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1.
Eur J Med Chem ; 187: 111904, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31806537

RESUMO

Aiming to develop potent autotaxin (ATX) inhibitors for fibrosis diseases, a novel series of tetrahydropyrido[4,3-d]pyrimidine derivatives was designed and synthesized based on our previous study. The enzymatic assay combined with anti-proliferative activities against cardiac fibroblasts (CFs) and hepatic stellate cell (HSC) in vitro were applied for preliminary evaluation of anti-fibrosis potency of target compounds, resulting in two outstanding ATX inhibitors 8b and 10g with the IC50 values in a nanomolar range (24.6 and 15.3 nM). Differently, 8b was the most prominent compound against CFs with inhibition ratio of 81.5%, while 10g exhibited the maximum inhibition ratio of 83.7% against t-HSC/Cl-6 cells. In the further pharmacological evaluations in vivo, collagen deposition assay demonstrated the conspicuous capacity of 8b to suppress TGF-ß-mediated cardiac fibrosis. Simultaneously, H&E and Masson stains assays of mice liver validated 10g as an excellent anti-hepatofibrosis candidate, which reduced CCl4-induced hepatic fibrosis level prominently. Besides, the molecular binding models identified the essential interactions between 8b and ATX which was coincided with the SARs.

2.
Am J Physiol Heart Circ Physiol ; 318(1): H165-H180, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31834839

RESUMO

Normal pregnancy involves extensive remodeling of uterine and spiral arteries and matrix metalloproteinases (MMPs)-mediated proteolysis of extracellular matrix (ECM). Preeclampsia is characterized by hypertension in pregnancy (HTN-Preg) and intrauterine growth restriction (IUGR) with unclear mechanisms. Initial faulty placentation and reduced uterine perfusion pressure (RUPP) could release cytoactive factors and trigger an incessant cycle of suppressed trophoblast invasion of spiral arteries, further RUPP, and progressive placental ischemia leading to HTN-Preg and IUGR; however, the extent and depth of uterine vascularization and the proteolytic enzymes and ECM proteins involved are unclear. We hypothesized that HTN-Preg involves decreased uterine vascularization and arterial remodeling by MMPs and accumulation of ECM collagen. Blood pressure (BP) and fetal parameters were measured in normal Preg rats and RUPP rat model, and the uteri were assessed for vascularity, MMP levels, and collagen deposition. On gestational day 19, BP was higher, and the uterus weight, litter size, and pup weight were reduced in RUPP vs. Preg rats. Histology of uterine tissue sections showed reduced number (5.75 ± 0.95 vs. 11.50 ± 0.87) and size (0.05 ± 0.01 vs. 0.12 ± 0.02 mm2) of uterine spiral arterioles in RUPP vs. Preg rats. Immunohistochemistry showed localization of endothelial cell marker cluster of differentiation 31 (CD31) and smooth muscle marker α-actin in uterine arteriolar wall and confirmed decreased number/size of uterine arterioles in RUPP rats. The cytotrophoblast marker cytokeratin-7 showed less staining and invasion of spiral arteries in the deep decidua of RUPP vs. Preg rats. Uterine arteries showed less expansion in response to increases in intraluminal pressure in RUPP vs. Preg rats. Western blot analysis, gelatin zymography, and immunohistochemistry showed decreases in MMP-2 and MMP-9 and increases in the MMP substrate collagen-IV in uterus and uterine arteries of RUPP vs. those in Preg rats. The results suggest decreased number, size and expansiveness of spiral and uterine arteries with decreased MMP-2 and MMP-9 and increased collagen-IV in HTN-Preg. Decreased uterine vascularization and uterine arterial expansive remodeling by MMPs could be contributing mechanisms to uteroplacental ischemia in HTN-Preg and preeclampsia.NEW & NOTEWORTHY Preeclampsia is a pregnancy-related disorder in which initial inadequate placentation and RUPP cause the release of cytoactive factors and trigger a ceaseless cycle of suppressed trophoblast invasion of spiral arteries, further RUPP, and progressive placental ischemia leading to HTN-Preg and IUGR; however, the extent/depth of uterine vascularization and the driving proteolytic enzymes and ECM proteins are unclear. This study shows decreased number, size, and expansiveness of uterine spiral arteries, with decreased MMP-2 and MMP-9 and increased collagen-IV in HTN-Preg rats. The decreased uterine vascularization and uterine arterial expansive remodeling by MMPs could contribute to progressive uteroplacental ischemia in HTN-Preg and preeclampsia.

