyltin(IV) butyrate (BT2) was selected as the most efficacious. BT2 induced G2/M cell cycle arrest, ER stress, and apoptotic cell death. These effects were obtained using low concentrations of BT2 up to 1 µM, whereas butyric acid alone was completely inefficacious, and the parent compound TBT was poorly effective at the same treatment conditions. To assess whether butyrate in the coordinated form maintains its epigenetic effects, histone acetylation was evaluated and a dramatic decrease in acetyl-H3 and -H4 histones was found. In contrast, butyrate alone stimulated histone acetylation at a higher concentration (5 mM). BT2 was also capable of preventing histone acetylation induced by SAHA, another potent HDAC inhibitor, thus suggesting that it may activate HDACs. These results support a potential use of BT2, a novel epigenetic modulator, in colon cancer treatment.


Assuntos
Apoptose/genética , Ácido Butírico/química , Neoplasias do Colo/patologia , Estresse do Retículo Endoplasmático/genética , Epigênese Genética/efeitos dos fármacos , Compostos de Trialquitina/química , Compostos de Trialquitina/farmacologia , Acetilação/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Histona Desacetilases/metabolismo , Humanos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos
2.
ACS Appl Mater Interfaces ; 13(33): 39003-39017, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433253

RESUMO

Improving tumor immunogenicity is critical for increasing the responsiveness of triple-negative breast cancer (TNBC) to anti-PD-(L)1 treatment. Here, we verified that chidamide (CHI), an epigenetic modulator, could elicit immunogenic cell death within TNBC to enhance cancer immunogenicity and elicit an antitumor immune response. Additionally, CHI increased the expression level of PD-L1, MHC I, and MHC II on cancer cells, which contributed to T-cell recognition and PD-1/PD-L1 blockade therapy response. The synergistic antitumor efficacy of CHI and PD-L1 blockade therapy was further explored through liposomes co-delivering CHI and BMS-202 (a small-molecule PD-L1 inhibitor). The liposomes possessed good biocompatibility, security, and controllable drug release and endowed therapeutics drugs with favorable tumor accumulation. Furthermore, the drug-loaded liposomes could obviously boost the antitumor immunity of TNBC through CHI-enhanced tumor immunogenicity and BMS-202-mediated PD-L1 blockade, thereby effectively inhibiting the growth of primary and metastatic tumors with an inhibitory rate of metastasis of up to 96%. In summary, this work provided a referable and optional approach for clinical antitumor therapy based on the combination of an epigenetic modulator and PD-1/PD-L1 blockade therapy.


Assuntos
Acetamidas/química , Aminopiridinas/química , Antineoplásicos/farmacologia , Benzamidas/química , Portadores de Fármacos/química , Inibidores de Checkpoint Imunológico/química , Piridinas/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/imunologia , Acetamidas/farmacologia , Aminopiridinas/farmacologia , Animais , Benzamidas/farmacologia , Materiais Biocompatíveis/química , Linhagem Celular Tumoral , Terapia Combinada/métodos , Liberação Controlada de Fármacos , Epigênese Genética/efeitos dos fármacos , Feminino , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia/métodos , Lipossomos/química , Camundongos , Camundongos Endogâmicos BALB C , Piridinas/farmacologia , Bibliotecas de Moléculas Pequenas/química , Distribuição Tecidual , Resultado do Tratamento
3.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360879

