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1.
Anticancer Res ; 40(1): 229-238, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892571

RESUMO

BACKGROUND/AIM: We previously reported the potential of aminonaphthoquinone derivatives as therapeutic agents against breast and other oestrogen-responsive tumours when combined with curcumin. This study aimed at screening of novel aminonaphthoquinone derivatives (Rau 008, Rau 010, Rau 015 and Rau 018) combined with curcumin for cytotoxic, anti-angiogenic and anti-metastatic effects on MCF-7 and MDA-MB-231 breast cancer cells. MATERIALS AND METHODS: Cytotoxic and anti-angiogenic effects were analysed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and enzyme-linked immunosorbent assay; while anti-metastatic effects were measured using adhesion assay, Boyden chambers and Matrigel. RESULTS: Curcumin combined with Rau 008 elicited marked cytotoxic effects in MCF-7 cells compared with the individual treatments, whereas when it was combined with Rau 015 and with Rau 018, it displayed similar effects in MDA-MB-231 cells. The anti-angiogenic effect of Rau 015 plus curcumin in MCF-7 cells and Rau 018 plus curcumin in MDA-MB-231 cells was more effective than individual treatments, while the metastatic capability of MDA-MB-231 cells was significantly reduced after treatment with the aminonaphthoquinone-curcumin combinations. CONCLUSION: Aminonaphthoquinones may offer significant promise as therapeutic agents against breast cancer, particularly when combined with curcumin.


Assuntos
Neoplasias da Mama/patologia , Curcumina/farmacologia , Progressão da Doença , Naftoquinonas/farmacologia , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/tratamento farmacológico , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcumina/química , Curcumina/uso terapêutico , Matriz Extracelular/metabolismo , Feminino , Humanos , Células MCF-7 , Naftoquinonas/química , Invasividade Neoplásica , Neovascularização Patológica/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/metabolismo
2.
Medicine (Baltimore) ; 98(51): e18333, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31860985

RESUMO

To determine characteristics of diabetic macular edema patients with serous retinal detachment (SRD).We classified naïve diabetic macular edema (DME) patients with or without SRD, and compared their baseline characteristics; intravitreal bevacizumab (IVB) responsiveness; aqueous concentrations of IL (interleukin)-1ß, -2, -8, -10, -17, placental growth factor (PlGF), and vascular endothelial growth factor (VEGF). In addition, factors associated with the existence of SRD were identified.Of the 64 DME patients, 14 had SRD. The average levels of aqueous VEGF and PlGF were significantly higher in the SRD group than in the control group (P = .022 and P = .041, respectively). The best-corrected visual acuity (BCVA) and central subfield thickness (CST) did not differ significantly between the 2 groups at baseline or after 3 consecutive monthly IVBs. In multivariate logistic regression analysis, the level of aqueous VEGF was the only factor associated with the existence of SRD (odds ratio: 1.03; P = .038).Rather than aqueous inflammatory cytokines, levels of aqueous VEGFs were associated with the occurrence of SRD in DME patients. In terms of prognosis, the existence of SRD was not related with BCVA or CST changes.


Assuntos
Humor Aquoso/metabolismo , Bevacizumab/uso terapêutico , Retinopatia Diabética/tratamento farmacológico , Edema Macular/tratamento farmacológico , Descolamento Retiniano/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Estudos de Casos e Controles , Retinopatia Diabética/metabolismo , Feminino , Humanos , Interleucina-1beta/metabolismo , Injeções Intravítreas , Edema Macular/metabolismo , Masculino , Pessoa de Meia-Idade , Fator de Crescimento Placentário/metabolismo , Prognóstico , Retina/patologia , Descolamento Retiniano/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Acuidade Visual/efeitos dos fármacos
3.
Bull Cancer ; 106(11): 946-958, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31711572

RESUMO

AIM: A HER2-specific second-generation chimeric antigen receptor (5.137.z) was introduced into NK-92 cells, designated as NK-92/5.137.z cells. To evaluate the function and effectiveness of NK-92/5.137.z cells against gastric cancer cells and further determined whether combination with apatinib can synergize with this NK cell-based practice to better suppress gastric cancer. METHODS: The expression of HER2 was examined in gastric cancer. The in vitro and in vivo cytotoxic activities of NK-92/5.137.z cells with or without apatinib were evaluated against gastric cancer cell lines. RESULTS: HER2 proteins were over-expressed in a considerable proportion of gastric cancer cells. NK-92/5.137.z cells specifically lysed gastric cancer cells expressing HER2 and had higher levels of cytokine production. In vivo, NK-92/5.137.z cells were particularly efficient at eliminating small tumor xenografts, whereas larger solid tumors were not effectively controlled with NK-92/5.137.z cells. Treatment with apatinib increased NK cell infiltration into large tumor xenografts and improved the therapeutic efficacy of NK-92/5.137.z cells. CONCLUSION: NK-92/5.137.z cells could represent a novel treatment option for patients with gastric cancer, either used alone or combined with apatinib.


