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1.
Exp Ther Med ; 22(3): 970, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34335912

RESUMO

Neuroinflammation is associated with many neurodegenerative diseases. Abnormal activation of microglial cells in the central nervous system (CNS) is a major characteristic of neuroinflammation. Nitric oxide (NO) free radicals are produced by activated microglia and prolonged presence of large quantities of NO in the CNS can lead to neuroinflammation and disease. Hispidin is a polyphenol derived from Phellinus linteus (a valuable medicinal mushroom) with strong antioxidant, anticancer and antidiabetic properties. A previous study demonstrated that hispidin significantly inhibited NO production via lipopolysaccharide (LPS)-induced RAW264.7 macrophages. Therefore, the present study used MTT assay was used to detect the effect of hispdin on cell viability. Griess reagent analysis was used to measure NO production. Reverse transcription-semi quantitative PCR and western blotting were used to evaluate the effects of hispdin on iNOS mRNA and MAPK/ERK/JNK protein levels. Fluorescence microscopy and flow cytometry were used to detect the effects of hispdin on the production of ROS and phagocytosis of cells. The present results indicated that hispidin could significantly inhibit the increase of NO production and iNOS expression in BV-2 microglial cells stimulated by LPS. The inhibitory effect of hispidin on NO production was similar to that of S-methylisothiourea sulfate, an iNOS inhibitor. Signaling studies demonstrated that hispidin markedly suppresses LPS-induced mitogen activated protein kinases and JAK1/STAT3 activation, although not the NF-κB signaling pathway. The present observations in LPS-stimulated BV-2 microglial cells indicated that hispidin might serve as a therapeutic candidate for the treatment of NO-induced neuroinflammation and, potentially, as a novel iNOS inhibitor.

2.
In Vivo ; 35(1): 249-257, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33402471

RESUMO

BACKGROUND/AIM: Curcumin is a polyphenol that exerts a variety of pharmacological activities and plays an anti-cancer role in many cancer cells. It was recently reported that gasdermin E (GSDME) is involved in the progression of pyroptosis. MATERIALS AND METHODS: HepG2 cells were treated with various concentrations of curcumin and cell viability was examined using MTT assay, apoptosis was analysed using flow cytometry, reactive oxygen species (ROS) levels using dihydroethidium, LDH release using an LDH cytotoxicity assay, and protein expression using western blot. RESULTS: Curcumin increased the expression of the GSDME N-terminus and proteins involved in pyrolysis, promoted HspG2 cell pyrolysis and increased intracellular ROS levels. Moreover, inhibition of the production of intracellular ROS with n-acetylcysteine (NAC) improved the degree of apoptosis and pyrolysis induced by curcumin. CONCLUSION: Curcumin induces HspG2 cell death by increasing apoptosis and pyroptosis, and ROS play a key role in this process. This study improves our understanding of the potential anti-cancer properties of curcumin in liver cancer.


Assuntos
Carcinoma Hepatocelular , Curcumina , Neoplasias Hepáticas , Apoptose , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Curcumina/farmacologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Piroptose , Espécies Reativas de Oxigênio
3.
Ther Adv Med Oncol ; 10: 1758835918783132, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30034549

RESUMO

Background: Treatment of metastatic castration-resistant prostate cancer (mCRPC) with docetaxel often fails due to the emergence of chemoresistance. Thus, restoring chemosensitivity to docetaxel-based therapies remains a challenge in mCRPC treatment. Methods: microRNA (miR)-451 expression was measured in docetaxel-treated prostate cancer cells and tumor tissues by quantitative reverse-transcription polymerase chain reaction . Cell-counting kit 8 assay was performed to determine docetaxel chemoresistance. Neural-precursor-cell-expressed developmentally downregulated protein 9 (NEDD9) was identified as a novel target of miR-451 by dual-luciferase reporter system. Chromatin immunoprecipitation and co-immunoprecipitation assay were performed to confirm that histone deacetylase 3 (HDAC3)/Sp1 (a highly evolutionarily conserved transcription factor) interacted with the Sp1 binding sites in miR-451 promoter. Results: miR-451 was found to be silenced in docetaxel-treated prostate cancer cells and mCRPC tissues. Low miR-451 expression was closely associated with a high Gleason score, high Eastern Cooperative Oncology Group performance status score, visceral metastasis and poor prognosis. Low expression of miR-451 was significantly correlated with short progression-free survival (PFS) and overall survival (OS) according to Kaplan-Meier analysis, and miR-451 was determined to be an independent poor prognostic factor for PFS and OS in mCRPC patients by univariate and multivariate Cox regression analyses. NEDD9 was identified as a new and functional target of miR-451. Restoration of NEDD9 partially reversed the effects of miR-451 on enhancing chemosensitivity of prostate cancer cells. HDAC3 was confirmed to be involved in silencing of miR-451 expression in prostate cancer cells. Conclusions: The current data revealed a new HDAC3/Sp1/miR-451/NEDD9 signaling axis that regulates the chemosensitivity of prostate cancer cells and represents a novel therapeutic target for chemosensitizing mCRPC.

