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1.
J Agric Food Chem ; 68(7): 2256-2262, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31927923

RESUMO

Fat deposition is one of the most important economic traits of pigs. Decreasing the subcutaneous fat and increasing the intramuscular fat are believed to be an effective way to improve pork quality, which is one of the main goals of pig breeding. Identifying key genes that control porcine lipid metabolism is essential for achieving this goal. Apolipoprotein R (apoR) was identified as the crucial molecule in the process of pig adipose reduction by clenbuterol. In this study, transgenic mice with adipose-tissue-specific overexpression of pig apoR (apoR mice) were constructed. The apoR mice gained less weight than wild-type (WT) mice after 18 weeks of feeding a high-fat diet. A comparison of organs between the two genotypes revealed that the weight of white adipose tissue, including inguinal and epididymal fat tissue, was significantly decreased and the weight of liver tissue was increased in apoR mice compared with WT mice. Glucose and insulin intolerance tests showed that the glucose metabolism of apoR mice was similar to that of WT mice. Histological staining proved that the adipocytes of apoR mice had a reduced average size, and gene expression analysis indicated that lipolysis in the adipose tissue of apoR mice was enhanced. Finally, the primary culture of inguinal adipocytes revealed that apoR promotes lipolysis via the Erk1/2 pathway. Taken together, the results indicate that adipose-tissue-specific expression of pig apoR protects mice from diet-induced obesity by enhancing lipolysis.


Assuntos
Tecido Adiposo/metabolismo , Apolipoproteínas/genética , Obesidade/genética , Obesidade/prevenção & controle , Adipócitos/metabolismo , Animais , Apolipoproteínas/metabolismo , Dieta Hiperlipídica/efeitos adversos , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Glucose/metabolismo , Lipólise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Obesidade/metabolismo , Obesidade/fisiopatologia , Suínos
2.
J Agric Food Chem ; 68(1): 193-205, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31826610

RESUMO

Gynostemma pentaphyllum possesses neuroprotective bioactivity. However, the effect of gypenosides on hypoxia-induced neural damage remains obscure. In this study, Gyp, the active fraction extracted from G. pentaphyllum and its bioactive compounds as well as the underlying molecular mechanisms were investigated. Eighteen dammarane-type saponins were isolated from Gyp. The absolute configurations of six unreported compounds (13-18) were assessed via electron capture detection (ECD) analyses. The results of cell viability assay showed that Gyp and its bioactive compounds (13-16 and 18) effectively protected PC12 cells from hypoxia injury. Gyp pretreatment also improved mice spatial memory impairment caused by hypoxia exposure. At the molecular level, Gyp and its bioactive compounds could activate the signaling pathways of ERK, Akt, and CREB in vitro and in vivo. In summary, Gyp and its bioactive compounds could prevent hypoxia-induced injury via ERK, Akt, and CREB signaling pathways.


Assuntos
Proteína de Ligação a CREB/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Gynostemma/química , Hipóxia/tratamento farmacológico , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Proteína de Ligação a CREB/genética , Sobrevivência Celular , MAP Quinases Reguladas por Sinal Extracelular/genética , Humanos , Hipóxia/genética , Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Células PC12 , Extratos Vegetais/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Saponinas/administração & dosagem
3.
Neurochem Res ; 44(11): 2643-2657, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31606837

RESUMO

Schwann cells (SCs) play an important role in producing myelin for rapid neurotransmission in the peripheral nervous system. Activation of the differentiation and myelination processes in SCs requires the expression of a series of transcriptional factors including Sox10, Oct6/Pou3f1, and Egr2/Krox20. However, functional interactions among several transcription factors are poorly defined and the important components of the regulatory network are still unknown. Until now, available evidence suggests that SCs require cAMP signaling to initiate the myelination program. Heat shock protein 90 (Hsp90) is known as a chaperone required to stabilize ErbB2 receptor. In recent years, it was reported that cAMP transactivated the ErbB2/ErbB3 signaling in SCs. However, the relationship between Hsp90 and cAMP-induced differentiation in SCs is undefined. Here we investigated the role of Hsp90 during cAMP-induced differentiation of SCs using Hsp90 inhibitor, geldanamycin and Hsp90 siRNA transfection. Our results showed that dibutyryl-cAMP (db-cAMP) treatment upregulated Hsp90 expression and led to nuclear translocation of Gab1/ERK, the downstream signaling pathway of the ErbB2 signaling mechanism in myelination. The expression of myelin-related genes and nuclear translocation of Gab1/ERK following db-cAMP treatment was inhibited by geldanamycin pretreatment and Hsp90 knockdown. These findings suggest that Hsp90 might play a role in cAMP-induced differentiation via stabilization of ErbB2 and nuclear translocation of Gab1/ERK in SCs.


