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1.
Cancer Control ; 30: 10732748231188261, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37523422

RESUMO

OBJECTIVES: This retrospective cohort study investigated the association of socioeconomic status with survival outcomes among patients with nasopharyngeal carcinoma in an endemic area of China. METHODS: The primary endpoint was overall survival. Survival outcomes were estimated by the Kaplan-Meier method and compared by the log-rank test, and the multivariate Cox proportional hazards model was used to estimate hazard ratios, 95% CIs, and independent prognostic factors. RESULTS: A total of 11 069 adult patients with NPC were enrolled and included in the analysis. Kaplan-Meier survival analysis revealed that overall survival was significantly different among socioeconomic status. Compared with high socioeconomic status patients, low socioeconomic status patients (HR, 1.190; 95% CI, 1.063-1.333) and medium socioeconomic status patients (HR, 1.111; 95% CI, 1.006-1.226) were associated with increased hazard ratio (HR) of overall survival. CONCLUSION: This analysis highlights patients with nasopharyngeal carcinoma who had high socioeconomic status had better overall survival compared with those who had low and medium socioeconomic status.


Assuntos
Neoplasias Nasofaríngeas , Adulto , Humanos , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Estudos Retrospectivos , Disparidades Socioeconômicas em Saúde , Modelos de Riscos Proporcionais , Prognóstico
2.
Drug Dev Res ; 84(7): 1468-1481, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37534761

RESUMO

Distant metastasis is the primary reason for treatment failure in patients with nasopharyngeal carcinoma (NPC). In this study, we investigated the effect of ulinastatin (UTI) on NPC metastasis and its underlying mechanism. Highly-metastatic NPC cell lines S18 and 58F were treated with UTI and the effect on cell proliferation, migration, and invasion were determined by MTS and Transwell assays. S18 cells with luciferase-expressing (S18-1C3) were injected into the left hind footpad of nude mice to establish a model of spontaneous metastasis from the footpad to popliteal lymph node (LN). The luciferase messenger RNA (mRNA) was measured by quantitative polymerase chain reaction (qPCR), and the metastasis inhibition rate was calculated. Key molecular members of the UTI-related uPA, uPAR, and JAT/STAT3 signaling pathways were detected by qPCR and immunoblotting. UTI suppressed the migration and infiltration of S18 and 5-8F cells and suppressed the metastasis of S18 cells in vivo without affecting cell proliferation. uPAR expression decreased from 24 to 48 h after UTI treatment. The antimetastatic effect of UTI is partly due to the suppression of uPA and uPAR. UTI partially suppresses NPC metastasis by downregulating the expression of uPA and uPAR.


Assuntos
Neoplasias Nasofaríngeas , Animais , Camundongos , Humanos , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Camundongos Nus , Linhagem Celular Tumoral , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/patologia , Luciferases , Movimento Celular , Invasividade Neoplásica , Metástase Neoplásica
3.
J Neurooncol ; 159(3): 685-693, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35976547

RESUMO

INTRODUCTION: Anti-programmed cell death-ligand 1 (Anti-PD-L1) blockades have become the first-line treatment of extensive-stage small-cell lung cancer (ES-SCLC) from CASPIAN and IMpower133 trials. SCLC has a high incidence of brain metastasis (BM) and brain radiotherapy (BRT) is the main local treatment method, but there is limited data on the BRT-immunotherapy scheme. The aim of the retrospective study is to investigate the clinical efficacy and safety of the first-line anti-PD-L1 blockades combined with BRT in ES-SCLC with BM. METHODS: Patients with newly diagnosed ES-SCLC with baseline BMs at Shandong Cancer Hospital and Research Institute between 2017 and 2021 were selected. Patients were divided into the anti-PD-L1+BRT group and BRT group. We also assessed the leukoencephalopathy in both groups. RESULTS: A total of 46 patients were selected. Fifteen were divided into anti-PD-L1+BRT group and 31 to BRT group. The median overall survival (OS) was not reached (NR) vs 15.9 m (P = 0.172). Progression-free survival (PFS) was numerically prolonged with anti-PD-L1 blockades, but the significance was not reached (median: 9.4 m vs 7.4 m, P = 0.362). The median intracranial PFS was not improved, neither (median: 8.2 m vs 8.9 m, P = 0.620). Objective response rate (ORR) in the two groups was 73.33% vs 77.42% (P = 0.949) and disease control rate (DCR) was both 100%. Intracranial ORR and DCR were 53.33% vs 70.97% (P = 0.239) and 73.33% vs 80.65% (P = 0.855), respectively. There was no significant difference in leukoencephalopathy incidence between the two groups. CONCLUSION: The combination of first-line anti-PD-L1 blockades with BRT did not confer a significant survival benefit in ES-SCLC with BM, without enhancing cranial neurotoxicity.