RESUMO

Globally, breast cancer has remained the most commonly diagnosed cancer and the leading cause of cancer death among women. Breast cancer is a highly heterogeneous and phenotypically diverse group of diseases, which require different selection of treatments. Breast cancer stem cells (BCSCs), a small subset of cancer cells with stem cell-like properties, play essential roles in breast cancer progression, recurrence, metastasis, chemoresistance and treatments. Epigenetics is defined as inheritable changes in gene expression without alteration in DNA sequence. Epigenetic regulation includes DNA methylation and demethylation, as well as histone modifications. Aberrant epigenetic regulation results in carcinogenesis. In this review, the mechanism of epigenetic regulation involved in carcinogenesis, therapeutic resistance and metastasis of BCSCs will be discussed, and finally, the therapies targeting these biomarkers will be presented.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Carcinogênese/genética , Epigênese Genética , Terapia de Alvo Molecular/métodos , Células-Tronco Neoplásicas/metabolismo , Animais , Biomarcadores Tumorais/genética , Neoplasias da Mama/metabolismo , Carcinogênese/metabolismo , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Código das Histonas/efeitos dos fármacos , Código das Histonas/genética , Humanos
4.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445488

RESUMO

Prenatal alcohol exposure (PAE) can have immediate and long-lasting toxic and teratogenic effects on an individual's development and health. As a toxicant, alcohol can lead to a variety of physical and neurological anomalies in the fetus that can lead to behavioral and other impairments which may last a lifetime. Recent studies have focused on identifying mechanisms that mediate the immediate teratogenic effects of alcohol on fetal development and mechanisms that facilitate the persistent toxic effects of alcohol on health and predisposition to disease later in life. This review focuses on the contribution of epigenetic modifications and intercellular transporters like extracellular vesicles to the toxicity of PAE and to immediate and long-term consequences on an individual's health and risk of disease.


Assuntos
Etanol/toxicidade , Desenvolvimento Fetal/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/genética , Teratogênese/genética , Adolescente , Desenvolvimento do Adolescente/efeitos dos fármacos , Adulto , Epigênese Genética/efeitos dos fármacos , Vesículas Extracelulares/efeitos dos fármacos , Vesículas Extracelulares/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Gravidez
5.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445342

RESUMO

Epigenetic regulation by histone deacetylase (HDAC) is associated with synaptic plasticity and memory formation, and its aberrant expression has been linked to cognitive disorders, including Alzheimer's disease (AD). This study aimed to investigate the role of class IIa HDAC expression in AD and monitor it in vivo using a novel radiotracer, 6-(tri-fluoroacetamido)-1-hexanoicanilide ([18F]TFAHA). A human neural cell culture model with familial AD (FAD) mutations was established and used for in vitro assays. Positron emission tomography (PET) imaging with [18F]TFAHA was performed in a 3xTg AD mouse model for in vivo evaluation. The results showed a significant increase in HDAC4 expression in response to amyloid-ß (Aß) deposition in the cell model. Moreover, treatment with an HDAC4 selective inhibitor significantly upregulated the expression of neuronal memory-/synaptic plasticity-related genes. In [18F]TFAHA-PET imaging, whole brain or regional uptake was significantly higher in 3xTg AD mice compared with WT mice at 8 and 11 months of age. Our study demonstrated a correlation between class IIa HDACs and Aßs, the therapeutic benefit of a selective inhibitor, and the potential of using [18F]TFAHA as an epigenetic radiotracer for AD, which might facilitate the development of AD-related neuroimaging approaches and therapies.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Inibidores de Histona Desacetilases/farmacocinética , Histona Desacetilases/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Modelos Animais de Doenças , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/fisiologia , Radioisótopos de Flúor/química , Radioisótopos de Flúor/farmacocinética , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/química , Histona Desacetilases/classificação , Histona Desacetilases/genética , Humanos , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuroimagem/métodos , Tomografia por Emissão de Pósitrons/métodos , Células Tumorais Cultivadas
6.
Curr Opin Hematol ; 28(5): 356-363, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34267079