4.
Oncotarget ; 6(21): 18613-30, 2015 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-26164082

RESUMO

Increasing evidence indicates that dysregulation of microRNAs (miRNAs) plays critical roles in malignant transformation and tumor progression. Previously, we have shown that microRNA-451 (miR-451) inhibits growth, increases chemo- or radiosensitivity and reverses epithelial to mesenchymal transition (EMT) in lung cancer. However, the roles of miR-451 in hepatocelluar carcinoma (HCC) progression and metastasis are still largely unknown. Reduced miR-451 in HCC tissues was observed to be significantly correlated with advanced clinical stage, metastasis and worse disease-free or overall survival. Through gain- and loss-of function experiments, we demonstrated that miR-451 inhibited cell growth, induced G0/G1 arrest and promoted apoptosis in HCC cells. Importantly, miR-451 could inhibit the migration and invasion in vitro, as well as in vivo metastasis of HCC cells through regulating EMT process. Moreover, the oncogene c-Myc was identified as a direct and functional target of miR-451 in HCC cells. Knockdown of c-Myc phenocopied the effects of miR-451 on EMT and metastasis of HCC cells, whereas overexpression of c-Myc partially attenuated the functions of miR-451 restoration. Furthermore, miR-451 downregulation-induced c-Myc overexpression leads to the activation of Erk1/2 signaling, which induces acquisition of EMT phenotype through regulation of GSK-3ß/snail/E-cadherin and the increased expression of MMPs family members in HCC cells. Collectively, these data demonstrated that miR-451 is a novel prognostic biomarker for HCC patients and that function as a potential metastasis inhibitor in HCC cells through activation of the Erk1/2 signaling, at least partially by targeting c-Myc. Thus, targeting miR-451/c-Myc/Erk1/2 axis may be a potential strategy for the treatment of metastatic HCC.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Transição Epitelial-Mesenquimal/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , Apoptose/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases/genética , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sobrevida
5.
PLoS One ; 9(10): e109578, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25279705

RESUMO

The presence of cancer stem-like cells (CSCs) is one of the mechanisms responsible for chemoresistance that has been a major hindrance towards lung adenocarcinoma (LAD) treatment. Recently, we have identified microRNA (miR)-200b as a key regulator of chemoresistance in human docetaxel-resistant LAD cells. However, whether miR-200b has effects on regulating CSCs remains largely unclear and needs to be further elucidated. Here, we showed that miR-200b was significantly downregulated in CD133+/CD326+ cells that exhibited properties of CSCs derived from docetaxel-resistant LAD cells. Also, restoration of miR-200b could inhibit maintenance and reverse chemoresistance of CSCs. Furthermore, suppressor of zeste-12 (Suz-12) was identified as a direct and functional target of miR-200b, and silencing of Suz-12 phenocopied the effects of miR-200b on CSCs. Additionally, overexpression of histone deacetylase (HDAC) 1 was identified as a pivotal mechanism responsible for miR-200b repression in CSCs through a specificity protein (Sp) 1-dependent mechanism, and restoration of miR-200b by HDAC1 repression significantly suppressed CSCs formation and reversed chemoresistance of CSCs by regulating Suz-12-E-cadherin signaling. Also, downregulation of HDAC1 or upregulation of miR-200b reduced the in vivo tumorigenicity of CSCs. Finally, Suz-12 was inversely correlated with miR-200b, positively correlated with HDAC1 and up-regulated in docetaxel-resistant LAD tissues compared with docetaxel-sensitive tissues. Taken together, the HDAC1/miR-200b/Suz-12-E-cadherin signaling might account for maintenance of CSCs and formation of chemoresistant phenotype in docetaxel-resistant LAD cells.


