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1.
Acta Cir Bras ; 34(7): e201900708, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31531541

RESUMO

PURPOSE: To investigate the effect of astragaloside IV (As-IV) on myocardial ischemia-reperfusion (I/R) injury in rats and reltaed mechanisms. METHODS: Sixty rats were randomly divided into sham-operated, control I/R and 2.5, 5 and 10 mg/kg As-IV groups, 12 rats in each group. The later three groups were intragastrically administered with As-IV for 7 days, with a dose of 2.5, 5 and 10 mg/kg, respectively. The myocardial I/R injury model was constructed in later four groups. At the end of reperfusion, the cardiac function indexes, serum lactate dehydrogenase (LDH) and creatine kinase (CK) levels, heart weight (HW)/body weight (BW) ratio and infarct size, and expressions of phosphatidylinositol-3 kinase/serine-threonine protein kinase (PI3K/AKT) and glycogen synthase kinase-3ß (GSK-3ß) proteins and the phosphorylated forms (p-AKT, p-GSK-3ß) were determined. RESULTS: Compared with control I/R group, in 5 and 10 mg/kg As-IV groups the left ventricular systolic pressure, fractional shortening and ejection fraction were increased, the left ventricular end-diastolic pressure was decreased, the serum LDH and CK levels were decreased, the HW/BW ratio and myocardial infarct size were decreased, and the p-Akt/Akt ratio and p-GSK-3ß/GSK-3ß ratio were increased (all P < 0.05). CONCLUSION: As-IV can alleviate the myocardial I/R injury in rats through regulating PI3K/AKT/GSK-3ß signaling pathways.


Assuntos
Glicogênio Sintase Quinase 3 beta/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Saponinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Masculino , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Fosforilação , Ratos , Ratos Sprague-Dawley
2.
Adv Exp Med Biol ; 1155: 555-563, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468431

RESUMO

Taurine plays an important role in improving immunity, regulating cell proliferation and differentiation, apoptosis and so on. Traditional Chinese herb formula (TCHF) is a wealth of medicine materials for diseases control. There are many studies on Chinese herb formula in inducing cell apoptosis, differentiation and improving animal immunity. The factors in phosphatidylinositol 3-kinase/Protein Kinase (PI3K-Akt) signaling pathway are central regulators of normal cells, which integrates extra-cellular signals into cells and activates affects cell activities including cell proliferation, differentiation and apoptosis. We find the key factors (PIK3CA, PDPK1, AKT1, MDM2, ITGA2B, ITGB1, FAK and p53) in PI3K-Akt signaling pathway by RNA-Seq analysis in our previous research. The overall goal of this study to investigate the influence of taurine TCHF (Tau-TCHF) on cell proliferation, differentiation and apoptosis by estimating the factors above. The layers were fed with normal diet plus 1% of Tau-TCHF and the control group with normal diet to 42 days old. The spleen tissue samples from individual layers were used to analyze the influence of Tau-TCHF on the factors PIK3CA, PDPK1, AKT1, MDM2, ITGA2B, ITGB1, FAK and p53 in PI3K-Akt signaling pathway. The levels of transcription and protein expression of various factors were assessed by quantitative PCR (qPCR) and Western Blot. The results showed that the transcription levels of itgb1, fak, pik3ca, akt1 and mdm2 on 42-day-old chicken spleen tissues were increased significantly in Tau-TCHF group comparing with control group (P < 0.01); the transcription levels of itga2b, pdpk1 and p53 were no significant difference (P > 0.05). The protein levels of PDPK1 and AKT (Ser437) were increased significantly (P < 0.05), but ITGA2B, ITGB1, FAK, PIK3CA, AKT1, MDM2 and p53 had no significant difference (P > 0.05). The results suggest that Tau-TCHF may influence proliferation and differentiation of chickens spleen via regulating PI3K-Akt signaling pathway. And Tau-TCHF may be provided as feed additives in improving the immunity of animals. AKT (Ser473) and PDPK1 may be considered as further targets to study mechanism of Tau-TCHF on anti-apoptosis via PI3K-Akt signaling pathway.


Assuntos
Apoptose , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Baço/citologia , Taurina/farmacologia , Animais , Galinhas
3.
Sheng Li Xue Bao ; 71(4): 575-580, 2019 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-31440754

