Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 986
Filtrar
1.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(4): 536-540, 2019 Aug 30.
Artigo em Chinês | MEDLINE | ID: mdl-31484618

RESUMO

Apoptosis plays important roles in maintaining normal development and homeostasis and in the pathophysiological processes of various diseases.Previous studies have shown that cardiomyocyte apoptosis is involved in the development of various cardiovascular diseases.The apoptosis repressor with caspase recruitment domain(ARC)is abundantly expressed in heart,which makes ARC a unique and central cardioprotective factor via anti-apoptotic pathway.This article reviews the structure and characteristics of ARC as well as the roles and mechanisms of ARC in cardiovascular diseases.


Assuntos
Proteínas Reguladoras de Apoptose/fisiologia , Apoptose , Doenças Cardiovasculares , Domínio de Ativação e Recrutamento de Caspases , Humanos
2.
Int Immunopharmacol ; 68: 145-155, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30634142

RESUMO

Gasdermin D (GSDMD), a genetic substrate for inflammatory caspases, plays a central role in pyroptosis of macrophages and release of interleukin­1ß (IL-1ß), but was mainly referred to microbial infection. High mobility group box-1 (HMGB1), served as an alarm molecule during various pathological process, has been widely recognized to be involved in liver ischemia-reperfusion (I/R). Glycyrrhizin, a natural anti-inflammatory and antiviral triterpene in clinical use, was recently referred to have ability to prevent I/R induced liver injury by inhibiting HMGB1 expression and activity. However, the mechanisms responsible for damage amelioration subsequently to HMGB1 inhibition during liver I/R remain enigmatic. This study was designed to explore the functional role and molecular mechanism of glycyrrhizin in the regulation of I/R induced liver injury. We found that liver I/R promotes GSDMD-mediated pyroptotic cell death of Kupffer cells, which was inhibited by glycyrrhizin. Interestingly, endogenous HMGB1, not exogenous one, was involved in hypoxia-reoxygenation (H/R) induced pyroptosis. Moreover, GSDMD knockdown protects kupffer cells against H/R induced pyroptosis in vitro. Here, we report, for the first time, that glycyrrhizin attenuated tissue damage and kupffer cells pyroptosis during liver ischemia-reperfusion injury (LIRI) and identify a previously unrecognized HMGB1- dependent GSDMD- mediated signaling pathway in the mechanism of kupffer cells pyroptosis induced by H/R. Our findings provide the first demonstration of GSDMD-determined pyroptotic cell death responsible for I/R induced release of IL-1ß and this would provide a mandate to better understand the unconventional mechanisms of cytokine release in the sterile innate immune system.


Assuntos
Anti-Inflamatórios , Proteínas Reguladoras de Apoptose/fisiologia , Ácido Glicirrízico , Proteína HMGB1/metabolismo , Macrófagos do Fígado/efeitos dos fármacos , Hepatopatias , Piroptose/efeitos dos fármacos , Traumatismo por Reperfusão , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Ácido Glicirrízico/farmacologia , Ácido Glicirrízico/uso terapêutico , Interleucina-1beta/metabolismo , Macrófagos do Fígado/fisiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Hepatopatias/tratamento farmacológico , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , Camundongos Endogâmicos C57BL , Peroxidase/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
3.
Life Sci ; 219: 129-135, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30639391