Assuntos
Adenocarcinoma/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Histona Desacetilase 1/metabolismo , Neoplasias Pulmonares/patologia , MicroRNAs/genética , Células-Tronco Neoplásicas/patologia , Fator de Transcrição Sp1/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Animais , Apoptose , Western Blotting , Caderinas/genética , Caderinas/metabolismo , Proliferação de Células , Imunoprecipitação da Cromatina , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Histona Desacetilase 1/genética , Humanos , Técnicas Imunoenzimáticas , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição Sp1/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Oncotarget ; 5(15): 6113-29, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25026294

RESUMO

Chemoresistant tumors usually fail to respond to radiotherapy. However, the mechanisms involved in chemo- and radiotherapy cross resistance are not fully understood. Previously, we have identified microRNA (miR)-451 as a tumor suppressor in lung adenocarcinoma (LAD). However, whether miR-451 plays critical roles in chemo- and radiotherapy cross resistance in LAD is unclear. Here, we established two docetaxel-resistant LAD cell models (SPC-A1/DTX and H1299/DTX), and showed that miR-451 was significantly downregulated in docetaxel-resistant LAD cells. Gain - and loss - of - function assays indicated that re-expression of miR-451 could reverse radioresistance of docetaxel-resistant LAD cells both in vitro and in vivo through promoting apoptosis and DNA double-strand breaks (DSBs). The proto-oncogene c-Myc was identified as a direct target of miR-451, and re-expression of miR-451 inhibited survivin and rad-51 expression by reducing the amount of c-Myc protein binding to their promoters. Silencing of c-Myc could phenocopy the effects of miR-451 upregulation, and restoration of c-Myc could partially rescue the effect of miR-451 upregulation on radiosensitivity of docetaxel-resistant LAD cells. Therefore, dysregulation of miR-451/c-Myc-survivin/rad-51 signaling is responsible for radioresistance of docetaxel-resistant LAD cells, and targeting it will be a potential strategy for reversing chemo- and radiotherapy cross resistance of LAD patients.


Assuntos
Adenocarcinoma/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Adenocarcinoma de Pulmão , Linhagem Celular Tumoral , Docetaxel , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Transdução de Sinais , Taxoides
7.
Oncotarget ; 5(10): 3333-49, 2014 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-24830600

RESUMO

Chemoresistance is one of the most significant obstacles in lung adenocarcinoma (LAD) treatment, and this process involves genetic and epigenetic dysregulation of chemoresistance-related genes. Previously, we have shown that restoration of microRNA (miR)-200b significantly reverses chemoresistance of human LAD cells by targeting E2F3. However, the molecular mechanisms involved in the silencing of miR-200b are still unclear. Here we showed that histone deacetylase (HDAC) inhibitors could restore the expression of miR-200b and reverse chemoresistant phenotypes of docetaxel-resistant LAD cells. HDAC1/4 repression significantly increased miR-200b expression by upregulating histone-H3 acetylation level at the two miR-200b promoters partially via a Sp1-dependent pathway. Furthermore, silencing of HDAC1/4 suppressed cell proliferation, promoted cell apoptosis, induced G2/M cell cycle arrest and ultimately reversed in vitro and in vivo chemoresistance of docetaxel-resistant LAD cells, at least partially in a miR-200b-dependent manner. HDAC1/4 suppression-induced rescue of miR-200b contributed to downregulation of E2F3, survivin and Aurora-A, and upregulation of cleaved-caspase-3. HDAC1/4 levels in docetaxel-insensitive human LAD tissues, inversely correlated with miR-200b, were upregulated compared with docetaxel-sensitive tissues. Taken together, our findings suggest that the HDAC1/4/Sp1/miR-200b/E2F3 pathway is responsible for chemoresistance of docetaxel-resistant LAD cells.