RESUMO

The aim of the present study was to investigate the effect of salidroside (Sal) on inflammatory activation induced by lipopolysaccharide (LPS) in the co-culture of rat alveolar macrophages (AM) NR 8383 and type II alveolar epithelial cells (AEC II) RLE-6TN. CCK-8 colorimetric method was used to detect cell proliferation percentage. The enzyme-linked immunosorbent assay (ELISA) was used to determine the content of tumor necrosis factor alpha (TNF-α), macrophage inflammatory protein-2 (MIP-2) and interleukin-10 (IL-10) in the supernatant. Western blot was used to examine the expression levels of phosphorylated AKT (p-AKT) and total AKT protein. The results showed that pretreatment of RLE-6TN cells or co-culture of RLE-6TN and NR 8383 cells with 32 and 128 µg/mL Sal for 1 h, followed by continuous culture for 24 h, significantly increased the cell proliferation (P < 0.05). Compared with control group, 32 and 128 µg/mL Sal pretreatment significantly increased the ratio of p-AKT/AKT in RLE-6TN cells (P < 0.05). Pretreatment of 32 µg/mL Sal not only inhibited the secretion of TNF-α and MIP-2 by NR 8383 cells induced by LPS (P < 0.05), but also enhanced the inhibitory effect of RLE-6TN and NR 8383 cells co-culture on the secretion of TNF-α and MIP-2 by NR 8383 cells induced by LPS (P < 0.05). In addition, 32 µg/mL Sal pretreatment promoted LPS-induced IL-10 secretion by NR 8383 cells (P < 0.05), and enhanced the promoting effect of co-culture of RLE-6TN and NR 8383 cells on the IL-10 secretion by LPS-induced NR 8383 cells (P < 0.05). In conclusion, Sal may directly inhibit LPS-induced inflammatory activation of AM (NR 8383), promote the proliferation of AEC II (RLE-6TN) through PI3K/AKT signaling pathway, and enhance the regulatory effect of AEC II on LPS-induced inflammatory activation of AM.


Assuntos
Células Epiteliais Alveolares/efeitos dos fármacos , Glucosídeos/farmacologia , Macrófagos Alveolares/efeitos dos fármacos , Fenóis/farmacologia , Transdução de Sinais , Células Epiteliais Alveolares/metabolismo , Animais , Linhagem Celular , Quimiocina CXCL2/metabolismo , Técnicas de Cocultura , Interleucina-10/metabolismo , Lipopolissacarídeos , Macrófagos Alveolares/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Fator de Necrose Tumoral alfa/metabolismo
4.
Cancer Invest ; 37(7): 311-324, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31412710

RESUMO

Enthusiasms into the application of PI3K-δ inhibitor CAL-101 has been muted due to the over-activation of compensatory molecules. Our results delineated that c-Myc suppression using 10058-F4 enhanced CAL-101 cytotoxicity in less sensitive cells through different mechanisms based on p53 status; while CAL-101-plus-10058-F4 induced G1 arrest in wild-type p53-expressing leukemic cells, no conspicuous increase in G1 was noted in U937 cells harboring mutant p53. Conclusively, this study shed lights on the role of c-Myc oncoprotein in acute leukemia cells sensitivity to PI3K inhibitor and outlined that the combination of c-Myc inhibitor and CAL-101 may be a promising therapeutic approach in leukemia.


Assuntos
Antineoplásicos/farmacologia , Leucemia Mieloide Aguda/genética , Purinas/farmacologia , Quinazolinonas/farmacologia , Tiazóis/farmacologia , Proteína Supressora de Tumor p53/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo
5.
Cell Physiol Biochem ; 53(2): 301-322, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31343125

RESUMO

BACKGROUND/AIMS: Propolis is one of the most promising natural products, exhibiting not only therapeutic but also prophylactic actions. Propolis has several biological and pharmacological properties, including hepatoprotective activities. The present study aimed to investigate the underlying molecular mechanisms of propolis against CCl4-mediated liver fibrosis. METHODS: Three groups of male BALB/c mice (n=15/ group) were used: group 1 comprised control mice; groups 2 and 3 were injected with CCl4 for the induction of liver fibrosis. Group 3 was then orally supplemented with propolis (100 mg/kg body weight) for four weeks. Different techniques were used to monitor the antifibrotic effects of propolis, including histopathological investigations using H&E, Masson's trichrome and Sirius red staining; Western blotting; flow cytometry; and ELISA. RESULTS: We found that the induction of liver fibrosis by CCl4 was associated with a significant increase in hepatic collagen and α-smooth muscle actin (α-SMA) expression. Moreover, CCl4-treated mice also exhibited histopathological alterations in the liver architecture. Additionally, the liver of CCl4-treated mice exhibited a marked increase in proinflammatory signals, such as increased expression of HSP70 and increased levels of proinflammatory cytokines and ROS. Mechanistically, the liver of CCl4-treated mice exhibited a significant increase in the phosphorylation of AKT and mTOR; upregulation of the expression of BAX and cytochrome C; downregulation of the expression of Bcl2; a significant elevation in the levels of TGF-ß followed by increased phosphorylation of SMAD2; and a marked increase in the expression of P53 and iNOS. Interestingly, oral supplementation of CCl4-treated mice with propolis significantly abolished hepatic collagen deposition, abrogated inflammatory signals and oxidative stress, restored CCl4-mediated alterations in the signaling cascades, and hence repaired the hepatic architecture nearly to the normal architecture observed in the control mice. CONCLUSION: Our findings revealed the therapeutic potential and the underlying mechanisms of propolis against liver fibrosis.


