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1.
Bratisl Lek Listy ; 120(10): 752-756, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31663350

RESUMO

AIM: Tamoxifen engages mitochondrial estrogen receptor beta as an antagonist, increases mitochondrial cytotoxicity and induces tumor cell death. Tamoxifen also engages plasma membrane estrogen receptor alpha as an agonist, while it is suggested that in some users its activation is put into action by mechanism of resistance to tamoxifen. Apoptotic inducers have been shown to promote tamoxifen-induced cell death, which might be of great importance in overcoming tamoxifen resistance. Considering the pleiotropic effects of statins, in the present study, we investigated the effects of atorvastatin on tamoxifen-induced intrinsic apoptotic pathway activity in melanoma cells. METHODS: Melanoma B16F10 cells were treated for 24 and 48 h with various concentrations of tamoxifen, atorvastatin and combination of tamoxifen + atorvastatin. Cells with no treatment were considered a control group, and the study was then followed by quantitative RT- PCR assay. Bax and cytochrome c gene expressions were calculated by ΔΔct method. RESULTS: Co-treatment of atorvastatin + tamoxifen could strongly enhance the expression of pro/apoptotic factors of Bax and cytochrome c in melanoma cells compared to the tamoxifen and atorvastatin groups. CONCLUSION: In general, we conclude that the atorvastatin-induced increase in Bax and cytochrome c gene expression might be a permissive response to tamoxifen-induced cell death (Fig. 2, Ref. 37).


Assuntos
Apoptose/efeitos dos fármacos , Atorvastatina/farmacologia , Melanoma Experimental , Tamoxifeno/farmacologia , Animais , Linhagem Celular Tumoral , Citocromos c/metabolismo , Sinergismo Farmacológico , Camundongos , Proteína X Associada a bcl-2/metabolismo
2.
BMC Res Notes ; 12(1): 584, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533801

RESUMO

OBJECTIVE: The aim of this study was to compare in vivo effect of five pharmacological options on inflammation and pulmonary fibrosis induced by paraquat. METHODS: 54 Wistar SPF rats were used. After 2 h post-intoxication with paraquat ion, groups of 9 animals were randomly assigned to (1) cyclophosphamide plus dexamethasone (2) low molecular weight heparin (3) unfractionated heparin (4) vitamin C every 24 h, (5) atorvastatin or (6) placebo with intraperitoneal saline. Lung inflammation, alveolar injury, hepatocyte damage, hepatic regeneration, acute tubular necrosis and kidney congestion were evaluated. RESULTS: In the control group 100% of animals presented moderate and severe lung inflammation, while in the groups with atorvastatin and intratracheal heparin this proportion was lower (55.5%; CI 26.6-81.3%) (p = 0.025). A lower degree of moderate or severe hepatic regeneration was evident in the treatment groups with atorvastatin (p = 0.009). In this study was demonstrated that statins and heparin might have a protective effect in the paraquat-induced destructive phase. More evidence is needed to evaluated of dose-response effects of these drugs before to study in clinical trials.


Assuntos
Tratamento Farmacológico/métodos , Pulmão/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Alvéolos Pulmonares/efeitos dos fármacos , Fibrose Pulmonar/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Atorvastatina/farmacologia , Ciclofosfamida/farmacologia , Dexametasona/farmacologia , Quimioterapia Combinada , Heparina/farmacologia , Heparina de Baixo Peso Molecular/farmacologia , Pulmão/patologia , Paraquat/toxicidade , Pneumonia/patologia , Alvéolos Pulmonares/patologia , Fibrose Pulmonar/induzido quimicamente , Ratos Wistar , Resultado do Tratamento
3.
Mediators Inflamm ; 2019: 1868170, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396016

RESUMO

Myeloid angiogenic cells (MAC) derive from hematopoietic stem/progenitor cells (HSPCs) that are mobilized from the bone marrow. They home to sites of neovascularization and contribute to angiogenesis by production of paracrine factors. The number and function of proangiogenic cells are impaired in patients with diabetes or cardiovascular diseases. Both conditions can be accompanied by decreased levels of heme oxygenase-1 (HMOX1), cytoprotective, heme-degrading enzyme. Our study is aimed at investigating whether precursors of myeloid angiogenic cells (PACs) treated with known pharmaceuticals would produce media with better proangiogenic activity in vitro and if such media can be used to stimulate blood vessel growth in vivo. We used G-CSF-mobilized CD34+ HSPCs, FACS-sorted from healthy donor peripheral blood mononuclear cells (PBMCs). Sorted cells were predominantly CD133+. CD34+ cells after six days in culture were stimulated with atorvastatin (AT), acetylsalicylic acid (ASA), sulforaphane (SR), resveratrol (RV), or metformin (Met) for 48 h. Conditioned media from such cells were then used to stimulate human aortic endothelial cells (HAoECs) to enhance tube-like structure formation in a Matrigel assay. The only stimulant that enhanced PAC paracrine angiogenic activity was atorvastatin, which also had ability to stabilize endothelial tubes in vitro. On the other hand, the only one that induced heme oxygenase-1 expression was sulforaphane, a known activator of a HMOX1 inducer-NRF2. None of the stimulants changed significantly the levels of 30 cytokines and growth factors tested with the multiplex test. Then, we used atorvastatin-stimulated cells or conditioned media from them in the Matrigel plug in vivo angiogenic assay. Neither AT alone in control media nor conditioned media nor AT-stimulated cells affected numbers of endothelial cells in the plug or plug's vascularization. Concluding, high concentrations of atorvastatin stabilize tubes and enhance the paracrine angiogenic activity of human PAC cells in vitro. However, the effect was not observed in vivo. Therefore, the use of conditioned media from atorvastatin-treated PAC is not a promising therapeutic strategy to enhance angiogenesis.


