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1.
Molecules ; 26(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34500557

RESUMO

In this study, we aimed to evaluate the anticancer effect of benzimidazole derivatives on triple-negative breast cancer (TNBC) and investigate its underlying mechanism of action. Several types of cancer and normal breast cells including MDA-MB-231, radiotherapy-resistant (RT-R) MDA-MB-231, and allograft mice were treated with six benzimidazole derivatives including mebendazole (MBZ). Cells were analyzed for viability, colony formation, scratch wound healing, Matrigel invasion, cell cycle, tubulin polymerization, and protein expression by using Western blotting. In mice, liver and kidney toxicity, changes in body weight and tumor volume, and incidence of lung metastasis were analyzed. Our study showed that MBZ significantly induced DNA damage, cell cycle arrest, and downregulation of cancer stem cell markers CD44 and OCT3/4, and cancer progression-related ESM-1 protein expression in TNBC and RT-R-TNBC cells. In conclusion, MBZ has the potential to be an effective anticancer agent that can overcome treatment resistance in TNBC.


Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Mebendazol/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Biomarcadores Tumorais/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Neoplasias Pulmonares/metabolismo , Células MCF-7 , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo
2.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445501

RESUMO

Lipid dysregulation in diabetes mellitus escalates endothelial dysfunction, the initial event in the development and progression of diabetic atherosclerosis. In addition, lipid-laden macrophage accumulation in the arterial wall plays a significant role in the pathology of diabetes-associated atherosclerosis. Therefore, inhibition of endothelial dysfunction and enhancement of macrophage cholesterol efflux is the important antiatherogenic mechanism. Rosmarinic acid (RA) possesses beneficial properties, including its anti-inflammatory, antioxidant, antidiabetic and cardioprotective effects. We previously reported that RA effectively inhibits diabetic endothelial dysfunction by inhibiting inflammasome activation in endothelial cells. However, its effect on cholesterol efflux remains unknown. Therefore, in this study, we aimed to assess the effect of RA on cholesterol efflux and its underlying mechanisms in macrophages. RA effectively reduced oxLDL-induced cholesterol contents under high glucose (HG) conditions in macrophages. RA enhanced ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) expression, promoting macrophage cholesterol efflux. Mechanistically, RA differentially regulated ABCA1 expression through JAK2/STAT3, JNK and PKC-p38 and ABCG1 expression through JAK2/STAT3, JNK and PKC-ERK1/2/p38 in macrophages. Moreover, RA primarily stabilized ABCA1 rather than ABCG1 protein levels by impairing protein degradation. These findings suggest RA as a candidate therapeutic to prevent atherosclerotic cardiovascular disease complications related to diabetes by regulating cholesterol efflux in macrophages.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Colesterol/metabolismo , Cinamatos/farmacologia , Depsídeos/farmacologia , Glucose/efeitos adversos , Lipoproteínas LDL/efeitos adversos , Macrófagos/citologia , Transportador 1 de Cassete de Ligação de ATP/química , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Modelos Biológicos , Proteólise/efeitos dos fármacos , Transdução de Sinais , Células THP-1
3.
Biochem Pharmacol ; 182: 114246, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33011160

RESUMO

Elevated glucose levels in diabetes mellitus is associated with increased oxidized low density lipoprotein (oxLDL). High glucose (HG) and oxLDL are key inducers of oxidative stress and inflammatory processes responsible for diabetic vascular disorders. Rosmarinic acid is a polyphenol with antioxidant, anti-inflammatory and insulin-sensitizing effects. However, whether rosmarinic acid protects against diabetic atherosclerosis remains unknown. In this study, we aimed to investigate the protective effect of rosmarinic acid against diabetic atherosclerosis and the related signaling pathway. oxLDL-mediated oxidative stress upregulated thioredoxin-interacting protein (TXNIP) and subsequently induced binding of TXNIP to NLRP3 to mediate NLRP3 inflammasome assembly and activation under HG conditions in ECs. Reactive oxygen species (ROS) scavengers, p38 and FOXO1 inhibitors and TXNIP siRNA inhibited TXNIP protein upregulation and NLRP3 inflammasome assembly and activation. Rosmarinic acid abrogated TXNIP protein upregulation and the interaction between TXNIP and NLRP3 to attenuate NLRP3 inflammasome assembly and activation and eventually IL-1ß secretion in ECs through downregulating ROS production, p38 phosphorylation and FOXO1 protein induction in ECs. These findings show that rosmarinic acid inhibits endothelial dysfunction which is shown in diabetic atherosclerosis through downregulating the p38-FOXO1-TXNIP pathway and inhibiting inflammasome activation.