Assuntos
Apoptose/efeitos dos fármacos , Cirrose Hepática Experimental/patologia , Própole/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Tetracloreto de Carbono/toxicidade , Citocinas/metabolismo , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase Tipo II/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína Smad2/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/metabolismo
6.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 31(6): 762-767, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31315738

RESUMO

OBJECTIVE: To explore the protective effect of hydrogen-rich water on the oxidative stress injury of astrocytes in mice and its effect on phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) signal pathway. METHODS: In vitro, mice astrocytes were cultured and the logarithmic growth period cells were taken for experiment. (1) Experiment one: some cells were acted by 1.25, 2.50, 5.00, 10.00 µmol/L hydrogen peroxide (H2O2) for 20 minutes to determine the appropriate concentration required for astrocyte damage induced by H2O2; cultivating 3, 6, 9, and 12 hours with hydrogen-rich water of 25, 50, 100, and 200 µmol/L, respectively, to determine the concentration and time of hydrogen-rich water pretreatment; the 50 µmol/L hydrogen-rich water was cultured together with PI3K/Akt signal pathway inhibitors wortmannin (WM) 200 nmol/L or 400 nmol/L to determine the best inhibition concentration of wortmannin. Astrocyte activity was detected by methyl thiazolyl tetrazolium (MTT) colorimetry. (2) Experiment two: some cells were divided into blank control group, H2O2 injury group, hydrogen-rich water pretreatment group (HW+H2O2 group), and co-culture of hydrogen-rich water and wortmannin pretreatment group (HW+WM+H2O2 group). The mRNA expressions of PI3K and Akt were detected by reverse transcription-polymerase chain reaction (RT-PCR); the protein expressions of PI3K, Akt and phosphorylated Akt (p-Akt) were detected by Western Blot. RESULTS: (1) Experiment one: the survival rate of the blank control group was 100%. Cell activity gradually decreased with the increase of H2O2 concentration, and the survival rate of the H2O2 action 20 minutes cells of 2.50 µmol/L was reduced to about 50%, so a cell injury model was established at this concentration. With the increase of hydrogen-rich water pretreatment concentration, and the duration of action, the cell survival rate increased first and then decreased. The cell survival rate was highest when 50 µmol/L hydrogen-rich water was pretreated with 9 hours, so a hydrogen-rich water pre-protection model was established. After 200 nmol/L or 400 nmol/L wortmannin was cultured together with hydrogen-rich water, cell activity was inhibited, and the cell survival rate of 200 nmol/L wortmannin group was no significantly different compared with that of H2O2 injury group, so the astrocyte suppression model was established. (2) Experiment two: compared with the blank control group, the mRNA expressions of PI3K and Akt and the protein expressions of PI3K, Akt and p-Akt were significantly decreased in the H2O2 injury group. Compared with the H2O2 injury group, the PI3K, Akt mRNA expressions and PI3K, Akt, p-Akt protein expressions were significantly increased in the HW+H2O2 group [PI3K mRNA (2-ΔΔCT): 0.843±0.019 vs. 0.631±0.038, Akt mRNA (2-ΔΔCT): 0.591±0.025 vs. 0.558±0.037, PI3K/ß-actin: 1.277±0.008 vs. 0.757±0.004, Akt/ß-actin: 1.308±0.015 vs. 0.682±0.006, p-Akt/ß-actin: 1.210±0.005 vs. 0.614±0.005, all P < 0.05]. The mRNA expressions of PI3K, Akt in the HW+WM+H2O2 group was 0.784±0.159 and 0.556±0.037, respectively, and the protein expressions of PI3K, Akt, p-Akt was 0.715±0.006, 0.686±0.005, and 0.606±0.004, respectively, both were significantly lower than those in HW+H2O2 group (all P < 0.05), and there was no significant difference with H2O2 injury group (all P > 0.05). CONCLUSIONS: Hydrogen-rich water activates the PI3K/Akt pathway, thereby mediates mice astrocytes to exert the biological function of antioxidant.


Assuntos
Hidrogênio/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Água/química , Água/farmacologia , Animais , Modelos Animais de Doenças , Peróxido de Hidrogênio/farmacologia , Camundongos
7.
Zhonghua Gan Zang Bing Za Zhi ; 27(6): 450-456, 2019 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-31357762