RESUMO

PURPOSE OF REVIEW: Comprehensive sequencing studies aimed at determining the genetic landscape of myeloid neoplasms have identified epigenetic regulators to be among the most commonly mutated genes. Detailed studies have also revealed a number of epigenetic vulnerabilities. The purpose of this review is to outline these vulnerabilities and to discuss the new generation of drugs that exploit them. RECENT FINDINGS: In addition to deoxyribonucleic acid-methylation, novel epigenetic dependencies have recently been discovered in various myeloid neoplasms and many of them can be targeted pharmacologically. These include not only chromatin writers, readers, and erasers but also chromatin movers that shift nucleosomes to allow access for transcription. Inhibitors of protein-protein interactions represent a novel promising class of drugs that allow disassembly of oncogenic multiprotein complexes. SUMMARY: An improved understanding of disease-specific epigenetic vulnerabilities has led to the development of second-generation mechanism-based epigenetic drugs against myeloid neoplasms. Many of these drugs have been introduced into clinical trials and synergistic drug combination regimens have been shown to enhance efficacy and potentially prevent drug resistance.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hematológicas , Transtornos Mieloproliferativos , Transcrição Genética/efeitos dos fármacos , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Humanos , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Nucleossomos/genética , Nucleossomos/metabolismo
7.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298869

RESUMO

Interactions of drugs with the classical epigenetic mechanism of DNA methylation or histone modification are increasingly being elucidated mechanistically and used to develop novel classes of epigenetic therapeutics. A data science approach is used to synthesize current knowledge on the pharmacological implications of epigenetic regulation of gene expression. Computer-aided knowledge discovery for epigenetic implications of current approved or investigational drugs was performed by querying information from multiple publicly available gold-standard sources to (i) identify enzymes involved in classical epigenetic processes, (ii) screen original biomedical scientific publications including bibliometric analyses, (iii) identify drugs that interact with epigenetic enzymes, including their additional non-epigenetic targets, and (iv) analyze computational functional genomics of drugs with epigenetic interactions. PubMed database search yielded 3051 hits on epigenetics and drugs, starting in 1992 and peaking in 2016. Annual citations increased to a plateau in 2000 and show a downward trend since 2008. Approved and investigational drugs in the DrugBank database included 122 compounds that interacted with 68 unique epigenetic enzymes. Additional molecular functions modulated by these drugs included other enzyme interactions, whereas modulation of ion channels or G-protein-coupled receptors were underrepresented. Epigenetic interactions included (i) drug-induced modulation of DNA methylation, (ii) drug-induced modulation of histone conformations, and (iii) epigenetic modulation of drug effects by interference with pharmacokinetics or pharmacodynamics. Interactions of epigenetic molecular functions and drugs are mutual. Recent research activities on the discovery and development of novel epigenetic therapeutics have passed successfully, whereas epigenetic effects of non-epigenetic drugs or epigenetically induced changes in the targets of common drugs have not yet received the necessary systematic attention in the context of pharmacological plasticity.


Assuntos
Epigênese Genética/efeitos dos fármacos , Preparações Farmacêuticas/administração & dosagem , Metilação de DNA/efeitos dos fármacos , Epigenômica/métodos , Expressão Gênica/efeitos dos fármacos , Histonas/metabolismo , Humanos , Canais Iônicos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo
8.
Nat Commun ; 12(1): 4560, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34315876

RESUMO

Alcoholic hepatitis (AH) is associated with liver neutrophil infiltration through activated cytokine pathways leading to elevated chemokine expression. Super-enhancers are expansive regulatory elements driving augmented gene expression. Here, we explore the mechanistic role of super-enhancers linking cytokine TNFα with chemokine amplification in AH. RNA-seq and histone modification ChIP-seq of human liver explants show upregulation of multiple CXCL chemokines in AH. Liver sinusoidal endothelial cells (LSEC) are identified as an important source of CXCL expression in human liver, regulated by TNFα/NF-κB signaling. A super-enhancer is identified for multiple CXCL genes by multiple approaches. dCas9-KRAB-mediated epigenome editing or pharmacologic inhibition of Bromodomain and Extraterminal (BET) proteins, transcriptional regulators vital to super-enhancer function, decreases chemokine expression in vitro and decreases neutrophil infiltration in murine models of AH. Our findings highlight the role of super-enhancer in propagating inflammatory signaling by inducing chemokine expression and the therapeutic potential of BET inhibition in AH treatment.