Assuntos
Diferenciação Celular/fisiologia , Proteínas de Choque Térmico HSP90/fisiologia , Células de Schwann/fisiologia , Animais , Benzoquinonas/farmacologia , Bucladesina/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Expressão Gênica , Técnicas de Silenciamento de Genes , Proteínas de Choque Térmico HSP90/genética , Lactamas Macrocíclicas/farmacologia , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Ratos Sprague-Dawley , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Células de Schwann/citologia , Regulação para Cima
4.
J Agric Food Chem ; 67(40): 11230-11235, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31523955

RESUMO

Ochratoxin A (OTA) is a mycotoxin which could cause strong immunosuppressive toxicological effects in animals and humans. Heterophil extracellular traps (HETs) as a novel defense of chicken heterophils play an important role against pathogen infection. It has been reported that OTA can weaken the phagocytosis function of neutrophils. However, whether or not OTA shows immunosuppressive effects on HET release remains unclear. In the present study, we aim to first investigate the effects of OTA on HET release and then try to clarify the mechanisms in this process. OTA-induced HET structures were observed and analyzed by fluorescence confocal microscopy. The quantitative determination of OTA-induced HETs was measured by PicoGreen and a fluorescence microplate. The results clearly showed that OTA obviously induced the release of HET-like structures in heterophils, and these extracellular networks were composed by chromatin decorated with histones and neutrophil elastase. Reactive oxygen species (ROS) production was also increased in the process of OTA-induced HET formation. Furthermore, the inhibitors of NADPH oxidase, ERK [Formula: see text], and p38 MAPK signaling pathways significantly decreased OTA-induced HET formation. The abovementioned results suggest that OTA-induced HET formation is related to ROS production dependent on the activation of NADPH oxidase, ERK [Formula: see text], and p38 MAPK signaling pathways. Taken together, this study first shows that OTA possesses the ability to trigger HET formation, which provides our understanding of the host that continuously suffered OTA exposure leading to the hyporeactivity of the immune system against infection.


Assuntos
Galinhas/imunologia , MAP Quinases Reguladas por Sinal Extracelular/imunologia , Armadilhas Extracelulares/imunologia , NADPH Oxidases/imunologia , Neutrófilos/efeitos dos fármacos , Ocratoxinas/toxicidade , Espécies Reativas de Oxigênio/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia , Animais , Galinhas/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , Armadilhas Extracelulares/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , NADPH Oxidases/genética , Neutrófilos/enzimologia , Neutrófilos/imunologia , Fagocitose , Proteínas Quinases p38 Ativadas por Mitógeno/genética
5.
Nucleic Acids Res ; 47(16): 8606-8619, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31372646

RESUMO

Epithelial-mesenchymal transition (EMT) has been a subject of intense scrutiny as it facilitates metastasis and alters drug sensitivity. Although EMT-regulatory roles for numerous miRNAs and transcription factors are known, their functions can be difficult to disentangle, in part due to the difficulty in identifying direct miRNA targets from complex datasets and in deciding how to incorporate 'indirect' miRNA effects that may, or may not, represent biologically relevant information. To better understand how miRNAs exert effects throughout the transcriptome during EMT, we employed Exon-Intron Split Analysis (EISA), a bioinformatic technique that separates transcriptional and post-transcriptional effects through the separate analysis of RNA-Seq reads mapping to exons and introns. We find that in response to the manipulation of miRNAs, a major effect on gene expression is transcriptional. We also find extensive co-ordination of transcriptional and post-transcriptional regulatory mechanisms during both EMT and mesenchymal to epithelial transition (MET) in response to TGF-ß or miR-200c respectively. The prominent transcriptional influence of miRNAs was also observed in other datasets where miRNA levels were perturbed. This work cautions against a narrow approach that is limited to the analysis of direct targets, and demonstrates the utility of EISA to examine complex regulatory networks involving both transcriptional and post-transcriptional mechanisms.