Assuntos
Antineoplásicos/uso terapêutico , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/imunologia , Piridinas/uso terapêutico , Receptor ErbB-2/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Neoplasias Gástricas/terapia , Animais , Antígeno CD56/metabolismo , Degranulação Celular , Linhagem Celular Tumoral , Terapia Combinada/métodos , Xenoenxertos , Humanos , Células Matadoras Naturais/fisiologia , Células Matadoras Naturais/transplante , Lentivirus , Camundongos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Carga Tumoral , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(9): 828-831, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31750826

RESUMO

Objective To investigate the correlations between the expression of vascular endothelial growth factor (VEGF) and thrombospondin 1 (TSP-1) in breast cancer and the prognosis. Methods Immunohistochemical staining was used to detect the expression of VEGF and TSP-1 in 160 cases of breast cancer tissues and adjacent tissues, and the relationships between them were analyzed. Results The expression of TSP-1 significantly decreased and the expression of VEGF significantly increased in breast cancer tissues. Low expression of TSP-1 and high expression of VEGF were significantly associated with high clinical stage, poor differentiation, and lymph node metastasis. After 3 years of follow-up, the recurrence rate was 15.6%. Spearman rank correlation analysis showed that there was a positive correlation between the prognosis recurrence rate and the positive expression rate of VEGF (r=0.459), but negatively correlated with the positive expression rate of TSP-1 (r=-0.543). Logistic regression analysis showed that TSP-1 positive expression rate, VEGF positive expression rate, lymph node metastasis and clinical stage were the main independent risk factors for prognosis and recurrence. Conclusion The high expression of VEGF and the low expression of TSP-1 in breast cancer tissues are significantly correlated with the main clinical features. The recurrence rate of patients with high expression of VEGF and low expression of TSP is high.


Assuntos
Neoplasias da Mama/diagnóstico , Trombospondina 1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Neoplasias da Mama/metabolismo , Feminino , Humanos , Recidiva Local de Neoplasia , Prognóstico
5.
J Photochem Photobiol B ; 201: 111634, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31715551

RESUMO

Skin Flap is used in reconstructive plastic surgery. However, complications such as ischemia followed by local necrosis may occur, requiring a new surgical procedure. It is well known that photobiomodulation therapy (PBMT) is an effective technique for improving microcirculation and neoangiogenesis, which contributes positively to the blood supply in the pre and post surgical period. Thus, the objective of the present study was to investigate the effects of preemptive treatment with laser PBMT with different energies on the viability in skin flaps in rats. Sixty-three Wistar rats, male, were randomized into five groups: Control Group (CG) (n = 15): PBMT simulation; Preemptive group 1.1 J laser (GP1) (n = 15): preemptive laser PBMT with 1.1 J of energy per point; Preemptive group 4 J laser (GP4) (n = 15): preemptive PBMT with 4 J of energy per point; Laser group 11 J (G1) (n = 9): PBMT immediately after surgery with 1.1 J of energy per point; Laser group 4 J (G4) (n = 9): TFMB immediately after surgery with 4 J of energy per point. The CG, GP1 and GP4 groups started treatment 72 h prior to surgery and were subdivided into two experimental periods, one of them on the day of the flap and the other along with the other groups on the seventh postoperative day. Three days after the randomization, the animals underwent random skin flap surgery. PBMT was performed with a 660 nm laser at three points. In the first experimental period, a greater number of vessels were found, as well as mast cells in GP1 compared to the CG and greater expression of fibroblast growth factor and vascular endothelial growth factor in the GP1 and GP4 groups compared to the CG. In the second experimental period, GP1 presented a lower percentage of necrotic tissue, a higher number of vessels and a percentage of cells labeled with both VEGF and hypoxia indicible factor alpha (HIF-1α) compared to the CG, FGF in GP1, GP4 and G4 when compared to the CG. Thus, it was concluded that preemptive treatment with PBMT with the application of 1.1 J of energy per point is effective in improving the viability of the skin flap.