Assuntos
Quimiocinas/biossíntese , Citocinas/farmacologia , Elementos Facilitadores Genéticos , Hepatite Alcoólica/genética , Animais , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Epigênese Genética/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Histonas/metabolismo , Humanos , Lipopolissacarídeos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Regiões Promotoras Genéticas/genética , RNA-Seq , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
9.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34204008

RESUMO

Assisted reproductive technologies impact transcriptome and epigenome of embryos and can result in long-term phenotypic consequences. Whole-genome DNA methylation profiles from individual bovine blastocysts in vivo- and in vitro-derived (using three sources of protein: reproductive fluids, blood serum and bovine serum albumin) were generated. The impact of in vitro culture on DNA methylation was analyzed, and sex-specific methylation differences at blastocyst stage were uncovered. In vivo embryos showed the highest levels of methylation (29.5%), close to those produced in vitro with serum, whilst embryos produced in vitro with reproductive fluids or albumin showed less global methylation (25-25.4%). During repetitive element analysis, the serum group was the most affected. DNA methylation differences between in vivo and in vitro groups were more frequent in the first intron than in CpGi in promoters. Moreover, hierarchical cluster analysis showed that sex produced a stronger bias in the results than embryo origin. For each group, distance between male and female embryos varied, with in vivo blastocyst showing a lesser distance. Between the sexually dimorphic methylated tiles, which were biased to X-chromosome, critical factors for reproduction, developmental process, cell proliferation and DNA methylation machinery were included. These results support the idea that blastocysts show sexually-dimorphic DNA methylation patterns, and the known picture about the blastocyst methylome should be reconsidered.


Assuntos
Blastocisto/metabolismo , Reprogramação Celular/genética , Meios de Cultura/farmacologia , Epigênese Genética/efeitos dos fármacos , Caracteres Sexuais , Animais , Blastocisto/efeitos dos fármacos , Bovinos , Cromossomos de Mamíferos/genética , Ilhas de CpG/genética , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Feminino , Fertilização In Vitro , Ontologia Genética , Modelos Logísticos , Masculino , Anotação de Sequência Molecular , Análise de Componente Principal
10.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209014

RESUMO

Elevated concentrations of heavy metals such as cadmium (Cd) have a negative impact on staple crop production due to their ability to elicit cytotoxic and genotoxic effects on plants. In order to understand the relationship between Cd stress and plants in an effort to improve Cd tolerance, studies have identified genetic mechanisms which could be important for conferring stress tolerance. In recent years epigenetic studies have garnered much attention and hold great potential in both improving the understanding of Cd stress in plants as well as revealing candidate mechanisms for future work. This review describes some of the main epigenetic mechanisms involved in Cd stress responses. We summarize recent literature and data pertaining to chromatin remodeling, DNA methylation, histone acetylation and miRNAs in order to understand the role these epigenetic traits play in cadmium tolerance. The review aims to provide the framework for future studies where these epigenetic traits may be used in plant breeding and molecular studies in order to improve Cd tolerance.


Assuntos
Cádmio/toxicidade , Produtos Agrícolas/crescimento & desenvolvimento , Resistência a Medicamentos , Epigênese Genética/efeitos dos fármacos , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Produtos Agrícolas/efeitos dos fármacos , Produtos Agrícolas/genética , Metilação de DNA/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Código das Histonas/efeitos dos fármacos , MicroRNAs/efeitos dos fármacos , MicroRNAs/genética , RNA de Plantas/efeitos dos fármacos , RNA de Plantas/genética
11.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201550

RESUMO

With the improvement of the survival rate of acute lymphoblastic leukemia (ALL) in children, some children ALL survivors reveal inferior intellectual and cognition outcome. Methotrexate (MTX), while serving as an essential component in ALL treatment, has been reported to be related to various neurologic sequelae. Using combined intrathecal (IT) and intraperitoneal (IP) MTX model, we had demonstrated impaired spatial memory function in developing rats, which can be rescued by melatonin treatment. To elucidate the impact of MTX treatment on the epigenetic modifications of the myelination process, we examined the change of neurotrophin and myelination-related transcriptomes in the present study and found combined IT and IP MTX treatment resulted in altered epigenetic modification on the myelination process, mainly in the hippocampus. Further, melatonin can restore the MTX effect through alterations of the epigenetic pathways.