Assuntos
Transição Epitelial-Mesenquimal/genética , Redes Reguladoras de Genes , MicroRNAs/genética , Processamento Pós-Transcricional do RNA , RNA Mensageiro/genética , Transcrição Genética , Linhagem Celular , Biologia Computacional/métodos , Conjuntos de Dados como Assunto , Fator de Crescimento Epidérmico/farmacologia , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Éxons , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Íntrons , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais , Transfecção , Fator de Crescimento Transformador beta/farmacologia
6.
Int J Mol Sci ; 20(15)2019 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-31382554

RESUMO

Extracellular signal-regulated kinase (ERK) is a member of the mitogen-activated protein kinase family of signaling molecules. ERK is predominantly found in two forms, ERK1 (p44) and ERK2 (p42), respectively. There are also several atypical forms of ERK, including ERK3, ERK4, ERK5 and ERK7. The ERK1/2 signaling pathway has been implicated in many and diverse cellular events, including proliferation, growth, differentiation, cell migration, cell survival, metabolism and transcription. ERK1/2 is activated (i.e., phosphorylated) in the cytosol and subsequently translocated to the nucleus, where it activates transcription factors including, but not limited to, ETS, c-Jun, and Fos. It is not surprising that the ERK1/2 signaling cascade has been implicated in many pathological conditions, namely, cancer, arthritis, chronic inflammation, and osteoporosis. This narrative review examines many of the cellular events in which the ERK1/2 signaling cascade plays a critical role. It is anticipated that agents designed to inhibit ERK1/2 activation or p-ERK1/2 activity will be developed for the treatment of those diseases characterized by dysregulated gene expression through ERK1/2 activation.


Assuntos
Proliferação de Células/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , Inflamação/genética , Sistema de Sinalização das MAP Quinases/genética , Diferenciação Celular/genética , Condrócitos/metabolismo , Regulação da Expressão Gênica/genética , Humanos , Inflamação/patologia , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Osteócitos/metabolismo , Osteócitos/patologia
7.
J Toxicol Sci ; 44(7): 493-503, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31270305

RESUMO

Methamphetamine (METH) is a potent and highly addictive central nervous system stimulant. The association between METH exposure and Alzheimer's disease (AD) has gained more attention, but, the mechanisms behind METH-induced neuron-related adverse outcomes remain poorly understood. With the western blot assay, our results revealed that METH exposure significantly increased the expression of AD-associated pathological proteins, including the amyloid precursor protein (APP) and the phosphorylated tau protein (p-tau). Meanwhile, the insulin signaling was disturbed after the administration of METH, since the key insulin signaling proteins, such as p-AKT, p-GSK3α, p-GSK3ß and p-ERK, were reduced. Additionally, the linking between the pathological proteins and the insulin signaling mediated by METH in the present work was verified by the treatment with the insulin signaling enhancer rosiglitazone, which was shown to improve the insulin signaling and decrease APP and p-tau expression. Thus, targeting insulin signaling may provide novel insights into potential therapeutic intervention for METH-mediated AD-like neurodegeneration.


Assuntos
Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Estimulantes do Sistema Nervoso Central/efeitos adversos , Expressão Gênica , Insulina/fisiologia , Metanfetamina/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteínas tau/genética , Proteínas tau/metabolismo , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/genética , Linhagem Celular Tumoral , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia
8.
Oncogene ; 38(34): 6196-6210, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31332289

RESUMO

Apoptosis of cancer cells occurs by a complex gene regulatory network. Here we showed that SOX7 was significantly downregulated in different cancer types, especially in lung and breast cancers. Low expression of SOX7 was associated with advantage stage of cancer with shorter overall survival. Cancer cells with loss of SOX7 promoted cell survival and colony formation, suppressed cellular apoptosis and produced a drug resistant phenotype against a variety of chemo/targeting therapeutic agents. Mechanistically, SOX7 induced cellular apoptosis through upregulation of genes associated with both P38 and apoptotic signaling pathway, as well as preventing the proteasome mediated degradation of pro-apoptotic protein BIM. Treatment of either a proteasome inhibitor MG132 or bortezomib, or with a p-ERK/MEK inhibitor U0126 attenuate the SOX7 promoted BIM degradation. We identified Panobinostat, an FDA approved pan-HDAC inhibitor, could elevate and restore SOX7 expression in SOX7 silenced lung cancer cells. Taken together, these data revealed an unappreciated role of SOX7 in regulation of cellular apoptosis through control of MAPK/ERK-BIM signaling.


