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1.
Nat Commun ; 11(1): 4496, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901024

RESUMO

Aging is characterized by the loss of homeostasis and the general decline of physiological functions, accompanied by various degenerative diseases and increased rates of mortality. Aging targeting small molecule screens have been performed many times, however, few have focused on endogenous metabolic intermediates-metabolites. Here, using C. elegans lifespan assays, we conducted a worm metabolite screen and identified an eukaryotes conserved metabolite, myo-inositol (MI), to extend lifespan, increase mobility and reduce fat content. Genetic analysis of enzymes in MI metabolic pathway suggest that MI alleviates aging through its derivative PI(4,5)P2. MI and PI(4,5)P2 are precursors of PI(3,4,5)P3, which is negatively related to longevity. The longevity effect of MI is dependent on the tumor suppressor gene, daf-18 (homologous to mouse Pten), independent of its classical pathway downstream genes, akt or daf-16. Furthermore, we found MI effects on aging and lifespan act through mitophagy regulator PTEN induced kinase-1 (pink-1) and mitophagy. MI's anti-aging effect is also conserved in mouse, indicating a conserved mechanism in mammals.


Assuntos
Envelhecimento/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Inositol/metabolismo , Longevidade/fisiologia , PTEN Fosfo-Hidrolase/metabolismo , Envelhecimento/efeitos dos fármacos , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Linhagem Celular Tumoral , Feminino , Fatores de Transcrição Forkhead/genética , Inositol/administração & dosagem , Locomoção/fisiologia , Longevidade/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Metabolômica , Camundongos , Mitofagia/fisiologia , Modelos Animais , Fosfatos de Fosfatidilinositol/metabolismo , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , RNA-Seq
2.
Nat Commun ; 11(1): 4516, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908137

RESUMO

Acinar metaplasia is an initial step in a series of events that can lead to pancreatic cancer. Here we perform single-cell RNA-sequencing of mouse pancreas during the progression from preinvasive stages to tumor formation. Using a reporter gene, we identify metaplastic cells that originated from acinar cells and express two transcription factors, Onecut2 and Foxq1. Further analyses of metaplastic acinar cell heterogeneity define six acinar metaplastic cell types and states, including stomach-specific cell types. Localization of metaplastic cell types and mixture of different metaplastic cell types in the same pre-malignant lesion is shown. Finally, single-cell transcriptome analyses of tumor-associated stromal, immune, endothelial and fibroblast cells identify signals that may support tumor development, as well as the recruitment and education of immune cells. Our findings are consistent with the early, premalignant formation of an immunosuppressive environment mediated by interactions between acinar metaplastic cells and other cells in the microenvironment.


Assuntos
Células Acinares/patologia , Carcinoma Ductal Pancreático/genética , Regulação Neoplásica da Expressão Gênica , Pâncreas/patologia , Neoplasias Pancreáticas/genética , Lesões Pré-Cancerosas/genética , Animais , Animais Geneticamente Modificados , Biópsia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Diferenciação Celular , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Heterogeneidade Genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Estimativa de Kaplan-Meier , Masculino , Metaplasia/genética , Camundongos , Mutação , Pâncreas/citologia , Pâncreas/cirurgia , Pancreatectomia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Lesões Pré-Cancerosas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA-Seq , Análise de Célula Única , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Microambiente Tumoral/genética
3.
Chem Biol Interact ; 329: 109222, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32771325

RESUMO

Extensive application of methylene blue (MB) for therapeutic and diagnostic purposes, and reports for unwanted side effects, demand better understanding of the mechanisms of biological action of this thiazine dye. Because MB is redox-active, its biological activities have been attributed to transfer of electrons, generation of reactive oxygen species, and antioxidant action. Results of this study show that MB is more toxic to a superoxide dismutase-deficient Escherichia coli mutant than to its SOD-proficient parent, which indicates that superoxide anion radical is involved. Incubation of E. coli with MB induced the enzymes fumarase C, SOD, nitroreductase A, and glucose-6-phosphate dehydrogenase, all controlled by the soxRS regulon. Induction of these enzymes was prevented by blocking protein synthesis with chloramphenicol and was not observed when soxRS-negative mutants were incubated with MB. These results show that MB is capable of inducing the soxRS regulon of E. coli, which plays a key role in protecting bacteria against oxidative stress and redox-cycling compounds. Irrespective of the abundance of heme-containing proteins in living cells, which are preferred acceptors of electrons from the reduced form of MB, reduction of oxygen to superoxide radical still takes place. Induction of the soxRS regulon suggests that in humans, beneficial effects of MB could be attributed to activation of redox-sensitive transcription factors like Nrf2 and FoxO. If defense systems are compromised or genes coding for protective proteins are not induced, MB would have deleterious effects.