Assuntos
Lasers Semicondutores , Retalhos Cirúrgicos/patologia , Animais , Vasos Sanguíneos/patologia , Vasos Sanguíneos/efeitos da radiação , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Mastócitos/citologia , Mastócitos/metabolismo , Mastócitos/efeitos da radiação , Necrose , Distribuição Aleatória , Ratos , Ratos Wistar , Retalhos Cirúrgicos/irrigação sanguínea , Fator A de Crescimento do Endotélio Vascular/metabolismo
6.
Cell Physiol Biochem ; 53(5): 832-850, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31703162

RESUMO

BACKGROUND/AIMS: Runt-related transcription factor 2 (Runx2) is a master regulator of osteogenic differentiation, but most of the direct downstream targets of RUNX2 during osteogenesis are unknown. Likewise, High-temperature requirement factor A1 (HTRA1) is a serine protease expressed in bone, yet the role of Htra1 during osteoblast differentiation remains elusive. We investigated the role of Htra1 in osteogenic differentiation and the transcriptional regulation of Htra1 by RUNX2 in primary mouse mesenchymal progenitor cells. METHODS: Overexpression of Htra1 was carried out in primary mouse mesenchymal progenitor cells to evaluate the extent of osteoblast differentiation. Streptavidin agarose pulldown assay, chromatin immunoprecipitation assay, and dual luciferase assay were carried out to investigate the interaction of RUNX2 protein at the Htra1 promoter during osteoblast differentiation. RESULTS: Overexpression of Htra1 increased the production of mineralized bone matrix, upregulating several osteoblast genes, such as Sp7 transcription factor (Sp7) and Alkaline phosphatase, liver/bone/kidney (Alpl). In addition, Htra1 upregulated osteogenesis-related signalling genes, such as Fibroblast growth factor 9 (Fgf9) and Vascular endothelial growth factor A (Vegfa). A series of experiments confirmed Htra1 as a direct RUNX2 transcriptional target. Overexpression of Runx2 resulted in the upregulation of Htra1 mRNA and protein. Chromatin immunoprecipitation and streptavidin agarose pull-down assays showed that RUNX2 binds a proximal -400 bp region of the Htra1 promoter during osteogenic differentiation. Dual luciferase assays confirmed that RUNX2 activates the proximal Htra1 promoter during osteogenic differentiation. Mutation of putative RUNX2 binding sites revealed that RUNX2 interacts with the Htra1 promoter at -252 bp and -84 bp to induce Htra1 expression. CONCLUSION: We demonstrate that Htra1 is a positive regulator of osteogenic differentiation, showing for the first time that Htra1 is a direct downstream target of RUNX2.


Assuntos
Diferenciação Celular , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Serina Peptidase 1 de Requerimento de Alta Temperatura A/metabolismo , Animais , Sítios de Ligação , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Fator 9 de Crescimento de Fibroblastos/metabolismo , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Osteogênese , Regiões Promotoras Genéticas , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
Artigo em Chinês | MEDLINE | ID: mdl-31623040

RESUMO

Objective:To explore the signal pathway that mediates the effect of 2-methoxyestradiol(2ME2) on human laryngeal papilloma cell line, in terms of cell proliferation and neovascularization. Method:HIF-1α expression of human laryngeal papilloma cell line(Hs840. T) was interfered using siRNA, and the cells were then processed by 2ME2 in two concentrations. RT-PCR and ELISA were performed to detect the difference of HIF-1α in cells with normal or lower HIF-1α mRNA level, with ELISA test of excretory VEGF level and CCK8 test of cell viability. Result:The IC50of 2ME2 in Hs840. T was 0.309 µmol/L in terms of the inhibition effect of cell proliferation(P<0.01). Baseline level of intracellular HIF-1α was detectable, and procession of Hs840. T cells by 2ME2 of 0.4 µmol/L inhibited the transcription and expression of HIF-1α by(76.8±2.0)% and(68.6±3.5)% [vs blank group(100.0±2.7)% and(100.0±6.9)%, P<0.01]. VEGF excretion decreased to(50.8±2.1) and(28.1±4.0)% [vs blank group(100.0±3.1)%, P<0.01]after procession by 2ME2 of 0.2 µmol/L and 0.4 µmol/L. After the successful interference of HIF-1α by siRNA, the inhibition effect on cell proliferation by 2ME2 of 0.4 µmol/L decreased to(51.5±3.8)% [vs control group(65.7±1.7)%, P<0.01]. siRNA interference of HIF-1α lead to a decrease of HIF-α mRNA and protein level to(16.3±0.9)% and(7.4±0.8)% [vs cells not interfered(76.8±2.0)% vs(68.6±3.5)%, P<0.01]. Secretory VEGF dropped to(41.0±2.9)% [vs cells not interfered(28.1±4.0)%, P<0.05]. Conclusion:2ME2 has a significant inhibitory effect on human laryngeal cell line. The inhibition of cell proliferation was mediated by a lower level of HIF-1α and therefore lower VEGF. 2ME2 might serve as a novel potential therapy for patients of recurrent respiratory papillomatosis.