Assuntos
Apoptose/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Neoplasias/patologia , Fatores de Transcrição SOXF/fisiologia , Animais , Proteína 11 Semelhante a Bcl-2/genética , Proteína 11 Semelhante a Bcl-2/metabolismo , Sobrevivência Celular/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Camundongos SCID , Neoplasias/genética , Neoplasias/metabolismo , Fatores de Transcrição SOXF/genética , Células Tumorais Cultivadas
9.
BMC Complement Altern Med ; 19(1): 139, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221142

RESUMO

BACKGROUND: Several studies have found that caffeic acid (CA), a well-known phytochemical, displays important antioxidant and anti-cancer activities. However, no evidence exists on the protective effect and its mechanisms that CA treatment alone has against oxidative stress induced by tert-butyl hydroperoxide (t-BHP) in HepG2 cells. METHODS: Hepatoprotective activities such as cell viability, mRNA expression, and report gene assay were measured using HepG2 cell. Three types of genes and proteins related with detoxification in liver were used for measuring the hepatoprotective effects. Statistical analysis was performed using one-way ANOVA test and differences among groups were evaluated by Tukey's studentized range tests. RESULTS: The present study indicate that treatment with CA up-regulates heme oxygenase-1 (HO-1) and glutamate-cysteine ligase (GCL) mRNA and protein expressions in a CA-dose-dependent manner. In addition, translocation of nuclear factor-E2 p45-related factor (Nrf2) from the cytoplasm to the nucleus and phosphorylation of extracellular signal-regulated kinase, ERK and c-Jun N-terminal kinase, JNK which have been shown to be involved in mitogen-activated protein kinases, MAPKs are significantly enhanced by CA treatment. Furthermore, in cell nuclei, CA enhances the 5'-flanking regulatory region of human antioxidant response element (ARE) and activates the ARE binding site. CONCLUSION: Therefore, CA proved to be a stimulant of the expression of detoxification enzymes such as HO-1, GCLC, and GCLM through the ERK/Nrf2 pathway, and it may be an effective chemoprotective agent for protecting liver damage against oxidative damage.


Assuntos
Ácidos Cafeicos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Neoplasias Hepáticas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , terc-Butil Hidroperóxido/toxicidade , Elementos de Resposta Antioxidante/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/genética , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Células Hep G2 , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Neoplasias Hepáticas/genética , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo
10.
Int J Mol Sci ; 20(13)2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31252615

RESUMO

Interleukin (IL)-6 plays a crucial role in the progression, invasion, and metastasis of breast cancer. Triple-negative breast cancer (TNBC) cell line MDA-MB-231 is known for its aggressive metastasis. Epithelial to mesenchymal transition (EMT) is a critical process in cancer metastasis. The positive correlation between IL-6 and EMT in tumor microenvironment is reported. We found significantly upregulated IL-6 expression in MDA-MB-231 cells. A blockade of IL-6 expression decreased levels of phosphorylated signal transducer and activator of transcription 3 (pSTAT3), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), phosphorylated protein kinase B (pAkt), and cell cycle-related molecules, including cyclin-dependent kinases (CDKs) and cyclins in MDA-MB-231 cells. A short-hairpin RNA (shRNA)-mediated blockade of IL-6 expression inhibited migration and N-cadherin expression and induced E-cadherin expression in MDA-MB-231 cells. Growth rate was slower for the tumors derived from IL-6 shRNA-treated MDA-MB-231 cells than for those derived from control shRNA-treated MDA-MB-231 cells. The expression of pSTAT3, phosphorylated extracellular signal-regulated kinase (pERK), PI3K, pAkt, snail, vimentin, and N-cadherin was significantly lower in tumors from IL-6 shRNA-treated MDA-MB cells. In addition, apigenin treatment significantly inhibited the growth of MDA-MB-231-derived xenograft tumors along with the protein expressions of pSTAT3, pERK, IL-6, PI3K, pAkt, and N-cadherin. Our results demonstrate that the anti-invasive effect of apigenin in MDA-MB-231-derived xenograft tumors is mediated by the inhibition of IL-6-linked downstream signaling pathway.


Assuntos
Antineoplásicos/uso terapêutico , Apigenina/uso terapêutico , Carcinoma/tratamento farmacológico , Interleucina-6/metabolismo , Neoplasias Mamárias Experimentais/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Apigenina/farmacologia , Ciclinas/genética , Ciclinas/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Interleucina-6/genética , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos
11.
Biofactors ; 45(5): 750-762, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31188510