RESUMO

Objective: To observe the effect of differentiated mature adipocytes on hepatic steatosis and aquaporin-9 (AQP9) expressions in HepG2 cells and further explore its possible mechanism of action. Methods: Human preadipocytes were cultured and differentiated to full maturity. HepG2 cells were co-cultured with non-differentiated adipocytes and differentiated mature adipocytes for 48 h, and then labeled as control group and experimental group. Oil red O staining and intracellular triglyceride content were performed on co-cultured HepG2 cells and simultaneous changes in phosphatidylinositol 3-kinase (PI3K) - serine/threonine kinase (Akt) signaling pathway, and AQP9 mRNA and protein levels were detected. The experimental group was co-cultured with recombinant human insulin-like growth factor-I (IGF-I), with the addition of 100ng/ml PI3K-Akt pathway agonist, labeled as experimental group + IGF-I group. The activation of PI3K-Akt pathway was verified by Western blotting (WB). The expression of AQP9 was detected by RT-q PCR and WB. The recombinant lentivirus LV-AQP9 or empty-loaded virus LV-PWPI was transfected with HepG2 cells by recombinant lentiviral transfection tecnique, and labeled as HepG2-AQP9 and HepG2-PWPI. The transfection efficiency was assessed by confocal laser scanning microscopy and RT-qPCR and WB detected the change of AQP9 expression level after virus transfection. Afterwards, the stable over-expressed HepG2-AQP9 cells and the empty-loaded HepG2-PWPI cells were co-cultured with differentiated mature adipocytes for 48h, and labeled as HepG2-AQP9 co-culture group, and then intracellular triglyceride content were detected with Oil red O staining. Finally, IGF-I was added to the HepG2-AQP9 co-culture group, which was recorded as HepG2-AQP9 co-culture + IGF-I group. Intracellular triglyceride content was detected with Oil red O staining, and WB verified PI3K-Akt signaling pathway activation and changes in AQP9 mRNA and protein levels. A t-test was used to compare the two independent samples. Results: The intracellular lipid droplets and triglyceride content (0.052 ± 0.005) in the experimental group was increased significantly than the control group (0.033 ± 0.003) (t= 5.225,P= 0.006), suggesting that adipocyte co-culture had induced steatosis in HepG2 cells. RT-qPCR and WB results indicated that the expression levels of AQP9 mRNA (3.615 ± 0.330) and protein levels (0.072 ± 0.005) in the experimental group were significantly higher than the control group (t= 13.708, 11.225,P= 0.005, < 0.001). WB results showed that the expression level of phosphorylated Akt (p-Akt) protein (0.116±0.003) in the experimental group was significantly lower than the control group (0.202 ± 0.003) (t= 27.136,P< 0.001). The total Akt protein was constant, and the p-Akt/total Akt (0.182 ± 0.017)was significantly lower than the control group (0.327 ± 0.019) (t= 2.431,P= 0.001), suggesting that adipocyte co-culture had inhibited PI3K- Akt signaling pathway in HepG2 cells and up-regulated the expression level of AQP9. WB results indicated that the expression level of p-Akt protein (0.194 ± 0.021) in the experimental group + IGF-I group was significantly higher than the experimental group (0.132 ± 0.003) (t= 5.082,P= 0.007). The total Akt protein was constant, and the p-Akt/total Akt (0.281 ± 0.009) was significantly higher than the control group (0.184 ± 0.132) (t= 10.311,P< 0.001). Simultaneously, RT-qPCR and WB results indicated that the expression levels of AQP9 mRNA (0.327 ± 0.347) and protein levels (0.042 ± 0.004) in the experimental group + IGF-I group were significantly lower than the experimental group (t= 33.573, 5.598,P< 0.001, 0.005), suggesting that adipocyte co-culture had possibility to regulate the expression level of AQP9 through the PI3K-Akt pathway. Confocal laser microscopy analysis showed that the transfection efficiency was more than 90%. RT-q PCR and WB results indicated that the expression levels of AQP9 mRNA and protein levels (0.373 ± 0.221) in HepG2-AQP9 group were significantly higher than HepG2-PWPI group (t=14.953, 28.931,P= 0.002 and 0.000), suggesting that the stable overexpression of AQP9 cell line was successfully constructed. The intracellular lipid droplets and triglyceride content in HepG2-AQP9 co-culture group was significantly increased (t= 5.478, 5.369,P= 0.005) than HepG2-PWPI co-culture group and HepG2-AQP9 co-culture+ IGF-I group, suggesting that the increased expression of AQP9 had promoted HepG2 steatosis in co-cultured adipocytes. WB results showed the expression levels of p-Akt protein (0.168 ± 0.006) and p-Akt/total Akt (0.265±0.009) in HepG2-AQP9 co-culture + IGF-1 group was significantly increased (t= 16.311, 8.769,P< 0.001) than HepG2-AQP9 co-culture group, while the expression levels of AQP9 mRNA (0.327 ± 0.034) and protein (0.375 ± 0.025) was significantly decreased (t= 33.573, 9.146,P< 0.001 and 0.001). Conclusion: Adipocytes co-culture can induce steatosis in HepG2 cells, and may participate in inhibiting PI3K-Akt signaling pathway to upregulate the expression of AQP9 in steatotic HepG2 cells.


Assuntos
Adipócitos , Aquaporinas , Regulação da Expressão Gênica no Desenvolvimento , Adipócitos/citologia , Adipócitos/metabolismo , Aquaporinas/genética , Técnicas de Cocultura , Células Hep G2 , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
8.
Life Sci ; 232: 116626, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276688