Assuntos
Encéfalo/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Metotrexato/toxicidade , Bainha de Mielina/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Animais , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/toxicidade , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Ilhas de CpG , Metilação de DNA/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Injeções Intraperitoneais , Injeções Espinhais , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Bainha de Mielina/patologia , Síndromes Neurotóxicas/patologia , Regiões Promotoras Genéticas/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteína-Arginina N-Metiltransferases/genética , Ratos Sprague-Dawley , Fatores de Transcrição SOXE/genética
12.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206404

RESUMO

Metabolic syndrome (MetS) is a cluster of several disorders, such as hypertension, central obesity, dyslipidemia, hyperglycemia, insulin resistance and non-alcoholic fatty liver disease. Despite health policies based on the promotion of physical exercise, the reduction of calorie intake and the consumption of healthy food, there is still a global rise in the incidence and prevalence of MetS in the world. This phenomenon can partly be explained by the fact that adverse events in the perinatal period can increase the susceptibility to develop cardiometabolic diseases in adulthood. Individuals born after intrauterine growth restriction (IUGR) are particularly at risk of developing cardiovascular diseases (CVD) and metabolic disorders later in life. It has been shown that alterations in the structural and functional integrity of the endothelium can lead to the development of cardiometabolic diseases. The endothelial progenitor cells (EPCs) are circulating components of the endothelium playing a major role in vascular homeostasis. An association has been found between the maintenance of endothelial structure and function by EPCs and their ability to differentiate and repair damaged endothelial tissue. In this narrative review, we explore the alterations of EPCs observed in individuals with cardiometabolic disorders, describe some mechanisms related to such dysfunction and propose some therapeutical approaches to reverse the EPCs dysfunction.


Assuntos
Células Progenitoras Endoteliais/metabolismo , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Animais , Senescência Celular/efeitos dos fármacos , Gerenciamento Clínico , Suscetibilidade a Doenças , Metabolismo Energético , Epigênese Genética/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/terapia , Especificidade de Órgãos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais , Pesquisa Médica Translacional
13.
Biomolecules ; 11(5)2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065479

RESUMO

The success of cannabinoids with chronic neuropathic pain and anxiety has been demonstrated in a multitude of studies. With the high availability of a non-intoxicating compound, cannabidiol (CBD), an over-the-counter medication, has generated heightened interest in its use in the field of oncology. This review focuses on the widespread therapeutic potential of CBD with regard to enhanced wound healing, lowered toxicity profiles of chemotherapeutics, and augmented antitumorigenic effects. The current literature is sparse with regard to determining the clinically relevant concentrations of CBD given the biphasic nature of the compound's response. Therefore, there is an imminent need for further dose-finding studies in order to determine the optimal dose of CBD for both intermittent and regular users. We address the potential influence of regular or occasional CBD usage on therapeutic outcomes in ovarian cancer patients. Additionally, as the development of chemoresistance in ovarian cancer results in treatment failure, the potential for CBD to augment the efficacy of conventional chemotherapeutic and epigenetic drugs is a topic of significant importance. Our review is focused on the widespread therapeutic potential of CBD and whether or not a synergistic role exists in combination with epigenetic and classic chemotherapy medications.