Assuntos
Atorvastatina/farmacologia , Meios de Cultivo Condicionados/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Antígeno AC133/metabolismo , Antígenos CD34/metabolismo , Aspirina/farmacologia , Células Cultivadas , Heme Oxigenase-1/metabolismo , Humanos , Imunoensaio , Isotiocianatos/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Metformina/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Fenótipo , Resveratrol/farmacologia
4.
Nutrients ; 11(8)2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374931

RESUMO

To examine the effects of the alpha-amylase inhibitor isoform 1 called phaseolamin, a standardized extract from white kidney beans (Phaseolus vulgaris L) was tested against the hallmarks of metabolic syndrome. The efficacy of a per os repeated treatment with P. vulgaris extract (500 mg/kg) was compared with metformin (100 mg/kg) and atorvastatin (10 mg/kg) in a model of metabolic syndrome evoked by prolonged high fat diet (HFD; week 1 to week 19) in C57BL/6 mice. Bean extract and compounds administration started after metabolic syndrome establishment (week 11). P. vulgaris extract reduced the body weight overtime, as well as effectively lowered glycaemia, triglycerides, and cholesterol. On week 19, bean extract normalized the HFD-evoked tolerance to glucose and insulin. According to the phytochemical characterization, it inhibited the alpha-amylase activity. Animals treated with the extract were rescued from motor impairments and nociceptive threshold alterations induced by HFD. Specific organs analysis revealed that P. vulgaris extract decreased hepatic steatosis and lipid peroxidation in liver. It protected the heart from HFD oxidative alterations increasing the expression of the detoxifying enzymes catalase and glutathione reductase, and normalizing NADH dehydrogenase level. The histological analysis of aorta showed a protection about the development of fatty streaks in the muscular layers. In conclusion, a prolonged treatment with the standardized extract of P. vulgaris significantly reduced several pathological features related to a metabolic syndrome-like condition; a multifactorial approach that candidates this vegetal product as a possible therapeutic option against metabolic syndrome.


Assuntos
Inibidores de Glicosídeo Hidrolases/farmacologia , Síndrome Metabólica/tratamento farmacológico , Phaseolus/química , Extratos Vegetais/farmacologia , Lectinas de Plantas/farmacologia , Sementes/química , Animais , Atorvastatina/farmacologia , Comportamento Animal/efeitos dos fármacos , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Resistência à Insulina , Lipídeos/sangue , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/enzimologia , Síndrome Metabólica/patologia , Metformina/farmacologia , Camundongos Endogâmicos C57BL , Extratos Vegetais/isolamento & purificação , Lectinas de Plantas/isolamento & purificação , Fatores de Tempo
5.
Med Sci Monit ; 25: 6165-6173, 2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31420530

RESUMO

BACKGROUND Patients with diabetes mellitus (DM) commonly receive statins to suppress vulnerability to adverse cardiovascular events. It has been clinically proven that hepatotoxicity is one of the most severe adverse effects of statins. MATERIAL AND METHODS We constructed diabetic rat models by feeding rats with high-fat food and by injection of low-dose STZ. Rats were randomized into 2 groups: a DM group (n=10) and a control (CON) group (n=5). CON rats received a normal diet, whereas DM rats ate high-fat food. Rats in the DM group underwent intraperitoneal STZ (35 mg/kg) injection following 6-week diet restriction. On the seventh day following STZ or blank injection, rats with FBG concentration over 11.1 mM were regarded as successfully established models and were used for further research. RESULTS We showed that severe liver injury occurred in diabetic rats treated with 20 mg/kg atorvastatin, as evidenced by attenuation of liver enzyme activities, elevation of bilirubin levels, and alterations in the hepatic architecture, including hepatocyte death by necrosis, lymphocyte infiltration, and fibrosis. We also found that atorvastatin increased the secretion of pro-inflammatory factors such as L-1, TNF, IL-6, and IL-18 by enhancing activation of the NF-B signal pathway in the livers of diabetic rats. Atorvastatin elevated the levels of ROS and reduced the antioxidant enzyme (SOD and CAT) activities. Atorvastatin also increased the expression of anti-apoptotic protein BCL2 and decreased the expression of pro-apoptotic protein BAX in the livers of diabetic rats. CONCLUSIONS Atorvastatin exerts potentially hepatotoxic effects on diabetic rats by modulating oxidative/antioxidative status, pro-inflammatory cytokine production, and apoptosis inhibition.