Assuntos
Neoplasias Encefálicas , Leucoencefalopatias , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Antígeno B7-H1/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Humanos , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/radioterapia
4.
Bioorg Med Chem Lett ; 32: 127661, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33160023

RESUMO

We previously reported medicinal chemistry efforts that identified MK-5204, an orally efficacious ß-1,3-glucan synthesis inhibitor derived from the natural product enfumafungin. Further extensive optimization of the C2 triazole substituent identified 4-pyridyl as the preferred replacement for the carboxamide of MK-5204, leading to improvements in antifungal activity in the presence of serum, and increased oral exposure. Reoptimizing the aminoether at C3 in the presence of this newly discovered C2 substituent, confirmed that the (R) t-butyl, methyl aminoether of MK-5204 provided the best balance of these two key parameters, culminating in the discovery of ibrexafungerp, which is currently in phase III clinical trials. Ibrexafungerp displayed significantly improved oral efficacy in murine infection models, making it a superior candidate for clinical development as an oral treatment for Candida and Aspergillus infections.


Assuntos
Antifúngicos/farmacologia , Aspergillus/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Glicosídeos/química , Triterpenos/química , beta-Glucanas/metabolismo , Administração Oral , Animais , Antifúngicos/síntese química , Antifúngicos/farmacocinética , Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Candidíase/tratamento farmacológico , Modelos Animais de Doenças , Glicosídeos/farmacocinética , Glicosídeos/farmacologia , Glicosídeos/uso terapêutico , Meia-Vida , Camundongos , Relação Estrutura-Atividade , Triterpenos/farmacocinética , Triterpenos/farmacologia , Triterpenos/uso terapêutico
5.
J Cell Mol Med ; 24(17): 9999-10012, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32678482

RESUMO

The aldo-keto reductases family 1 member C2 (AKR1C2) has critical roles in the tumorigenesis and progression of malignant tumours. However, it was also discovered to have ambiguous functions in multiple cancers and till present, its clinical significance and molecular mechanism in oesophageal squamous cell carcinoma (ESCC) has been unclear. The aim of this study was to explore the role of AKR1C2 in the tumorigenesis of ESCC. Here, we showed that AKR1C2 expression was found to be up-regulated in ESCC tissues and was significantly associated with pathological stage, lymph node metastasis and worse outcomes. Functional assays demonstrated that an ectopic expression of AKR1C2 in ESCC cells resulted in increased proliferation, migration and cisplatin resistance, while knockdown led to inversing effects. Bioinformation analyses and mechanistic studies demonstrated that AKR1C2 activated the PI3K/AKT signalling pathway, furthermore, the inhibitor of PI3K or the selective inhibitor of AKR1C2 enzyme activity could reverse the aggressiveness and showed synergistic antitumour effect when combined with cisplatin, both in vitro and in vivo. In conclusion, Our findings revealed that AKR1C2 could function as an oncogene by activating the PI3K/AKT pathway, as a novel prognostic biomarker and/or as a potential therapeutic target to ESCC.


Assuntos
Carcinoma de Células Escamosas do Esôfago/genética , Hidroxiesteroide Desidrogenases/genética , Oncogenes/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/genética , Animais , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Metástase Linfática/genética , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Regulação para Cima/genética
6.
Biochem Biophys Res Commun ; 527(3): 770-777, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32446561

RESUMO

Nasopharyngeal carcinoma (NPC) is relatively sensitive to ionizing radiation, and radiotherapy is the main treatment modality for non-metastatic NPC. Radiation therapy generates overproduction of reactive oxygen species (ROS), which can cause DNA damage and induce apoptosis in tumors, thereby killing the malignant cells. Although dietary antioxidant supplementation reduces oxidative stress and promotes tumor progression, the effects of antioxidants on the NPC cells upon radiation have not been reported. In the present study, we showed that antioxidants (ß-Carotene, NAC, GSH) played an anti-apoptotic role in response to radiation via decreasing ROS production and inhibiting MAPK pathway in NPC cells. Based on that, we conclude that the use of supplemental antioxidants during radiotherapy should be avoided because of the possibility of tumor protection and reduced treatment efficacy.


Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/radioterapia , Linhagem Celular Tumoral , Humanos , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/metabolismo , Espécies Reativas de Oxigênio/metabolismo
7.
J Org Chem ; 85(2): 994-1000, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31850754

RESUMO

Relebactam, a potent ß-lactamase inhibitor, in combination with Primaxin is an FDA-approved (Recarbrio) treatment for serious and antibiotic-resistant bacterial infections. An efficient synthesis of key chiral piperidine intermediate 1 suitable for large-scale preparation of relebactam is described. The key steps include a unique highly diastereoselective FeCl3·6H2O/NaBH4 reduction of a chiral oxime ether and chemoselective amidation of the resulting unprotected pipecolic acid. Nuclear magnetic resonance studies and density functional theory calculations were carried out on the substrate-Fe(III) complexes, which shed light on diastereoselective reduction.


Assuntos
Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/farmacologia , Boroidretos/química , Cloretos/química , Compostos Férricos/química , Oximas/química , Inibidores de beta-Lactamases/síntese química , Inibidores de beta-Lactamases/farmacologia , Compostos Azabicíclicos/química , Éteres/química , Estrutura Molecular , Oxirredução , Análise Espectral/métodos , Estereoisomerismo , Água/química
8.
Bioorg Med Chem Lett ; 30(17): 127357, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738971

RESUMO

Our previously reported efforts to produce an orally active ß-1,3-glucan synthesis inhibitor through the semi-synthetic modification of enfumafungin focused on replacing the C2 acetoxy moiety with an aminotetrazole and the C3 glycoside with a N,N-dimethylaminoether moiety. This work details further optimization of the C2 heterocyclic substituent, which identified 3-carboxamide-1,2,4-triazole as a replacement for the aminotetrazole with comparable antifungal activity. Alkylation of either the carboxamidetriazole at C2 or the aminoether at C3 failed to significantly improve oral efficacy. However, replacement of the isopropyl alpha amino substituent with a t-butyl, improved oral exposure while maintaining antifungal activity. These two structural modifications produced MK-5204, which demonstrated broad spectrum activity against Candida species and robust oral efficacy in a murine model of disseminated Candidiasis without the N-dealkylation liability observed for the previous lead.


Assuntos
Antifúngicos/química , Triazóis/química , beta-Glucanas/metabolismo , Administração Oral , Animais , Antifúngicos/metabolismo , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida/efeitos dos fármacos , Candidíase/tratamento farmacológico , Modelos Animais de Doenças , Glucosiltransferases/antagonistas & inibidores , Glucosiltransferases/metabolismo , Glicosídeos/química , Meia-Vida , Camundongos , Testes de Sensibilidade Microbiana , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/metabolismo , Triazóis/farmacologia , Triazóis/uso terapêutico , Triterpenos/química , beta-Glucanas/química
9.
Int J Med Sci ; 17(13): 1897-1908, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32788868