Assuntos
Proteínas de Bactérias/metabolismo , Proteínas de Escherichia coli/metabolismo , Escherichia coli/metabolismo , Azul de Metileno/farmacologia , Regulon/efeitos dos fármacos , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Proteínas de Bactérias/genética , Cloranfenicol/farmacologia , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Fumarato Hidratase/genética , Fumarato Hidratase/metabolismo , Glucosefosfato Desidrogenase/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Superóxidos/metabolismo , Transativadores/genética , Fatores de Transcrição/genética
4.
Gene ; 763: 145073, 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-32827684

RESUMO

BACKGROUND: The role of FoxP3, a master regulator of T regulatory cells, in allergic diseases such as asthma is of immense importance yet the effect of its gene variants on the disease predisposition is not fully understood. We studied the association of FoxP3 polymorphisms (-2383C/T and -3279C/A) in allergic asthma patients and their correlation with serum IL-4, IL-13, Total IgE, and Vitamin D levels. METHODS: In this study 350 individuals were enrolled, 150 allergic asthma patients and 200 healthy controls. SNP analyses were performed by RFLP. IL-4, IL-13 vitamin D and Total IgE were measured by ELISA. RESULTS: The AA homozygous mutant of -3279C/A posed a three-fold risk [P < 0.005; OR, 3.52] whereas the -2383C/T variants TT genotype carried a fourfold risk [P = 0.002; OR, 4.04]. Haplotype analysis exhibited predisposition to allergic asthmawith CC/TT [P = 0.01; OR 5.93 (95%CI)], AA/CC [P = 0.01; OR 3.29] and AA/TT haplotypes [P = 0; OR 11.86 (1.31-85.87)]. A negative correlation between IgE and Vitamin D was found [r = -0.30p-value 0.001] but a negative correlation betweenIgE and Vit D was established in the haplotype CC/TT [r = -0.45P = 0.002] and CC/CT [r = -0.52P = 0.04]. In allergic patients, the eosinophils count was high [p = 0.003] and the mean levels of pro-inflammatory cytokines IL-4 and IL-13 were elevated [P < 0.001] as well. CONCLUSIONS: The study suggests SNP -3279 -AA genotype and, -2383-TT genotype in association with certain haplotypes pose a risk for allergy development. There was no correlation between different genotypes and serum levels of various cytokines.


Assuntos
Asma/genética , Fatores de Transcrição Forkhead/genética , Polimorfismo de Nucleotídeo Único , Adulto , Asma/sangue , Eosinofilia/sangue , Eosinofilia/genética , Feminino , Humanos , Imunoglobulina E/sangue , Interleucina-13/sangue , Interleucina-4/sangue , Masculino , Vitamina D/sangue
5.
Proc Natl Acad Sci U S A ; 117(33): 20088-20099, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32732436

RESUMO

T lymphocyte motility and interaction dynamics with other immune cells are vital determinants of immune responses. Regulatory T (Treg) cells prevent autoimmune disorders by suppressing excessive lymphocyte activity, but how interstitial motility patterns of Treg cells limit neuroinflammation is not well understood. We used two-photon microscopy to elucidate the spatial organization, motility characteristics, and interactions of endogenous Treg and Th17 cells together with antigen-presenting cells (APCs) within the spinal cord leptomeninges in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Th17 cells arrive before the onset of clinical symptoms, distribute uniformly during the peak, and decline in numbers during later stages of EAE. In contrast, Treg cells arrive after Th17 cells and persist during the chronic phase. Th17 cells meander widely, interact with APCs, and exhibit cytosolic Ca2+ transients and elevated basal Ca2+ levels before the arrival of Treg cells. In contrast, Treg cells adopt a confined, repetitive-scanning motility while contacting APCs. These locally confined but highly motile Treg cells limit Th17 cells from accessing APCs and suppress Th17 cell Ca2+ signaling by a mechanism that is upstream of store-operated Ca2+ entry. Finally, Treg cell depletion increases APC numbers in the spinal cord and exaggerates ongoing neuroinflammation. Our results point to fundamental differences in motility characteristics between Th17 and Treg cells in the inflamed spinal cord and reveal three potential cellular mechanisms by which Treg cells regulate Th17 cell effector functions: reduction of APC density, limiting access of Th17 cells to APCs, and suppression of Th17 Ca2+ signaling.