Assuntos
2-Metoxiestradiol/metabolismo , Linhagem Celular Tumoral , Estradiol , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Laríngeas , Papiloma , Fator A de Crescimento do Endotélio Vascular/metabolismo
8.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3520-3525, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602917

RESUMO

The effect of triptolide( TP) on VEGFA,SDF-1,CXCR4 pathway were investigated in vitro to explore the mechanism in improving platelet activation in patients with ankylosing spondylitis( AS). Peripheral blood mononuclear cells( PBMC) were used for the experiment and divided into 4 groups: normal group( NC),model group( MC),triptolide group( TP),and AMD3100 group. The optimal concentration of TP was measured by the MTT method. The expressions of TNF-α,IL-1ß,IL-4,IL-10,VEGFA and VEGFR were detected by ELISA. The expressions of SDF-1,CXCR4 and VEGFA were detected by real-time quantitative PCR( RT-qPCR).The expressions of SDF-1,CXCR4,VEGFA and VEGFR were detected by Western blot. The expression levels of CD62 p,CD40 L and PDGFA were detected by immunofluorescence. MTT results showed that medium-dose TP had the strongest inhibitory effect on cells at24 h. The results of ELISA and PCR showed that TP inhibited mRNA expressions of IL-1ß,TNF-α,VEGFA,VEGFR and SDF-1,CXCR4 and VEGFA. The results of Western blot indicated that TP inhibited SDF-1,CXCR4 and VEGFA,VEGFR protein expressions; immunofluorescence results indicate that TP can inhibit the expressions of CD62 p,CD40 L,PDGFA. TP may regulate platelet activation by down-regulating SDF-1,CXCR4,VEGFA and VEGFR mRNA expressions,thereby down-regulating IL-1ß and TNF-αexpressions,and up-regulating the expressions of IL-4 and IL-10 cytokines.


Assuntos
Diterpenos/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Fenantrenos/farmacologia , Ativação Plaquetária , Espondilite Anquilosante , Células Cultivadas , Quimiocina CXCL12/metabolismo , Citocinas/metabolismo , Compostos de Epóxi/farmacologia , Compostos Heterocíclicos/farmacologia , Humanos , Receptores CXCR4/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
9.
Zhonghua Shao Shang Za Zhi ; 35(9): 683-689, 2019 Sep 20.
Artigo em Chinês | MEDLINE | ID: mdl-31594187

RESUMO

Objective: To explore the effects of autologous platelet-rich plasma (PRP) in the repair of soft tissue defects of rabbits with free flap. Methods: Thirty 6-month-old New Zealand white rabbits, male and female unlimited, were used to harvest blood from the heart. PRP was prepared by Aghaloo method, then free flap model with size of 5 cm×3 cm was reproduced on each ear of the rabbit. According to the random number table, one ear of each rabbit was recruited to PRP group, and the other ear was recruited to normal saline group. The base of flap on rabbit ear in PRP group was evenly spread with 1.0 mL autologous PRP, and equivalent volume of normal saline was applied to that in normal saline group. Then, the flap was replanted in situ. On post surgery day (PSD) 2, 3, 5, 7, and 14, 6 rabbits in each group were taken. The survival of flap was observed and recorded. The morphology of the basal tissue of flap was observed by hematoxylin-eosin staining. The expressions of CD31 and α smooth muscle actin (α-SMA) in the basal tissue of flap were detected by immunofluorescence method. Another 6-month-old male New Zealand white rabbit without making flap under the same experimental conditions was used for harvesting whole blood and preparing PRP. Then blood platelet count in whole blood and PRP was determined, and the content of vascular endothelial growth factor (VEGF) and transforming growth factor ß (TGF-ß) was detected by double-antibody sandwich enzyme-linked immunosorbent assay. Data were processed with analysis of variance of factorial design, paired sample t test, and Bonferroni correction. Results: (1) On PSD 2, the flaps of wounds of rabbits in PRP group were reddish and adhered well to the basal tissue; the flaps of wounds of rabbits in normal saline group were dark red and poorly attached to the basal tissue. On PSD 3, the flaps of wounds of rabbits in PRP group were ruddy and closely adhered to the basal tissue; the flaps of wounds of rabbits in normal saline group were scattered in the plaque-like dark red and generally attached to the base. On PSD 5, the flaps of wounds of rabbits in PRP group were reddish and closely adhered to the basal tissue, and the flaps were alive; while flaps of wounds of rabbits in normal saline group were rosy and closely adhered to the basal tissue. On PSD 7, the surface of flaps of wounds of rabbits in PRP group was covered with a medium amount of rabbit hair. The color of flap was similar to that of the surrounding skin. The flaps of wounds of rabbits in normal saline group were generally attached to the base, and the surface was only covered with a small amount of fluff. On PSD 14, the incisions were healed well in PRP group, while small wounds in normal saline group were not healed. (2) On PSD 2, inflammatory cell infiltration was observed in flaps of wounds of rabbits in both groups. On PSD 3, the flaps of wounds of rabbits in PRP group showed neovascularization, with less interstitial hemorrhage; while there were less neovascularization in the flaps of wounds of rabbits in normal saline group. On PSD 5, a medium number of inflammatory cell infiltration and a small amount of new microvessels were observed in flaps of wounds of rabbits in normal saline group. Many fibroblasts, a small amount of inflammatory cells, and scattered new microvessels were observed in flaps of wounds of rabbits in PRP group. On PSD 7, the number of new microvessels in normal saline group was significantly lower than that in PRP group. On PSD 14, the new microvessels in the flaps of wounds of rabbits in PRP group gradually matured, and a large number of fibroblasts distributed around them. Some of the newly formed microvessels in the flaps of wounds of rabbits in normal saline group were mature, and the healing was slower than that of PRP group. (3) On PSD 2, 3, 5, 7, and 14, the expressions of CD31 and α-SMA in the basal tissue of flaps of wounds of rabbits in PRP group were significantly higher than those in normal saline group (t=10.133, 5.444, 9.450, 6.986, 8.394, 14.896, 10.328, 9.295, 13.902, 10.814, P<0.01). (4) The platelet count in activated PRP of rabbits was (2 863±962)×10(9)/L, which was significantly higher than (393±49)×10(9)/L in whole blood (t=7.690, P<0.05). (5) The content of VEGF and TGF-ß in activated PRP of rabbits was (564.3±3.2) and (1 143±251) pg/mL, which was significantly higher than (99.7±0.4) and (274±95) pg/mL in whole blood, respectively (t=287.390, 9.648, P<0.05 or P<0.01). Conclusions: PRP of rabbits contains high concentrations of VEGF and TGF-ß. Therefore, PRP can effectively promote microvascular regeneration in free flap tissue and accelerate the survival of free flap.