RESUMO

PURPOSE: The aim of this study was to investigate the role of the suppressor of activator protein-1 regulated by interferon (SARI), in the development and progression of prostate cancer. METHODS: Sixty-seven prostate cancer tissue specimens and 20 benign prostatic hyperplasia specimens were used to investigate the correlation between SARI expression and clinicopathologic parameters. Immunohistochemistry was used to detect the SARI and E-cadherin protein expression in the prostate cancer and benign prostatic hyperplasia specimens, and their correlation was established. Quantitative PCR (qPCR) was used to determine the SARI mRNA expression in a normal prostate cell line (RWPE-1) and prostate cancer cell lines (LNCaP and PC3). Western blotting was used to detect the SARI protein expression in the RWPE-1, LNCaP, and PC3 cell lines. RESULTS: SARI protein expression did not correlate with the prostate cancer patients' age or serum Prostate-Specific Antigen value but did show a correlation with the tumor stage of prostate cancer and Gleason score. SARI and E-cadherin expression in the prostate cancer tissue was significantly lower than in the benign prostatic hyperplasia specimens, suggesting a positive correlation between the SARI and E-cadherin expression. SARI mRNA and protein were highly expressed in RWPE-1, the normal prostate cell line, but SARI mRNA and protein expression were reduced in the prostate cancer cell lines, LNCaP and PC3. Significant differences in the expression were found between the prostate cancer cell lines and the normal prostate cell line. CONCLUSION: In this study, high SARI expression was found to be negatively correlated with the development and progression of prostate cancer.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Neoplasias da Próstata/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Idoso , Western Blotting , Caderinas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Imuno-Histoquímica , Interferons/metabolismo , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Fosfatidilinositol 3-Quinases/metabolismo , Próstata/citologia , Próstata/patologia , Hiperplasia Prostática/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , Fator de Transcrição AP-1/metabolismo , beta Catenina/metabolismo
9.
Life Sci ; 232: 116624, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276689

RESUMO

AIMS: Monocyte-endothelial adhesion is considered to be the primary initiator of inflammatory vascular diseases, such as atherosclerosis. Connexin 43 (Cx43) has been reported to play an important part in this process, however, the underlying mechanisms are not fully understood. Intravenous anesthetics, propofol is commonly used in the perioperative period and in the intensive care unit, and considered to have good anti-inflammatory and antioxidant effects. Thus, we speculate that propofol could influence monocyte-endothelial adhesion, and explore whether its possible mechanism is relative with Cx43 expression in U937 monocytes influencing cell adhesion of U937 monocytes to human umbilical vein endothelial cells (HUVEC). MAIN METHODS: Cx43-siRNAs or pc-DNA-Cx43 were used to alter Cx43 expression in U937 monocytes. Propofol was given as pretreatments to U937 monocytes. Then, cell adhesion, ZO-1, LFA-1, VLA-4, COX and MCP-1 were determined. PI3K/AKT/NF-κB signaling pathway was explored to clarify the possible mechanism. KEY FINDINGS: Alternation of Cx43 expression affects cell adhesion and adhesion molecules significantly, such as ZO-1, LFA-1, VLA-4, COX-2 and MCP-1, the mechanism of which is relative with Cx43 influencing the activation of PI3K/AKT/NF-κB signaling pathway. Preconditioning with propofol at its clinically relevant anesthesia concentration attenuates cell adhesion. Propofol not only decreases Cx43 expression in U937 monocytes, but also depresses the activation of PI3K/AKT/NF-κB signaling pathway. SIGNIFICANCE: Modulation Cx43 expression in U937 monocytes could affect cell adhesion via regulating the activation of PI3K/AKT/NF-κB signaling pathway. Propofol attenuates cell adhesion via inhibiting Cx43 and its downstream signaling pathway of PI3K/AKT/NF-κB.


Assuntos
Adesão Celular/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Propofol/farmacologia , Aterosclerose/metabolismo , Moléculas de Adesão Celular/metabolismo , Conexina 43/efeitos dos fármacos , Conexina 43/genética , Conexina 43/metabolismo , Endotélio Vascular/metabolismo , Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Monócitos/fisiologia , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Propofol/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células U937/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo
10.
Chem Biol Interact ; 310: 108726, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31255635

RESUMO

Tetrandrine (TET) and cepharanthine (CEP) are two bisbenzylisoquinoline alkaloids isolated from the traditional herbs. Recent molecular investigations firmly supported that TET or CEP would be a potential candidate for cancer chemotherapy. Prognosis of patients with glucocorticoid resistant T cell acute lymphoblastic leukemia (T-ALL) remains poor; here we examined the anti-T-ALL effects of TET and CEP and the underlying mechanism by using the glucocorticoid resistant human leukemia Jurkat T cell line in vitro. TET and CEP significantly inhibited cell viabilities and induced apoptosis in dose- and time-dependent manner. Further investigations showed that TET or CEP not only upregulated the expression of initiator caspases such as caspase-8 and 9, but also increased the expression of effector caspases such as caspase-3 and 6. As the important markers of apoptosis, p53 and Bax were both upregulated by the treatment of TET and CEP. However, TET and CEP paradoxically increased the expression of anti-apoptotic proteins such as Bcl-2 and Mcl-1, and activated the survival protein NF-κB, leading to high expression of p-NF-κB. Cell cycle arrest at S phase accompanied by increase in the amounts of cyclin A2 and cyclin B1, and decrease in cylcin D1 amount in cells treated with TET or CEP will be another possible mechanism. During the process of apoptosis in Jurkat T cells, treatment with TET or CEP also increased the phosphorylation of JNK and p38. The PI3K/Akt/mTOR signaling pathway modification appears to play significant role in the Jurkat T cell apoptosis induced by TET or CEP. Moreover, TET and CEP seemed to downregulate the expressions of p-PI3K and mTOR in an independent way from Akt, since these two drugs strongly stimulated the p-Akt expression. These results provide fundamental insights into the clinical application of TET or CEP for the treatment of patients with relapsed T-ALL.