Assuntos
Proteínas de Transporte/metabolismo , Cinamatos/farmacologia , Depsídeos/farmacologia , Proteína Forkhead Box O1/metabolismo , Glucose/toxicidade , Inflamassomos/metabolismo , Lipoproteínas LDL/toxicidade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Antioxidantes/farmacologia , Proteínas de Transporte/antagonistas & inibidores , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Proteína Forkhead Box O1/antagonistas & inibidores , Humanos , Inflamassomos/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
4.
Int J Mol Sci ; 21(21)2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33126606

RESUMO

Cancer stem cells (CSCs) exist in solid tumors and contribute to therapeutic resistance and disease recurrence. Previously, we reported that radiotherapy-resistant (RT-R)-MDA-MB-231 cells from highly metastatic MDA-MB-231 cells produced more CSCs than any other RT-R-breast cancer cells and showed therapeutic resistance and enhanced invasiveness. Hypoxia inducible factor-1α (HIF-1α) induced in the tumor microenvironment leads to the release of lysyl oxidase (LOX), which mediates collagen crosslinking at distant sites to facilitate environmental changes that allow cancer cells to easily metastasize. Therefore, in this study, we investigated whether RT-R-MDA-MB-231 cells induce greater HIF-1α expression, LOX secretion, and premetastatic niche formation than MDA-MB-231 cells do. RT-R-MDA-MB-231 cells increased HIF-1α expression and LOX secretion compared with MDA-MB-231 cells. Mice harboring RT-R-MDA-MB-231 cell xenografts showed enhanced tumor growth and higher expression of the CSC markers, CD44, Notch-4, and Oct3/4. In addition, mice injected with RT-R-MDA-MB-231 cells exhibited a higher level of HIF-1α in tumor tissue, increased secretion of LOX in plasma, higher induced levels of crosslinked collagen, and a higher population of CD11b+ BMDC recruitment around lung tissue, compared with those injected with MDA-MB-231 cells. These results suggest that RT-R-MDA-MB-231 cells contribute to tumor progression by enhancing premetastatic niche formation through the HIF-1α-LOX axis.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteína-Lisina 6-Oxidase/metabolismo , Tolerância a Radiação , Animais , Apoptose , Biomarcadores Tumorais/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/radioterapia , Proliferação de Células , Feminino , Raios gama , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Metástase Neoplásica , Proteína-Lisina 6-Oxidase/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Cancers (Basel) ; 12(6)2020 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-32466580

RESUMO

The key barrier to the effectiveness of radiotherapy remains the radioresistance of breast cancer cells, resulting in increased tumor recurrence and metastasis. Thus, in this study, we aimed to clarify the difference between radiotherapy-resistant (RT-R) breast cancer (BC) and BC, and accordingly, analyzed gene expression levels between radiotherapy-resistant (RT-R) MDA-MB-231 cells and MDA-MB-231 cells. Gene expression array showed that ESM-1 was the most upregulated in RT-R-MDA-MB-231 cells compared to MDA-MB-231 cells. Then, we aimed to investigate the role of ESM-1 in the increased tumorigenesis of RT-R-BC cells. RT-R-MDA-MB-231, which showed an increased expression level of ESM1, exhibited significantly enhanced proliferation, colony forming ability, migration, and invasion compared to MDA-MB-231 cells, and ESM-1 knockdown effectively reversed these effects. In addition, compared to MDA-MB-231 cells, RT-R-MDA-MB-231 cells displayed improved adhesion to endothelial cells (ECs) due to the induction of adhesion molecules and increased MMP-9 activity and VEGF-A production, which were decreased by ESM-1 knockdown. Moreover, the expression of HIF-1α and activation of NF-κB and STAT-3 were increased in RT-R-MDA-MB-231 cells compared to MDA-MB-231 cells, and these effects were abolished by the knockdown of ESM-1. Finally, we confirmed the role of ESM-1 in tumorigenesis in an in vivo mouse model. Tumor volume, lung metastasis, and tumorigenic molecules (VEGF-A, HIF-1α, MMP-9, ICAM-1, VCAM-1, and phospho-NF-κB and phospho-STAT-3) were significantly induced in mice injected with ESM-1-overexpressing 4T1 cells and greatly enhanced in those injected with ESM-1-overexpressing RT-R-4T1 cells. Taken together, these results suggest for the first time that ESM-1 plays a critical role in tumorigenesis of breast cancer cells, especially RT-R-breast cancer cells, through the induction of cell proliferation and invasion.

6.
Molecules ; 25(8)2020 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-32326231

RESUMO

Artemisia annua L. has been reported to show anti-cancer activities. Here, we determined whether polyphenols extracted from Artemisia annua L. (pKAL) exhibit anti-cancer effects on radio-resistant MDA-MB-231 human breast cancer cells (RT-R-MDA-MB-231 cells), and further explored their molecular mechanisms. Cell viability assay and colony-forming assay revealed that pKAL inhibited cell proliferation on both parental and RT-R-MDA-MB-231 cells in a dose-dependent manner. The anti-proliferative effects of pKAL on RT-R-MDA-MB-231 cells were superior or similar to those on parental ones. Western blot analysis revealed that expressions of cluster of differentiation 44 (CD44) and Oct 3/4, matrix metalloproteinase-9 (MMP-9) and signal transducer and activator of transcription-3 (STAT-3) phosphorylation were significantly increased in RT-R-MDA-MB-231 cells compared to parental ones, suggesting that these proteins could be associated with RT resistance. pKAL inhibited the expression of CD44 and Oct 3/4 (CSC markers), and ß-catenin and MMP-9 as well as STAT-3 phosphorylation of RT-R-MDA-MB-231. Regarding upstream signaling, the JNK or JAK2 inhibitor could inhibit STAT-3 activation in RT-R-MDA-MB-231 cells, but not augmented pKAL-induced anti-cancer effects. These findings suggest that c-Jun N-terminal kinase (JNK) or Janus kinase 2 (JAK2)/STAT3 signaling are not closely related to the anti-cancer effects of pKAL. In conclusion, this study suggests that pKAL exhibit anti-cancer effects on RT-R-MDA-MB-231 cells by suppressing CD44 and Oct 3/4, ß-catenin and MMP-9, which appeared to be linked to RT resistance of RT-R-MDA-MB-231 cells.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Artemisia annua/química , Metaloproteinase 9 da Matriz/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , beta Catenina/metabolismo , Antineoplásicos Fitogênicos/química , Biomarcadores , Biomarcadores Tumorais , Neoplasias da Mama , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Expressão Gênica , Humanos , Imunofenotipagem , Janus Quinase 2/metabolismo , Extratos Vegetais/química , Polifenóis/química , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Biochem Pharmacol ; 174: 113815, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31972167