3.
Bioorg Med Chem ; 27(20): 115051, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31492532

RESUMO

The pyrimidine-2,4-diamine analogs exerted excellent activities in down-regulation of ALK phosphorylation. However, the prevalent drug-resistant site-mutation has gradually prevented the agents from being widely used. Herein, we conducted an exploration of high affinity moiety that bound to the solvent-front region (G1202R located) within the ATP binding site of ALK leading to the synthesis of thirty-five pyrimidine-2,4-diamine derivatives. Among these compounds, urea group was extensively derivatized which finally resulted in the identification of the 'semi-free urea' compound 39. All compounds were assayed cytotoxicity and enzymatic activities and 39 turned out to be the most potent one with IC50 values of 2.1, 0.91, 4.3 and 0.73 nM towards ALKwt, ALKL1196M, ALKG1202R and ROS1, respectively. The performances of 39 on ALK- & ROS1-dependent cell lines were in good accordance with enzymatic activities with IC50 values below 0.06 µM. Besides, 39 induced cell apoptosis in a dose-dependent manner in H2228 cells. Finally, the binding models of 39 with ALKwt, ROS1, ALKL1196M and ALKG1202R were ideally established which further clearly elucidated their mode of action within the active site.

4.
Bioorg Med Chem ; 27(18): 4089-4100, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31378597

RESUMO

Aiming to develop potent JAK inhibitors, two series of 4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine derivatives (8a-8p and 11a-11i) were designed and synthesized by coalescing various N-acylpiperidine motifs with baricitinib. The pharmacological results based on enzymatic and cellular assays identified the optimized compound 11e, which exerted over 90% inhibition rates against JAK1 and JAK2, and displayed the most compelling anti-inflammatory efficacy superior to baricitinib by inhibiting NO generation from LPS-induced RAW264.7 macrophages. Importantly, low cytotoxity of 11e was revealed by the IC50 value of 88.2 µM against normal RAW264.7 cells. The binding mode of 11e with JAK1 and JAK2 identified the essential structural bases in accord with SARs analysis. Furthermore, cellular morphology observation and western blot analysis disclosed the ability of 11e to relieve cells inflammatory damage by significantly down-regulating LPS-induced high expression of JAK1, JAK2, as well as pro cytokine IL-1ß. Together, 11e was verified as a promising lead for JAK inhibitors for the treatment of inflammatory diseases.

5.
Cancer Biomark ; 24(3): 371-382, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30883337

RESUMO

Lung cancer is a malignant tumor with high morbidity and mortality, of which 80% is non-small cell lung cancer (NSCLC). And lung adenocarcinoma (LUAD) is the most important and common subtype in the NSCLC. In current study, the microarray data GSE31210 containing LUAD (n= 226) and normal lung tissue (n= 20) was analyzed to identify 965 differentially expressed genes, on which weighted gene co-expression network analysis was performed. Finally, it was confirmed that there was a significant correlation between brown module and LUAD stage. In the significant module, a total of 54 network hub genes were identified, and six of them were also identified as hub genes of the protein-protein interaction network. In validation, KIF2C showed a higher correlation with disease stage than other hub genes (p< 0.001, R2 = 0.955). Functional enrichment suggests that KIF2C is associated with cell mitosis and cell cycle. Combined with clinicopathological parameters, we found that the high expression of KIF2C is closely related to the relapse and tumor stage of LUAD. Survival analysis showed a significant reduction in overall survival in LUAD patients with high expression of KIF2C. Gene set enrichment analysis (GSEA) also showed that the "cell cycle signaling pathway" and "P53 related pathway" were significantly enriched in LUAD samples with high expression of KIF2C (FDR < 0.05). In conclusion, based on the co-expression analysis, KIF2C was identified in the association with progression and prognosis of LUAD, which might refer a poor prognosis probably by regulating cell cycle signaling pathway.