Assuntos
Antineoplásicos/uso terapêutico , Canabidiol/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Antineoplásicos/farmacologia , Canabidiol/farmacologia , Sinergismo Farmacológico , Epigênese Genética/efeitos dos fármacos , Feminino , Humanos , Medicamentos sem Prescrição , Neoplasias Ovarianas/genética , Resultado do Tratamento
14.
Biomolecules ; 11(5)2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34070036

RESUMO

Thalassemia, an inherited quantitative globin disorder, consists of two types, α- and ß-thalassemia. ß-thalassemia is a heterogeneous disease that can be asymptomatic, mild, or even severe. Considerable research has focused on investigating its underlying etiology. These studies found that DNA hypomethylation in the ß-globin gene cluster is significantly related to fetal hemoglobin (HbF) elevation. Histone modification reactivates γ-globin gene expression in adults and increases ß-globin expression. Down-regulation of γ-globin suppressor genes, i.e., BCL11A, KLF1, HBG-XMN1, HBS1L-MYB, and SOX6, elevates the HbF level. ß-thalassemia severity is predictable through FLT1, ARG2, NOS2A, and MAP3K5 gene expression. NOS2A and MAP3K5 may predict the ß-thalassemia patient's response to hydroxyurea, a HbF-inducing drug. The transcription factors NRF2 and BACH1 work with antioxidant enzymes, i.e., PRDX1, PRDX2, TRX1, and SOD1, to protect erythrocytes from oxidative damage, thus increasing their lifespan. A single ß-thalassemia-causing mutation can result in different phenotypes, and these are predictable by IGSF4 and LARP2 methylation as well as long non-coding RNA expression levels. Finally, the coinheritance of ß-thalassemia with α-thalassemia ameliorates the ß-thalassemia clinical presentation. In conclusion, the management of ß-thalassemia is currently limited to genetic and epigenetic approaches, and numerous factors should be further explored in the future.


Assuntos
Epigênese Genética , Globinas beta/genética , Talassemia beta/genética , Autoantígenos/genética , Molécula 1 de Adesão Celular/genética , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Código das Histonas/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Mutação , RNA não Traduzido/genética , Ribonucleoproteínas/genética , Talassemia beta/tratamento farmacológico
15.
Mol Cell Biol ; 41(9): e0044920, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34124933

RESUMO

A desynchronized circadian rhythm in tumors is coincident with aberrant inflammation and dysregulated metabolism. As their interrelationship in cancer etiology is largely unknown, we investigated the link among the three in glioma. The tumor metabolite lactate-mediated increase in the proinflammatory cytokine interleukin-1ß (IL-1ß) was concomitant with elevated levels of the core circadian regulators Clock and Bmal1. Small interfering RNA (siRNA)-mediated knockdown of Bmal1 and Clock decreased (i) lactate dehydrogenase A (LDHA) and IL-1ß levels and (ii) the release of lactate and proinflammatory cytokines. Lactate-mediated deacetylation of Bmal1 and its interaction with Clock regulate IL-1ß levels and vice versa. Site-directed mutagenesis and luciferase reporter assays indicated the functionality of E-box sites on LDHA and IL-1ß promoters. Sequential chromatin immunoprecipitation (ChIP-re-ChIP) revealed that lactate-IL-1ß cross talk positively affects the corecruitment of Clock-Bmal1 to these E-box sites. Clock-Bmal1 enrichment was accompanied by decreased H3K9me3 and increased H3K9ac and RNA polymerase II (Pol II) occupancy. The lactate-IL-1ß-Clock (LIC) loop positively regulated the expression of genes associated with the cell cycle, DNA damage, and cytoskeletal organization involved in glioma progression. TCGA (The Cancer Genome Atlas) data analysis suggested the presence of lactate-IL-1ß cross talk in other cancers. The responsiveness of stomach and cervical cancer cells to lactate inhibition followed the same trend as that exhibited by glioma cells. In addition, components of the LIC loop were found to be correlated with (i) patient survival, (ii) clinically actionable genes, and (iii) anticancer drug sensitivity. Our findings provide evidence for potential cancer-specific axis wiring of IL-1ß and LDHA through Clock-Bmal1, the outcome of which is to fuel an IL-1ß-lactate autocrine loop that drives proinflammatory and oncogenic signals.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Relógios Circadianos , Glioma/metabolismo , Homeostase , Interleucina-1beta/metabolismo , Ácido Láctico/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Relógios Circadianos/efeitos dos fármacos , Relógios Circadianos/genética , Citocinas/metabolismo , Progressão da Doença , Elementos E-Box/genética , Epigênese Genética/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Glioma/tratamento farmacológico , Glioma/genética , Glioma/patologia , Homeostase/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-1beta/genética , Lactato Desidrogenase 5/genética , Lactato Desidrogenase 5/metabolismo , Regiões Promotoras Genéticas , Análise de Sobrevida
16.
Eur J Med Chem ; 222: 113588, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34107385