Assuntos
Adenocarcinoma/genética , Resistencia a Medicamentos Antineoplásicos/genética , Fator de Transcrição E2F3/genética , Histona Desacetilase 1/genética , Histona Desacetilases/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Proteínas Repressoras/genética , Adenocarcinoma/mortalidade , Adenocarcinoma de Pulmão , Western Blotting , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Intervalo Livre de Doença , Citometria de Fluxo , Inativação Gênica , Humanos , Imunoprecipitação , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção
8.
Clin Exp Pharmacol Physiol ; 37(8): 795-802, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20374261

RESUMO

1. G-Protein-coupled receptors (GPCR) and electrical field stimulation (EFS) regulate cardiac function and pathological remodelling, including cardiac hypertrophy. Cardiac Ca(2+)/calmodulin-dependent protein kinase (CaMK) IIdelta expression and activity are altered in cardiac hypertrophy and heart failure. The aim of the present study was to determine the effects of CaMKIIdelta isoforms on neonatal rat cardiomyocyte hypertrophy induced by GPCR and EFS. 2. Cardiac hypertrophy was induced by angiotensin II, phenylephrine or EFS and was confirmed by increases in cell volume, [(3)H]-leucine incorporation, sarcomere assembly and mRNA expression of atrial natriuretic factor and beta-myosin heavy chain. The effects of the CaMKII inhibitors KN93 and autocamtide 2-related inhibitory peptide (AIP) on cardiomyocyte hypertrophy were investigated, as was the effect of overexpression of dominate negative CaMKIIdelta. 3. Cardiomyocyte hypertrophy was inhibited by the CaMKII inhibitors KN93 and AIP and by overexpression of dominate negative CaMKIIdelta, but was potentiated by overexpression of wild-type CaMKIIdeltaB or CaMKIIdeltaC. Activation of CaMKII by GPCR agonists or EFS was inhibited by the CaMKII inhibitors. 4. The GPCR agonists and EFS synergistically activated CaMKII and upregulated CaMKIIdeltaB and CaMKIIdeltaC mRNA expression and protein synthesis. All these effects were abolished by the CaMKII inhibitors. 5. The findings of the present study indicate that CaMKII orchestrates additive prohypertrophic factors between GPCR agonists and EFS. Thus, CaMKII may be a useful target in the clinical treatment of hypertrophy and cardiac remodelling.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Miócitos Cardíacos/fisiologia , Miócitos Cardíacos/ultraestrutura , Receptores Acoplados a Proteínas G/fisiologia , Adenoviridae/genética , Angiotensina II/farmacologia , Animais , Animais Recém-Nascidos , Western Blotting , Proteínas de Ligação ao Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Tamanho Celular/efeitos dos fármacos , Células Cultivadas , Estimulação Elétrica , Imuno-Histoquímica , Leucina/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Peptídeos/metabolismo , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa
9.
J Cardiovasc Pharmacol ; 55(1): 96-105, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19935079

RESUMO

Calcium-calmodulin-dependent protein kinase II (CaMKII) is one of the main protein kinases mediating intracellular Ca changes. It is also involved in the process of cardiac diseases, such as cardiac hypertrophy, but its effects on myocardial fibrosis remain unclear. The present study investigates whether CaMKII is involved in cardiac fibroblast proliferation and extracellular matrix (ECM) secretion induced by angiotensin II (AngII) or electrical field stimulation (EFS) in cultured neonatal rat cardiac fibroblasts. Cardiac fibroblast proliferation was assessed by a cell survival assay (MTT) and manual cell enumeration. Cellular matrix production was demonstrated by matrix metalloproteinases (MMP) 1, 2, 9, and collagen I/III messenger RNA expression, MMP-2, 9 protein expression, and secretion of transforming growth factor beta1 and tumor necrosis factor alpha. Either AngII or EFS promoted cardiac fibroblast proliferation and ECM secretion, while also up-regulating expression of CaMKII deltaB and deltaC. More importantly, CaMKII inhibitors, autocamtide-2-related inhibitory peptide (AIP 5 microM) or KN93 (0.5 microM), suppressed cardiac fibroblast proliferation, inhibited the excretion of transforming growth factor beta1 and tumor necrosis factor alpha, decreased the messenger RNA expression of MMP-1, 2, 9 and collagen I/III, and decreased the protein expression of MMP-2, 9. These results suggest that CaMKII mediates cardiac fibroblast proliferation and ECM secretion induced by either AngII or EFS.


Assuntos
Angiotensina II/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Animais , Animais Recém-Nascidos , Benzilaminas/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Estimulação Elétrica , Matriz Extracelular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Sulfonamidas/farmacologia
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