RESUMO

AIMS: Aberrantly expressed miRNAs are demonstrated to be involved in the development of congenital heart disease (CHD). miR-9 was proposed to be upregulated in cardiac tissues from CHD cases. However, the role of miR-9 in hypoxia-induced cardiomyocytes and the potential mechanism are far from being addressed. MAIN METHODS: qRT-PCR and western blot analysis were performed to detect miR-9 and Yes-associated protein 1 (Yap1) expressions in hypoxic H9c2 cells. CCK-8, flow cytometry analysis, caspase-3/7 activity assay were applied to evaluate cell proliferation, apoptosis, and caspase-3/7 activity, respectively. The interaction between miR-9 and Yap1 was explored by luciferase reporter assay, qRT-PCR and western blot. KEY FINDINGS: miR-9 was upregulated and Yap1 was downregulated in H9c2 cells in response to hypoxia in a time-dependent manner. Knockdown of miR-9 promoted cell proliferation, and inhibited apoptosis and caspase-3/7 activity in hypoxic H9c2 cells, while miR-9 overexpression exerted the opposite effects on hypoxic H9c2 cells. In addition, Yap1 was a direct target of miR-9 in H9c2 cells. Yap1 knockdown suppressed cell proliferation and promoted apoptosis in hypoxia-exposed H9c2 cells. Yap1 knockdown attenuated the effect of anti-miR-9 on cell proliferation and apoptosis in hypoxia-exposed H9c2 cells. SIGNIFICANCE: miR-9 knockdown inhibited hypoxia-induced cardiomyocyte apoptosis by targeting Yap1. Our study provided a novel insight into the mechanism of the adaptation of cardiomyocytes to chronic hypoxia.


Assuntos
Proteínas Reguladoras de Apoptose/fisiologia , Apoptose , Hipóxia/fisiopatologia , MicroRNAs/fisiologia , Miócitos Cardíacos/fisiologia , Proteínas Proto-Oncogênicas c-yes/fisiologia , Animais , Western Blotting , Caspase 3/metabolismo , Caspase 7/metabolismo , Proliferação de Células , Citometria de Fluxo , Técnicas de Silenciamento de Genes , Hipóxia/metabolismo , Miócitos Cardíacos/metabolismo , Ratos , Reação em Cadeia da Polimerase em Tempo Real
4.
Hum Mol Genet ; 28(8): 1343-1356, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30590536

RESUMO

Dystonia is a movement disorder characterized by involuntary and repetitive co-contractions of agonist and antagonist muscles. Dystonia 6 (DYT6) is an autosomal dominant dystonia caused by loss-of-function mutations in the zinc finger transcription factor THAP1. We have generated Thap1 knock-out mice with a view to understanding its transcriptional role. While germ-line deletion of Thap1 is embryonic lethal, mice lacking one Thap1 allele-which in principle should recapitulate the haploinsufficiency of the human syndrome-do not show a discernable phenotype. This is because mice show autoregulation of Thap1 mRNA levels with upregulation at the non-affected locus. We then deleted Thap1 in glial and neuronal precursors using a nestin-conditional approach. Although these mice do not exhibit dystonia, they show pronounced locomotor deficits reflecting derangements in the cerebellar and basal ganglia circuitry. These behavioral features are associated with alterations in the expression of genes involved in nervous system development, synaptic transmission, cytoskeleton, gliosis and dopamine signaling that link DYT6 to other primary and secondary dystonic syndromes.


Assuntos
Proteínas de Ligação a DNA/genética , Distonia Muscular Deformante/genética , Distúrbios Distônicos/genética , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/fisiologia , Proteínas de Ligação a DNA/fisiologia , Modelos Animais de Doenças , Distonia/genética , Distonia Muscular Deformante/fisiopatologia , Distúrbios Distônicos/fisiopatologia , Regulação da Expressão Gênica/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Proteínas Nucleares/genética , Proteínas Nucleares/fisiologia , Síndrome , Dedos de Zinco
5.
Behav Brain Res ; 356: 8-17, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30092249