Assuntos
Apoptose/efeitos dos fármacos , Benzilisoquinolinas/farmacologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Benzilisoquinolinas/uso terapêutico , Caspases/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/farmacologia , Humanos , Células Jurkat , Sistema de Sinalização das MAP Quinases , Fosfatidilinositol 3-Quinases/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
11.
Life Sci ; 233: 116696, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31351969

RESUMO

AIMS: To explore the mechanism of how LSD1 regulates autophagy and the correlation between LSD1 and Ox-LDL-induced inflammation. MAIN METHODS: RAW264.7 cells were used during the whole study. Firstly, the effect of Ox-LDL-stimulation on LSD1 expression was detected. Through loss-of-function assay, the associations between LSD1 interference and SESN2 expression, autophagy, NLRP3 inflammasome and inflammatory cytokines were explored. Finally, the function of LSD1 exerted on activation of PI3K/Akt/mTOR signal pathway was detected using western blotting assay. KEY FINDINGS: The expression of LSD1 was significantly elevated in Ox-LDL-treated RAW264.7 cells. Inhibition of LSD1 promoted autophagy, inhibited inflammation and activated NLRP3 inflammasome. SESN2 was elevated by LSD1 inhibition, and thus activate the PI3K/Akt/mTOR signal pathway. What' more, Knockdown of SESN2 or deactivate the PI3K/Akt/mTOR signal pathway partly reversed the effect of LSD1 inhibition on autophagy. SIGNIFICANCE: Our present study drew the finding that the knockdown of LSD1 meliorated Ox-LDL-stimulated NLRP3 activation and inflammation through promoting autophagy via SESN2-mediated PI3K/Akt/mTOR pathway.


Assuntos
Autofagia , Regulação da Expressão Gênica/efeitos dos fármacos , Histona Desmetilases/metabolismo , Inflamação/patologia , Lipoproteínas LDL/efeitos adversos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas Nucleares/metabolismo , Animais , Células Cultivadas , Histona Desmetilases/antagonistas & inibidores , Histona Desmetilases/genética , Inflamação/etiologia , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas Nucleares/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
12.
Adv Exp Med Biol ; 1143: 1-39, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31338813

RESUMO

Hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs) utilize many of the same signaling pathways for their maintenance and survival. In this review, we will focus on several signaling pathways whose roles have been extensively studied in both HSCs and LSCs. Our main focus will be on the PI3K/AKT/mTOR pathway and several of its regulators and downstream effectors. We will also discuss several other signaling pathways of particular importance in LSCs, including the WNT/ß-catenin pathway, the NOTCH pathway, and the TGFß pathway. For each of these pathways, we will emphasize differences in how these pathways operate in LSCs, compared to their function in HSCs, to highlight opportunities for the specific therapeutic targeting of LSCs. We will also highlight areas of crosstalk between multiple signaling pathways that may affect LSC function.


Assuntos
Células-Tronco Hematopoéticas , Células-Tronco Neoplásicas , Transdução de Sinais , Células-Tronco Hematopoéticas/fisiologia , Humanos , Células-Tronco Neoplásicas/fisiologia , Proteína Oncogênica v-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Serina-Treonina Quinases TOR/metabolismo
13.
Gene ; 715: 143995, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31336140

RESUMO

Diabetic cardiomyopathy (DCM) refers to the myocardial dysfunction in the absence of coronary artery disease and hypertension. Recently, the role of microRNAs (miRs) in gene expression regulation has attracted much more attention. Studies have shown that the PI3K/Akt signaling pathway is involved in the growth, metabolism and apoptosis of myocardial cells. Therefore, this study aimed to explore the regulatory role of miR-203 in myocardial fibrosis in mice with DCM via involvement of the PI3K/Akt signaling pathway. Firstly, mouse model of diabetes mellitus (DM) was established and injected with agomir, antagomir or IGF-1 (PI3K/Akt signaling pathway activator) for investigating the role of miR-203 in PIK3CA and the PI3K/Akt signaling pathway. PIK3CA was identified as a target gene of miR-203, and overexpressed miR-203 inhibited the activation of PI3K/Akt signaling pathway. The obtained results indicated that up-regulation of miR-203 reduced myocardial hypertrophy, myocardial fibrosis, myocardial apoptosis, and levels of PIK3CA, PI3K, Akt, CoI I, CoI III, ANP, MDA and ROS in the myocardial tissues, by which DM-induced cardiac dysfunction and pathological changes could be ameliorated. Collectively, our present study highlighted that overexpression of miR-203 may function as a cardioprotective regulator in DCM by targeting PIK3CA via inactivation of PI3K/Akt signaling pathway.