RESUMO

Retinal dehydrogenase 5 (RDH5) is an important enzyme in the visual cycle. Several studies have reported that the RDH family may play crucial roles in tumor prognosis. However, the role of RDH5 in tumor prognosis is still unclear. We examined the mRNA level of RDH5 by using q-PCR in hepatocellular carcinoma (HCC) and adjacent non-cancerous tissues. The proliferation rate of HCC cells was detected by MTS assay, and the invasive ability was examined by transwell and scratch wound assays. The YAP protein localization and expression were visualized by immunofluorescence in two different cell lines. CpG islands in the promoter region were predicted by using the methprimer database. Clinical characteristics of a patient cohort data came from The Cancer Genome Atlas database. RDH5 was significantly downregulated in hepatocellular carcinoma tissues, and low RDH5 expression was associated with metastasis and poor patient prognosis. Functional assays revealed that the RDH5 promoter is methylated in HCC cell lines. Moreover, overexpressing RDH5 can suppress metastasis by reversing the epithelial-mesenchymal transition (EMT) process, and RDH5 also inhibits cell proliferation in HCC cell lines. Furthermore, suppressing RDH5 can activate the Hippo/YAP signaling pathway and promote the nuclear translocation of YAP. Clinical data demonstrated that RDH5 is an independent prognostic factor in HCC. In our study, we provided the first evidence that RDH5 plays a crucial role in suppressing proliferation and metastasis, and the RDH5 promoter is methylated in hepatocellular carcinoma. And as an important regulator, RDH5 can suppress the Hippo/YAP signaling pathway. Taken together, it revealed that RDH5 might be a potential therapeutic target in HCC patients.


Assuntos
Carcinoma Hepatocelular/genética , Proteínas de Ciclo Celular/genética , Neoplasias Hepáticas/genética , Proteínas Serina-Treonina Quinases/genética , Retinal Desidrogenase/genética , Fatores de Transcrição/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Ilhas de CpG/genética , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Via de Sinalização Hippo , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Regiões Promotoras Genéticas/genética , Transdução de Sinais/genética
10.
Bioorg Med Chem Lett ; 25(21): 4945-4949, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25978966

RESUMO

Using structure based drug design (SBDD), a novel class of potent coagulation Factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds demonstrated oral bioavailability in rat IV/PO pharmacokinetic (PK) studies. Finally, the pharmacodynamics (PD) of this class of molecules was evaluated in Thrombin Generation Assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.


Assuntos
Aminas/farmacologia , Inibidores Enzimáticos/farmacologia , Fator IXa/antagonistas & inibidores , Administração Oral , Aminas/síntese química , Aminas/química , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Fator IXa/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-Atividade
11.
Bioorg Med Chem Lett ; 25(22): 5437-43, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26318999

RESUMO

Using structure based drug design, a novel class of potent coagulation factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds were evaluated in rat IV/PO pharmacokinetic (PK) studies and demonstrated desirable oral PK profiles. Finally, the pharmacodynamics (PD) of this class of molecules were evaluated in thrombin generation assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Fator IXa/antagonistas & inibidores , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Administração Oral , Animais , Cristalografia por Raios X , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Compostos Heterocíclicos com 3 Anéis/síntese química , Humanos , Estrutura Molecular , Ratos
12.
Cancer Gene Ther ; 31(3): 454-463, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38135697

RESUMO

Nasopharyngeal carcinoma (NPC) originates in the epithelial cells of the nasopharynx and is a common malignant tumor in southern China and Southeast Asia. Metastasis of NPC remains the main cause of death for NPC patients even though the tumor is sensitive to radiotherapy and chemotherapy. Here, we found that the transmembrane protein tetraspanin1 (TSPAN1) potently inhibited the in vitro migration and invasion, as well as, the in vivo metastasis of NPC cells via interacting with the IKBB protein. In addition, TSPAN1 was essential in preventing the overactivation of the NF-kB pathway in TSPAN1 overexpressing NPC cells. Furthermore, reduced TSPAN1 expression was associated with NPC metastasis and the poor prognosis of NPC patients. These results uncovered the suppressive role of TSPAN1 against NF-kB signaling in NPC cells for preventing NPC metastasis. Its therapeutic value warrants further investigation.


Assuntos
Carcinoma , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Linhagem Celular Tumoral , Transdução de Sinais , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Tetraspaninas/genética , Tetraspaninas/metabolismo
13.
Ann Med ; 55(1): 2203515, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37190975