RESUMO

Ischemia/reperfusion (I/R) injuries commonly lead to breakdown of the blood-brain barrier (BBB). Restoration of the BBB can relieve neurologic damage caused by I/R injuries. The Hippo/YAP signaling pathway mediates cell proliferation, regulated cell death, and differentiation in various organisms and has been shown to participate in the restoration of the heart after I/R. In this study, we investigated whether the Hippo/YAP pathway plays a role in I/R injury in brain, especially in regard to I/R-induced BBB breakdown. The results of our study indicate that I/R injury led to an overall decrease in activity of the core proteins, YAP and TAZ, over a 24-h period. The most dramatic change was observed 1.5 h after reperfusion. In rats that underwent 1.5 h of reperfusion, intraperitoneal injection of YAP agonist dexamethasone activated YAP and TAZ and led to improved neurologic function, smaller brain infarct sizes, increased levels of tight junction proteins, decreased BBB permeability, decreased cerebral edema, and less apoptosis. Our results suggest that YAP exerts neuroprotective effects on the damaged brain that are likely related to restoration of the BBB.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Fatores de Transcrição/metabolismo , Animais , Proteínas Reguladoras de Apoptose/fisiologia , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Edema Encefálico/fisiopatologia , Isquemia Encefálica/fisiopatologia , Dexametasona/farmacologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Fármacos Neuroprotetores/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais/fisiologia
6.
Biochim Biophys Acta Mol Cell Res ; 1866(1): 167-174, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30077638

RESUMO

Pseudophosphatases are atypical members of the protein tyrosine phosphatase superfamily. Mutations within their catalytic signature motif render them catalytically inactive. Despite this lack of catalytic function, pseudophosphatases have been implicated in various diseases such as Charcot Marie-Tooth disorder, cancer, metabolic disorder, and obesity. Moreover, they have roles in various signaling networks such as spermatogenesis, apoptosis, stress response, tumorigenesis, and neurite differentiation. This review highlights the roles of pseudophosphatases as essential regulators in signaling cascades, providing insight into the function of these catalytically inactive enzymes.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Tirosina Fosfatases/metabolismo , Animais , Proteínas Reguladoras de Apoptose/fisiologia , Proteínas de Caenorhabditis elegans , Doença de Charcot-Marie-Tooth , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Doenças Metabólicas , Neoplasias , Proteínas Nucleares/fisiologia , Obesidade , Monoéster Fosfórico Hidrolases/metabolismo , Fosfotransferases/metabolismo , Proteínas Tirosina Fosfatases/fisiologia , Transdução de Sinais
7.
Cells ; 8(1)2018 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-30586922

RESUMO

Tumor necrosis factor (TNF)-α-induced protein 8 (TNFAIP8) is a founding member of the TIPE family, which also includes TNFAIP8-like 1 (TIPE1), TNFAIP8-like 2 (TIPE2), and TNFAIP8-like 3 (TIPE3) proteins. Expression of TNFAIP8 is strongly associated with the development of various cancers including cancer of the prostate, liver, lung, breast, colon, esophagus, ovary, cervix, pancreas, and others. In human cancers, TNFAIP8 promotes cell proliferation, invasion, metastasis, drug resistance, autophagy, and tumorigenesis by inhibition of cell apoptosis. In order to better understand the molecular aspects, biological functions, and potential roles of TNFAIP8 in carcinogenesis, in this review, we focused on the expression, regulation, structural aspects, modifications/interactions, and oncogenic role of TNFAIP8 proteins in human cancers.


Assuntos
Proteínas Reguladoras de Apoptose/fisiologia , Autofagia , Transformação Celular Neoplásica/patologia , Neoplasias/metabolismo , Oncogenes , Animais , Apoptose , Proteínas Reguladoras de Apoptose/química , Proteínas Reguladoras de Apoptose/genética , Drosophila melanogaster , Resistencia a Medicamentos Antineoplásicos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Camundongos , Metástase Neoplásica , Neoplasias/genética , Neoplasias/patologia , Neoplasias Experimentais , Transdução de Sinais , Transplante Heterólogo , Fator de Necrose Tumoral alfa/metabolismo
9.
Biomed Pharmacother ; 101: 129-136, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29482058