RESUMO

Diabetes is related to alterations in glucose and lipid metabolism, which are linked to endothelial cell (EC) dysfunction. Salvianolic acid B (Sal B), one of the major ingredient of Danshen (Salvia miltiorrhiza), possesses many of the biological activities. However, protective effect of Sal B against oxLDL induced ECs dysfunction under high glucose condition (high Glu) is not well known. Thus, in this study, we investigated the protective effects of Sal B against EC dysfunction induced by oxLDL and high Glu and examined the associated mechanisms. Our results showed that Sal B significantly and dose-dependently decreased oxLDL- and high Glu-mediated induction of lectin-like oxLDL receptor-1 and significantly decreased oxLDL- and high Glu-induced mitochondrial ROS (mtROS) production and mitochondrial DNA (mtDNA) expression. In addition, oxLDL stimulation under high-Glu conditions activated the intrinsic apoptosis pathway in ECs. These effects were abolished by Sal B through reductions in mtROS and mtDNA. Furthermore, Sal B inhibited oxLDL- and high Glu-induced increases in fission protein (p-DRP 1 and FIS 1) levels. OxLDL and high Glu activated the ROCK1 pathway, which is involved in apoptosis and mitophagy, while Sal B significantly reduced ROCK1 protein levels. The protective effects of Sal B against oxLDL- and high Glu-induced endothelial dysfunction may be mediated by reductions in apoptosis-related proteins and fission proteins through suppression of the ROCK1-mediated pathway.


Assuntos
Benzofuranos/farmacologia , Células Endoteliais/metabolismo , Glucose/toxicidade , Lipoproteínas LDL/toxicidade , Mitofagia/fisiologia , Quinases Associadas a rho/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Medicamentos de Ervas Chinesas/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Mitofagia/efeitos dos fármacos , Quinases Associadas a rho/antagonistas & inibidores
8.
Molecules ; 24(13)2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31277363

RESUMO

Berberine is reported to have multiple biological effects, including antimicrobial, anti-inflammatory, and antitumor activities, and 13-alkyl-substituted berberines show higher activity than berberine against certain bacterial species and human cancer cell lines. In particular, 13-ethylberberine (13-EBR) was reported to have anti-inflammatory effects in endotoxin-activated macrophage and septic mouse models. Thus, in this study, we aimed to examine the anticancer effects of 13-EBR and its mechanisms in radiotherapy-resistant (RT-R) MDA-MB-231 cells derived from the highly metastatic MDA-MB-231 cells. When we compared the gene expression between MDA-MB-231 and RT-R MDA-MB-231 cells with an RNA microarray, RT-R MDA-MB-231 showed higher levels of anti-apoptotic genes and lower levels of pro-apoptotic genes compared to MDA-MB-231 cells. Accordingly, we examined the effect of 13-EBR on the induction of apoptosis in RT-R MDA-MB-231 and MDA-MB-231 cells. The results showed that 13-EBR reduced the proliferation and colony-forming ability of both MDA-MB-231 and RT-R MDA-MB-231 cells. Moreover, 13-EBR induced apoptosis by promoting both intracellular and mitochondrial reactive oxygen species (ROS) and by regulating the apoptosis-related proteins involved in the intrinsic pathway, not in the extrinsic pathway. These results suggest that 13-EBR has pro-apoptotic effects in RT-R MDA-MB-231 and MDA-MB-231 cells by inducing mitochondrial ROS production and activating the mitochondrial apoptotic pathway, providing useful insights into new potential therapeutic strategies for RT-R breast cancer treatment.


Assuntos
Apoptose/efeitos dos fármacos , Berberina/farmacologia , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Mitocôndrias/metabolismo , Transdução de Sinais , Berberina/química , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mitocôndrias/efeitos dos fármacos , Modelos Biológicos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
9.
Free Radic Biol Med ; 136: 109-117, 2019 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-30959169