Assuntos
Sinalização do Cálcio/fisiologia , Medula Espinal/metabolismo , Células Th17/metabolismo , Animais , Autoantígenos , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Proteínas de Fluorescência Verde , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Bainha de Mielina , Linfócitos T Reguladores
6.
Sci Total Environ ; 746: 141181, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32768781

RESUMO

Circular RNA (circRNA) has been shown to be widely involved in a variety of lung diseases. Cigarette smoke (CS) may induce epithelial-mesenchymal transition (EMT) of airway remodeling in chronic obstructive pulmonary disease (COPD), however, in which the roles and mechanisms of circRNA have not been elucidated. In this study, we aimed to determine whether circ0061052 is involved in the EMT of human bronchial epithelial (HBE) cells and its potential mechanism for playing a biological role. Cigarette smoke extract (CSE) caused elevated EMT indicators and the increases of circ0061052 in HBE cells. Circ0061052 has a ring structure and is mainly present in the cytoplasm of HBE cells. We analyzed the regulatory relationship between circ0061052 and miR-515-5p using bioinformatics, a luciferase reporter gene, and qRT-PCR. We found that circ0061052 is mainly distributed in the cytoplasm and competitively binds to miR-515-5p, acting as a sponge for miR-515-5p. The luciferase reporter gene showed that miR-515-5p binds to the 3'UTR region of FoxC1 mRNA to inhibit its transcription. For HBE cells, overexpression of miR-515-5p antagonized the CSE-induced EMT. In addition, circ0061052 acts by binding miR-515-5p competitively to regulate the expression of FoxC1/Snail. When circ0061052 siRNA and miR-515-5p inhibitor were co-transfected into HBE cells, the inhibitor reversed the effect of circ0061052 siRNA on reducing EMT. Chronic exposure of mice to CS induced increases of circ0061052 levels, decreases of miR-515-5p levels, and the EMT in lung tissue, which caused dysfunction and airway obstruction. Overall, the results show that, by regulating miR-515-5p through a FoxC1/Snail regulatory axis, circ0061052 is involved in the CS-induced EMT and airway remodeling in COPD.


Assuntos
Transição Epitelial-Mesenquimal , MicroRNAs/genética , Remodelação das Vias Aéreas , Animais , Células Epiteliais , Fatores de Transcrição Forkhead/genética , Humanos , Camundongos , Fumar
7.
PLoS Genet ; 16(8): e1008982, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32841230

RESUMO

High glucose diets are unhealthy, although the mechanisms by which elevated glucose is harmful to whole animal physiology are not well understood. In Caenorhabditis elegans, high glucose shortens lifespan, while chemically inflicted glucose restriction promotes longevity. We investigated the impact of glucose metabolism on aging quality (maintained locomotory capacity and median lifespan) and found that, in addition to shortening lifespan, excess glucose negatively impacts locomotory healthspan. Conversely, disrupting glucose utilization by knockdown of glycolysis-specific genes results in large mid-age physical improvements via a mechanism that requires the FOXO transcription factor DAF-16. Adult locomotory capacity is extended by glycolysis disruption, but maximum lifespan is not, indicating that limiting glycolysis can increase the proportion of life spent in mobility health. We also considered the largely ignored role of glucose biosynthesis (gluconeogenesis) in adult health. Directed perturbations of gluconeogenic genes that specify single direction enzymatic reactions for glucose synthesis decrease locomotory healthspan, suggesting that gluconeogenesis is needed for healthy aging. Consistent with this idea, overexpression of the central gluconeogenic gene pck-2 (encoding PEPCK) increases health measures via a mechanism that requires DAF-16 to promote pck-2 expression in specific intestinal cells. Dietary restriction also features DAF-16-dependent pck-2 expression in the intestine, and the healthspan benefits conferred by dietary restriction require pck-2. Together, our results describe a new paradigm in which nutritional signals engage gluconeogenesis to influence aging quality via DAF-16. These data underscore the idea that promotion of gluconeogenesis might be an unappreciated goal for healthy aging and could constitute a novel target for pharmacological interventions that counter high glucose consequences, including diabetes.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Fatores de Transcrição Forkhead/genética , Gluconeogênese/genética , Envelhecimento Saudável/genética , Animais , Restrição Calórica , Regulação da Expressão Gênica no Desenvolvimento/genética , Glucose/metabolismo , Humanos , Expectativa de Vida , Longevidade/genética , Fosfoenolpiruvato Carboxiquinase (ATP)/genética , Transdução de Sinais/genética
8.
Gene ; 757: 144931, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32640308