Assuntos
Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Cinesina/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/mortalidade , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Biologia Computacional , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Cinesina/metabolismo , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas , Transcriptoma
6.
J Cell Biochem ; 120(1): 105-114, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30216488

RESUMO

The correlation between lung cancer tumor markers and sex differences in lung cancer remains a clinical problem that is worthy of further study. This study investigated the significance of the combined detection of 17ß-estrogen (E2) and tumor markers in the diagnosis and prognosis of lung cancer. A total of 174 patients, including 117 patients with non-small-cell lung cancer (NSCLC) and 57 patients with benign pulmonary lesions (BPL), were enrolled. An enzyme-linked immunosorbent assay was used to detect the expression of E2, carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and cytokeratin 19 fragment antigen 21-1 (CYFRA21-1) in patients with NSCLC and BPL to analyze the correlation between E2 and CEA, NSE or CYFRA21-1 expression, and its correlation with clinicopathological features and prognosis. The expression of tumor markers was then examined in different lung cancer cells (A549, H1795, H460, and SK-MES-1). The expression of tumor markers was detected by a real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. The expressions of p-p44/42 mitogen-activated protein kinase (MAPK) and phospho-AKT (p-AKT) were detected by Western blot analysis. The expression levels of E2, CEA, NSE, and CYFRA21-1 in patients with NSCLC were significantly higher than those in patients with BPL ( P < .05); E2 was positively correlated with tumor markers ( P < .01). Patients with a high expression of E2 and tumor markers showed a poor prognosis ( P < .05). RT-quantitative PCR and Western blot analysis showed that the expression levels of CEA, NSE, CYFRA21-1, p-p44/42 MAPK, and p-AKT in the E2 group were higher than those in the other groups ( P < .05). These studies indicate that the interaction of E2 and tumor markers can significantly improve the role of tumor markers in the diagnosis and prognosis of lung cancer.


Assuntos
Antígenos de Neoplasias/sangue , Antígeno Carcinoembrionário/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Estrogênios/sangue , Queratina-19/sangue , Neoplasias Pulmonares/sangue , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfopiruvato Hidratase/sangue , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células A549 , Biomarcadores Tumorais/sangue , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/sangue , Ensaio de Imunoadsorção Enzimática , Estrogênios/farmacologia , Feminino , Proteínas Ligadas por GPI/sangue , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Menopausa , Pessoa de Meia-Idade , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Taxa de Sobrevida
7.
J Cell Biochem ; 2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30216513

RESUMO

Numerous studies have shown that the estrogen receptor beta (ERß) and interleukin 6 receptor (IL-6R) had interaction in many tumors, including lung cancer. Previous studies found that ERß5 exhibits a different biological function compared with the other subtypes of ERß. Therefore, this study mainly explores the interaction between ERß5 and IL-6R in the progression of lung cancer. We found that the expression of ERß5, IL-6 and glycoprotein 130 (GP130) were significantly increased (P < 0.001) and the 5-year survival rate with the co-expression of ERß5 and GP130 is significantly lower (P = 0.0315) in non-small cell lung cancer (NSCLC) patients. The cell proliferation, invasion, and cell cycle were markedly increased, and the cell apoptotic was markedly inhibited with the concurrent action of ERß5 and IL-6 in A549 cells (P < 0.05). In addition, the expression of ERß5, GP130, p-AKT, and p-44/42 MAPK was also significantly increased in A549 cells (P < 0.05). These results indicate that ERß5 and GP130 can synergistically promote the progression of NSCLC and maybe combined as an independent prognostic factor in patients. In addition, these results also provide a theoretical basis for the combined targeting therapy of ERß5 and GP130 in NSCLC.