Assuntos
Retalhos de Tecido Biológico/transplante , Plasma Rico em Plaquetas , Lesões dos Tecidos Moles/terapia , Cicatrização , Animais , Feminino , Masculino , Coelhos , Fator de Crescimento Transformador beta/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
10.
Anticancer Res ; 39(10): 5483-5494, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570442

RESUMO

BACKGROUND/AIM: Canine mammary gland tumors (CMGTs) are the most common tumors in female dogs. Rivoceranib (also known as apatinib) is a novel anti-angiogenic tyrosine kinase inhibitor that selectively binds to vascular endothelial growth factor receptor-2 (VEGFR2). The aim of this study was to disclose the antitumor effects of rivoceranib on CMGT cell lines. MATERIALS AND METHODS: The direct effects of rivoceranib on CMGT cells in vitro were analyzed by cell proliferation and migration assays. Cell-cycle distribution and apoptotic ratio were analyzed by flow cytometry. Expression levels of phosphorylated VEGFR2 were evaluated by western blot analysis. RESULTS: Rivoceranib treatment significantly reduced the proliferation and migration of CMGT cells in a dose-dependent manner. Flow cytometry results revealed significant increases in G0/G1 phase arrest and apoptosis proportional to the drug concentration used. Rivoceranib reduced the level of phosphorylated VEGFR2. CONCLUSION: We confirm that rivoceranib exerts antitumor effects on CMGT cells by inhibiting biological functions.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cães , Feminino , Fase G1/efeitos dos fármacos , Neoplasias Mamárias Animais/metabolismo , Fosforilação/efeitos dos fármacos , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
11.
Chem Biol Interact ; 314: 108849, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610157

RESUMO

To provide novel insight into approaches designed to combat glioblastoma, the molecular details of the cytotoxicity of gamabufotalin, were investigated in the human glioblastoma cell line U-87. A dose-dependent cytotoxicity was observed in the cells, whereas no detectable toxicity was confirmed in mouse primary astrocytes. LDH leakage was only observed in the cells treated with a relatively high concentration (>80 ng/ml). Downregulation of the expression levels of Aurora B, cdc25A, cdc25C, cdc2, Cyclin B1 and survivin, and upregulation of the expression level of p21 were observed in treated cells and occurred in parallel with G2/M phase arrest. Treatment with gamabufotalin also downregulated the expression level of uPA, CA9, and upregulated the expression level of TIMP3, all of which are closely associated with invasion/metastasis. Autophagy induction was observed in the treated cells and the addition of wortmannin, a potent autophagy inhibitor, significantly rescued U-87 cells. These results indicate that gamabufotalin exhibits cytotoxicity against cancerous glial cells with high potency and selectivity through multiple cytotoxic signaling pathways. The activation of p38 MAPK pathway along with the upregulation of VEGF/VEGFR2 was observed in the treated cells, both of which are likely to be compensatory changes in response to gamabufotalin treatment. Intriguingly, a specific inhibitor of p38 MAPK enhanced the cytotoxicity of the drug, suggesting an important prosurvival role for p38 MAPK. We thus suggest that developing a new combination regimen of gamabufotalin plus a p38 MAPK inhibitor and/or inhibitors for VEGF/VEGFR could improve the efficacy of the drug, and may provide more therapeutic benefits to patients with glioblastoma.