RESUMO

OBJECTIVE: The aim of this study is to investigate the role of close homolog of L1 (CHL1) on inflammatory bowel disease (IBD), and the correlation with the balance of Th17/Treg. METHODS: Dextran sodium sulfate (DSS)-induced IBD mice model was established. CHL1 knockout (KO) mice and CHL1 wild-type (WT) mice were subjected to DSS. CHL1 expression was detected using qRT-PCR. Weight was recorded daily, and disease activity index (DAI) score was assessed. The colon length and histological changes were measured. The number of neutrophils, macrophages and T cells was observed by immunohistochemistry. The expression of inflammatory cytokines and the proportion of Th17/Treg cells were detected by qRT-PCR and flow cytometry. The expression of RORγt, STAT3 and Foxp3 was detected by using immunohistochemistry and Western blot. RESULTS: CHL1 expression was upregulated in DSS-induced IBD mice. DSS-CHLl-KO mice exhibited less weight loss than the DSS-CHLl-WT mice. The DAI score and histological score were decreased in DSS-CHLl-KO mice compared with DSS-CHLl-WT mice, while colon length was increased. Number of neutrophils, macrophages and T cells, and expression of TNF-α, IL-6, IL-17A, IL-21 and IL-23 were decreased in DSS-CHLl-KO mice, while IL-10 expression was increased. Moreover, CHL1-deficient inhibited Th17 cells differentiation and promoted Treg cells differentiation in IBD mice. CHL1-deficient also inhibited the expression of RORγt and STAT3, and promoted the expression of Foxp3 in IBD mice. CONCLUSION: CHL1-deficient reduces the inflammatory response by regulating the balance of Th17/Treg in mice with IBD. CHL1 is expected to be a new target for the treatment of IBD.


Assuntos
Moléculas de Adesão Celular/genética , Doenças Inflamatórias Intestinais/genética , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Moléculas de Adesão Celular/deficiência , Diferenciação Celular , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/imunologia , Interleucinas/genética , Interleucinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Linfócitos T Reguladores/citologia , Células Th17/citologia
9.
Brain Tumor Pathol ; 37(3): 100-104, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32535663

RESUMO

A subset of central nervous system neuroblastomas (CNS NB), rare primary embryonal CNS tumors, has been encompassed in CNS NB with FOXR2 activation (CNS NB-FOXR2) and usually shows the primitive neuronal architecture and occasional neurocytic differentiation. Here, we report a rare case of 3-year-old female with uncommon morphology of CNS embryonal tumor with FOXR2 activation presenting bidirectional differentiation to neurocytic small primitive cells and astrocytic spindle cells both of which are positive for synaptophysin and GFAP. Ultrastructural study also showed that there were presynaptic structure and intermediate filament in the tumor cells, suggesting glioneuronal differentiation. This case indicates the possibility of CNS neuroblastic tumor to differentiate neuronal and glial lineages.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Fatores de Transcrição Forkhead/genética , Neuroblastoma/genética , Neuroblastoma/patologia , Neuroglia/patologia , Neurônios/patologia , Ativação Transcricional , Neoplasias Encefálicas/diagnóstico por imagem , Pré-Escolar , Feminino , Humanos , Imagem por Ressonância Magnética , Neuroblastoma/diagnóstico por imagem , Tomografia Computadorizada por Raios X
10.
Medicine (Baltimore) ; 99(26): e20630, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32590737

RESUMO

Previous studies have suggested that the anticancer agent, arsenic trioxide (ATO), could attenuate T cell mediated immunity by not only inhibiting the proliferative response of T cells but by also increasing the frequency of regulatory T cells (Tregs). Furthermore, ATO represents a reasonable salvage treatment in some patients with refractory severe aplastic anemia (SAA). The current study aimed to evaluate the function of ATO on the Tregs percentage and cytokines changes in the peripheral blood mononuclear cells (PBMCs) of SAA patients.PBMCs were collected from 20 newly diagnosed SAA patients in Henan Cancer Hospital and treated with different concentrations of ATO (0, 1, 2.5, and 5 µmol/L). Then we investigated the efficacy of ATO on Tregs ratio and the levels of interferon (IFN)-γ, interleukin (IL)-4, IL-17 and transforming growth factor (TGF)-ß1 in the peripheral blood of SAA patients in vitro.The results showed that ATO significantly increased the proportion of Tregs (P < .001) at 2.5 and 5 µmol/L concentrations, and the proportion of Tregs was increased with increasing ATO concentration (r = 0.524). At 1 (P = .03), 2.5 (P < .001) and 5 µmol/L (P < .001), ATO significantly up-regulated the expression levels of Foxp3 mRNA, which was positively and linearly correlated with the increase of Tregs cell-frequency (r = 0.52, 95%CI, 0.37-0.67). In addition, ATO significantly reduced the levels of IFN-γ (at 1, 2.5 and 5 µmol/L, P < .001), IL-4 (at 2.5 µmol/L, P = .009; at 5 µmol/L, P < .001), and IL-17 (at 2.5, P = .016; at 5 µmol/L, P < .001). ATO significantly reduced the levels of TGF-ß1 at 5 µmol/L (P = .03), but showed no significant effects at 1 and 2.5 µmol/L (P > .05).ATO could mediate the immune regulation, which might contribute to improve hematopoietic recovery in SAA patients.