RESUMO

Oxidative stress and the related inflammatory responses are closely associated with many diseases including cardiovascular diseases such as atherosclerosis. Especially, mitochondrial damage and inflammasome activation have been reported to be directly involved in atherogenesis. In addition, we previously reported that endothelial cells (ECs) exposed to oxidized LDL (oxLDL) release ATP, which activates P2Y2R, resulting in the expression of receptors for advanced glycation end products and adhesion molecules that are involved in the pathogenesis of atherosclerosis. Therefore, it is expected that P2Y2R activation by ATP released under inflammatory conditions may be linked to the inflammasome-mediated pathogenesis of cardiovascular diseases such as atherosclerosis. However, the exact association remains unclear. Thus, in this study, we investigated the role of P2Y2R in oxLDL-mediated inflammasome activation and the related atherosclerotic pathogenesis in ECs. ECs stimulated with oxLDL demonstrated increased intracellular production and extracellular secretion of ATP. In addition, mitochondrial reactive oxygen species (mtROS) production and mitochondrial DNA (mtDNA) expression and cytosolic release were increased in ECs stimulated with oxLDL or the P2Y2R agonists ATP and UTP. Moreover, caspase-1 activity and IL-1ß production were increased in ECs stimulated with oxLDL, ATP or UTP through the modulation of mtROS production and mtDNA expression, in a P2Y2R-dependent manner. Furthermore, TLR-9 and NF-κB activation was increased in ECs in response to oxLDL, ATP or UTP, in a mtDNA-dependent manner. Taken together, our findings suggest that P2Y2R activation by ATP is involved in oxLDL-mediated inflammasome activation and subsequent IL-1ß production through the modulation of mtROS-mtDNA induction and the TLR9-NF-κB signaling pathway.


Assuntos
Trifosfato de Adenosina/metabolismo , Células Endoteliais/metabolismo , Inflamassomos/metabolismo , Lipoproteínas LDL/metabolismo , Mitocôndrias/metabolismo , Receptores Purinérgicos P2Y2/metabolismo , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Células Cultivadas , Células Endoteliais/patologia , Humanos , Mitocôndrias/patologia , Estresse Oxidativo/fisiologia , Transdução de Sinais/fisiologia
10.
Int J Mol Sci ; 19(11)2018 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-30373171

RESUMO

The cardiac glycosides oleandrin and odoroside A, polyphenolic monomer compounds extracted from Nerium oleander, have been found to have antitumor effects on various tumors at low doses. However, the mechanisms of anticancer effects of oleandrin and odoroside A are not well known. Therefore, in this study, we aimed to investigate the anticancer effects of oleandrin and odoroside A and their associated mechanisms in highly metastatic MDA-MB-231 breast cancer cells and radiotherapy-resistant (RT-R) MDA-MB-231 cells. Our results showed that oleandrin and odoroside A dose-dependently decreased the colony formation and the invasion of both cell lines at nanomolar ranges. Furthermore, oleandrin (50 nM) and odoroside A (100 nM) reduced octamer-binding transcription factor 3/4 (OCT3/4) and ß-catenin levels and matrix metalloproteinase-9 (MMP-9) activity. Finally, we found that phospho-STAT-3 levels were increased in MDA-MB-231 and RT-R-MDA-MB-231, but not in endothelial cells (ECs), and that the levels were significantly decreased by oleandrin (50 nM) and odoroside A (100 nM). Inhibition of phospho-signal transducer and activator of transcription (STAT)-3 significantly reduced OCT3/4 and ß-catenin levels and MMP-9 activity, ultimately resulting in reduced invasion. These results suggest that the anticancer effects of oleandrin and odoroside A might be due to the inhibition of invasion through of phospho-STAT-3-mediated pathways that are involved in the regulation of invasion-related molecules.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Cardenolídeos/farmacologia , Invasividade Neoplásica/prevenção & controle , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Invasividade Neoplásica/patologia , Fator de Transcrição STAT3/antagonistas & inibidores
11.
Oncol Rep ; 40(6): 3752-3762, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30272295

RESUMO

Previous studies suggest that cancer stem cells (CSCs) exist in solid tumors, and contribute to therapeutic resistance and disease recurrence. Therefore, the present study aimed to investigate whether radioresistant (RT­R) breast cancer cells derived from breast cancer cells increase the number of CSCs, and whether these CSCs are responsible to increased invasiveness and therapeutic resistance. MCF­7, T47D and MDA­MB­231 cells were irradiated 25 times (2 Gy each; 50 Gy total) to generate radioresistant breast cancer cells (RT­R­MCF­7, RT­R­T47D and RT­R­MDA­MB­231). RT­R­breast cancer cells demonstrated increased cell viability against irradiation and increased colony forming abilities compared with parental breast cancer cells. Particularly, RT­R­MDA­MB­231 cells derived from highly metastatic MDA­MB­231 cells exhibited most radioresistance and chemoresistance of the three cell lines. In addition, MDA­MB­231 cells exhibited the most increased protein levels of CSCs markers cluster of differentiation 44, Notch­4, octamer­binding transcription factor 3/4 and aldehyde dehydrogenase 1, compared with RT­R­MCF­7 cells, suggesting highly metastatic breast cancer cells MDA­MB­231 produce more CSCs. RT­R­MDA­MB­231 cells increased intercellular adhesion molecule­1 and vascular cell adhesion molecule­1 levels, resulting in enhanced migration and adhesion to endothelial cells (ECs), and enhanced invasiveness through ECs by inducing matrix metalloproteinase­9, Snail­1 and ß­catenin, and by downregulating E­cadherin compared with MDA­MB­231 cells. These results suggest that highly metastatic breast cancer cells may increase the number of CSCs following radiation therapy, and CSCs present in RT­R­MDA­MB­231 cells contribute to the enhanced invasiveness by increasing migration, adhesion to ECs and invasion through ECs by promoting epithelial­mesenchymal transition (EMT) via the upregulation of adhesion molecules and EMT­associated proteins.