Assuntos
Apoptose/efeitos dos fármacos , Bufanolídeos/farmacologia , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Autofagia/efeitos dos fármacos , Bufanolídeos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Wortmanina/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
Adv Clin Exp Med ; 28(10): 1285-1292, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31647203

RESUMO

BACKGROUND: Interleukin 9 (IL-9) has been implicated in the pathogenesis of several tumor types, but the role of anti-IL-9 in pancreatic cancer remains unclear. OBJECTIVES: We aimed to explore the mechanism and effects of blockading IL-9 in a pancreatic cancer mouse model. MATERIAL AND METHODS: Panc02 cells were injected subcutaneously into mice to establish a mouse model. The mice were randomly categorized into 3 groups - the control group, the immunoglobulin G (IgG) group and the anti-IL-9 group - corresponding to intravenous tail injection of phosphate-buffered saline (PBS), IgG isotype antibody and anti-IL-9 antibody, respectively. Then, the expression of IL-9, interleukin-9 receptor (IL-9r), Janus kinase 1 (Jak1), Jak3, and signal transducer and activator of transcription 3 (Stat3) mRNA was tested with quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Interleukin 9 in the tumor tissue was detected using enzyme-linked immunosorbent assay (ELISA). Western blotting and immunocytochemistry were performed to detect STAT3 and phosphorylation signal transducers and activators of transcription-3 (pSTAT3). Matrix metalloproteinase 2 (MMP2), MMP9 and vascular endothelial growth factor (VEGF) levels were assessed using immunocytochemistry. RESULTS: Tumor weight in the anti-IL-9 group was significantly lower than in the other groups (p < 0.05). There was a remarkable survival benefit in the anti-IL-9 group compared to the other groups (p < 0.05). The concentration of IL-9 in tumor tissue was significantly downregulated in the anti-IL-9-treated mice (p < 0.05). The expression of Jak1 and Jak3 mRNA and pSTAT3, MMP2 and MMP9 proteins in the anti-IL-9 group was lower than that of the PBS or IgG groups (p < 0.05), but the STAT3 and VEGF protein levels showed no significant difference (p < 0.05). CONCLUSIONS: Anti-IL-9 antibody could effectively restrain the growth of pancreatic cancer in mice, and this effect may partly occur by blocking the STAT3 pathway.


Assuntos
Interleucina-9/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Modelos Animais de Doenças , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Distribuição Aleatória , Fator de Transcrição STAT3/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Biol Res ; 52(1): 49, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492195

RESUMO

BACKGROUND: Psoriasis is a common and intractable skin disease affecting the physical and mental health of patients. The accumulation of ROS is involved in the pathogenesis of psoriasis and antioxidants are believed to be therapeutic. This study aimed to investigate the therapeutic efficacy of astilbin on ROS accumulation in psoriasis. RESULTS: The study showed that 50 µg/ml astilbin could inhibit the growth and reduce the accumulation of ROS in HaCaT cells stimulated by IL-17 and TNF-α. Astilbin could elevate the Nrf2 accumulation in the nuclei, eventually leading to the transcriptional activation of various antioxidant proteins and reducing the expression of VEGF. CONCLUSIONS: Our results collectively suggest that astilbin could induce Nrf2 nucleus translocation, which is contribute to reduce the ROS accumulation and VEGF expression, and inhibit the proliferation of HaCaT cells.


Assuntos
Flavonóis/administração & dosagem , Queratinócitos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Psoríase/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Interleucina-17/metabolismo , Queratinócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/metabolismo , Psoríase/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
15.
Int J Nanomedicine ; 14: 6357-6369, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496691