Assuntos
Anemia Aplástica/sangue , Antineoplásicos/administração & dosagem , Trióxido de Arsênio/administração & dosagem , Interferon gama/sangue , Interleucina-17/sangue , Interleucina-4/sangue , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta1/sangue , Anemia Aplástica/tratamento farmacológico , Apoptose/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Humanos , Leucócitos Mononucleares/metabolismo , Macrófagos/metabolismo , RNA Mensageiro/metabolismo , Regulação para Cima
11.
Virology ; 548: 6-16, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32530809

RESUMO

Gastric carcinoma (GC) is an Epstein-Barr virus (EBV)-associated malignancy characterized by early metastasis. Unlike that of cellular micro(mi)RNAs, the role of viral miRNAs in epithelial-mesenchymal transition (EMT) and metastasis in cancers has not been fully investigated. In this study, we elucidated the involvement of miR-BART11, an EBV-encoded viral miRNA, in the EMT and metastasis of GC cells. EBV-miR-BART11 upregulation can lead to downregulation of forkhead box protein P1 (FOXP1) in both tissues and cell lines of gastric carcinoma. Downregulation of FOXP1 might trigger the secretion of interleukin 1ß (IL-1ß), IL-6, and 1L-10 in cancer cells, resulting in poor survival of GC patients. We found that the observed EMT phenotypes resulted from the EBV-miR-BART11 overexpression-induced FOXP1 downregulation, which impacted the expression of the EMT-transcription factors E-cadherin and snail. We further demonstrated that conditioned medium-derived tumor-associated macrophages (TAMs) promoted phenotypic changes and expression of EMT-related molecules in GC cells. Additionally, EMT changes were significantly promoted in GC cells cultured in conditioned medium from TAMs infected with EBV-miR-BART11-containing lentivirus. On the contrary, GC cells cultured in conditioned medium from TAMs infected with FOXP1-carrying lentivirus showed little or no EMT change. Taken together, our results suggest that EBV-encoded viral miRNA BART11 downregulates the FOXP1 transcription factor, and promotes EMT by directly influencing gastric tumor cells or indirectly affecting the tumor microenvironment, which might, in turn, accelerate cancer invasion and metastasis, thereby affecting the survival and prognosis of patients.


Assuntos
Transição Epitelial-Mesenquimal , Infecções por Vírus Epstein-Barr/fisiopatologia , Fatores de Transcrição Forkhead/metabolismo , Herpesvirus Humano 4/metabolismo , Macrófagos/citologia , MicroRNAs/metabolismo , Proteínas Repressoras/metabolismo , Neoplasias Gástricas/fisiopatologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/metabolismo , Infecções por Vírus Epstein-Barr/virologia , Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica , Herpesvirus Humano 4/genética , Interações Hospedeiro-Patógeno , Humanos , Macrófagos/metabolismo , MicroRNAs/genética , Proteínas Repressoras/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/virologia
13.
Zhonghua Zhong Liu Za Zhi ; 42(5): 369-375, 2020 May 23.
Artigo em Chinês | MEDLINE | ID: mdl-32482025

RESUMO

Objective: To investigate the effects and the mechanism of FoxO6 on the proliferation and invasion of colorectal cancer cells. Methods: FoxO6 siRNA was transfected into colorectal cancer cell HCT116 and SW480. The overexpression vector pcDNA.3.1-c-Myc was constructed and co-transfected into HCT116 and SW480 cells with FoxO6 siRNA. Real-time fluorescent quantitative PCR (RT-qPCR) and western blot were used to detect the mRNA and protein expressions of FoxO6, c-Myc, and p21 in HCT116 and SW480 cells. Bromodeoxyuridine (BrdU) was used to detect cell proliferation and Transwell assay was performed to detect the invasion ability of these cells. SW480 cells transfected with FoxO6 shRNA lentivirus (LV-FoxO6) and were injected into the right armpit of BAL b/c nude mice to construct a tumor-bearing mode and the tumor volumes were measured on the days of 10, 13, 16, 19, 22, and 25 after injection. Results: The FoxO6 mRNA were 0.91±0.04, 1.72±0.07, and 2.03±0.06, and protein expression were 0.70±0.04, 1.35±0.08, and 1.56±0.07 in normal colon cell FHC, colorectal cancer cells HT116 and SW480, respectively. The protein and mRNA levels of FoxO6 in HCT116 and SW480 were significantly higher than those in FHC (both P<0.05). Knockdown of FoxO6 in HCT116 and SW480 cells decreased the mRNA and protein expressions of FoxO6 (both P<0.05), the cell proliferation ability (absorbances were 0.26±0.07 and 0.27±0.06, both P<0.05), cell invasion ability (the invaded cell numbers were 42.3±3.3 and 45.7±4.1, both P<0.05), and the mRNA and protein expressions of c-Myc, while increased the mRNA and protein expressions of p21 (both P<0.01). Overexpression of Myc in FoxO6 silenced HCT116 and SW480 cells decreased the expression of p21, while increased the cell proliferation ability (absorbances were 0.54±0.09 and 0.58±0.07, both P<0.01) and invasion ability (the invaded cell numbers were 79.2±5.9 and 80.5±6.4, both P<0.01). On the 25th day after cell inoculation in nude mice, the tumor volume of LV-FoxO6 group was (190.6±36.2) mm(3), significantly lower than (437.8.6±69.2) mm(3) of LV-NC group (P<0.05). Conclusion: FoxO6 promotes the proliferation and invasion of colorectal cancer cells through facilitating c-Myc mediated p21 expression inhibition.