Assuntos
Atorvastatina/efeitos adversos , Atorvastatina/toxicidade , Fígado/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Atorvastatina/farmacologia , Glicemia/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , China , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Hepatócitos/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Fígado/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo
6.
J Med Microbiol ; 68(10): 1497-1506, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31460860

RESUMO

Aim. The aim of this work was to characterize the response of Candida albicans to atorvastatin, and to assess its in vivo antifungal capability.Methodology. The effect of atorvastatin on the growth and viability of C. albicans was assessed. The ability of the statin to alter cell permeability was quantified by measuring amino acid and protein leakage. The response of C. albicans to atorvastatin was assessed using label-free quantitative proteomics. The in vivo antifungal activity of atorvastatin was assessed using Galleria mellonella larvae infected with C. albicans.Results. Atorvastatin inhibited the growth of C. albicans. The atorvastatin-treated cells showed lower ergosterol levels than the controls, demonstrated increased calcofluor staining and released elevated quantities of amino acids and protein. Larvae infected with C. albicans showed a survival rate of 18.1±4.2 % at 144 h. In contrast, larvae administered atorvastatin (9.09 mg kg-1) displayed a survival rate of 60.2±6.4 % (P<0.05). Label-free quantitative proteomics identified 1575 proteins with 2 or more peptides and 465 proteins were differentially abundant (P<0.05). There was an increase in the abundance of enzymes with oxidoreductase and hydrolase activity in atorvastatin-treated cells, and squalene monooxygenase (4.52-fold increase) and lanosterol synthase (2.84-fold increase) were increased in abundance. Proteins such as small heat shock protein 21 (-6.33-fold) and glutathione peroxidase (-2.05-fold) were reduced in abundance.Conclusion. The results presented here indicate that atorvastatin inhibits the growth of C. albicans and is capable of increasing the survival of G. mellonella larvae infected with C. albicans.


Assuntos
Antifúngicos/farmacologia , Atorvastatina/farmacologia , Candida albicans/efeitos dos fármacos , Animais , Candida albicans/genética , Candida albicans/crescimento & desenvolvimento , Candida albicans/metabolismo , Candidíase/microbiologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Humanos , Larva/microbiologia , Mariposas/microbiologia
7.
Mol Carcinog ; 58(11): 2052-2064, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31397499

RESUMO

Recent studies have indicated that using statins to inhibit the mevalonate pathway induces mutant p53 degradation by impairing the interaction of mutant p53 with DnaJ subfamily A member 1 (DNAJA1). However, the role of the C-terminus of DNAJA1 with a CAAX box for farnesylation in the binding, folding, and translocation of client proteins such as mutant p53 is not known. In the present study, we used a genetically engineered mouse model of pancreatic carcinoma and showed that atorvastatin significantly increased animal survival and inhibited pancreatic carcinogenesis. There was a dramatic decrease in mutant p53 protein accumulation in the pancreatic acini, pancreas intraepithelial neoplasia lesions, and adenocarcinoma. Supplementation with farnesyl pyrophosphate, a substrate for protein farnesylation, rescued atorvastatin-induced mutant p53 degradation in pancreatic cancer cells. Tipifarnib, a farnesyltransferase inhibitor, mirrored atorvastatin's effects on mutant p53, degraded mutant p53 in a dose-dependent manner, and converted farnesylated DNAJA1 into unfarnesylated DNAJA1. Farnesyltransferase gene knockdown also significantly promoted mutant p53 degradation. Coimmunoprecipitation either by an anti-DNAJA1 or p53 antibody confirmed the direct interaction of mutant p53 and DNAJA1 and higher doses of atorvastatin treatments converted more farnesylated DNAJA1 into unfarnesylated DNAJA1 with much less mutant p53 pulled down by DNAJA1. Strikingly, C394S mutant DNAJA1, in which the cysteine of the CAAX box was mutated to serine, was no longer able to be farnesylated and lost the ability to maintain mutant p53 stabilization. Our results show that farnesylated DNAJA1 is a crucial chaperone in maintaining mutant p53 stabilization and targeting farnesylated DNAJA1 by atorvastatin will be critical for inhibiting p53 mutant cancer.


Assuntos
Atorvastatina/farmacologia , Proteínas de Choque Térmico HSP40/genética , Neoplasias Pancreáticas/tratamento farmacológico , Proteína Supressora de Tumor p53/genética , Animais , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Farnesiltranstransferase/antagonistas & inibidores , Farnesiltranstransferase/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Chaperonas Moleculares/genética , Proteínas Mutantes/genética , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Prenilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas p21(ras)/genética , Quinolonas/farmacologia
8.
Biomed Chromatogr ; 33(11): e4639, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31256419

RESUMO

Atorvastatin (ATO) inhibits the synthesis of nonsteroidal isoprenoid compounds and possesses a pleiotropic effect. However, the detailed mechanism of ATO in preventing gentamicin (GM)-induced renal injury remains obscure. Although underlying multifaceted mechanisms involving GM-induced nephrotoxicity were well known, further work on elucidating the essential mechanism was needed. Using a fluorogenic derivatization-liquid chromatography tandem mass spectrometry proteomic method (FD-LC-MS/MS method), we investigated the effects and mechanisms of ATO treatment on GM-induced nephrotoxicity in rats. Consequently, 49 differentially expressed proteins were identified. The most significant mechanisms of nephrotoxicity caused by GM were mitochondrial dysfunction, fatty acid metabolism and oxidative stress. Their upstream regulator was found to be PPARα. The proteins involved in GM nephrotoxicity were sodium-hydrogen exchanger regulatory factor (SLC9A3R1), cathepsin V (CTSV), macrophage migration inhibitory factor (MIF) and RhoGDP dissociation inhibitor alpha (ARHGDIA). After ATO intervention, we observed a reversed enrichment pattern of their expression, especially in CTSV and SLC9A3R1 (P-value<0.05). We predicted that ATO may improve abnormal phospholipid metabolism and phospholipidosis caused by GM and also alleviate cell volume homeostasis and reverse the interference of GM with the transporter. Furthermore, proteomic results also provided clues as to GM-induced nephrotoxicity biomarkers such as CTSV and transthyretin.