RESUMO

Drug resistance, a major challenge in cancer chemotherapy, is a result of several mechanistic alterations including resistance to apoptosis. Apoptosis is a well-controlled cell death mechanism which is regulated by several signaling pathways. Alterations in structure, function, and expression pattern of the proteins involved in the regulation of apoptosis have been linked to drug resistance. Programmed Cell Death 10 (PDCD10) protein is recently associated with the regulation of cell survival and apoptosis. However, the role of PDCD10 in drug resistance has not been clearly established. Here, we aimed to figure out the role of PDCD10 in resistance to anti-cancer agents in different cell lines. We found that PDCD10 expression was cell- and anti-cancer agent-specific; down-regulated in doxorubicin- and docetaxel-resistant MCF7 cells while up-regulated in doxorubicin-resistant HeLa cells. Down-regulation of PDCD10 expression by siRNA in parental MCF7 cells increased the resistance while it increased sensitivity in doxorubicin-resistant HeLa cells. Similarly, over-expression of PDCD10 in parental HeLa cells increased the resistance to doxorubicin while it re-sensitized doxorubicin-resistant MCF7 cells. Moreover, the alterations in PDCD10 expression led to changes in caspase 3/7 activity and the levels of apoptosis-related genes. Our results point out a possible dual role of PDCD10 in drug resistance for the first time in the literature and emphasize PDCD10 as a novel target for reversal of drug resistance in cancer.


Assuntos
Antineoplásicos/farmacologia , Proteínas Reguladoras de Apoptose/fisiologia , Apoptose/fisiologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Proteínas de Membrana/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células HeLa , Humanos , Células K562 , Células MCF-7
10.
Exp Eye Res ; 169: 122-133, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29355736

RESUMO

Recent studies indicate an important role for the transcriptional co-activator Yes-associated protein (YAP), and its regulatory pathway Hippo, in controlling cell growth and fate during lens development; however, the exogenous factors that promote this pathway are yet to be identified. Given that fibroblast growth factor (FGF)-signaling is an established regulator of lens cell behavior, the current study investigates the relationship between this pathway and Hippo/YAP-signaling during lens cell proliferation and fibre differentiation. Rat lens epithelial explants were cultured with FGF2 to induce epithelial cell proliferation or fibre differentiation. Immunolabeling methods were used to detect the expression of Hippo-signaling components, Total and Phosphorylated YAP, as well as fibre cell markers, Prox-1 and ß-crystallin. FGF-induced lens cell proliferation was associated with a strong nuclear localisation of Total-YAP and low-level immuno-staining for phosphorylated-YAP. FGF-induced lens fibre differentiation was associated with a significant increase in cytoplasmic phosphorylated YAP (inactive state) and enhanced expression of core Hippo-signaling components. Inhibition of YAP with Verteporfin suppressed FGF-induced lens cell proliferation and ablated cell elongation during lens fibre differentiation. Inhibition of either FGFR- or MEK/ERK-signaling suppressed FGF-promoted YAP nuclear translocation. Here we propose that FGF promotes Hippo/YAP-signaling during lens cell proliferation and differentiation, with FGF-induced nuclear-YAP expression playing an essential role in promoting the proliferation of lens epithelial cells. An FGF-induced switch from proliferation to differentiation, hence regulation of lens growth, may play a key role in mediating Hippo suppression of YAP transcriptional activity.


Assuntos
Proteínas Reguladoras de Apoptose/fisiologia , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Fator 2 de Crescimento de Fibroblastos/farmacologia , Cristalino/metabolismo , Proteínas Serina-Treonina Quinases/fisiologia , Transdução de Sinais/fisiologia , Animais , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Western Blotting , Células Cultivadas , Células Epiteliais/metabolismo , Técnica Indireta de Fluorescência para Anticorpo , Proteínas de Homeodomínio/metabolismo , Cristalino/citologia , Morfogênese , Fosforilação , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Ratos , Ratos Wistar , Proteínas Supressoras de Tumor/metabolismo , Verteporfina , beta-Cristalinas/metabolismo
11.
Laryngoscope ; 128(4): E130-E134, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29280495