Assuntos
Neoplasias do Colo/metabolismo , Neoplasias Colorretais/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias do Colo/patologia , Neoplasias Colorretais/patologia , Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica/genética , Células HCT116 , Humanos , Camundongos , Camundongos Nus
14.
Gene ; 753: 144777, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32428695

RESUMO

As a crucial member of the Forkhead Box family, class O (FoxO) plays an essential role in growth, cell differentiation, metabolism, immunization, and apoptosis. Meanwhile, FoxO3 is the primary regulator and effective inhibitor of primordial follicle activation. In this study, seven foxo genes were identified in black rockfish (Sebastes schlegelii), including two foxo1 genes (foxo1a, foxo1b), two foxo3 genes (foxo3, foxo3l), one foxo4 gene, and two foxo6 genes (foxo6a, foxo6b). foxo3l was derived from teleost-specific whole-genome duplication events. Evaluation of tissue expression pattern revealed that foxo3l displayed sexually dimorphic expression with a high level in the ovary and spatial expression only in the cytoplasm of follicle cells and oocytes. When the ovaries were stimulated by estrogen and gonadotropin, foxo3l expression was remarkably reduced, and the effect of androgen was completely different. We considered that foxo3l lost its ability to inhibit follicular precocity because of mass ovulation by hormone stimulation, resulting in its decreased expression. Such evidence indicated that foxo3l is an important regulator of reproduction-related functions in black rockfish. This study provides new insights into foxo3l genes for further functional research in teleost.


Assuntos
Proteína Forkhead Box O3/genética , Perciformes/genética , Sequência de Aminoácidos , Animais , Feminino , Doenças dos Peixes/imunologia , Proteínas de Peixes/genética , Proteína Forkhead Box O3/metabolismo , Fatores de Transcrição Forkhead/genética , Duplicação Gênica/genética , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Imunidade Inata/genética , Oócitos/metabolismo , Oogênese/genética , Ovário/metabolismo , Filogenia , Alinhamento de Sequência
15.
Chemosphere ; 256: 127172, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32470744

RESUMO

Nanoplastic exposure could cause toxicity to Caenorhabditis elegans at various aspects. Nevertheless, the effects of chronic exposure to nanoplastics remain largely unclear in nematodes. In this study, we employed C. elegans as an animal model to determine the effects of nanopolystyrene (30 nm) exposure from adult day-1 for 8-day. After the exposure, only 1000 µg/L nanopolystyrene reduced the lifespan. In contrast, nanopolystyrene ≥1 µg/L decreased locomotion behavior and activated oxidative stress. Meanwhile, in 10 µg/L nanopolystyrene exposed nematodes, both expression of SOD-3, a Mn-SOD, and autophagy induction as indicated by LGG-1:GFP expression were significantly increased. RNAi knockdown of daf-2 encoding an insulin receptor enhanced the autophagy induction, and RNAi knockdown of daf-16 encoding a FOXO transcriptional factor in insulin signaling pathway suppressed the autophagy induction in 10 µg/L nanopolystyrene exposed nematodes. Moreover, DAF-16 acted upstream of LGG-1, an ortholog of Atg8/LC3, to regulate the toxicity of nanopolystyrene toxicity in inducing ROS production and in decreasing locomotion behavior at adult day-9. Our data implied the potential toxicity of chronic exposure to nanoplastics at predicted environmental concentrations on organisms.


Assuntos
Autofagia/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Poliestirenos/toxicidade , Animais , Proteínas de Caenorhabditis elegans/biossíntese , Proteínas de Caenorhabditis elegans/genética , Fatores de Transcrição Forkhead/genética , Insulina/metabolismo , Locomoção/genética , Longevidade , Modelos Animais , Interferência de RNA , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Transdução de Sinais , Superóxido Dismutase/biossíntese
16.
Invest Ophthalmol Vis Sci ; 61(5): 31, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32428232