Assuntos
Atorvastatina/farmacologia , Gentamicinas/toxicidade , Rim/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/metabolismo , Animais , Rim/metabolismo , Rim/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
9.
Biomed Res Int ; 2019: 7284767, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281844

RESUMO

The potential of oxidized-LDL (Ox-LDL) to elicit inflammatory responses in macrophages leading to the atherosclerosis (AS) progression is well known. Since proprotein convertase subtilisin/Kexin-9 (PCSK-9), the posttranslational regulator of LDL-receptor, is associated with elevated LDL in the circulation, the present report was aimed to uncover the ameliorative effects of Ginkgolide B, a terpenic lactone from Ginkgo biloba, against Ox-LDL-induced alterations in cholesterol metabolism in HUVECs. Consequently, our results demonstrated that incubation with Ox-LDL significantly upregulated the PCSK-9 expression in HUVECs, which was significantly downregulated, both at mRNA and protein level, after Ginkgolide B treatment via subsequent suppression of sterol element binding protein (SREBP-2) expression. Moreover, Ginkgolide B-mediated inhibition of PCSK-9 activity was also validated by in silico methods which revealed that it interferes the PSCK-9 interaction with LDL-receptor (LDL-R). Interestingly, Ox-LDL-induced LDL-R expression was further enhanced by Ginkgolide B treatment in HUVECs. Moreover, Ginkgolide B treatment lead to downregulation of lectin-like Ox-LDL receptor (LOX-1) and NADPH oxidase (NOX-4) expression which was upregulated in Ox-LDL-treated HUVECs, along with the attenuation of mitochondrial ROS generation. Furthermore, Ginkgolide B significantly inhibited the augmented expression of intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) in Ox-LDL-activated HUVECs. Ginkgolide B also significantly ameliorated the inflammatory response in Ox-LDL-activated HUVECs by suppressing the expression of IL-1α, IL-1ß, IL-6, CXCL-1, CXCL-2, and monocyte chemotactic protein (MCP-1), at mRNA and protein level. Our in vitro and in silico study established that Ginkgolide B alleviated the Ox-LDL-induced inflammatory cascades and altered lipid metabolism in HUVECs by suppressing the PCSK-9 and, thus, could be established as a treasured alternative therapeutic candidate in the atherosclerosis management.


Assuntos
Ginkgolídeos/uso terapêutico , Células Endoteliais da Veia Umbilical Humana/metabolismo , Inflamação/tratamento farmacológico , Lactonas/uso terapêutico , Metabolismo dos Lipídeos , Pró-Proteína Convertase 9/metabolismo , Atorvastatina/farmacologia , Moléculas de Adesão Celular/metabolismo , Colesterol/metabolismo , Citocinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Ginkgolídeos/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Lactonas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , NADPH Oxidase 4/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de LDL/química , Receptores de LDL/metabolismo , Receptores Depuradores Classe E/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo
10.
J Pharm Pharmacol ; 71(8): 1301-1310, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31215034

RESUMO

OBJECTIVES: The present study investigated the effects of atorvastatin on kidney injury in mice with pulmonary fibrosis (PF). METHODS: Adult mice were divided into four groups: mice treated with intratracheal bleomycin (I) and their controls (II), and mice treated with atorvastatin for 10 days after 7 days from bleomycin treatment (III) and their controls (IV). Mice were dissected on the 21st day. KEY FINDINGS: Mononuclear cell infiltrations, injured proximal tubule epithelium and p-c-Jun level increased, while cell proliferation and the levels of p-SMAD2, ELK1, p-ELK1, p-ATF2 and c-Jun decreased in the kidney tissue of mice with PF. The atorvastatin treatments to mice with PF resulted in significant increases at the TGF-ß activation, cell proliferation and kidney damage and decreases in the levels of p-SMAD2, p-ELK1, p-ATF2 and p-c-Jun, but not change the p-SMAD3, ELK1 and ATF2 in kidneys. CONCLUSIONS: The depletion of MAPK signals, rather than SMAD signalling, is effective in kidney damage of mice with PF. Atorvastatin did not regress kidney damage in these mice, whereas it increases the kidney injury. The c-Jun-mediated JNK signals could help kidney repair through cell proliferation. The treatment time and doses of atorvastatin should be optimized for regression of kidney damage.


Assuntos
Atorvastatina/farmacologia , Nefropatias/tratamento farmacológico , Rim/efeitos dos fármacos , Fibrose Pulmonar/metabolismo , Animais , Bleomicina/farmacologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Rim/metabolismo , Nefropatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos
11.
Int J Neurosci ; 129(11): 1133-1138, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31232139