RESUMO

Chronic kidney disease (CKD) is one of the major global health concerns and is responsible for end-stage renal disease (ESRD) complications. Inflammation plays a pivotal role in the progression of CKD. In the present study, we evaluated the renoprotective effects of a potent immunomodulator steroidal lactone, Withaferin A (WfA), in an animal model of renal injury (unilateral ureteral obstruction, UUO) and further investigated if the inhibition of inflammatory signaling can be a useful approach to reduce renal injury. Animals were randomly divided into five groups: Sham control, UUO control, WfA control, WfA low dose (1 mg/kg), and WfA high dose (3 mg/kg). Oxidative stress was measured by the estimation of reduced glutathione and lipid peroxidation levels. H&E and Picrosirius Red staining were performed to assess the extent of histological damage and collagen deposition. Furthermore, the molecular mechanism of the WfA effects was explored by immunohistochemistry, enzyme-linked immunosorbent assay, multiplex analysis of transforming growth factor ß (TGF-ß) pathway, and an array of inflammatory cytokines/chemokines. Interestingly, our pharmacological intervention significantly attenuated tissue collagen, inflammatory signaling, and macrophage signaling. WfA intervention abrogated the inflammatory signaling as evident from the modulated levels of chemokines and cytokines. The levels of TGF-ß along with downstream signaling molecules were also attenuated by WfA treatment as revealed by inhibition in the expression of TGF-ß1, TGF-ß2, p-Smad2, p-Smad3, total Smad4, p-Akt, and p-ERK. We, to the best of our knowledge, prove for the first time that WfA has potential renoprotective activity against UUO-induced nephropathy due to its outstanding anti-inflammatory properties.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Obstrução Ureteral/tratamento farmacológico , Vitanolídeos/farmacologia , Animais , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Glutationa/agonistas , Glutationa/metabolismo , Inflamação , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Proteína Smad4/genética , Proteína Smad4/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta2/genética , Fator de Crescimento Transformador beta2/metabolismo , Resultado do Tratamento , Obstrução Ureteral/genética , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia
12.
Int J Med Sci ; 16(4): 494-500, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31171899

RESUMO

Aim: Sulfasalazine (SSZ) displayed anti-cancer activities. Vitamin E succinate (VES) could inhibit cell growth in various cancer cells. However, chemical therapies were often not useful for triple-negative breast cancer cells (TNBCs) treatment. Here, this study investigated the anti-cancer effects and the mechanisms on TNBCs under combination treatment with SSZ and VES. Methods: Cell viability was analyzed by using the MTT assay. The H2O2 levels were determined by using lucigenin-amplified chemiluminescence method. In addition, caspase and MAPs signals were studied by using western blotting. Results: Low-dose VES antagonized the SSZ-induced cytotoxicity effects while high-dose VES promoted the SSZ-induced cytotoxicity effects on TNBCs. In addition, SSZ alone treatment activated both caspase-3 and ERK signals, however, VES alone treatment only activated JNK signals. On the other hand, activation of caspase-3, JNK, and ERK were found in SSZ plus VES-treated cells. Conclusion: Combined SSZ and VES has synergistic or antagonistic cytotoxic effects depending on VES concentration. In addition, different cytotoxic signals are induced on SSZ-treated, VES-treated and SSZ plus VES-treated cells.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Sulfassalazina/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , alfa-Tocoferol/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , MAP Quinases Reguladas por Sinal Extracelular/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Peróxido de Hidrogênio/isolamento & purificação , MAP Quinase Quinase 4/genética , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
13.
Oncol Rep ; 42(2): 717-725, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173266

RESUMO

Glioma is the most common primary brain tumor and is characterized by a poor prognosis. Protein tyrosine phosphatase 1B (PTPN1), as a non­transmembrane protein tyrosine phosphatase, has been reported to serve a critical role in different diseases, including cancer. However, the role of PTPN1 in the progression of glioma remains unclear. The present study investigated the expression and clinicopathological characteristics of PTPN1 by analyzing the data from The Cancer Genome Atlas and 136 patients with glioma. It was indicated that PTPN1 was overexpressed in glioma tissues and served as a predictor for poor prognosis in patients with glioma. In addition, a series of in vitro experiments were performed to examine the underlying mechanism of PTPN1 overexpression and the clinical prognosis in patients with glioma. Knockdown of PTPN1 by small interfering RNA suppressed proliferation of glioma cells, including SF295 and A172. In addition, cell mobility was also inhibited by PTPN1 knockdown, downregulating the expression of matrix metallopeptidase 2 (MMP­2) and MMP­9. As indicated by western blot analysis, the mitogen­activated protein kinase (MAPK)/extracellular­signal­regulated kinase (ERK) signaling pathway and the phosphatidylinositol 3­kinase (PI3K)/AKT serine/threonine kinase (AKT) signaling pathway was regulated by PTPN1, while knockdown of PTPN1 significantly suppressed the MAPK/ERK and PI3K/AKT pathways, in addition to the downstream oncogenic transcription factor MYC Proto­Oncogene. In conclusion, it was demonstrated that PTPN1 is upregulated in glioma tissue and the overexpression of PTPN1 predicted the poor prognosis of patients with glioma. PTPN1 promotes the progression of glioma by activating the MAPK/ERK and PI3K/AKT pathways.