RESUMO

Purpose: More recently, literature has emerged providing findings about the novelty of microRNAs (miR)-targeted therapeutics in the treatment of retinoblastoma (RB). The prime objective of this study was to identify the potential role of miR-378a-3p and its regulation in RB cells via forkhead box G1 (FOXG1). Methods: The expression of miR-378a-3p and FOXG1 in the clinical RB tissues was determined using RNA quantitation and Western blot assays. The interaction between miR-378a-3p and FOXG1 was identified using dual luciferase reporter gene assay. The potential effects of miR-378a-3p on the RB cell biological processes were evaluated by conducting gain- and loss-of-function studies of miR-378a-3p and FOXG1, followed by cell viability, cell cycle progression, and apoptosis measurements. Furthermore, experiments were performed in nude mice to assess its effects on tumor formation. Results: miR-378a-3p was poorly expressed, whereas FOXG1 was highly expressed in RB tissues and cells. miR-378a-3p bound to the FOXG1 3' untranslated region and negatively modulated its expression. The overexpression of miR-378a-3p was found to decrease RB cell viability and to promote cell apoptosis in vitro, whereas overexpressed FOXG1 reversed the regulatory effects of miR-378a-3p on RB cellular behaviors. In nude mice, the restoration of miR-378a-3p by miR-378a-3p agomir was shown to play a role in the reduction of tumor volume and size relative to nude mice injected with negative control-agomir. Conclusions: Our findings identified that increased miR-378a-3p exerted an inhibitory effect on RB cell proliferation by targeting FOXG1, suggesting the role of miR-378a-3p as a novel therapeutic target for RB.


Assuntos
Apoptose , Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , MicroRNAs/fisiologia , Proteínas do Tecido Nervoso/genética , Neoplasias da Retina/patologia , Retinoblastoma/patologia , Animais , Western Blotting , Ciclo Celular/fisiologia , Proliferação de Células/fisiologia , Sobrevivência Celular/fisiologia , Pré-Escolar , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Perfilação da Expressão Gênica , Humanos , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas do Tecido Nervoso/metabolismo , Plasmídeos/genética , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias da Retina/metabolismo , Retinoblastoma/metabolismo , Organismos Livres de Patógenos Específicos , Transfecção , Transplante Heterólogo , Células Tumorais Cultivadas
17.
Biochim Biophys Acta Rev Cancer ; 1874(1): 188376, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32437734

RESUMO

The pathogenesis of hepatocellular carcinoma (HCC) is a multistep process, involving the progressive accumulation of molecular alterations and transcriptomic alterations. The Forkhead-box (FOX) transcription factor family is characterized by its unique DNA binding domain (FKH or winged-helix domain). Human FOX family consists of about 17 subfamilies, at least 43 members. Some of them are liver-enriched transcription factors, suggesting that they may play a crucial role in the development or/and functions of the liver. Dysregulation of FOX transcription factors may contribute to the pathogenesis of HCC because they can activate or suppress the expression of various tumor-related molecules, and pinpoint different molecular and cellular events. Here we summarized, analyzed and discussed the status and the functions of the human FOX family of transcription factors in HCC, aiming to help the further development of them as potential therapeutic targets or/and diagnostic/prognostic markers for HCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Hepáticas/genética , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/antagonistas & inibidores , Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Fígado/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Mutação , Prognóstico
18.
Autoimmun Rev ; 19(6): 102526, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32234571

RESUMO

BACKGROUND: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a monogenic disorder characterized by early onset fatal multi-system autoimmunity due to loss-of-function mutations in the gene encoding the forkhead box P3 (FOXP3) transcription factor which is crucial for the development, maturation, and maintenance of CD4+ regulatory T (T-reg) cells. Various autoimmune phenomena such as enteropathy, endocrinopathies, cytopenias, renal disease, and skin manifestations are characteristic findings in patients affected by IPEX syndrome. OBJECTIVES: In this systematic review, we focus on both clinical and demographic characteristics of IPEX patients, highlighting possible genotype-phenotype correlations and address prognostic factors for disease outcome. METHODS: We performed a literature search to systematically investigate the case reports of IPEX which were published before August 7th, 2017. RESULTS: A total of 75 articles (195 patients) were identified. All IPEX patients included had FOXP3 mutations which were most frequently located in the forkhead domain (n = 68, 34.9%) followed by the leucine-zipper domain (n = 30, 15.4%) and repressor domain (n = 36, 18.4%). Clinical manifestations were as follows: enteropathy (n = 191, 97.9%), skin manifestations (n = 121, 62.1%), endocrinopathy (n = 104, 53.3%), hematologic abnormalities (n = 75, 38.5%), infections (n = 78, 40.0%), other immune-related complications (n = 43, 22.1%), and renal involvement (n = 32, 16.4%). Enteropathic presentations (P = 0.017), eczema (P = 0.030), autoimmune hemolytic anemia (P = 0.022) and food allergy (P = 0.009) were associated with better survival, while thrombocytopenia (P = 0.034), septic shock (P = 0.045) and mutations affecting the repressor domain (P = 0.021), intron 7 (P = 0.033) or poly A sequence (P = 0.025) were associated with increased risk of death. Immunosuppressive therapy alone was significantly associated with increased cumulative survival compared to patients who received no treatment (P = 0.041). CONCLUSIONS: We report the most comprehensive summary of demographic and clinical profiles derived from a total of 195 IPEX patients with deleterious mutations in FOXP3. Analysis of our findings provides new insights into genotype/phenotype correlations, and clinical and genetic factors associated with increased risk of death and response to treatment strategies.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X , Doenças do Sistema Imunitário , Enteropatias , Poliendocrinopatias Autoimunes , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Enteropatias/imunologia , Enteropatias/patologia , Mutação , Poliendocrinopatias Autoimunes/imunologia , Poliendocrinopatias Autoimunes/patologia , Síndrome , Linfócitos T Reguladores/imunologia
19.
Prostate ; 80(9): 674-686, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32294305