RESUMO

Background: Diabetic retinopathy (DR) is a complication of diabetes that affects the eyes and vision. It is a leading cause of visual impairment and blindness in working-age people. Vascular endothelial growth factor-A (VEGF-A) is a primary initiator and potential mediator of DR. Matrix metalloproteinase-9 (MMP-9) plays a progressive role in the onset and severity of DR. Interleukin-12 (IL-12) is a cytokine of the chemokine family that could reduce the levels of MMP-9 and VEGF-A and suppress tumor angiogenesis. We hypothesize that IL-12 may also have superior therapeutic efficacy against DR. However, protein drugs are prone to degradation by various proteases after drug injection. Therefore, they have short half-lives and low blood concentrations. The objective of this study was to develop IL-12-loaded nanoparticles for long-term and sustained DR treatment. Methods: IL-12-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (IL-12-PNP) were developed by double emulsion. The characteristics, anti-DR activity, and mechanisms of IL-12-PNP were examined in vitro and in vivo. Results: The nanoparticles had suitable particle size (~132.8 nm), drug encapsulation efficiency (~34.7%), and sustained drug release profile. Compared with IL-12 and blank nanoparticles, IL-12-PNP showed better inhibitory efficacy against VEGF-A and MMP-9 expression in rat endothelial cells and DR mouse retina. Intraocular IL-12-PNP administration significantly reduced retinal damage in DR mice as they presented with increased thickness and decreased neovascularization after treatment. Conclusion: These data indicate that IL-12-PNP is an effective drug delivery platform for DR therapy. It restores the thickness and reduces neovascularization of the retinas of DR mice.


Assuntos
Retinopatia Diabética/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Interleucina-12/administração & dosagem , Interleucina-12/uso terapêutico , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Preparações de Ação Retardada/farmacologia , Retinopatia Diabética/patologia , Células Endoteliais/metabolismo , Injeções Intravítreas , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Nanopartículas/ultraestrutura , Neovascularização Patológica/tratamento farmacológico , Ratos Sprague-Dawley , Retina/efeitos dos fármacos , Retina/metabolismo , Retina/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
16.
Chem Biol Interact ; 312: 108816, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31505164

RESUMO

Indirubins E804 (indirubin-3'-(2,3 dihydroxypropyl)-oximether) and 7BIO (7-Bromoindirubin-3'-oxime) are synthetic derivatives of natural indirubin, the active compound in Danggui Longhui Wan, a traditional Chinese remedy for cancer and inflammation. Herein, we explore E804 and 7BIO for their potential to modulate key pro-inflammatory genes and cytokines in LN-18 and T98G glioblastoma cells. High grade gliomas typically secrete large amounts of inflammatory cytokines and growth factors that promote tumor growth in an autocrine fashion. Inflammation is emerging as a key concern in the success of new treatment modalities for glioblastomas. Studies indicate that select indirubin derivatives bind and activate signaling of the AHR pathway, as well as inhibit cyclin-dependent kinases and STAT3 signaling. AHR signaling is involved in hematopoiesis, immune function, cell cycling, and inflammation, and thus may be a possible target for glioma treatment. To determine the significance of the AHR pathway in LN-18 and T98G glioma inflammatory profiles, and on the effects of E804 and 7BIO on these profiles, we used 6,2',4'-trimethoxyflavone (TMF), a putative selective AHR antagonist. It was confirmed that E804 and 7BIO activates the AHR leading to cyp1b1 expression, and that TMF antagonizes expression. We then employed a commercial cancer inflammation and immunity crosstalk qRT-PCR array to screen for anti-inflammatory related properties. TMF alone inhibited expression of ifng, ptsg2, il12b, tnfa, il10, il13, the balance between pd1 and pdl1, and even expression of mhc1a/b. E804 was very potent in suppressing many pro-inflammatory genes, including il1a, il1b, il12a, ptgs2, tlr4, and others. E804 also affected expression of il6, vegfa, and stat3. Conversely, 7BIO induced cox2, but suppressed a different selection of pro-inflammatory genes including nos2, tnfa, and igf1. Secretion of IL-6 protein, an iconic inflammatory cytokine, was decreased by E804. VEGF (vascular endothelial growth factor) protein secretion was upregulated by 7BIO, yet downregulated by E804 and E804 plus TMF. Thus, E804 is both an AHR ligand and regulator of important pro-inflammatory cytokines such as IL-6 and oncogene STAT3, among others. Our results point to the use of E804 and TMF in combination as a promising new treatment for glioblastoma.


Assuntos
Indóis/farmacologia , Oximas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Citocinas/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Indóis/química , Oximas/química , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
17.
J Biol Regul Homeost Agents ; 33(5): 1451-1463, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31507151