Assuntos
Biomarcadores Tumorais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioma/mortalidade , Fosfatidilinositol 3-Quinases/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Apoptose , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Progressão da Doença , MAP Quinases Reguladas por Sinal Extracelular/genética , Feminino , Seguimentos , Glioma/genética , Glioma/metabolismo , Glioma/patologia , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/genética , Prognóstico , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais , Taxa de Sobrevida , Células Tumorais Cultivadas
14.
BMC Cancer ; 19(1): 643, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253108

RESUMO

BACKGROUND: Investigations of colorectal carcinogenesis have mainly focused on examining neoplastic tissue. With our aim of identifying potentially cancer-predisposing molecular compositions, we chose a different approach by examining endoscopically normal appearing colonic mucosa of patients with and without colorectal neoplasia (CRN). Directed by this focus, we selected 18 genes that were previously found with altered expression in colorectal cancer affected mucosa. METHODS: Biopsies of colonic mucosa were sampled from 27 patients referred for colonoscopy on suspicion of colorectal disease. Of these, 14 patients had present or previous CRN and the remaining 13 patients served as controls. Using qPCR and Western blot technique, we investigated mRNA and protein expressions. Expressions were investigated for selected kinases in the extracellular signal-regulated kinase/mitogen activated protein kinase (ERK/MAPK), the phosphoinositide 3-kinase/Akt, and the Wnt/ß-catenin pathways as well as for selected phosphatases and several entities associated with prostaglandin E2 (PGE2) signaling. Colonic mucosal contents of PGE2 and PGE2 metabolites were determined by use of ELISA. RESULTS: We found up-regulation of ERK1, ERK2, Akt1, Akt2, PLA2G4A, prostanoid receptor EP3 and phosphatase scaffold subunit PPP2R1B mRNA expression in normal appearing colonic mucosa of CRN patients compared to controls. CONCLUSION: Present study supports that even normal appearing mucosa of CRN patients differs from that of non-CRN patients at a molecular level. Especially expression of ERK1 mRNA was increased (p = 0.007) in CRN group. ERK1 may therefore be considered a potential candidate gene as predictive biomarker for developing CRN. Further validation in larger cohorts are required to determine such predictive use in translational medicine and clinics.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença/genética , Mucosa Intestinal/metabolismo , Biomarcadores Tumorais/metabolismo , Colo/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Ciclo-Oxigenase 1/metabolismo , Dinoprostona/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Fosfolipases A2 do Grupo IV/genética , Fosfolipases A2 do Grupo IV/metabolismo , Humanos , Hidroxiprostaglandina Desidrogenases/metabolismo , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/metabolismo , Receptores de Prostaglandina E Subtipo EP3/genética , Receptores de Prostaglandina E Subtipo EP3/metabolismo , Transdução de Sinais/genética , Regulação para Cima , beta Catenina/metabolismo
15.
Oncol Rep ; 42(3): 1183-1193, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31233204

RESUMO

Liver cancer is the fifth most commonly occurring cancer in men and the ninth most commonly occurring cancer in women, worldwide, and is associated with a high mortality rate. Sorafenib is a new inhibitor of multiple kinases, that is regarded as standard treatment for liver cancer. Human breast carcinoma metastasis­suppressor 1 (BRMS1) is a tumor­suppressor gene, that reduces the metastatic ability of tumor cells without affecting their tumorigenicity. In the present study, a model of BRMS1 overexpression and BRMS1 knockdown was established in HepG2 cells. The results revealed that the proliferation of HepG2 cells was inhibited in response to sorafenib treatment using MTT assay. Furthermore, BRMS1 overexpression enhanced the effect of sorafenib. In addition, expression of inflammatory response­related genes was increased, while secretion of angiogenesis­related molecules was decreased, and apoptosis was also activated after sorafenib treatment using qPCR method, and it was further demonstrated that this effect was mediated by inhibition of the PI3K/AKT/mTOR/ERK signaling pathway using western blot analysis. In conclusion, overexpression of BRMS1 potentiated the effect of sorafenib via PI3K/AKT/mTOR/ERK signaling, while knockdown of BRMS1 expression attenuated this effect. These findings may present a novel therapeutic strategy for liver cancer.