8.
Am J Physiol Heart Circ Physiol ; 315(1): H33-H47, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29569955

RESUMO

Preeclampsia is a complication of pregnancy manifested as maternal hypertension (HTN) and fetal intrauterine growth restriction, with unclear mechanisms. Placental ischemia increases antiangiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) relative to angiogenic placental growth factor (PlGF); however, the molecular targets are unclear. To test the hypothesis that placental ischemia-induced changes in sFlt-1 and PlGF target vascular and uteroplacental matrix metalloproteinases (MMPs), we tested whether raising the sFlt-1-to-PlGF ratio by infusing sFlt-1 (10 µg·kg-1·day-1) in pregnant (Preg) rats increases blood pressure (BP) and alters MMPs and whether correcting sFlt-1/PlGF by infusing PlGF (20 µg·kg-1·day-1) in Preg rats with reduced uterine perfusion pressure (RUPP) improves BP and reverses the changes in MMPs. On gestational day 19, BP was higher and the litter size and uterine, placenta, and pup weight were less in Preg + sFlt-1 and RUPP than Preg rats and restored in RUPP + PlGF versus RUPP rats. Gelatin and casein zymography and Western blots revealed decreases in MMP-2 and MMP-9 and increases in MMP-1 and MMP-7 in the aorta, uterine artery, uterus, and placenta of Preg + sFlt-1 and RUPP versus Preg rats, which were reversed in RUPP + PlGF versus RUPP rats. Collagen types I and IV were more abundant in Preg + sFlt-1 and RUPP versus Preg rats and were reversed in RUPP + PlGF versus RUPP rats. Thus, PlGF reverses decreased vascular and uteroplacental MMP-2 and MMP-9 and increased MMP-1, MMP-7, and collagen types I and IV induced by placental ischemia and sFlt-1 in HTN in pregnancy. Angiogenic factors and MMP modulators could rectify changes in MMPs and collagen, restore vascular and uteroplacental remodeling, and improve HTN and intrauterine growth restriction in preeclampsia. NEW & NOTEWORTHY Understanding the mechanisms of preeclampsia could help in its prevention and management. This study shows that correcting soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) imbalance by infusing PlGF reverses the decreases in vascular and uteroplacental matrix metalloproteinase (MMP)-2 and MMP-9 and the increases in MMP-1, MMP-7, and collagen types I and IV induced by placental ischemia and antiangiogenic sFlt-1 in hypertension in pregnancy. Angiogenic factors and MMP modulators could rectify changes in vascular and uteroplacental MMPs and collagen content and ameliorate hypertension and intrauterine growth restriction in preeclampsia.


Assuntos
Indutores da Angiogênese/farmacologia , Colágeno/metabolismo , Metaloproteinases da Matriz/metabolismo , Fator de Crescimento Placentário/farmacologia , Placenta/efeitos dos fármacos , Pré-Eclâmpsia/tratamento farmacológico , Útero/efeitos dos fármacos , Indutores da Angiogênese/uso terapêutico , Animais , Pressão Sanguínea , Colágeno/genética , Feminino , Retardo do Crescimento Fetal/prevenção & controle , Metaloproteinases da Matriz/genética , Placenta/irrigação sanguínea , Placenta/metabolismo , Fator de Crescimento Placentário/uso terapêutico , Gravidez , Ratos , Ratos Sprague-Dawley , Útero/irrigação sanguínea , Útero/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/farmacologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Remodelação Vascular
9.
J Pharmacol Exp Ther ; 364(2): 258-274, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29212831

RESUMO

Pulmonary vasoreactivity could determine the responsiveness to vasodilators and, in turn, the prognosis of pulmonary hypertension (PH). We hypothesized that pulmonary vasoreactivity is impaired, and we examined the underlying mechanisms in the Sugen-hypoxia rat model of severe PH. Male Sprague-Dawley rats were injected with Sugen (20 mg/kg s.c.) and exposed to hypoxia (9% O2) for 3 weeks, followed by 4 weeks in normoxia (Su/Hx), or treated with Sugen alone (Su) or hypoxia alone (Hx) or neither (Nx). After hemodynamic measurements, the heart was assessed for right ventricular hypertrophy (Fulton's index); the pulmonary artery, aorta, and mesenteric arteries were isolated for vascular function studies; and contractile markers were measured in pulmonary arteries using quantitative polymerase chain reaction (PCR). Other rats were used for morphometric analysis of pulmonary vascular remodeling. Right ventricular systolic pressure and Fulton's index were higher in Su/Hx versus Su, Hx, and Nx rats. Pulmonary vascular remodeling was more prominent in Su/Hx versus Nx rats. In pulmonary artery rings, contraction to high KCl (96 mM) was less in Su/Hx versus Nx and Su, and phenylephrine-induced contraction was reduced in Su/Hx versus Nx, Hx, and Su. Acetylcholine (ACh)-induced relaxation was less in Su/Hx versus Nx and Hx, suggesting reduced endothelium-dependent vasodilation. ACh relaxation was inhibited by nitric oxide synthase (NOS) and guanylate cyclase blockade in all groups, suggesting a role of the NO-cGMP pathway. Nitrate/nitrite production in response to ACh was less in Su/Hx versus Nx, supporting reduced endothelial NO production. Sodium nitroprusside (10-8 M) caused less relaxation in Su/Hx versus Nx, Hx, and Su, suggesting a decreased responsiveness of vascular smooth muscle (VSM) to vasodilators. Neither contraction nor relaxation differed in the aorta or mesenteric arteries of all groups. PCR analysis showed decreased expression of contractile markers in pulmonary artery of Su/Hx versus Nx. The reduced responsiveness to vasoconstrictors and NO-mediated vasodilation in the pulmonary, but not systemic, vessels may be an underlying mechanism of severe PH in Su/Hx rats and appears to involve attenuation of the NO relaxation pathway and a switch of pulmonary VSM cells to a synthetic less reactive phenotype.