RESUMO

BACKGROUND: Obesity is associated with an increased risk of fracture in adults, but is unclear in postmenopausal women. We aim to determine the association of obesity with the risk of fracture in postmenopausal women. METHODS: PubMed, EMBASE, Cochrane Library and Web of Science were searched up to 11 April 2022 for cohort studies. And the included studies regarding the relationship between obesity with all cause of fracture in postmenopausal women were included in our meta-analysis. Data were screened and extracted independently by two reviewers. The relative risks (RR) were estimated using a random-effects model. Between-study heterogeneity was assessed using Cochran's Q and I2 statistics. RESULTS: Eight cohort studies comprising 671,532 postmenopausal women and 40,172 fractures were included. Overall, the pooling analysis shows that obesity in postmenopausal women is associated with an increased risk of all-cause fracture (relative ratio (RR) = 1.18; 95% confidence interval (CI):1.09-1.28, I2 = 86.3%, p = .000). Sub-analyses for each site of fracture indicate that obesity was associated with an increased risk of vertebral fracture in postmenopausal women (RR = 1.154, 95% CI: 1.020-1.305, I2 = 94.5%, p = .023), but reduced the risk of pelvic fracture (RR = 0.575, 95% CI:0.470-0.702, I2 = 0.0%, p = .000). There is no statistically significant difference in the risk of hip and humerus fractures associated with obesity in postmenopausal women. CONCLUSION: Obesity is associated with an increased risk of all-cause and vertebral fractures in postmenopausal women, but is a protective factor for pelvic fractures. Our findings suggest that postmenopausal women who regulate their weight might lower their risk of fractures.Registration: (PROSPERO: CRD42022324973)KEY MESSAGESObesity is associated with an increased risk of all-cause and vertebral fractures in postmenopausal women.Obesity maybe a protective factor for pelvic fractures in postmenopausal women.Postmenopausal women should regulate their weight to prevent fractures.


Assuntos
Fraturas Ósseas , Osteoporose Pós-Menopausa , Fraturas da Coluna Vertebral , Adulto , Feminino , Humanos , Pós-Menopausa , Osteoporose Pós-Menopausa/complicações , Osteoporose Pós-Menopausa/epidemiologia , Osteoporose Pós-Menopausa/prevenção & controle , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/etiologia , Fraturas da Coluna Vertebral/epidemiologia , Fraturas da Coluna Vertebral/etiologia , Obesidade/complicações , Obesidade/epidemiologia , Estudos de Coortes
14.
Biochim Biophys Acta Mol Basis Dis ; 1869(5): 166696, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36963524

RESUMO

BACKGROUND: Metastasis is one of the main obstacles impeding the survival of nasopharyngeal carcinoma (NPC) patients, with the molecular mechanism underlying NPC metastasis still unclear. RESULTS: In this study, Cystatin A (CSTA) was found downregulated in NPC tissues with metastasis compared with those without metastasis. Shorter overall survival and distant metastasis-free survival were found in NPC patients with lower CSTA expression. Using functional assays, we found that CSTA prevented both the in vitro motility of NPC cells and their ability to metastasize in vivo. Transcriptome sequencing and western blot analysis revealed that CSTA inhibited the phosphorylation of AKT. Moreover, activating AKT using AKT agonist SG79 rescued the motility of CSTA-overexpressing NPC cells, whereas, treatment with AKT inhibitor MK2206 inhibited the motility of CSTA-knockdown NPC cells. Mechanically, immunoprecipitation coupled mass spectrometry found that CSTA interacted with the N6-adenosine-methyltransferase subunit METTL3 and promoted its ubiquitin-proteasome-mediated degradation following the upregulation of NKX3-1 and LHPP, which are negative regulators of AKT. Furthermore, knock-down of NKX3-1 and LHPP enhanced the motility of CSTA-overexpressing NPC cells. CONCLUSIONS: The inhibitory effect of CSTA upon NPC metastasis mainly depended on suppressing AKT signaling by the upregulation of NKX3-1 and LHPP expression resulting from the binding between CSTA and METLL3. Our study suggests that the CSTA-METLL3-NKX3-1/LHPP-AKT axis could be of therapeutic value for inhibiting NPC metastasis.