Assuntos
Carcinoma Hepatocelular/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Repressoras/metabolismo , Sorafenibe/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Proliferação de Células , Sinergismo Farmacológico , MAP Quinases Reguladas por Sinal Extracelular/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Repressoras/genética , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Células Tumorais Cultivadas
16.
Int J Mol Sci ; 20(12)2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31200510

RESUMO

Epithelial-mesenchymal transition (EMT) is a reversible cellular process, characterized by changes in gene expression and activation of proteins, favoring the trans-differentiation of the epithelial phenotype to a mesenchymal phenotype. This process increases cell migration and invasion of tumor cells, progression of the cell cycle, and resistance to apoptosis and chemotherapy, all of which support tumor progression. One of the signaling pathways involved in tumor progression is the MAPK pathway. Within this family, the ERK subfamily of proteins is known for its contributions to EMT. The ERK subfamily is divided into typical (ERK 1/2/5), and atypical (ERK 3/4/7/8) members. These kinases are overexpressed and hyperactive in various types of cancer. They regulate diverse cellular processes such as proliferation, migration, metastasis, resistance to chemotherapy, and EMT. In this context, in vitro and in vivo assays, as well as studies in human patients, have shown that ERK favors the expression, function, and subcellular relocalization of various proteins that regulate EMT, thus promoting tumor progression. In this review, we discuss the mechanistic roles of the ERK subfamily members in EMT and tumor progression in diverse biological systems.


Assuntos
Transição Epitelial-Mesenquimal , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Neoplasias/metabolismo , Animais , MAP Quinases Reguladas por Sinal Extracelular/química , MAP Quinases Reguladas por Sinal Extracelular/genética , Humanos , Sistema de Sinalização das MAP Quinases , Neoplasias/genética , Neoplasias/patologia
17.
Int J Mol Sci ; 20(9)2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31052505

RESUMO

Glioblastoma (GBM) is one of the most aggressive cancers, with median survival of less than 2 years. Despite of considerable advance in molecular classification of GBMs, no improvements in therapy have been described. The scenario is further complicated by tumor heterogeneity and the relationship among genetic, transcriptional and functional findings. Classically, gene expression has been evaluated by steady-state mRNA, however, this does not take translational control into consideration, which contributes considerably to the composition of the proteome. In this study, we evaluated the transcriptomic and translatomic signature of a GBM obtained from a single patient focusing in tumor heterogeneity. In a sampling of eight fragments, we investigated the translation rates, mTORC1 and ERK1/2 pathways and identified both total and polysome associated mRNAs. An increased translation rate was observed in fragments with high-grade histological features. High-grade histology was also associated with the expression of genes related to extracellular matrix (ECM) and angiogenesis, in both transcriptomes and translatomes. However, genes associated with epithelial to mesenchymal transition and stress response, were observed only in translatomes from high-grade fragments. Overall, our results demonstrate that isolation of translated mRNA can be used to identify biomarkers and reveal previously unrecognized determinants of heterogeneity in GBMs.


Assuntos
Neoplasias do Sistema Nervoso Central/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Linhagem Celular Tumoral , Neoplasias do Sistema Nervoso Central/patologia , MAP Quinases Reguladas por Sinal Extracelular/genética , Feminino , Glioblastoma/patologia , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Pessoa de Meia-Idade , Biossíntese de Proteínas , RNA Mensageiro/genética
18.
BMC Immunol ; 20(1): 13, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31046669

RESUMO

BACKGROUND: Tristetraprolin (TTP) is an RNA binding protein that plays a critical role in regulating proinflammatory immune responses by destabilizing target mRNAs via binding to their AU-rich elements (AREs) in the 3'-UTRs of mRNAs. A recent CLIP-seq study revealed that TTP-binding sites are enriched in the intronic regions of RNA. TTP is also a nuclear protein that exhibits putative DNA-binding activity. These features suggested that TTP might regulate gene transcription and/or alternative splicing of pre-mRNAs in the absence of stimulation. RESULTS: To elucidate the regulatory pattern of TTP, we cloned and overexpressed the human TTP-encoding gene, ZFP36, in HeLa cells in the absence of inflammatory stimuli. The transcriptomes of the control and ZFP36-overexpressing cells were sequenced and subjected to analysis and validation. Upon ZFP36 overexpression, the expression of genes associated with innate immunity, including those in the type I interferon signaling pathway and viral response, were specifically upregulated, implying a transcriptional regulatory mechanism associated with the predicted DNA binding activity of TTP. TTP preferentially regulated the alternative splicing of genes involved in the positive regulation of the I-κB/NF-κB cascade and the TRIF-dependent toll-like receptor, MAPK, TNF, and T cell receptor signaling pathways. CONCLUSIONS: Our findings indicated that TTP may regulate the immune response via the regulation of alternative splicing and potentially transcription, which greatly expands the current understanding of the mechanisms of TTP-mediated gene regulation.