Assuntos
Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Óxido Nítrico/metabolismo , Artéria Pulmonar/fisiopatologia , Vasodilatação , Animais , Hipóxia Celular , GMP Cíclico/metabolismo , Modelos Animais de Doenças , Hemodinâmica , Hipertensão Pulmonar/metabolismo , Masculino , Músculo Liso Vascular/patologia , Fenótipo , Artéria Pulmonar/patologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Remodelação Vascular
10.
J Huazhong Univ Sci Technolog Med Sci ; 37(6): 904-909, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29270751

RESUMO

Myeloperoxidase (MPO) is released from activated neutrophils. The inflammation in preeclampsia was found to be associated with endothelial dysfunction. We hypothesized that cardiac and circulating MPO levels are elevated in hypertensive pregnancy. Systolic and diastolic blood pressure and heart rate were measured on pregnancy days 14, 16, 18 and 20 in normal pregnant and hypertensive pregnant rats. Left and right ventricle weights, the number of viable fetuses, litter size, fetal and placenta weights were recorded on gestational day 21. Circulating and cardiac MPO activities, soluble fms-like tyrosine kinase-1 (sFlt-1) and vascular endothelial growth factor (VEGF) and nitric oxide (NO) were detected. The results showed increases in cardiac (left, but not right ventricle) and circulating MPO activities, and concomitantly lower number of viable fetuses, litter size, and fetal and placenta weights, and decreases in NO in hypertensive pregnant rats. Also, the increases in circulating sFlt-1 and VEGF were found in hypertensive pregnant group. In conclusion, maternal and fetal detrimental changes along with increases in circulating sFlt-1 and VEGF in hypertensive pregnancy may be associated with increases in cardiac and circulating MPO activities, confirming the causative role of inflammatory response in preeclampsia.


Assuntos
Ventrículos do Coração/metabolismo , Peroxidase/genética , Pré-Eclâmpsia/genética , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Animais , Modelos Animais de Doenças , Feminino , Feto , Regulação da Expressão Gênica , Idade Gestacional , Ventrículos do Coração/patologia , Humanos , Tamanho da Ninhada de Vivíparos , Óxido Nítrico/metabolismo , Peroxidase/metabolismo , Placenta/metabolismo , Placenta/patologia , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/patologia , Gravidez , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
11.
Exp Ther Med ; 14(6): 6169-6175, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29285175

RESUMO

Quercetin is a type of flavonoid compound, which has potent antioxidant and anti-inflammatory activities, capable of treating a variety of diseases including neurodegenerative diseases, tumors, diabetes and obesity. The present study selected alcohol-induced liver injury model mice and aimed at studying the protective role of quercetin in preventing alcohol-induced liver injury. In alcohol-induced liver injury mice treated with quercetin, it was demonstrated that levels of aspartate transaminase, alanine transaminase, total bilirubin and triglyceride were reduced. In addition to this, the activities of the antioxidant enzymes superoxide dismutase and glutathione peroxidase were increased, malondialdehyde was inhibited, and interleukin (IL)-1ß, IL-6, IL-10 and inducible nitric oxide synthase were suppressed. Quercetin additionally suppressed the protein expression levels of B-cell lymphoma (Bcl)-2, Bcl-2 associated X apoptosis regulator, Caspase-3, poly ADP-ribose polymerase, and signal transducer and activator of transcription (STAT) 3 phosphorylation, nuclear factor (NF)-κB and protein kinase B (Akt) phosphorylation levels in alcohol-induced liver injured mice. These results suggested that the protective role of quercetin prevents alcohol-induced liver injury through the phosphoinositide 3-kinase/Akt/NF-κB and STAT3 pathway.