Assuntos
Carcinoma , Neoplasias Nasofaríngeas , Humanos , Carcinoma/patologia , Cistatina A , Transição Epitelial-Mesenquimal , Metiltransferases , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo
15.
J Biomed Biotechnol ; 2012: 623062, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23093851

RESUMO

Statistical experimental designs provided by statistical analysis system (SAS) software were applied to optimize the fermentation medium composition for the production of atrazine-degrading Acinetobacter sp. DNS(32) in shake-flask cultures. A "Plackett-Burman Design" was employed to evaluate the effects of different components in the medium. The concentrations of corn flour, soybean flour, and K(2)HPO(4) were found to significantly influence Acinetobacter sp. DNS(32) production. The steepest ascent method was employed to determine the optimal regions of these three significant factors. Then, these three factors were optimized using central composite design of "response surface methodology." The optimized fermentation medium composition was composed as follows (g/L): corn flour 39.49, soybean flour 25.64, CaCO(3) 3, K(2)HPO(4) 3.27, MgSO(4)·7H(2)O 0.2, and NaCl 0.2. The predicted and verifiable values in the medium with optimized concentration of components in shake flasks experiments were 7.079 × 10(8) CFU/mL and 7.194 × 10(8) CFU/mL, respectively. The validated model can precisely predict the growth of atrazine-degraing bacterium, Acinetobacter sp. DNS(32).


Assuntos
Acinetobacter/metabolismo , Atrazina/metabolismo , Reatores Biológicos/microbiologia , Meios de Cultura/química , Meios de Cultura/metabolismo , Modelos Biológicos , Modelos Estatísticos , Acinetobacter/classificação , Atrazina/isolamento & purificação , Biodegradação Ambiental , Simulação por Computador , Interpretação Estatística de Dados , Especificidade da Espécie
16.
Bioorg Med Chem Lett ; 22(22): 6811-6, 2012 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-22672801

RESUMO

Orally bioavailable inhibitors of ß-(1,3)-D-glucan synthase have been pursued as new, broad-spectrum fungicidal therapies suitable for treatment in immunocompromised patients. Toward this end, a collaborative medicinal chemistry program was established based on semisynthetic derivatization of the triterpenoid glycoside natural product enfumafungin in order to optimize in vivo antifungal activity and oral absorption properties. In the course of these studies, it was hypothesized that the pharmacokinetic properties of the semisynthetic enfumafungin analog 3 could be improved by tethering the alkyl groups proximal to the basic nitrogen of the C3-aminoether side chain into an azacyclic system, so as to preclude oxidative N-demethylation. The results of this research effort are disclosed herein.


Assuntos
Antifúngicos/síntese química , Inibidores Enzimáticos/síntese química , Glucosiltransferases/antagonistas & inibidores , Glicosídeos/química , Triterpenos/química , Administração Oral , Animais , Antifúngicos/química , Antifúngicos/farmacocinética , Candida albicans/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Glucosiltransferases/metabolismo , Glicosídeos/síntese química , Glicosídeos/farmacocinética , Meia-Vida , Camundongos , Relação Estrutura-Atividade , Triterpenos/síntese química , Triterpenos/farmacocinética
17.
AAPS J ; 24(3): 52, 2022 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-35384529

RESUMO

In-clinic dried blood spot (DBS) pharmacokinetic (PK) sampling was incorporated into two phase 3 studies of verubecestat for Alzheimer's disease (EPOCH [NCT01739348] and APECS [NCT01953601]), as a potential alternative to plasma PK sampling for improved logistical feasibility and decreased blood volume burden. However, an interim PK analysis revealed verubecestat concentrations in DBS samples declined with time to assay in both trials. An investigation revealed wide variation in implementation practices for DBS sample handling procedures resulting in insufficient desiccation which caused verubecestat instability. High-resolution mass spectrometry evaluations of stressed and aged verubecestat DBS samples revealed the presence of two hydrolysis degradants. To minimize instability, new DBS handling procedures were implemented that provided additional desiccant and minimized the time to analysis. Both verubecestat hydrolysis products were previously discovered and synthesized during active pharmaceutical ingredient stability characterization. A liquid chromatography-mass spectrometry assay to quantitate the dominant verubecestat degradant in DBS samples was developed and validated. The application of this method to stressed and aged verubecestat DBS samples confirmed that degradant concentrations accounted for the observed decreases in the verubecestat concentration. Furthermore, after increasing desiccant amounts, degradant concentrations accounted for approximately 7% of the verubecestat concentration in DBS clinical samples, indicating that issues with sample handling were minimized with new storage and shipping conditions. This case study illustrates the challenges with employing new sampling techniques in large, global trials, and the importance of anticipating and mitigating implementation risks.