Assuntos
Neoplasias da Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos , Células-Tronco Neoplásicas/metabolismo , Tolerância a Radiação , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/radioterapia , Adesão Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos da radiação , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Células MCF-7 , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos da radiação , Regulação para Cima
12.
Int J Oncol ; 53(5): 1953-1966, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30226596

RESUMO

In the tumor microenvironment, extracellular nucleotides are released and accumulate, and can activate the P2Y2 receptor (P2Y2R), which regulates various responses in tumor cells, resulting in tumor progression and metastasis. Moreover, the inflammasome has recently been reported to be associated with tumor progression. However, the role of P2Y2R in inflammasome activation in breast cancer cells is not yet well defined. Therefore, in this study, we investigated the role of P2Y2R in inflammasome-mediated tumor progression in breast cancer using breast cancer cells and radiotherapy-resistant (RT­R) breast cancer cells. We established RT­R-breast cancer cells (RT­R­MDA­MB­231, RT­R­MCF­7, and RT­R-T47D cells) by repeated irradiation (2 Gy each, 25 times) in a previous study. In this study, we found that the RT­R breast cancer cells exhibited an increased release of adenosine triphosphate (ATP) and P2Y2R activity. In particular, the RT­R­MDA­MB­231 cells derived from highly metastatic MDA­MB­231 cells, exhibited a markedly increased ATP release, which was potentiated by tumor necrosis factor (TNF)-α. The MDA­MB­231 cells exhibited inflammasome activation, as measured by caspase­1 activity and interleukin (IL)-1ß secretion following treatment with TNF­α and ATP; these effects were enhanced in the RT­R­MDA­MB­231 cells. However, the increased caspase­1 activities and IL­1ß secretion levels induced in response to treatment with TNF­α or ATP were significantly reduced by P2Y2R knockdown or the presence of apyrase in both the MDA­MB­231 and RT­R­MDA­MB­231 cells, suggesting the involvement of ATP-activated P2Y2R in inflammasome activation. In addition, TNF­α and ATP increased the invasive and colony-forming ability of the MDA­MB­231 and RT­R­MDA­MB­231 cells, and these effects were caspase­1-dependent. Moreover, matrix metalloproteinase (MMP)-9 activity was modulated by caspase-1, in a P2Y2R-dependent manner in the MDA­MB­231 and RT­R­MDA­MB­231 cells. Finally, nude mice injected with the RT­R­MDA­MB­231-EV cells (transfected with the empty vector) exhibited increased tumor growth, and higher levels of MMP-9 in their tumors and IL­1ß levels in their serum compared with the mice injected with the RT­R­MDA­MB­231-P2Y2R shRNA cells (transfected with P2Y2R shRNA). On the whole, the findings of this study suggest that extracellular ATP promotes tumor progression in RT­R-breast cancer cells and breast cancer cells by modulating invasion and associated molecules through the P2Y2R-inflammasome activation pathway.


Assuntos
Trifosfato de Adenosina/metabolismo , Neoplasias da Mama/imunologia , Inflamassomos/imunologia , Tolerância a Radiação/imunologia , Receptores Purinérgicos P2Y2/metabolismo , Animais , Mama/patologia , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Humanos , Inflamassomos/metabolismo , Camundongos , Camundongos Nus , Invasividade Neoplásica/imunologia , RNA Interferente Pequeno/metabolismo , Receptores Purinérgicos P2Y2/genética , Receptores Purinérgicos P2Y2/imunologia , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Int Immunopharmacol ; 52: 297-304, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28982049

RESUMO

Tetrahydroisoquinoline alkaloids (THIs) have shown to increase survival and beneficial effect on animal model of sepsis, partly due to heme oxygenase-1 (HO-1) induction. Here, we aimed to compare a limited series of synthesized THIs on HO-1 induction and inhibitory effect of iNOS and COX-2 expression in lipopolysaccharide (LPS)-activated RAW264.7 cells. To the end, most promising compound (THI-61) was tested whether this compound reduces iNOS protein expression and inflammatory markers (HMGB1, TNF-α) in LPS-treated mice lung tissue. The results indicated that N-carbonyl substituted THI seem to affect HO-1 induction depending on which functional group is attached to C1 position. All compounds that reduce LPS-activated NF-κB-luciferase activity showed to preferential inhibition of iNOS/NO but not COX-2/PGE2 that was partly related to inhibition of STAT-1 phosphorylation. In particular, THI-61 induced translocation of Nrf2 from cytosol into the nucleus by an increased Nrf2-ARE binding activity, and reduced IL-1ß production in LPS-activated RAW264.7 cells. The reduced expression of iNOS/NO by THI-61 was reversed by siHO-1RNA-transfection. In LPS-treated mice, THI-61 significantly reduced iNOS protein in lung tissues, and HMGB1 and TNF-α levels in the BALF. We concluded that 1) lipophilic moiety of 1C substituent is much more important in N-carbonyl substituted THI for induction of HO-1, 2) newly synthesized THI-61 may be beneficial for treatment of lung injury.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Alcaloides/farmacologia , Heme Oxigenase-1/metabolismo , Inflamação/tratamento farmacológico , Pulmão/metabolismo , Macrófagos/imunologia , Proteínas de Membrana/metabolismo , Tetra-Hidroisoquinolinas/farmacologia , Alcaloides/síntese química , Animais , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Proteína HMGB1/metabolismo , Heme Oxigenase-1/genética , Humanos , Lipopolissacarídeos/imunologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Fator de Transcrição STAT1/metabolismo , Tetra-Hidroisoquinolinas/síntese química , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
14.
Biomed Pharmacother ; 86: 48-56, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27939519