12.
Mol Med Rep ; 16(6): 8900-8906, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28990072

RESUMO

Lung cancer is considered to be a serious disease that poses a significant threat to human health. 2,3,5,4­tetrahydroxy diphenylethylene­2­O­glucoside (THSG) is a bioactive compound derived from Polygonum multiflorum Thunb. That has been demonstrated to possess antioxidative, anti­inflammatory and antitumor activities. However, little is currently known regarding the potential anticancer effects of this compound in lung cancer. Therefore, the present study aimed to investigate the effects of THSG on the adhesion and invasion of A549 human lung cancer cells in vitro, and to identify the putative mechanisms involved. Cell Counting kit­8 assay was performed to determine A549 cell viability following treatment with various doses (0, 5, 10, 25, 50, 100, 150 and 200 µM) of THSG for 12, 24 and 48 h. In addition, cell adhesion and invasion were determined following treatment of A549 cells with 0, 10, 25 or 50 µM THSG for 1, 2 or 3 h, respectively. Reverse transcription­quantitative polymerase chain reaction analysis was performed to examine the mRNA expression levels of Snail, E­cadherin, vimentin, matrix metalloproteinase (MMP) 2 and MMP9 following THSG treatment for 12 h. Western blot analysis was conducted to detect the protein expression levels of Snail, E­cadherin, vimentin, MMP2 and MMP9 following THSG treatment for 24 h. Treatment with THSG (10, 25 and 50 µM) significantly suppressed the adhesion and invasion of A549 human lung cancer cells in a dose­dependent manner. In addition, the mRNA and protein expression levels of adhesion and invasion­associated factors were decreased significantly in A549 cells treated with THSG. In conclusion, THSG effectively suppressed the adhesion and invasion of human lung cancer cells potentially by inhibiting the expression of adhesion and invasion­related genes.


Assuntos
Antineoplásicos/farmacologia , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Glucosídeos/farmacologia , Estilbenos/farmacologia , Biomarcadores , Linhagem Celular Tumoral , Regulação da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo
13.
Biochem Pharmacol ; 146: 101-116, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-28912068

RESUMO

Preeclampsia is a form of hypertension-in-pregnancy (HTN-Preg) with unclear mechanism. Generalized reduction of uterine perfusion pressure (RUPP) could be an initiating event leading to uteroplacental ischemia, angiogenic imbalance, and HTN-Preg. Additional regional differences in uteroplacental blood flow could further affect the pregnancy outcome and increase the risk of preeclampsia in twin or multiple pregnancy, but the mechanisms involved are unclear. To test the hypothesis that regional differences in angiogenic balance and matrix metalloproteinases (MMPs) underlie regional uteroplacental vascularization and feto-placental development, we compared fetal and placental growth, and placental and myoendometrial vascularization in the proximal, middle and distal regions of the uterus (in relation to the iliac bifurcation) in normal pregnant (Preg) and RUPP rats. Maternal blood pressure and plasma anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1)/placenta growth factor (PIGF) ratio were higher, and average placentae number, placenta weight, litter size, and pup weight were less in RUPP than Preg rats. The placenta and pup number and weight were reduced, while the number and diameter of placental and adjacent myoendometrial arteries, and MMP-2 and MMP-9 levels/activity were increased, and sFlt-1/PlGF ratio was decreased in distal vs proximal uterus of Preg rats. In RUPP rats, the placenta and pup number and weight, the number and diameter of placental and myoendometrial arteries, and MMP-2 and -9 levels/activity were decreased, and sFlt-1/PlGF ratio was increased in distal vs proximal uterus. Treatment with sFlt-1 or RUPP placenta extract decreased MMP-2 and MMP-9 in distal segments of Preg uterus, and treatment with PIGF or Preg placenta extract restored MMP levels in distal segments of RUPP uterus. Thus, in addition to the general reduction in placental and fetal growth during uteroplacental ischemia, localized angiogenic imbalance and diminished MMP-2 and MMP-9 could cause further decrease in placental and myoendometrial vascularization and placental and fetal growth in distal vs proximal uterus of HTN-Preg rats. Regional differences in uteroplacental perfusion, angiogenic balance and MMPs could be a factor in the incidence of preeclampsia in multiple pregnancy.