RESUMO

Objective: To make comparative studies on the effects of different doses of atorvastatin combined with aspirin on inflammatory cytokines, blood lipids, blood glucose, other biochemical indexes and carotid plaques in patients with ischemic cerebrovascular disease (ICVD) and carotid plaques. Method: One hundred and twenty patients with ICVD and carotid plaques admitted by Renmin Hospital, Hubei University of Medicine Hospital from December 2016 to December 2017 were selected and randomly divided into experimental group and control group, 60 cases in each group. Patients in the control group was asked to orally take standard dose of atorvastatin (20 mg/d) combined with aspirin enteric-coated tablets (100 mg/d). Patients in the experimental group was asked to orally take high-dose atorvastatin (40 mg/d) combined with the same amount of aspirin enteric-coated tablets. Patients in two groups were treated for 6 months averagely. The levels of inflammatory factors, changes in blood biochemical parameters and carotid plaque degrees of patients in two groups before and after treatment were inspected and compared. Results: The levels of serum high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor (TNF-a), interleukin-6 (IL-6) and homocysteine (Hcy) in patients of the experimental group after treatment were higher than those in the control group, difference with statistical significance (p < .05). The total cholesterol (TC), triglyceride (TG) and low density lipoprotein cholesterol (LDL-C) in patients of the experimental group after treatment were lower than those in the control group and before treatment. The high-density lipoprotein cholesterol (HDL-C) was higher than that of the control group and before treatment, the levels of fasting blood glucose (FBS) and glycosylated hemoglobin (HbAIc) in patients of the experimental group significantly increased compared to those before treatment, difference with statistical significance (p < .05). There was no significant change in the control group. The carotid intima-media thickness (IMT) and plaque area in patients of the experimental group were lower than those in the control group and before treatment, difference with statistical significance (p < .05). Conclusion: High-dose atorvastatin combined with aspirin for treatment of patients with ICVD can effectively reduce inflammatory inflammatory cytokine levels in serum and reduce IMT and carotid plaque area. With more obvious effect than lower dose of atorvastatin combined with aspirin, it is easy to cause blood glucose abnormality. So, it is necessary to pay attention to monitoring blood sugar during medication period.


Assuntos
Aspirina/farmacologia , Atorvastatina/farmacologia , Isquemia Encefálica/sangue , Isquemia Encefálica/tratamento farmacológico , Espessura Intima-Media Carotídea , Estenose das Carótidas/tratamento farmacológico , Citocinas/sangue , Citocinas/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Idoso , Idoso de 80 Anos ou mais , Aspirina/administração & dosagem , Atorvastatina/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inflamação/sangue , Inflamação/tratamento farmacológico , Masculino , Inibidores da Agregação de Plaquetas/administração & dosagem , Resultado do Tratamento
12.
J Recept Signal Transduct Res ; 39(1): 1-8, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31237181

RESUMO

Aims: A number of epidemiological and experimental documents emphasizes a close relation between type 2 diabetes mellitus (T2DM) and the progression of osteoarthritis (OA). In order to understand the underlying mechanisms of atorvastatin (ATO) in OA, we sought to explore the effect of ATO on high glucose (HG)-mediated NF-κB activation in cultured C28I2 chondrocytes. Methods: The effects of various concentrations of ATO on C28I2 human chondrocytes viability were assessed to obtain the non-cytotoxic concentrations of drug by MTT-assay. The cells were pretreated with 0.01 and 0.1 µM ATO for 6 h, followed by incubation with HG (75 mM) for 72 h. The protein expressions of IκBα (np), IκBα (p), NF-κB (p), and NF-κB (np) were analyzed by western blotting. The effects of ATO on the mRNA expressions of chondrogenic specific markers including SOX9, aggrecan, collagen type 2, and COMP were evaluated by reverse transcription-polymerase chain reaction. Results: ATO in determined concentrations had no cytotoxic effect on C28I2 cells after 72 h. ATO pretreatment exerted remarkable protective effects against HG-induced cytotoxicity. Moreover, ATO decreased IκBα phosphorylation and NF-κB nuclear translocation. It was also able to improve the gene expression of chondrogenic-specific markers in C28I2 cells compared to the control group. Conclusion: ATO could significantly decrease HG-induced inflammation in the cultured C28I2 chondrocytes through the activation of canonical NF-κB signaling pathway. These beneficial effects of ATO may be owing to its anti-inflammatory properties. Therefore, treatment with ATO may provide an effective approach to prevent HG-induced cartilage destruction in clinical setting.


Assuntos
Apoptose/efeitos dos fármacos , Atorvastatina/farmacologia , Proliferação de Células/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Glucose/farmacologia , NF-kappa B/metabolismo , Substâncias Protetoras/farmacologia , Células Cultivadas , Condrócitos/metabolismo , Condrócitos/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , NF-kappa B/genética , Transdução de Sinais , Edulcorantes/farmacologia
13.
Mol Med Rep ; 20(2): 1383-1392, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173243

RESUMO

Hypercholesterolemia is one of the major risk factors for the occurrence and development of atherosclerosis. The most common drugs used to treat hypercholesterolemia are 3­hydroxy­3­methyl­glutaryl­CoA reductase inhibitors, known as statins. Statins induce a beneficial increase in the levels of the low density lipoprotein receptor (LDLR) and additionally upregulate proprotein convertase subtilisin/kexin type 9 (PCSK9), which leads to LDLR degradation. This process causes a negative feedback response that attenuates the lipid lowering effects of statins. Therefore, the development of PCSK9 inhibitors may increase the lipid­lowering functions of statins. In the present study, a drug­screening assay was developed using the human PCSK9 promoter, based on data from a dual­luciferase reporter assay, and the efficacies of various compounds from Traditional Chinese Medicine were examined. Among the compounds examined, SIL was demonstrated to function by targeting PCSK9. It was identified that SIL treatment decreased the expression levels of PCSK9 in HepG2 cells by decreasing the activity of the PCSK9 promoter in a dose­and time­dependent manner. Notably, SIL antagonized the statin­induced phosphorylation of the p38 MAPK signaling pathway. The present study suggested that SIL may be developed as a novel PCSK9 inhibitor that may increase the efficiency of statin treatment.