RESUMO

Abnormal epigenetics is a critical hallmark of human cancers. Anticancer drug discovery directed at histone epigenetic modulators has gained impressive advances with six drugs available for cancer therapy and numerous other candidates undergoing clinical trials. However, limited therapeutic profile, drug resistance, narrow safety margin, and dose-limiting toxicities pose intractable challenges for their clinical utility. Because histone epigenetic modulators undergo intricate crosstalk and act cooperatively to shape an aberrant epigenetic profile, co-targeting histone epigenetic modulators with a different mechanism of action has rapidly emerged as an attractive strategy to overcome the limitations faced by the single-target epigenetic inhibitors. In this review, we summarize in detail the crosstalk of histone epigenetic modulators in regulating gene transcription and the progress of dual epigenetic inhibitors targeting this crosstalk.


Assuntos
Antineoplásicos/farmacologia , Epigênese Genética/efeitos dos fármacos , Histonas/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Epigênese Genética/genética , Histonas/genética , Humanos , Estrutura Molecular , Neoplasias/genética
17.
Methods Mol Biol ; 2326: 123-141, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34097265

RESUMO

Epigenetics is one of the most rapidly expanding fields in biology, which plays important roles in environmental pollutant-induced neurotoxicity. Analyses of epigenetic modification is of great significance in providing more accurate information for the risk assessment and management of harmful factors. However, few studies have systematically summarized the analysis and detection methods for epigenetic modification. In this chapter, we summarized several popular methods for analyses of epigenetic modifications, including Methylated DNA Immunoprecipitation Sequencing (MeDIP-Seq) for genome-wide DNA methylation analyses, Quantitative Methylation Specific PCR (qMSP) for genome-specific DNA methylation analyses, methylated RNA immunoprecipitation sequencing (MeRIP-seq) for genome-wide RNA methylation analyses, MeRIP-qPCR for genome-specific RNA methylation analyses, qRT-PCR for the non-coding RNA, and western blot for the histone modification analyses. It could be helpful to the research about environmental epigenetic toxicology.


Assuntos
Poluentes Ambientais/toxicidade , Epigênese Genética/efeitos dos fármacos , Animais , DNA/genética , Metilação de DNA/efeitos dos fármacos , Epigenômica/métodos , Código das Histonas/efeitos dos fármacos , Humanos , Imunoprecipitação/métodos , Reação em Cadeia da Polimerase/métodos , RNA/genética , Análise de Sequência de DNA/métodos , Análise de Sequência de RNA/métodos
18.
Vasc Health Risk Manag ; 17: 247-254, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079271