Assuntos
Cardiomiopatias Diabéticas/metabolismo , MicroRNAs/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Regulação para Cima , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Cardiomiopatias Diabéticas/patologia , Fibrose , Camundongos , Miocárdio/patologia
14.
J Agric Food Chem ; 67(32): 8884-8895, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31345029

RESUMO

Leucine is an essential amino acid in the milk production of bovine mammary glands, but the regulatory roles and molecular mechanisms of leucine are still not known well. This study investigated the roles of leucine on milk synthesis and explored the corresponding mechanism in bovine mammary epithelial cells (BMECs). Leucine (0, 0.25, 0.5, 0.75, 1.0, and 1.25 mM) was added to BMECs that were cultured in FBS-free OPTI-MEM medium. Leucine significantly promoted milk protein and milk fat synthesis and also increased phosphorylation of mTOR signaling protein and the protein expression levels of SREBP-1c, with the most significant effects at 0.75 mM concentration. Leucine increased the expression and nuclear localization of DDX59, and loss and gain of gene function experiments further reveal that DDX59 mediates the stimulation of leucine on the mRNA expression variation of mTOR and SREBP-1c genes. PI3K inhibition experiment further detected that leucine upregulated expression of DDX59 and its downstream signaling via PI3K activation. ChIP-qPCR analysis further proved the binding of DDX59 to the promoter regions of mTOR and SREBP-1c. In summary, these data prove that DDX59 positively regulates the mTOR and SREBP-1c signaling pathways leading to synthesis of milk, and leucine regulates these two signaling pathways through the PI3K-DDX59 signaling.


Assuntos
Bovinos/metabolismo , Células Epiteliais/metabolismo , Leucina/metabolismo , Glândulas Mamárias Animais/metabolismo , Leite/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , RNA Helicases/metabolismo , Animais , Bovinos/genética , Feminino , Fosfatidilinositol 3-Quinases/genética , RNA Helicases/genética , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
15.
Biochemistry (Mosc) ; 84(5): 553-561, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31234769

RESUMO

Obesity is accompanied by dyslipidemia, hypoxia, endoplasmic reticulum (ER) stress, and inflammation, representing the major risk factor for the development of insulin resistance (IR) and type 2 diabetes. We modeled these conditions in cultured 3T3-L1 adipocytes and studied their effect on insulin signaling, glucose uptake, and inflammatory response via activation of stress-dependent JNK1/2 kinases. Decreased insulin-induced phosphorylation of the insulin cascade components IRS, Akt, and AS160 was observed under all tested conditions (lipid overloading of cells by palmitate, acute inflammation induced by bacterial lipopolysaccharide, hypoxia induced by Co2+, and ER stress induced by brefeldin A). In all the cases, except the acute inflammation, glucose uptake by adipocytes was reduced, and the kinetics of JNK1/2 activation was bi-phasic exhibiting sustained activation for 24 h. By contrast, in acute inflammation, JNK1/2 phosphorylation increased transiently and returned to the basal level within 2-3 h of stimulation. These results suggest a critical role of sustained (latent) vs. transient (acute) inflammation in the induction of IR and impairment of glucose utilization by adipose tissue. The components of the inflammatory signaling can be promising targets in the development of new therapeutic approaches for preventing IR and type 2 diabetes.


Assuntos
Inflamação , Resistência à Insulina , Obesidade/patologia , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ácidos Graxos não Esterificados/farmacologia , Inflamação/etiologia , Insulina/farmacologia , Lipopolissacarídeos/farmacologia , Camundongos , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Obesidade/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
16.
Chem Biol Interact ; 308: 258-268, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31150630

RESUMO

The reactive oxygen species (ROS) induced oxidative stress is an inevitable factor for the pathogenesis of cardiovascular diseases. The edible marine algae-derived sulfated polysaccharides gained special attention as novel bioactive compounds having potential pharmacological activities. The present study evaluated in vitro and in vivo cardioprotective properties of sulfated polysaccharides from the edible brown marine algae Padina tetrastromatica (PSPS) against isoproterenol (ISO) induced cardiac damage. The cardioprotective properties of PSPS were first evaluated in H9c2 cardiac myoblasts and the results were confirmed by in vivo studies conducted in male Sprague-Dawley rats. The biochemical parameters, histopathological analysis, mRNA expressions, and ELISA studies indicated that PSPS significantly decreased (p < 0.05) the cardiac damage induced by ISO by reducing lipid peroxidation and improving antioxidant status, both in vitro and in vivo, via modulating PI3k/Akt/Nrf2 signaling pathway. The histopathological evidence further reinforced our findings and highlighted the promising cardioprotective activities offered by PSPS.


Assuntos
Isoproterenol/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Feófitas/metabolismo , Polissacarídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Linhagem Celular , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Polissacarídeos/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Sulfatos/química
17.
Gene ; 710: 103-113, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31158447

RESUMO

Epithelial-mesenchymal transition (EMT) symbolizes the predominant program of advanced-stage cancer, it is critical in cancer progression, metastasis, and chemotherapy resistance. In this study, the metastatic properties of nasopharyngeal carcinoma (NPC) cells were evaluated by morphological examination, wound healing assay, migration and invasion assay. Western blotting and qRT-PCR were used to ascertain the expression of markers which were associated with EMT. The effects of miR-205-5p on invasion, migration, EMT and proliferation of NPC cells were evaluated and the molecular mechanisms of their interaction were explored. In this study, we manifested firstly that the expression of miR-205-5p in cisplatin-resistant NPC cell line HNE1/DDP was obviously up-regulated than that in its parental cell line HNE1. Then we analyzed the specific role of miR-205-5p through functional assays by transfecting specific mimics and inhibitors. The results indicated that low expression of miR-205-5p restrained EMT progression of HNE1/DDP cells. Further studies on the mechanism of miR-205-5p manifested that PTEN was a downstream candidate gene of miR-205-5p, down-regulated PTEN expression could counteract the effect of miR-205-5p inhibitors, and the regulation of EMT by miR-205-5p on HNE1/DDP cells depended on the PI3K/AKT signaling pathway. Overall, our results indicated that miR-205-5p was targeting PTEN to regulate EMT through the PI3K/AKT pathway. This study will supply a new treatment target for advanced NPC.