Assuntos
Hepatoblastoma/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Neoplasias Hepáticas/metabolismo , Pró-Proteína Convertase 9/metabolismo , Silibina/farmacologia , Atorvastatina/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Hepatoblastoma/genética , Hepatoblastoma/patologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Fosforilação/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Pró-Proteína Convertase 9/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Silibina/química , Fatores de Tempo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
14.
Biomed Pharmacother ; 116: 109007, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31170663

RESUMO

It's critical for tube formation and angiogenesis to repair ischemic myocardium or stroke. This study aimed to investigate role of microRNA-126 (miR-126) in tube formation in human umbilical vein endothelial cells (HUVECs) and associated mechanisms. Primary neural stem cells (NSCs) and HUVECs were cultured and transfected with microRNA-126 mimics and miR-126 inhibitor. Cell counting kit-8 (CCK-8) and cell cycle assay were conducted for evaluating NSCs viability. Transwell assay was conducted to observe invasive ability of HUVECs. Quantitative real-time PCR (qRT-PCR) assay was used to examine epidermal growth factor like domain 7 (EGFL7) and miR-126 mRNA both in vitro and animal models. Tube forming capability was evaluated in HUVECs. Dual luciferase assay was performed to evaluate interaction between miR-126 and EGFL7 gene. Western blot assay was used to determine phosphoinositide-3-kinase/protein kinase-B (PI3K/AKT) signaling molecules and EGFL7. The results indicated that miR-126 significantly decreased cell viability, inhibited invasive ability and modulated cell cycle of NSCs compared to miR-NC group (p < 0.05). miR-126 significantly inhibited tube formation of HUVECs compared to miR-NC group (p < 0.05). miR-126 significantly down-regulated EGFL7 mRNA and protein expression compared to miR-NC (p < 0.05). Atorvastatin significantly increased CD34 and enhanced EGFL7 expression in traumatic brain injury (TBI) rats brain tissues compared to Model group (p < 0.05). miR-126 significantly down-regulated and atorvastatin up-regulated PI3K/AKT signaling pathway (p < 0.05). Atorvastatin significantly increased EGFL7 and down-regulated miR-126 expression in TBI rats brain tissues compared to Model group (p < 0.05). miR-126 interacted with and negatively correlated with EGFL7 gene both in vitro and in TBI models. In conclusion, microRNA-126 inhibited tube formation of HUVECs by interacting with EGFL7 and down-regulating PI3K/AKT signaling pathway.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Regulação para Baixo/genética , Família de Proteínas EGF/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , MicroRNAs/metabolismo , Neovascularização Fisiológica , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Animais , Antígenos CD34/metabolismo , Atorvastatina/administração & dosagem , Atorvastatina/farmacologia , Sequência de Bases , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/patologia , Proteínas de Ligação ao Cálcio/genética , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Regulação para Baixo/efeitos dos fármacos , Família de Proteínas EGF/genética , Fatores de Crescimento Endotelial/metabolismo , Humanos , MicroRNAs/genética , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/genética , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
15.
Int J Mol Sci ; 20(10)2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31121898

RESUMO

Previous studies demonstrated modifications of high-density lipoproteins (HDL) structure and apolipoprotein (apo) A-I catabolism induced by the atorvastatin and fenofibrate combination. However, it remains unknown whether such structural and metabolic changes of HDL were related to an improvement of the HDL-cholesteryl esters (HDL-CE) metabolism. Therefore, we determined the structure of HDL and performed kinetic studies of HDL-CE radiolabeled with tritium in rabbits treated with atorvastatin, fenofibrate, and a combination of both drugs. The atorvastatin and fenofibrate combination increased the HDL size and the cholesterol and phospholipid plasma concentrations of the largest HDL subclasses. Moreover, the relative amount of unsaturated fatty acids contained in HDL increased, in detriment of saturated fatty acids as determined by gas chromatography-mass spectrometry. The transfers of cholesteryl esters (CE) from HDL to very low-density lipoproteins/low-density lipoproteins (VLDL/LDL) and vice versa were enhanced with atorvastatin, alone or in combination. Moreover, the direct elimination of CE from plasma via VLDL/LDL decreased with fenofibrate, whereas the direct elimination of CE via HDL augmented with the combination treatment. Taken together, the rise of unsaturated fatty acid content and the size increase of HDL, suggest that atorvastatin and fenofibrate induce more fluid HDL particles, which in turn favor an enhanced CE exchange between HDL and VLDL/LDL. Our results contribute to a better understanding of the relationship between the structure and function of HDL during the use of anti-dyslipidemic drugs.


Assuntos
Atorvastatina/farmacologia , Ésteres do Colesterol/metabolismo , Fenofibrato/farmacologia , Hipolipemiantes/farmacologia , Lipoproteínas HDL/metabolismo , Animais , Anticolesterolemiantes/farmacologia , Ésteres do Colesterol/análise , Cinética , Lipoproteínas HDL/química , Coelhos
16.
PLoS One ; 14(5): e0216405, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31071151