RESUMO

High mobility group box 1 (HMGB1), a highly conserved non-histone DNA-binding protein, plays an important role in the pathogenesis of sepsis. Previously, the authors reported 13-ethylberberine (13-EBR) has anti-inflammatory and antibacterial effects. However, the effect of 13-EBR on HMGB1 release was not investigated. In the present study, it was hypothesized 13-EBR might reduce HMGB1 release by activating AMPK under septic conditions. The results obtained showed 13-EBR significantly reduced HMGB1 release from LPS-activated RAW264.7 cells, and that this reduction was reversed by silencing p38, or AMPK, or by co-treating cells with p38 MAPKinase inhibitor. 13-EBR increased the phosphorylations of p38 and AMPK, and the phosphorylation of p38 by 13-EBR was inhibited by AMPK-siRNA, indicating AMPK acted upstream of p38. In the lung tissues of LPS-treated mice, 13-EBR administration significantly increased p-AMPK but reduced inducible nitric oxide synthase (iNOS) protein levels. Hematoxylin and eosin staining revealed 13-EBR significantly reduced LPS-induced lung and liver damage. In addition, 13-EBR inhibited NF-kB in LPS-activated RAW264.7 cells, and in LPS-treated mice, 13-EBR administration significantly increased survival. Furthermore, co-administration of 13-EBR plus LPS prevented LPS-induced aortic rings hypocontractile response to phenylephrine in vitro. Taken together, these results indicate 13-EBR might offer a means of treating sepsis through AMPK activation.


Assuntos
Berberina/uso terapêutico , Endotoxemia/metabolismo , Endotoxemia/prevenção & controle , Proteína HMGB1/antagonistas & inibidores , Lipopolissacarídeos/toxicidade , Proteínas Quinases/metabolismo , Animais , Berberina/farmacologia , Endotoxemia/induzido quimicamente , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Proteína HMGB1/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Insuficiência de Múltiplos Órgãos/induzido quimicamente , Insuficiência de Múltiplos Órgãos/metabolismo , Insuficiência de Múltiplos Órgãos/prevenção & controle , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley
15.
Int Immunopharmacol ; 40: 269-276, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27632705

RESUMO

High mobility group box 1 (HMGB1), a late phase cytokine of sepsis, is viewed as a potential target for the treatment of sepsis. The authors considered that 13-methylberberine (13-MB) might reduce circulating HMGB1 levels and increase survival in a mouse model of sepsis by activating AMP-activated protein kinase (AMPK). Western blot analysis and vascular contraction testing were performed using RAW264.7 cells and rat thoracic aorta, respectively. The mechanisms responsible were investigated using various signal inhibitors and small interfering RNA techniques. 13-MB significantly reduced HMGB1 release by LPS-activated RAW264.7 cells, and this was prevented by silencing AMPK or p38, or by pretreating cells with p38 MAPKinase inhibitor, suggesting that the activations of p38 and AMPK were responsible for the observed reduction in HMGB1 release. As was expected, 13-MB increased the phosphorylations of p38 and AMPK. Interestingly, phosphorylations of p38 by 13-MB were inhibited by AMPKsiRNA, indicating that AMPK lies upstream of p38. Furthermore, 13-MB concentration-dependently inhibited IκB phosphorylation in LPS-activated RAW264.7 cells, and in aortic rings, co-treatment with 13-MB and LPS for 8h, in vitro, significantly restored the isometric contraction induced by phenylephrine. Importantly, 13-MB significantly increased the survival rate of LPS-induced endotoxemic mice. These results suggest 13-MB may be useful for treating diseases in which HMGB1 is viewed as a target.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Berberina , Proteína HMGB1/antagonistas & inibidores , Sepse/tratamento farmacológico , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Berberina/análogos & derivados , Berberina/farmacologia , Berberina/uso terapêutico , Proteína HMGB1/metabolismo , Técnicas In Vitro , Lipopolissacarídeos , Luciferases/genética , Luciferases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Células RAW 264.7 , RNA Interferente Pequeno/genética , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/genética
16.
Phytother Res ; 30(7): 1180-8, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27151203