RESUMO

Despite the current reductionist approach providing an optimal indication for diagnosis and treatment of patients with heart failure with reduced ejection fraction (HFrEF), there are no standard pharmacological therapies for heart failure with preserved ejection fraction (HFpEF). Although in its infancy in cardiovascular diseases, the epigenetic-based therapy ("epidrugs") is capturing the interest of physician community. In fact, an increasing number of controlled clinical trials is evaluating the putative beneficial effects of: 1) direct epigenetic-oriented drugs, eg, apabetalone, and 2) repurposed drugs with a possible indirect epigenetic interference, eg, metformin, statins, sodium glucose transporter inhibitors 2 (SGLT2i), and omega 3 polyunsaturated fatty acids (PUFAs) in both HFrEF and HFpEF, separately. Apabetalone is the first and unique direct epidrug tested in cardiovascular patients to date, and the BETonMACE trial has reported a reduction in first HF hospitalization (any EF value) and cardiovascular death in patients with type 2 diabetes and recent acute coronary syndrome, suggesting a possible role in secondary prevention. Patients with HFpEF seem to benefit from supplementation to the standard therapy with statins, metformin, and SGLT2i owing to their ability in reducing mortality. In contrast, the vasodilator hydralazine, with or without isosorbide dinitrate, did not provide beneficial effects. In HFrEF, metformin and SGLT2i could reduce the risk of incident HF and mortality in affected patients whereas clinical trials based on statins provided mixed results. Furthermore, PUFAs diet supplementation was significantly associated with reduced cardiovascular risk in both HFpEF and HFrEF. Future large trials will reveal whether direct and indirect epitherapy will remain a work in progress or become a useful way to customize the therapy in the real-world management of HFpEF and HFrEF. Our goal is to discuss the recent advancement in the epitherapy as a possible way to improve personalized therapy of HF.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Reposicionamento de Medicamentos , Epigênese Genética/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Quinazolinonas/uso terapêutico , Fármacos Cardiovasculares/efeitos adversos , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Humanos , Quinazolinonas/efeitos adversos , Resultado do Tratamento
19.
Nutrients ; 13(5)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062793

RESUMO

Selenium (Se) is an essential element for the maintenance of a healthy physiological state. However, due to environmental and dietary factors and the narrow safety range of Se, diseases caused by Se deficiency or excess have gained considerable traction in recent years. In particular, links have been identified between low Se status, cognitive decline, immune disorders, and increased mortality, whereas excess Se increases metabolic risk. Considerable evidence has suggested microRNAs (miRNAs) regulate interactions between the environment (including the diet) and genes, and play important roles in several diseases, including cancer. MiRNAs target messenger RNAs to induce changes in proteins including selenoprotein expression, ultimately generating disease. While a plethora of data exists on the epigenetic regulation of other dietary factors, nutrient Se epigenetics and especially miRNA regulated mechanisms remain unclear. Thus, this review mainly focuses on Se metabolism, pathogenic mechanisms, and miRNAs as key regulatory factors in Se-related diseases. Finally, we attempt to clarify the regulatory mechanisms underpinning Se, miRNAs, selenoproteins, and Se-related diseases.


Assuntos
Doenças Metabólicas/metabolismo , MicroRNAs/efeitos dos fármacos , Fenômenos Fisiológicos da Nutrição/genética , Selênio/metabolismo , Selenoproteínas/metabolismo , Epigênese Genética/efeitos dos fármacos , Humanos , Doenças Metabólicas/genética
20.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34066960

RESUMO

DNA replication timing (RT), reflecting the temporal order of origin activation, is known as a robust and conserved cell-type specific process. Upon low replication stress, the slowing of replication forks induces well-documented RT delays associated to genetic instability, but it can also generate RT advances that are still uncharacterized. In order to characterize these advanced initiation events, we monitored the whole genome RT from six independent human cell lines treated with low doses of aphidicolin. We report that RT advances are cell-type-specific and involve large heterochromatin domains. Importantly, we found that some major late to early RT advances can be inherited by the unstressed next-cellular generation, which is a unique process that correlates with enhanced chromatin accessibility, as well as modified replication origin landscape and gene expression in daughter cells. Collectively, this work highlights how low replication stress may impact cellular identity by RT advances events at a subset of chromosomal domains.


Assuntos
Período de Replicação do DNA , Estresse Fisiológico , Afidicolina/farmacologia , Linhagem Celular Tumoral , Cromatina/metabolismo , Dano ao DNA , Período de Replicação do DNA/genética , Epigênese Genética/efeitos dos fármacos , Loci Gênicos , Código das Histonas , Humanos , Modelos Biológicos , Estresse Fisiológico/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...