RESUMO

OBJECTIVES/HYPOTHESIS: Human laryngeal squamous cell carcinoma (LSCC) is a malignancy that was discovered originally in the epithelial tissue of laryngeal mucosa. However, the underlying molecular mechanism is still not clear. In this study, we aimed to investigate the potential molecular mechanisms of TSR2 in the LSCC cell apoptosis. STUDY DESIGN: The expression of TSR2 was first analyzed in LSCC tissues. Then functional effects of TSR2 on Hep-2 and AMC-HN-8 cell lines were performed by overexpression pcDNA3.1-TSR2. METHODS: We investigated the expression level of TSR2 in LSCC tissues and cells by performing quantitative real-time polymerase chain reaction (qRT-PCR). The pcDNA3.1-TSR2 was constructed to explore the effect of overexpressing TSR2 in Hep-2 cells and AMC-HN-8 cells. We further investigated the effect of overexpressing TSR2 on cell apoptosis-related protein and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 nuclear translocation through Western blot and terminal dUTP nick end-labeling assays. RESULTS: We found that TSR2 was downregulated in LSSC tissues and cells compared with the controls, and the overexpression of TSR2 in Hep-2 and AMC-HN-8 cells could promote cell apoptosis and related apoptosis proteins. The Western blot/qRT-PCR data further indicated that overexpression of TSR2 in Hep-2 and AMC-HN-8 cells could lead to a block of NF-κB signaling pathway via decreasing nuclear NF-κB p65 and increasing cytoplasm NF-κB p65. Moreover, overexpression of TSR2 significantly inhibited the phosphorylation of IκBα and IKKα/ß. CONCLUSIONS: The results indicated that TSR2-induced apoptosis was mediated by inhibiting the NF-κB signaling pathway, which may provide an effective target in gene therapy for LSCC. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:E130-E134, 2018.


Assuntos
Proteínas Reguladoras de Apoptose/fisiologia , Apoptose/fisiologia , Carcinoma de Células Escamosas/metabolismo , Neoplasias Laríngeas/metabolismo , NF-kappa B/metabolismo , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Humanos , Laringe/metabolismo , Transdução de Sinais/fisiologia , Fator de Transcrição RelA/metabolismo
12.
Cell Death Differ ; 25(1): 2017 Apr, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29077093

RESUMO

Intrinsic apoptosis is controlled by the BCL-2 family of proteins but the complexity of intra-family interactions makes it challenging to predict cell fate via standard molecular biology techniques. We discuss BCL-2 family regulation and how to determine cells' readiness for apoptosis and anti-apoptotic dependence. Cancer cells often adopt anti-apoptotic defense mechanisms in response to oncogenic stress or anti-cancer therapy. However, by determining their anti-apoptotic addiction, we can use novel BH3 mimetics to overwhelm this apoptotic blockade. We outline the development and uses of these unique anti-apoptotic inhibitors and how to possibly combine them with other anti-cancer agents using dynamic BH3 profiling (DBP) to improve personalized cancer treatment.


Assuntos
Antineoplásicos/uso terapêutico , Apoptose , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/fisiologia , Permeabilidade da Membrana Celular , Humanos , Membranas Mitocondriais/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia
13.
Cell Death Differ ; 25(1): 37-45, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29099482

RESUMO

Almost 30 years ago it was first appreciated that anti-apoptotic B-cell lymphoma-2 (BCL-2) prevents the induction of apoptosis not only in malignant cells, but also in normal cellular lineages. This critical observation has rapidly evolved from merely identifying new BCL-2 family members to understanding how their biochemical interactions trigger the cell death process, and, more recently, to pharmacological inhibition of anti-apoptotic BCL-2 function in disease. Indeed, the proper regulation of apoptosis is important in many aspects of life including development, homeostasis, and disease biology. To better understand these processes, scientists have used many tools to assess the contribution of individual anti-apoptotic BCL-2 family members. This review will focus on the prominent roles for BCL-2 and other pro-survival family members in promoting the development of mammals during early embryogenesis, neurogenesis, and hematopoiesis.