RESUMO

Recent evidence suggests that polyphenolic compounds from plants have anti-invasion and anti-metastasis capabilities. The Korean annual weed, Artemisia annua L., has been used as a folk medicine for treatment of various diseases. Here, we isolated and characterized polyphenols from Korean A. annua L (pKAL). We investigated anti-metastatic effects of pKAL on the highly metastatic MDA-MB-231 breast cancer cells especially focusing on cancer cell adhesion to the endothelial cell and epithelial-mesenchymal transition (EMT). Firstly, pKAL inhibited cell viability of MDA-MB-231 cells in a dose-dependent manner, but not that of human umbilical vein endothelial cells (ECs). Polyphenols from Korean A. annua L inhibited the adhesion of MDA-MB-231 cells to ECs through reducing vascular cell adhesion molecule-1 expression of MDA-MB-231 and ECs, but not intracellular adhesion molecule-1 at the concentrations where pKAL did not influence the cell viability of either MDA-MB-231 cells nor EC. Further, pKAL inhibited tumor necrosis factor-activated MDA-MB-231 breast cancer cell invasion through inhibition of matrix metalloproteinase-2 and matrix metalloproteinase-9 and EMT. Moreover, pKAL inhibited phosphorylation of Akt, but not that of protein kinase C. These results suggest that pKAL may serve as a therapeutic agent against cancer metastasis at least in part by inhibiting the cancer cell adhesion to ECs through suppression of vascular cell adhesion molecule-1 and invasion through suppression of EMT. Copyright © 2016 John Wiley & Sons, Ltd.


Assuntos
Artemisia annua/química , Neoplasias da Mama/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Polifenóis/farmacologia , Neoplasias da Mama/metabolismo , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Fosforilação/efeitos dos fármacos , Proteína Quinase C/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Molécula 1 de Adesão de Célula Vascular/metabolismo
17.
Oncol Rep ; 34(6): 3035-42, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26397047

RESUMO

The Korean prostrate spurge Euphorbia supina is abundant in polyphenols and has been used as a folk medicine in Korea against a variety of diseases. Thus, we aimed to investigate the effect of polyphenol mixtures of Korean Euphorbia supina (PES) on the invasion and metastasis of highly metastatic breast cancer MDA-MB-231 cells. Firstly, PES showed no cytotoxicity on cancer cells and endothelial cells (ECs) at the doses of 0.1-10 µg/ml, but showed significant cytotoxicity from 50 µg/ml. Thus, we performed subsequent experiments with PES at doses up to 5 µg/ml. PES dose­dependently suppressed epithelial-mesenchymal transition by downregulating the mesenchymal markers, Snail1 and N-cadherin, showing significant inhibition from 1 and 5 µg/ml, respectively. In addition, PES significantly inhibited MMP-9 activity and LOX release induced by TNF-α at 5 µg/ml. Then, we determined the effect of PES on the expression of adhesion molecules and VE-cadherin phosphorylation. The results showed that PES effectively reduced TNF-α-mediated VCAM-1 expression but not ICAM expression both in the MDA-MB-231 cells and ECs, resulting in the reduced adhesion of MDA-MB-231 to ECs. Finally, PES effectively inhibited MDA-MB-231 cell invasion through ECs, suggesting that PES may serve as a therapeutic agent against cancer metastasis with minimal cytotoxicity to normal cells.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Polifenóis/administração & dosagem , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Células Endoteliais/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Euphorbia/química , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Invasividade Neoplásica/genética , Metástase Neoplásica , Proteínas de Neoplasias/biossíntese , Fosforilação/efeitos dos fármacos , Extratos Vegetais/química , Polifenóis/química
18.
Oncol Rep ; 34(1): 195-202, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26063340

RESUMO

Tumor metastasis is considered the main cause of mortality in cancer patients, thus it is important to investigate the differences between high- and low-metastatic cancer cells. Our previous study showed that the highly metastatic breast cancer cell line MDA-MB-231 released higher levels of ATP and exhibited higher P2Y2R activity compared with the low-metastatic breast cancer cell line MCF-7. In addition, P2Y2R activation by ATP released from MDA-MB-231 cells induced hypoxia-inducible factor-1α expression, lysyl oxidase secretion and collagen crosslinking, generating a receptive microenvironment for pre-metastatic niche formation. Thus, in the present study, we investigated which P2Y2R-related signaling pathways are involved in the invasion of breast cancer cells. The highly metastatic breast cancer cells MDA-MB-231 and SK-BR-3 showed higher invasion than MCF-7 and T47D cells at a basal level, which was abolished through P2Y2R knockdown or in the presence of apyrase, an enzyme that hydrolyzes extracellular nucleotides. MDA-MB-231 cells also showed high levels of mesenchymal markers, such as Snail, Vimentin and N-cadherin, but not the epithelial marker E-cadherin and this expression was inhibited through ATP degradation or P2Y2R knockdown. Moreover, SK-BR-3 and MDA-MB231 cells exhibited higher ERK and PKC phosphorylation levels than T47D and MCF-7 cells and upregulated phospho-ERK and -PKC levels in MDA-MB-231 cells were significantly downregulated by apyrase or P2Y2R knockdown. Specific inhibitors of ERK, PKC and PLC markedly reduced the invasion and levels of mesenchymal marker expression in MDA-MB-231 cells. These results suggest that over-activated ERK and PKC pathways are involved in the P2Y2R-mediated invasion of breast cancer cells.