RESUMO

Statins exert pleiotropic and beneficial anti-inflammatory and antioxidant effects. We have previously reported that macrophages treated with statins increased the expression of heme oxygenase-1 (HO-1), an inducible anti-inflammatory and cytoprotective stress protein, responsible for the degradation of heme. In the present study, we investigated the effects of atorvastatin on inflammation in mice and analyzed its mechanism of action in vivo. Air pouches were established in 8 week-old female C57BL/6J mice. Atorvastatin (5 mg/kg, i.p.) and/or tin protoporphyrin IX (SnPPIX), a heme oxygenase inhibitor (12 mg/kg, i.p.), were administered for 10 days. Zymosan, a cell wall component of Saccharomyces cerevisiae, was injected in the air pouch to trigger inflammation. Cell number and levels of inflammatory markers were determined in exudates collected from the pouch 24 hours post zymosan injection by flow cytometry, ELISA and quantitative PCR. Analysis of the mice treated with atorvastatin alone displayed increased expression of HO-1, arginase-1, C-type lectin domain containing 7A, and mannose receptor C-type 1 in the cells of the exudate of the air pouch. Flow cytometry analysis revealed an increase in monocyte/macrophage cells expressing HO-1 and in leukocytes expressing MRC-1 in response to atorvastatin. Mice treated with atorvastatin showed a significant reduction in cell influx in response to zymosan, and in the expression of proinflammatory cytokines and chemokines such as interleukin-1α, monocyte chemoattractant protein-1 and prostaglandin E2. Co-treatment of mice with atorvastatin and tin protoporphyrin IX (SnPPIX), an inhibitor of heme oxygenase, reversed the inhibitory effect of statin on cell influx and proinflammatory markers, suggesting a protective role of HO-1. Flow cytometry analysis of air pouch cell contents revealed prevalence of neutrophils and to a lesser extent of monocytes/macrophages with no significant effect of atorvastatin treatment on the modification of their relative proportion. These findings identify HO-1 as a target for the therapeutic actions of atorvastatin and highlight its potential role as an in vivo anti-inflammatory agent.


Assuntos
Anti-Inflamatórios/farmacologia , Atorvastatina/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/biossíntese , Proteínas de Membrana/biossíntese , Zimosan/toxicidade , Animais , Movimento Celular/efeitos dos fármacos , Feminino , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/epidemiologia , Inflamação/patologia , Macrófagos/enzimologia , Macrófagos/patologia , Metaloporfirinas/farmacologia , Camundongos , Monócitos/enzimologia , Monócitos/patologia , Neutrófilos/enzimologia , Neutrófilos/patologia , Protoporfirinas/farmacologia
17.
Mol Biol Rep ; 46(4): 3921-3928, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31049833

RESUMO

10-Dehydrogingerdione (10-DHGD) was previously reported to possess a hypolipidemic, anti-inflammatory and anti-oxidant properties in hyperlipidemic rabbit model. In this study, we investigated a possible new role for 10-DHGD in modulating atherogenic lipid profile by targeting proprotein convertase subtilisin kexin-9 (PCSK-9). Cholesterol (0.2% w/w)-fed rabbits received either atorvastatin (20 mg/kg) or 10-DHGD (10 mg/kg) for 12 weeks along with cholesterol feeding (HCD). Lipid profile, serum PCSK-9 and macrophage migration inhibitory factor (MIF), and aorta level of tumor necrosis factor-alpha (TNF-α) and glycosaminoglycans (GAGs) were measured. HCD-fed rabbits revealed an atherogenic lipid profile along with increased serum level of PCSK-9 (p < 0.001) and increased serum MIF and aortic TNF-α and GAGs (p < 0.001). 10-DHGD administration to HCD-fed rabbits prevented this atheogenicity by modulating the release of PCSK-9, inflammation extent (serum MIF and aortic TNF-α) and GAGs. These results provide new insights on the hypolipidemic potential of 10-DHGD. The effects of 10-DHGD was superior to that of atorvastatin in most studied parameters modulating atherogenicity. 10-DHGD is found to be able to suppress the release of PCSK-9, decrease aortic expression of GAGs in cholesterol-fed rabbits and halt the inflammation extent. These effects may provide new insights on the hypolipidemic potential of 10-DHGD.


Assuntos
Glicosaminoglicanos/metabolismo , Guaiacol/análogos & derivados , Hiperlipidemias/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/fisiologia , Aterosclerose/metabolismo , Atorvastatina/farmacologia , Colesterol/metabolismo , Guaiacol/metabolismo , Guaiacol/farmacologia , Hiperlipidemias/sangue , Hiperlipidemias/metabolismo , Lipídeos/sangue , Masculino , Pró-Proteína Convertase 9/sangue , Pró-Proteína Convertase 9/metabolismo , Coelhos , Fator de Necrose Tumoral alfa/metabolismo
18.
Bratisl Lek Listy ; 120(3): 200-206, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31023038

RESUMO

OBJECTIVES: Aims of this study were to investigate the anti-arrhythmic and cardio-protective effect of atorvastatin and of a new pyridoindole derivative (SMe1EC2) on isolated and perfused hearts while following the Langendorff principles. BACKGROUND: Metabolic syndrome is a widely distributed condition progressing to cardiovascular disease. Many of the metabolic syndrome patients take (HMG)-co-enzyme A (CoA) reductase inhibitors with potential cardio-protective effects. SMe1EC2 is a promising new drug, exerting many positive effects in experimental settings. METHODS: Rats with induced metabolic syndrome were treated with atorvastatin (25 mg/kg) and SMe1EC2 (25 mg/kg and 0.5 mg/kg, respectively) daily for 3 weeks. After the treatment, the hearts were isolated and perfused according to Langendorff. RESULTS: Both atorvastatin and SMe1EC2 improved cardiac function by elevating the left ventricular developed pressure (VLDP) and cardiac contractility. Both SMe1EC2-treated groups improved LVDP during reperfusion, significantly increased ‒dP/dt, and moderately elevated +dP/dt values. The treatment with both atorvastatin and SMe1EC2 (25 mg/kg) significantly reduced malignant arrhythmia in comparison to control group and group treated with SMe1EC2 0.5 mg/kg. CONCLUSIONS: Owing to its anti-arrhythmic and cardio-protective effects, atorvastatin and SMe1EC2 could be of benefit to patients suffering from metabolic syndrome (Tab. 3, Fig. 3, Ref. 41).