RESUMO

BACKGROUND: Castrate-resistant prostate cancer (CRPC) is an aggressive and lethal disease. The pathogenesis of CRPC is not fully understood and novel therapeutic targets need to be identified to improve the patients' prognosis. MicroRNA-30a (miR-30a) has been demonstrated to be a tumor suppressor in many types of solid malignancies. However, its role in androgen-independent (AI) growth of prostate cancer (PCa) received limited attention as yet. METHODS: The clinical association of miR-30a and its potential targets with AI growth was characterized by bioinformatics analyses. Regulation of cell proliferation and colony formation rates by miR-30a were tested using PCa cell models. Xenograft models were used to measure the regulation of prostate tumor growth by miR-30a. The real-time quantitative polymerase chain reaction was used to validate whether miR-30a and its targets regulate cell cycle control genes and androgen receptor (AR)-dependent transcription. Bioinformatics tools, Western blot, and luciferase reporter assays were utilized to identify miR-30a targets. RESULTS: Bioinformatic analysis showed that low expression of miR-30a is associated with castration resistance of PCa patients and poor outcomes. Transfection of miR-30a mimics inhibited the AI growth of PCa cells in vitro and in vivo. Upregulation of miR-30a in 22RV1 cells altered the expression of cell cycle control genes and AR-mediated transcription, while downregulation of miR-30a in LNCaP cells had the opposite effects to AR-mediated transcription. MYBL2, FOXD1, and SOX4 were identified as miR-30a targets. Downregulation of MYBL2, FOXD1, and SOX4 affected the expression of cell cycle control genes and AR-mediated transcription and suppressed the AI growth of 22RV1 cells. CONCLUSIONS: Our results suggest that miR-30a inhibits AI growth of PCa by targeting MYBL2, FOXD1, and SOX4. They provide novel insights into developing new treatment strategies for CRPC.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Fatores de Transcrição Forkhead/metabolismo , MicroRNAs/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Fatores de Transcrição SOXC/metabolismo , Transativadores/metabolismo , Antagonistas de Androgênios/metabolismo , Androgênios/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Regulação para Baixo , Fatores de Transcrição Forkhead/genética , Células HEK293 , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Nus , MicroRNAs/genética , Prognóstico , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/metabolismo , Fatores de Transcrição SOXC/genética , Transativadores/genética , Regulação para Cima
20.
J Med Life ; 13(1): 50-55, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32341701

RESUMO

The mammalian target of rapamycin is not only a central regulator of lipid metabolism that controls the processes of adipogenesis and lipolysis but also a regulator of the immunometabolism of immune cells that infiltrate adipose tissue. In turn, the level of progression of diabetes is significantly influenced by the Treg subpopulation, the complexity and heterogeneity of which is confirmed by the detection of numerous tissue-specific Tregs, including the so-called VAT Tregs (visceral adipose tissue CD4+Foxp3+ regulatory T cells). Therefore, the purpose of the study was to determine the mRNA expression levels of mTOR, Foxp3, IL1ß, and IL17A genes in rat parapancreatic adipose tissue with experimental streptozotocin-induced diabetes mellitus, with or without metformin administration. The experiments were performed on male Wistar rats with induced diabetes as a result of streptozotocin administration. Molecular genetic studies were performed using real-time reverse transcription-polymerase chain reaction. The development of diabetes caused transcriptional activation of the mammalian target of rapamycin protein kinase gene, as well as increased mRNA expression of the pro-inflammatory cytokines IL1ß and IL17A, but did not affect Foxp3 mRNA expression. The intervention with metformin in diabetic rats inhibited the mammalian target of rapamycin mRNA expression and caused an increase in the transcriptional activity of the Foxp3 gene in parapancreatic adipose tissue.


Assuntos
Tecido Adiposo/patologia , Diabetes Mellitus Experimental/genética , Fatores de Transcrição Forkhead/genética , Metformina/farmacologia , Serina-Treonina Quinases TOR/genética , Transcrição Genética/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/patologia , Fatores de Transcrição Forkhead/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Estreptozocina , Serina-Treonina Quinases TOR/metabolismo
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