RESUMO

Gliomas represent over 50% of tumors occurring in children. Evidence suggests that glioma stem cells (GSCs), maintained by the transforming growth factor-beta (TGF-ß1) pathway, and vascularization substantially contribute to tumor aggressiveness. The identification of important angiogenic factors such as vascular endothelial growth factor (VEGF) may represent a crucial step in the therapeutic approach against tumor growth and metastatic diffusion. The aim of this study was to identify the expression of TGF-ß1, VEGF and VEGF-receptors in brain gliomas. Specimens of 16 gliomas and 4 controls from children aged 0.2-14 years were used in the study. Immunohistochemical analysis and gene expression study from specimens was performed. Flow cytometry analysis on GSCs was performed to ascertain the expression of VEGF and VEGF-R2 in the tumor stem cell compartment. Newly diagnosed gliomas mainly showed moderate to strong VEGF immunostaining and increased expression of pro-inflammatory molecules in glioma cells. The proportion of TGF-ß1 positive endothelial cells was markedly lower in normal brain vessels compared to tumor vessels. These findings demonstrate that the glioma mass is constituted by a phenotypically immature anoxic central area with a proliferating hypoxic layer; the peripheral area is characterized by cell types with a higher degree of differentiation expressing pro-angiogenic factors. Our data have proven that GSCs play a central role in promoting glioma neovascularization. These findings are useful to understand glioma vascularization, have relevant implications in the therapeutic options and may favor new insights into stem cells biology and suggest therapeutic opportunities for the anti-vascular treatment strategy.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Células-Tronco Neoplásicas/citologia , Neovascularização Patológica , Fator de Crescimento Transformador beta1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adolescente , Encéfalo , Criança , Pré-Escolar , Células Endoteliais , Citometria de Fluxo , Imunofluorescência , Humanos , Lactente , Reação em Cadeia da Polimerase Via Transcriptase Reversa
18.
Pol J Pathol ; 70(2): 84-90, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31556558

RESUMO

The purpose of the study is to investigate the clinicopathological and prognostic features of dual hypoxia-inducible factor 1a (HIF-1a) and vascular endothelial growth factor (VEGF) expression in oesophageal squamous cell carcinoma (OSCC) patients. A total of 73 patients were enrolled in this study. The positive expression of HIF-1a was identified in 69.9% of the cases. Hypoxia-inducible factor 1a expression was correlative with pT (p = 0.008) and pTNM stage (p = 0.002). The positive expression of VEGF was identified in 63.0% of the cases. Vascular endothelial growth factor expression was correlative with pT (p = 0.005), pN (p = 0.045), and pTNM stage (p < 0.05). HIF-1a and VEGF expressions had a significantly positive correlation (p = 0.010). Dual positive expression of HIF-1a and VEGF was identified in 50.7% (37/73) of the cases, and it was significantly correlative with pT (p = 0.025), pN (p = 0.008), and pTNM stage (p = 0.014). The OSCC patients' 5-year survival rate was correlative with pT (p < 0.05), pN (p < 0.01), pTNM stage (p < 0.01), VEGF expression (p < 0.01), and dual expressions of HIF-1a and VEGF (p < 0.01). Cox regression analysis showed that pN and dual HIF-1a and VEGF expression were independent prognostic factors for the 5-year survival rate of the patients. In conclusion, HIF-1a combined with VEGF could enable us to more accurately predict the prognosis of OSCC patients.


Assuntos
Carcinoma de Células Escamosas/diagnóstico , Neoplasias Esofágicas/diagnóstico , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Humanos , Prognóstico
20.
J Agric Food Chem ; 67(37): 10321-10329, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31419115

RESUMO

Pterostilbene (PTS) is a phenolic compound with diverse pharmacologic activities. However, its potential for inhibiting obesity-related colorectal cancer (CRC) remains unclear. Our study evaluated the mechanism of inhibitory effects of PTS on adipocyte conditioned-medium (aCM)-induced malignant transformation in HT-29 colorectal adenocarcinoma cells. The results demonstrated that PTS could downregulate the expression of aCM-induced fatty acid-binding protein 5 (FABP5) and prometastatic factors such as vascular endothelial growth factor, matrix metalloproteinase-2 (MMP2), MMP9, and extracellular tumor necrosis factor α via inhibiting aCM-induced nuclear factor-kappa B (NF-κB), ß-catenin, and peroxisome proliferator-activated receptor γ (PPAR-γ). Moreover, PTS can suppress aCM-stimulated phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinases 1/2 (JNK 1/2) signaling pathways activation that are upstream of NF-κB, ß-catenin, and PPAR-γ. Therefore, we suggest that PTS could alleviate adiposity-induced metastasis in CRC via inhibiting cell migration through downregulating FABP5 gene expression.


Assuntos
Adipócitos/metabolismo , Movimento Celular/efeitos dos fármacos , Neoplasias Colorretais/fisiopatologia , Meios de Cultivo Condicionados/química , Proteínas de Ligação a Ácido Graxo/metabolismo , Estilbenos/farmacologia , Células 3T3 , Animais , Linhagem Celular , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Meios de Cultivo Condicionados/metabolismo , Regulação para Baixo/efeitos dos fármacos , Proteínas de Ligação a Ácido Graxo/genética , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
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