Assuntos
Hipertensão/patologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Neovascularização Fisiológica/fisiologia , Circulação Placentária/fisiologia , Animais , Feminino , Desenvolvimento Fetal , Regulação Enzimológica da Expressão Gênica , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Placenta , Gravidez , Complicações na Gravidez , Ratos , Ratos Sprague-Dawley , Útero/irrigação sanguínea , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
14.
Biochem Pharmacol ; 138: 81-95, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28506758

RESUMO

Preeclampsia is a complication of pregnancy manifested as hypertension-in-pregnancy (HTN-Preg) and often intrauterine growth restriction (IUGR). Placental ischemia could be an initiating event, but the molecular mechanisms are unclear. To test the hypothesis that dimerization of matrix metalloproteinases (MMPs) plays a role in HTN-Preg and IUGR, the levels/activity of MMP-9, tissue inhibitor of metalloproteinase (TIMP-1), and their dimerization forms were measured in the placenta, uterus, and uterine artery of normal pregnant (Preg) rats and a rat model of reduced uteroplacental perfusion pressure (RUPP). Consistent with our previous report, blood pressure (BP) was higher, pup weight was lower, and gelatin zymography showed different gelatinolytic activity for pro-MMP-9, MMP-9, pro-MMP-2 and MMP-2 in RUPP vs Preg rats. Careful examination of the zymograms showed additional bands at 200 and 135kDa. Western blots with MMP-9 antibody suggested that the 200kDa band was a MMP-9 homodimer. Western blots with TIMP-1 antibody as well as reverse zymography suggested that the 135kDa band was a MMP-9/TIMP-1 complex. The protein levels and gelatinase activity of MMP-9 homodimer were decreased while MMP-9/TIMP-1 complex was increased in placenta, uterus and uterine artery of RUPP vs Preg rats. The epidermal growth factor (EGF) receptor blocker erlotinib and protein kinase C (PKC) inhibitor bisindolylmaleimide decreased MMP-9 homodimer and increased MMP-9/TIMP-1 complex in placenta, uterus and uterine artery of Preg rats. EGF and the PKC activator phorbol-12,13-dibutyrate (PDBu) reversed the decreases in MMP-9 homodimer and the increases in MMP-9/TIMP-1 complex in tissues of RUPP rats. Thus, the increased BP and decreased pup weight in placental ischemia model of HTN-Preg are associated with a decrease in MMP-9 homodimer and an increase in MMP-9/TIMP-1 complex in placenta, uterus, and uterine artery, which together would cause a net decrease in MMP-9 activity and reduce uteroplacental and vascular remodeling in the setting of HTN-Preg and IUGR. Enhancing EGFR/PKC signaling may reverse the MMP-9 unfavorable dimerization patterns and thereby promote uteroplacental and vascular remodeling in preeclampsia.


Assuntos
Modelos Animais de Doenças , Hipertensão Induzida pela Gravidez/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Placenta/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Artéria Uterina/metabolismo , Útero/metabolismo , Animais , Dimerização , Ativadores de Enzimas/farmacologia , Precursores Enzimáticos/química , Precursores Enzimáticos/metabolismo , Feminino , Retardo do Crescimento Fetal/etiologia , Gelatinases/química , Gelatinases/metabolismo , Hipertensão Induzida pela Gravidez/fisiopatologia , Metaloproteinase 2 da Matriz/química , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/química , Placenta/irrigação sanguínea , Placenta/efeitos dos fármacos , Pré-Eclâmpsia/etiologia , Gravidez , Inibidores de Proteínas Quinases/farmacologia , Multimerização Proteica/efeitos dos fármacos , Ratos Sprague-Dawley , Técnicas de Cultura de Tecidos , Inibidor Tecidual de Metaloproteinase-1/química , Artéria Uterina/efeitos dos fármacos , Útero/irrigação sanguínea , Útero/efeitos dos fármacos , Remodelação Vascular
15.
Am J Physiol Regul Integr Comp Physiol ; 311(3): R505-21, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27280428