Assuntos
Resistencia a Medicamentos Antineoplásicos , MicroRNAs/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , PTEN Fosfo-Hidrolase/genética , Regulação para Cima , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Cisplatino , Progressão da Doença , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Humanos , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J Agric Food Chem ; 67(25): 7005-7015, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31174423

RESUMO

Amino acids can enhance milk fat synthesis in bovine mammary epithelial cells (BMECs), but the molecular mechanism is not well-known. In this study, we explored the regulatory role and molecular mechanism of lysine (Lys) on milk fat synthesis induced by fatty acids (FAs). We show that Lys dose-dependently affects number of cells and milk fat synthesis, and has more stimulatory effects in the presence of FAs. Lys enhances FA-induced sterol regulatory element binding protein 1c (SREBP-1c) expression and maturation in a fatty-acid-binding protein 5 (FABP5)-dependent manner. We further show that the Lys stimulates FABP5 expression via the GPRC6A (GPCR, class C, group 6, subtype A)-PI3K (phosphatidylinositol 3-kinase) signaling. Lys dose-dependently affects GPRC6A expression and localization at the plasma membrane. In summary, our data reveals that Lys enhances FAs-stimulated SREBP-1c expression and maturation leading to milk fat synthesis via the GPRC6A-PI3K-FABP5 signaling in BMECs.


Assuntos
Bovinos/metabolismo , Células Epiteliais/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Ácidos Graxos/biossíntese , Glândulas Mamárias Animais/metabolismo , Leite/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Bovinos/genética , Gorduras/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Feminino , Lisina , Glândulas Mamárias Animais/citologia , Fosfatidilinositol 3-Quinases/genética , Receptores Acoplados a Proteínas-G/genética , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
19.
Biomed Environ Sci ; 32(4): 272-280, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31217063

RESUMO

OBJECTIVE: To explore the protective effect of NANOG against hydrogen peroxide (H2O2) -induced cell damage in the human hair follicle mesenchymal stem cells (hHF-MSCs). METHODS: NANOG was expressed from a lentiviral vector, pLVX-IRES-ZsGreen. NANOG hHF-MSCs and vector hHF-MSCs were treated with 400 µmol/L hydrogen peroxide (H2O2) for 2 h, the cell survival rate, cell morphology, ROS production, apoptosis and expression of AKT, ERK, and p21 were determined and compared. RESULTS: Our results showed that NANOG could activate AKT and upregulate the expression of p-AKT, but not p-ERK. When treated with 400 µmol/L H2O2, NANOG hHF-MSCs showed higher cell survival rate, lower ROS production and apoptosis, higher expression of p-AKT, higher ratio of p-AKT/AKT. CONCLUSION: Our results suggest that NANOG could protect hHF-MSCs against cell damage caused by H2O2 through activating AKT signaling pathway.


Assuntos
Folículo Piloso/citologia , Células-Tronco Mesenquimais/metabolismo , Proteína Homeobox Nanog/metabolismo , Sobrevivência Celular , Avaliação Pré-Clínica de Medicamentos , Humanos , Peróxido de Hidrogênio , Lentivirus , Células-Tronco Mesenquimais/efeitos dos fármacos , Proteína Homeobox Nanog/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
20.
Eur J Med Chem ; 178: 667-686, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31228810

RESUMO

PI3K/Akt/mTOR signaling pathway plays an important role in cancer cell growth and survival. In this study, a new class of molecules with skeleton of 4-phenyl-2H-benzo[b] [1,4]oxazin-3(4H)-one were designed and synthesized targeting this pathway. Bioassays showed that, among all the molecules, 8d-1 was a pan-class I PI3K/mTOR inhibitor with an IC50 of 0.63 nM against PI3Kα. In a wide panel of protein kinases assays, no off-target interactions of 8d-1 were identified. 8d-1 was orally available, and displayed favorable pharmacokinetic parameters in mice (oral bioavailability of 24.1%). In addition, 8d-1 demonstrated significant efficiency in Hela/A549 tumor xenograft models (TGI of 87.7% at dose of 50 mg/kg in Hela model) without causing significant weight loss and toxicity during 30 days treatment. Based on the bioassays, compound 8d-1 could be used as an anti-cancer drug candidate.


Assuntos
Antineoplásicos/farmacologia , Benzoxazinas/farmacologia , Descoberta de Drogas , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Benzoxazinas/administração & dosagem , Benzoxazinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismo
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