Assuntos
Antiarrítmicos , Atorvastatina , Síndrome Metabólica , Traumatismo por Reperfusão Miocárdica , Animais , Antiarrítmicos/farmacologia , Atorvastatina/farmacologia , Coração , Humanos , Síndrome Metabólica/complicações , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Ratos , Ratos Wistar
19.
Pharmacol Rep ; 71(3): 417-421, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31003151

RESUMO

BACKGROUND: Individuals with non-classic congenital adrenal hyperplasia (NC-CAH) often show evidence of hyperandrogenism, including premature pubarche, accelerated linear growth velocity, short final height, hirsutism, acne, alopecia, impaired ovulation, menstrual dysfunction and subfertility. Although statins were found to reduce elevated levels of androgens in subjects with this disorder, no previous study has investigated whether 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors affect cardiometabolic risk factors in patients with NC-CAH. METHODS: We studied 12 women with NC-CAH, 6 of whom because of coexisting hypercholesterolemia received atorvastatin (20-40 mg daily). Circulating levels of lipids, glucose homeostasis markers, plasma levels of androgens, 17-hydroxyprogesterone, high-sensitivity C-reactive protein (hsCRP), uric acid, fibrinogen, homocysteine and 25-hydroxyvitamin D, as well as urinary albumin-to-creatinine ratio (UACR) were determined at the beginning of the study and 12 weeks later. RESULTS: Beyond affecting plasma lipids, atorvastatin reduced circulating levels of testosterone, dehydroepiandrosterone sulphate, androstenedione and 17-hydroxyprogesterone, and decreased free androgen index. Moreover, atorvastatin caused a decrease in plasma levels/urinary loss of uric acid, hsCRP, homocysteine and UACR, and insignificantly increased circulating levels of 25-hydroxyvitamin D. The drug produced no effect on plasma fibrinogen. The effect of atorvastatin on hsCRP, uric acid, homocysteine, 25-hydroxyvitamin D and UACR correlated with the magnitude of reduction in 17-hydroxyprogesterone and androgens. CONCLUSION: Our results suggest that statin therapy reduces cardiometabolic risk in women with NC-CAH.


Assuntos
Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Atorvastatina/farmacologia , Doenças Cardiovasculares/induzido quimicamente , Hiperplasia Suprarrenal Congênita/sangue , Hiperplasia Suprarrenal Congênita/metabolismo , Adulto , Androgênios/sangue , Androgênios/metabolismo , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/metabolismo , Sulfato de Desidroepiandrosterona/sangue , Feminino , Fibrinogênio/metabolismo , Homocisteína/sangue , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/metabolismo , Projetos Piloto , Fatores de Risco , Testosterona/sangue , Ácido Úrico/sangue , Vitamina D/análogos & derivados , Vitamina D/sangue
20.
Biomed Res Int ; 2019: 3235021, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31011573

RESUMO

Background: Breast cancer (BC) is one of the most common malignant tumors in women around the world. Atorvastatin (ATO) was found to be associated with a decreased risk of recurrence and mortality in cancer. But the exact mechanism of its carcinostatic effects is unclear. The expression level of Ras homolog family member B (RhoB) in breast cancer cells was found to be upregulated after being treated with ATO. Thus, we conjecture that altered expression of RhoB induced by ATO may be decisive for the migration and progression of breast cancer. Methods: The effects of ATO on breast tumor cells in vivo and in vitro were detected by clone formation assay, CCK-8 assay, flow cytometry, wound healing, transwell assays, tumor xenograft model, and immunohistochemistry. Distribution of RhoB in different breast cancer tissues and its influence on prognosis were analyzed using the data from TCGA or GEO databases. The relationship between RhoB and PTEN/AKT pathway was detected by Western blotting and RT-qPCR. Results: ATO inhibits proliferation, invasion, EMT, and PTEN/AKT pathway and promotes apoptosis in breast tumor cells. In addition, ATO inhibits the volume and weight of breast tumor in tumor-bearing mice and upregulated RhoB in tumor tissues. The expression of RhoB in mRNA and protein level was upregulated in statin-treated breast cancer cells and downregulated in cancer tissues. Low expression of RhoB links with poor prognosis in patients with breast cancer (HR = 0.74[0.66-0.83], p =7e-8, log-rank test). Further research found that RhoB inhibits the proliferation, invasion, EMT, and PTEN/AKT signal pathway in breast tumor cells. Conclusions: The exact mechanism of ATO's carcinostatic effects in breast cancer is related to downregulating PTEN/AKT pathway via promoting RhoB. Our study also demonstrates the potential applicability of RhoB as a therapeutic target for breast cancer.


Assuntos
Atorvastatina/farmacologia , Neoplasias da Mama/tratamento farmacológico , Regulação para Baixo/efeitos dos fármacos , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , Proteína rhoB de Ligação ao GTP/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Recidiva Local de Neoplasia/genética , Prognóstico , Transdução de Sinais/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
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