RESUMO

Preeclampsia (PE) is a pregnancy-related hypertensive disorder (HTN-Preg) with unclear mechanism. An imbalance between antiangiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) and angiogenic placental growth factor (PlGF) has been observed in PE, but the vascular targets and signaling pathways involved are unclear. We assessed the extent of sFlt-1/PlGF imbalance and vascular dysfunction in a rat model of HTN-Preg produced by reduction of uteroplacental perfusion pressure (RUPP), and tested whether inducing a comparable sFlt-1/PlGF imbalance by infusing sFlt-1 (10 µg·kg(-1)·day(-1)) in day 14 pregnant (Preg) rats cause similar increases in blood pressure (BP) and vascular reactivity. Using these guiding measurements, we then tested whether restoring sFlt-1/PlGF balance by infusing PIGF (20 µg·kg(-1)·day(-1)) in RUPP rats would improve BP and vascular function. On gestational day 19, BP was in Preg+sFlt-1 and RUPP > Preg, and in RUPP+PlGF < RUPP rats. Plasma sFlt-1/PlGF ratio was increased in Preg+sFlt-1, and RUPP and was reduced in RUPP+PlGF rats. In isolated endothelium-intact aorta, carotid, mesenteric, and renal artery, phenylephrine (Phe)- and high KCl-induced contraction was in Preg+sFlt-1 and RUPP > Preg, and in RUPP+PlGF < RUPP. The differences in vascular reactivity to Phe and KCl between groups were less apparent in vessels treated with the nitric oxide synthase (NOS) inhibitor l-NAME or guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or endothelium-denuded, suggesting changes in endothelial NO-cGMP pathway. In Phe precontracted vessels, ACh-induced relaxation was in Preg+sFlt-1 and RUPP < Preg, and in RUPP+PlGF > RUPP, and was blocked by N(ω)-nitro-l-arginine methyl ester (l-NAME) or ODQ treatment or endothelium removal. Western blots revealed that aortic total endothelial NOS (eNOS) and activated phosphorylated-eNOS were in Preg+sFlt-1 and RUPP < Preg and in RUPP+PlGF > RUPP. ACh-induced vascular nitrate/nitrite production was in Preg+sFlt-1 and RUPP < Preg, and in RUPP+PlGF > RUPP. Vascular relaxation to the exogenous NO donor sodium nitroprusside was not different among groups. Thus, a tilt in the angiogenic balance toward anti-angiogenic sFlt-1 is associated with decreased vascular relaxation and increased vasoconstriction and BP. Restoring the angiogenic/antiangiogenic balance using PlGF enhances endothelial NO-cGMP vascular relaxation and decreases vasoconstriction and BP in HTN-Preg rats and could offer a new approach in the management of PE.


Assuntos
Pressão Sanguínea , Hipertensão/fisiopatologia , Fator de Crescimento Placentário/metabolismo , Complicações Cardiovasculares na Gravidez/fisiopatologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Sistema Vasomotor/fisiopatologia , Animais , Feminino , Gravidez , Ratos , Ratos Sprague-Dawley
16.
Med Oncol ; 30(1): 319, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23254959

RESUMO

Recent advances in lung cancer biology presuppose their inflammatory origin. Thus, CRP is regarded to play a key role in the development of lung cancer. Nevertheless, this interesting hypothesis and the role of inflammation in tumor biology remain complex and incompletely sure. Meanwhile, the association between CRP and risk of lung cancer was not stable in many published results. This study was conducted to evaluate the association between serum CRP and SNPs in the aspect of lung cancer risks, in order to assess its possible diagnostic and prognostic importance. We conducted a case-control study of 96 patients newly diagnosed of lung cancer and 124 controls in this research. Controls were individuals matched to lung cancer cases on age, gender and tobacco use. In order to increase the statistical power, never smokers were matched to patients by using a 3:1 ratio, whereas former and current smokers were matched equal to the patients. CRP concentrations were measured using a chemiluminescent immunoassay, and SNPs were assessed at five loci within the CRP gene (rs1417938, rs1800947, rs1205, rs2808630 and rs3093077) as part of a Golden Gate assay. Logistic regression was used to calculate OR and 95 % CI for lung cancer. CRP concentrations tended to be in positive association with lung cancer risk in our research (Q4 vs Q1: OR = 2.11, 95 % CI, 1.66-2.91, p trend < 0.01). Although CRP SNPs were related to CRP levels, they were not associated with lung cancer risk. In combined analyses, we observed a significant interaction (p (interaction) = 0.02) that positive associations were suggestive in younger (Q4 vs Q1: OR = 1.65, 95 % CI, 1.02-2.67, p trend = 0.18) and older individuals (Q4 vs Q1: OR = 2.66, 95 % CI, 1.45-3.98 p trend = 0.42). The risks of lung cancer were higher with elevated CRP levels among former smokers and current smokers. High levels of CRP were associated with increasing lung cancer risk, suggesting that CRP could be used as surrogate biomarker of angiogenesis and prognosis in lung cancer.


Assuntos
Biomarcadores Tumorais/análise , Proteína C-Reativa/análise , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Proteína C-Reativa/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Inflamação/sangue , Inflamação/genética , Medições Luminescentes , Neoplasias Pulmonares/imunologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Fumar/efeitos adversos
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