Assuntos
Apoptose , Desenvolvimento Embrionário , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia , Animais , Proteínas Reguladoras de Apoptose/fisiologia , Hematopoese , Camundongos , Sistema Nervoso/embriologia
14.
Cell Death Differ ; 25(1): 27-36, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29099483

RESUMO

Impaired apoptosis plays a central role in cancer development and limits the efficacy of conventional cytotoxic therapies. Deepening understanding of how opposing factions of the BCL-2 protein family switch on apoptosis and of their structures has driven development of a new class of cancer drugs that targets various pro-survival members by mimicking their natural inhibitors, the BH3-only proteins. These 'BH3 mimetic' drugs seem destined to become powerful new weapons in the arsenal against cancer. Successful clinical trials of venetoclax/ABT-199, a specific inhibitor of BCL-2, have led to its approval for a refractory form of chronic lymphocytic leukaemia and to scores of on-going trials for other malignancies. Furthermore, encouraging preclinical studies of BH3 mimetics that target other BCL-2 pro-survival members, particularly MCL-1, offer promise for cancers resistant to venetoclax. This review sketches the impact of the BCL-2 family on cancer development and therapy, describes how interactions of family members trigger apoptosis and discusses the potential of BH3 mimetic drugs to advance cancer therapy.


Assuntos
Antineoplásicos/uso terapêutico , Apoptose , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia , Animais , Proteínas Reguladoras de Apoptose/fisiologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Humanos , Membranas Mitocondriais/metabolismo , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/química , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sulfonamidas/uso terapêutico
15.
Braz J Med Biol Res ; 51(2): e6793, 2017 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-29267503

RESUMO

Colon cancer is one of the most common digestive tumors. The present study aimed to explore the functional role, as well as the underlying mechanism of long non-coding RNA LINC00261 in colon cancer. Expression of LINC00261 was analyzed in colon cancer cell lines and human normal cell lines. Acquired resistance cell lines were then built and the acquired resistance efficiency was detected by evaluating cell viability. Thereafter, the effects of LINC00261 overexpression on cisplatin-resistant colon cancer cells were measured, as well as cell apoptosis, viability, migration, and invasion. Subsequently, we investigated the interaction of LINC00261 and ß-catenin. The results showed that the LINC00261 gene was down-regulated in colon cancer cell lines and tissues, and in cisplatin-resistant cells. LINC00261 overexpression might relieve cisplatin resistance of colon cancer cells via promoting cell apoptosis, and inhibiting cell viability, migration, and invasion. Moreover, LINC00261 might down-regulate nuclear ß-catenin through restraining ß-catenin from cytoplasm into nuclei or it could also promote ß-catenin degradation and inhibit activation of Wnt pathway. Finally, LINC00261 reduced cisplatin resistance of colon cancer in vivo and enhanced the anti-colon cancer effect of cisplatin through reducing tumor volume and weight.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , RNA Longo não Codificante/fisiologia , Análise de Variância , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/fisiologia , Western Blotting , Ensaios de Migração Celular , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/fisiologia , Células HCT116 , Células HT29 , Humanos , RNA Longo não Codificante/análise , RNA Longo não Codificante/efeitos dos fármacos , RNA Longo não Codificante/genética , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Sais de Tetrazólio , Tiazóis , beta Catenina/efeitos dos fármacos , beta Catenina/fisiologia
16.
Biol Res ; 50(1): 40, 2017 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-29228993