Assuntos
Processamento Alternativo/genética , Imunidade Inata/genética , Tristetraprolina/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Células HeLa , Humanos , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , NF-kappa B/genética , RNA Mensageiro/genética , Receptores de Antígenos de Linfócitos T/genética , Transdução de Sinais/genética , Tristetraprolina/genética , Fator de Necrose Tumoral alfa/genética
19.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1651-1665, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30954555

RESUMO

Loss of E-cadherin and epithelial to mesenchymal transition (EMT) are key steps in cancer progression. Reactive oxygen species (ROS) play significant roles in cellular physiology and homeostasis. Roles of E-cadherin (CDH1), EMT and ROS are intriguingly illustrated in many cancers without focusing their collective concert during cancer progression. We report that hydrogen peroxide (H2O2) treatment modulate CDH1 gene expression by epigenetic modification(s). Sublethal dosage of H2O2 treatment decrease E-cadherin, increase DNMT1, HDAC1, Snail, Slug and enrich H3K9me3 and H3K27me3 in the CDH1 promoter. The effect of H2O2 was attenuated by ROS scavengers; NAC, lupeol and beta-sitosterol. DNMT inhibitor, AZA prevented the H2O2 induced promoter-CpG-island methylation of CDH1. Treatment of cells with U0126 (inhibitor of ERK) reduced the expression of DNMT1, Snail and Slug, increased CDH1. This implicates that CDH1 is synergistically repressed by histone methylation, DNA methylation and histone deacetylation mediated chromatin remodelling and activation of Snail and Slug through ERK pathway. Increased ROS leads to activation of epigenetic machineries and EMT activators Snail/Slug which in their course of action inactivates CDH1 gene and lack of E-cadherin protein promotes EMT in breast cancer cells. ROS and ERK signaling facilitate epigenetic silencing and support the fact that subtle increase of ROS above basal level act as key cell signaling molecules. Free radical scavengers, lupeol and beta-sitosterol may be tested for therapeutic intervention of breast cancer. This work broadens the amplitude of epigenome and open avenues for investigations on conjoint effects of canonical and intrinsic metabolite signaling and epigenetic modulations in cancer.


Assuntos
Antígenos CD/genética , Neoplasias da Mama/genética , Caderinas/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Fatores de Transcrição da Família Snail/genética , Antioxidantes/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Butadienos/farmacologia , Caderinas/deficiência , Linhagem Celular , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA , Transição Epitelial-Mesenquimal/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Histona Desacetilase 1/genética , Histona Desacetilase 1/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Estimativa de Kaplan-Meier , Células MCF-7 , Nitrilos/farmacologia , Triterpenos Pentacíclicos/farmacologia , Transdução de Sinais , Sitosteroides/farmacologia , Fatores de Transcrição da Família Snail/metabolismo
20.
Lipids Health Dis ; 18(1): 100, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992016

RESUMO

Growing evidence suggests that ethanolamine plasmalogens (PlsEtns), a subtype of phospholipids, have a close association with Alzheimer's disease (AD). Decreased levels of PlsEtns have been commonly found in AD patients, and were correlated with cognition deficit and severity of disease. Limited studies showed positive therapeutic outcomes with plasmalogens interventions in AD subjects and in rodents. The potential mechanisms underlying the beneficial effects of PlsEtns on AD may be related to the reduction of γ-secretase activity, an enzyme that catalyzes the synthesis of ß-amyloid (Aß), a hallmark of AD. Emerging in vitro evidence also showed that PlsEtns prevented neuronal cell death by enhancing phosphorylation of AKT and ERK signaling through the activation of orphan G-protein coupled receptor (GPCR) proteins. In addition, PlsEtns have been found to suppress the death of primary mouse hippocampal neuronal cells through the inhibition of caspase-9 and caspase-3 cleavages. Further in-depth investigations are required to determine the signature molecular species of PlsEtns associated with AD, hence their potential role as biomarkers. Clinical intervention with plasmalogens is still in its infancy but may have the potential to be explored for a novel therapeutic approach to correct AD pathology and neural function.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/antagonistas & inibidores , Disfunção Cognitiva/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Plasmalogênios/farmacologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/biossíntese , Peptídeos beta-Amiloides/genética , Animais , Biomarcadores/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Plasmalogênios/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais
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