Assuntos
Neoplasias da Mama/genética , Proliferação de Células/genética , Proteína Quinase C/biossíntese , Receptores Purinérgicos P2Y2/biossíntese , Neoplasias da Mama/patologia , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Metástase Neoplásica , Proteína Quinase C/genética , Proteína-Lisina 6-Oxidase/biossíntese , Receptores Purinérgicos P2Y2/genética , Transdução de Sinais , Microambiente Tumoral/genética
19.
Vascul Pharmacol ; 72: 108-17, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25956731

RESUMO

Vascular smooth muscle cells (VSMCs) are the major cell type in blood vessel walls, and their proliferation and migration play important roles in the development of atherosclerosis. Recently, it has been reported that IL-1ß mediates the inflammatory response through the upregulation of the P2Y2 receptor (P2Y2R). Thus, we examined the role of P2Y2R in IL-1ß-mediated proliferation and migration of VSMCs and the underlying molecular mechanisms. VSMCs were pretreated with IL-1ß for 24h to upregulate P2Y2R expression. The cells were then stimulated with UTP or ATP for the indicated times, and cell proliferation and migration and the related signaling pathways were examined. The equipotent P2Y2R agonists ATP and UTP enhanced proliferation, RAGE expression and HMGB1 secretion in IL-1ß-pretreated VSMCs. Additionally, pretreatment with IL-1ß enhanced UTP-mediated VSMC migration and MMP-2 release, but these effects were not observed in the P2Y2R-siRNA- or RAGE-siRNA-transfected VSMCs. Next, the signaling molecules involved in P2Y2R-mediated cell proliferation and migration were determined. The ERK, AKT, PKC, Rac-1 and ROCK2 pathways were involved in UTP-induced cell proliferation and migration, MMP-2 and HMGB1 secretion and RAGE expression in the IL-1ß-pretreated VSMCs. UTP induced the phosphorylation of ERK, AKT and PKC and the translocation of Rac-1 and ROCK2 from cytosol to membrane as well as stress fiber formation, which were markedly increased in the IL-1ß-pretreated VSMCs but not in the P2Y2R-siRNA-transfected VSMCs. These results demonstrate that pro-inflammatory cytokines associated with atherosclerosis, such as IL-1ß, can accelerate the process of atherosclerosis through the upregulation of P2Y2R.


Assuntos
Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Proteína HMGB1/metabolismo , Interleucina-1beta/metabolismo , Músculo Liso Vascular/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Receptores Purinérgicos P2Y2/metabolismo , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Células Cultivadas , Músculo Liso Vascular/fisiologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/fisiologia , Fosforilação/fisiologia , Ratos , Transdução de Sinais/fisiologia , Regulação para Cima/fisiologia
20.
J Ethnopharmacol ; 139(2): 605-15, 2012 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-22179023

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Cinnamomum cassia Blume has been used as a traditional Chinese herbal medicine for alleviation of fever, inflammation, chronic bronchitis, and to improve blood circulation. AIM OF THE STUDY: We addressed whether 2-methoxycinnamaldehyde (2-MCA), one of active ingredients of Cinnamomum cassia, reduces vascular cell adhesion molecule-1 (VCAM-1) expression in tumor necrosis factor-alpha (TNF-α)-activated endothelial cells and protects ischemia/reperfusion (I/R)-injury due to heme oxygenase (HO)-1 induction. MATERIALS AND METHODS: Adult male rats were subjected to 30 min of ischemia by occlusion of the left anterior descending coronary artery followed by 24h of reperfusion. Rats were randomized to receive vehicle or 2-MCA (i.v.) 10 min before reperfusion. RESULTS: Administration of 2-MCA significantly improved I/R-induced myocardial dysfunction by increasing the values of the first derivative (±dp/dt) of left ventricular pressure and decreased infarct size. In addition, 2-MCA reduced the expression of high mobility group box 1 (HMGB1), an activator of the inflammatory cascade when released into the extracellular space, and VCAM-1 in I/R myocardium along with increase of HO-1 induction. The reduced injury was accompanied by significantly reduction of neutrophils infiltration and increased SOD activity in ischemic tissues and reduced serum level of cardiac troponin I (cTnI). Furthermore, 2-MCA significantly increased HO-1 induction by translocation of Nrf-2 from cytosol to nucleus in endothelial cells. Inhibition of VCAM-1 expression by 2-MCA was reversed both by SnPPIX, a HO-1 inhibitor and siHO-1 RNA trasfection in TNF-α-activated cells. In addition, 2-MCA significantly inhibited NF-κB luciferase activity in TNF-α-activated endothelial cells. As expected, 2-MCA significantly inhibited monocyte (U937) adhesion to endothelial cells. CONCLUSION: We concluded that 2-MCA protects of myocardial I/R-injury due to antioxidant and anti-inflammatory action possibly by HO-1 induction which can be explained why Cinnamomum cassia has been used in inflammatory disorders.


Assuntos
Acroleína/análogos & derivados , Cardiotônicos/farmacologia , Cinnamomum aromaticum , Heme Oxigenase (Desciclizante)/biossíntese , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/enzimologia , Extratos Vegetais/farmacologia , Acroleína/isolamento & purificação , Acroleína/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Cardiotônicos/isolamento & purificação , Cinnamomum aromaticum/química , Técnicas de Cocultura , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Indução Enzimática , Inibidores Enzimáticos/farmacologia , Proteína HMGB1/metabolismo , Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase-1/biossíntese , Hemodinâmica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/enzimologia , Células Endoteliais da Veia Umbilical Humana/imunologia , Humanos , Masculino , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Infiltração de Neutrófilos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Plantas Medicinais , Interferência de RNA , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Fatores de Tempo , Transfecção , Troponina I/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Células U937 , Molécula 1 de Adesão de Célula Vascular/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos , Pressão Ventricular/efeitos dos fármacos
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