RESUMO

BACKGROUND: Programmed cell death 5 (PDCD5) is an apoptosis-related gene cloned from TF-1 cells whose primary biological functions are to promote apoptosis and immune regulation. The effects and mechanisms exerted by key mediators of arthritic inflammation remain unclear in PDCD5 transgenic (PDCD5 tg) mice. RESULTS: In the current study, PDCD5 tg mice inhibited the progression of adjuvant-induced arthritis, specifically decreasing clinical signs and histological damage, compared with arthritis control mice. Additionally, the ratio of CD4+IFN-γ+ cells (Th1) and CD4+IL-17A+ cells (Th17), as well as the mRNA expression of the pro-inflammatory mediators IFN-γ, IL-6, IL-17A and TNF-α, were decreased in PDCD5 tg mice, while CD4+CD25+Foxp3+ regulatory T (Treg) cells and the anti-inflammatory mediators IL-4 and IL-10 were increased. Furthermore, PDCD5 tg mice demonstrated reduced serum levels of IFN-γ, IL-6, IL-17A and TNF-α and increased levels of IL-4. CONCLUSIONS: Based on our data, PDCD5 exerts anti-inflammatory effects by modifying the T lymphocytes balance, inhibiting the production of pro-inflammatory mediators and promoting the secretion of anti-inflammatory cytokines, validating PDCD5 protein as a possible treatment for RA.


Assuntos
Proteínas Reguladoras de Apoptose/fisiologia , Artrite Experimental/metabolismo , Proteínas de Neoplasias/fisiologia , Linfócitos T Reguladores/fisiologia , Animais , Proteínas Reguladoras de Apoptose/genética , Artrite Experimental/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas de Neoplasias/genética
17.
J Cell Sci ; 130(22): 3878-3890, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-28993463

RESUMO

The TORC1 complex is a key regulator of cell growth and metabolism in Saccharomyces cerevisiae The vacuole-associated EGO complex couples activation of TORC1 to the availability of amino acids, specifically glutamine and leucine. The EGO complex is also essential for reactivation of TORC1 following rapamycin-induced growth arrest and for its distribution on the vacuolar membrane. Pib2, a FYVE-containing phosphatidylinositol 3-phosphate (PI3P)-binding protein, is a newly discovered and poorly characterized activator of TORC1. Here, we show that Pib2 is required for reactivation of TORC1 following rapamycin-induced growth arrest. Pib2 is required for EGO complex-mediated activation of TORC1 by glutamine and leucine as well as for redistribution of Tor1 on the vacuolar membrane. Therefore, Pib2 and the EGO complex cooperate to activate TORC1 and connect phosphoinositide 3-kinase (PI3K) signaling and TORC1 activity.


Assuntos
Proteínas Reguladoras de Apoptose/fisiologia , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/fisiologia , Saccharomyces cerevisiae/enzimologia , Fatores de Transcrição/metabolismo , Autofagia , Ativação Enzimática , Membranas Intracelulares/enzimologia , Fosfatidilinositol 3-Quinases/metabolismo , Transporte Proteico , Transdução de Sinais , Vacúolos/enzimologia
18.
Neurobiol Aging ; 60: 104-115, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28941726

RESUMO

Many studies reveal that BAG3 plays a critical role in the regulation of protein degradation via macroautophagy. However, it remains unknown whether BAG3 affects the quality control of α-synuclein (SNCA), a Parkinson's disease-related protein. In this study, we demonstrated the increases of BAG3 expression in the ventral midbrain of SNCAA53T transgenic mice and also in MG132-treated PC12 cells overexpressing wild-type SNCA (SNCAWT-PC12). Moreover, we showed that BAG3 overexpression was sufficient to enhance the autophagy activity while knockdown of Bag3 reduced it in SNCAWT-PC12 cells. Immunoprecipitation revealed that BAG3 interacted with heat shock protein 70 and sequestosome 1. The immunostaining also showed the perinuclear accumulation and colocalization of BAG3 with these 2 proteins, as well as with LC3 dots in tyrosine hydroxylase-positive neurons in the midbrain of SNCAA53T mice. BAG3 overexpression was able to modulate SNCA degradation via macroautophagy which was prevented by Atg5 knockdown. Taken together, these results indicate that BAG3 plays a relevant role in regulating SNCA clearance via macroautophagy, and the heat shock protein 70-BAG3-sequestosome 1 complex may be involved in this process.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteínas Reguladoras de Apoptose/fisiologia , Autofagia/genética , Autofagia/fisiologia , alfa-Sinucleína/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Expressão Gênica , Proteínas de Choque Térmico HSP70/fisiologia , Masculino , Mesencéfalo/metabolismo , Camundongos Transgênicos , Células PC12 , Ratos , Proteína Sequestossoma-1/fisiologia
19.
PLoS One ; 12(9): e0185718, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28961278