Assuntos
Teste em Amostras de Sangue Seco , Espectrometria de Massas em Tandem , Óxidos S-Cíclicos , Teste em Amostras de Sangue Seco/métodos , Higroscópicos , Manejo de Espécimes , Espectrometria de Massas em Tandem/métodos , Tiadiazinas
18.
J Med Chem ; 65(7): 5575-5592, 2022 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-35349275

RESUMO

Vorapaxar is an approved drug for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. Subsequent to the discovery of Vorapaxar, medicinal chemistry efforts were continued to identify structurally differentiated leads. Toward this goal, extensive structure-activity relationship studies using a C-ring-truncated version of Vorapaxar culminated in the discovery of three leads, represented as 13, 14, and 23. Among these leads, compound 14 possessed favorable pharmacokinetic properties and an off-target profile, which supported additional profiling in an exploratory rat toxicology study.


Assuntos
Infarto do Miocárdio , Trombose , Animais , Humanos , Lactonas , Infarto do Miocárdio/tratamento farmacológico , Inibidores da Agregação Plaquetária , Ratos , Receptor PAR-1 , Receptores Ativados por Proteinase , Trombose/induzido quimicamente , Trombose/tratamento farmacológico
19.
Cancer Lett ; 498: 165-177, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33152401

RESUMO

Nasopharyngeal carcinoma (NPC) originates in the nasopharyngeal epithelium and has the highest metastatic rate among head and neck cancers. Distant metastasis is the main reason for treatment failure with the underlying mechanisms remaining unclear. By comparing the expression profiling of NPCs versus non-cancerous nasopharyngeal tissues, we found LACTB was highly expressed in the tumor tissues. We found that elevated expression of the LACTB protein in primary NPCs correlated with poorer patient survival. LACTB is known to be a serine protease and a ubiquitous mitochondrial protein localized in the intermembrane space. Its role in tumor biology remains controversial. We found that the different methylation pattern of LACTB promoter led to its differential expression in NPC cells. Overexpressing LACTB in NPC cells promoted their motility in vitro and metastasis in vivo. While knocking down LACTB reduced the metastasis capability of NPC cells. However, LACTB did not influence cellular proliferation. We further found the role of LACTB in promoting NPC metastasis depended on the activation of ERBB3/EGFR-ERK signaling, which in turn, affected the stability and the following acetylation of histone H3. These findings may shed light on unveiling the mechanisms of NPC metastasis.


Assuntos
Sistema de Sinalização das MAP Quinases/genética , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Metástase Neoplásica/genética , Receptor ErbB-3/genética , Transdução de Sinais/genética , beta-Lactamases/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Receptores ErbB/genética , Feminino , Humanos , Camundongos , Camundongos Nus , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Metástase Neoplásica/patologia , Regiões Promotoras Genéticas/genética
20.
Cancer Lett ; 482: 74-89, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32305558

RESUMO

Distant metastasis is the major cause of short survival in ccRCC patients. However, the development of effective therapies for metastatic ccRCC is limited. Herein, we reported that ETV4 was selected from among 150 relevant genes with in vivo evidence of promoting metastasis. In this study, we identified that ETV4 promoted ccRCC cell migration and metastasis in vitro and in vivo, and a positive correlation between ETV4 and FOSL1 expression was found in ccRCC tissues and cell lines. Further investigation suggested that ETV4 increase FOSL1 expression through direct binding with the FOSL1 promoter. Furthermore, ETV4/FOSL1 was proved as a novel upstream and downstream causal relationship in ccRCC in an AKT dependent manner. In addition, both ETV4 and FOSL1 serve as an independent, unfavorable ccRCC prognostic indicator, and the accumulation of the ETV4 and FOSL1 in ccRCC patients result in a worse survival outcome in ccRCC patients. Taken together, our results suggest that the ETV4/FOSL1 axis acts as a prognostic biomarker and ETV4 directly up-regulates FOSL1 by binding with its promoter in a PI3K-AKT dependent manner, leading to metastasis and disease progression of ccRCC.


Assuntos
Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-fos/genética , Regulação para Cima , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Transplante de Neoplasias , Fosfatidilinositol 3-Quinases/metabolismo , Medicina de Precisão , Prognóstico , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-ets/metabolismo , Transdução de Sinais , Análise de Sobrevida
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