RESUMO

Psbetaeudomonas (P.) aeruginosa infection of the cornea in BALB/c mice does not result in perforation and the mice have been classified as resistant. However, regulation of this response via inflammasome activation remained untested. Therefore, BALB/c mice were infected with P. aeruginosa ATCC strain 19660 and NLRP3 and NLRC4 protein tested by ELISA. Since NLRC4 vs NLRP3 protein levels were significantly higher in the corneas of BALB/c at 1 and 5 days postinfection we used silencing to knockdown NLRC4. Silencing NLRC4 vs scrambled siRNA treatment exacerbated disease in BALB/c mice, reduced myeloperoxidase levels and elevated bacterial plate counts at 5 days postinfection. It also increased pro IL-1beta, but reduced total protein for IL-1beta and IL-18 at 5 days postinfection. Flow cytometry to identify cells affected by silencing, showed reduced caspase-1 levels in a CD11blowLy6Glow population of cells, (but not PMN or macrophages) from the infected cornea of siNLRC4 treated mice that produced less mature IL-1beta. These data provide evidence that the NLRC4 inflammasome contributes to resistance through regulation of caspase-1, IL-1beta and IL-18 in a CD11blowLy6Glow population of cells.


Assuntos
Proteínas Reguladoras de Apoptose/fisiologia , Antígeno CD11b/imunologia , Proteínas de Ligação ao Cálcio/fisiologia , Caspase 1/biossíntese , Interleucina-1beta/biossíntese , Ceratite/imunologia , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa/isolamento & purificação , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas de Ligação ao Cálcio/genética , Contagem de Colônia Microbiana , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Técnicas de Silenciamento de Genes , Ceratite/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Pseudomonas/microbiologia
20.
J Exp Med ; 214(10): 3051-3066, 2017 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-28821568

RESUMO

Although genetic polymorphisms in the LRRK2 gene are associated with a variety of diseases, the physiological function of LRRK2 remains poorly understood. In this study, we report a crucial role for LRRK2 in the activation of the NLRC4 inflammasome during host defense against Salmonella enteric serovar Typhimurium infection. LRRK2 deficiency reduced caspase-1 activation and IL-1ß secretion in response to NLRC4 inflammasome activators in macrophages. Lrrk2-/- mice exhibited impaired clearance of pathogens after acute S. Typhimurium infection. Mechanistically, LRRK2 formed a complex with NLRC4 in the macrophages, and the formation of the LRRK2-NLRC4 complex led to the phosphorylation of NLRC4 at Ser533. Importantly, the kinase activity of LRRK2 is required for optimal NLRC4 inflammasome activation. Collectively, our study reveals an important role for LRRK2 in the host defense by promoting NLRC4 inflammasome activation.


Assuntos
Proteínas Reguladoras de Apoptose/fisiologia , Proteínas de Ligação ao Cálcio/fisiologia , Inflamassomos/imunologia , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/fisiologia , Salmonelose Animal/imunologia , Salmonella typhimurium/imunologia , Animais , Caspase 1/fisiologia , Inflamassomos/fisiologia , Interleucina-1beta/fisiologia , Macrófagos/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA