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1.
BMC Public Health ; 20(1): 478, 2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-32276617

RESUMO

BACKGROUND: Great changes have taken place in terms of people's lifestyles and behavioral habits. Diabetes has become a threat to human health and is the most important noncommunicable disease. More than 60% of rural diabetic patients experience delayed diagnosis and treatment. In this study, we explore the inner experience of the delayed diagnosis and treatment of patients with diabetes in rural areas and provide a reference for targeted intervention. METHODS: A qualitative research design was used to examine the cognitive behavioral intention of patients in rural areas with delayed diagnosis and treatment of diabetes. Thirteen diabetes patients with delayed diagnosis and treatment were sampled with maximum variation in rural Daqing City and Tangshan City in China. The data analysis involved several levels of analysis consistent with qualitative research. RESULTS: The following themes were relevant to diabetes patients in rural areas with delayed diagnosis and treatment delay: "Lacked knowledge of diabetes", "Negative coping style", "Dissatisfaction with the existing medical service" and "Influence of social support". CONCLUSIONS: The respondents' delayed diagnosis and treatment represent a common phenomenon. Medical personnel should provide interventions for patients and encourage them to go to the hospital on time.


Assuntos
Diagnóstico Tardio/psicologia , Diabetes Mellitus/terapia , Intenção , População Rural , Tempo para o Tratamento , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Diabetes Mellitus/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , População Rural/estatística & dados numéricos
2.
Phys Rev Lett ; 124(7): 075001, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32142350

RESUMO

The naturally persistent flow of hundreds of dust particles is experimentally achieved in a dusty plasma system with the asymmetric sawteeth of gears on the electrode. It is also demonstrated that the direction of the dust particle flow can be controlled by changing the plasma conditions of the gas pressure or the plasma power. Numerical simulations of dust particles with the ion drag inside the asymmetric sawteeth verify the experimental observations of the flow rectification of dust particles. Both experiments and simulations suggest that the asymmetric potential and the collective effect are the two keys in this dusty plasma ratchet. With the nonequilibrium ion drag, the dust flow along the asymmetric orientation of this electric potential of the ratchet can be reversed by changing the balance height of dust particles using different plasma conditions.

3.
Cell Death Dis ; 10(11): 819, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31659158

RESUMO

miR-18a has been reported to be upregulated in nasopharyngeal carcinoma (NPC) tissues by microarray assays. However, the roles and the underlying mechanisms of miR-18a in NPC remain poorly understood. Here we demonstrated by real-time RT-PCR that miR-18a expression is upregulated in NPC tissues, and positively correlated with tumor size and TNM stage. Moreover, miR-18a expression could be upregulated by NF-κB activation or Epstein-Barr virus encoded latent membrane protein 1 expression. The ectopic expression of miR-18a promoted NPC cell proliferation, migration and invasion, while the repression of miR-18a had opposite effects. Candidate genes under regulation by miR-18a were screened out through a whole-genome microarray assay, further identified by a reporter assay and verified in clinical samples. SMG1, a member of the phosphoinositide 3-kinase-related kinases family and an mTOR antagonist, was identified as functional target of miR-18a. Our results confirmed that miR-18a exerts its oncogenic role through suppression of SMG1 and activation of mTOR pathway in NPC cells. Importantly, in vivo xenograft tumor growth in nude mice was effectively inhibited by intratumor injection of miR-18a antagomir. Our data support an oncogenic role of miR-18a through a novel miR-18a/SMG1/mTOR axis and suggest that the antitumor effects of antagomir-18a may make it suitable for NPC therapy.

4.
Lung Cancer ; 137: 7-13, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520922

RESUMO

OBJECTIVES: We performed this meta-analysis to compare adjuvant EGFR-TKIs with a placebo or adjuvant chemotherapy among patients with resected non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: A literature search was performed using relevant keywords. All randomized controlled trials (RCTs) that compared the survival benefits of adjuvant EGFR-TKIs with those of placebo or adjuvant chemotherapy for resected NSCLC were eligible for inclusion. RESULTS: The literature search yielded five eligible RCTs including three RCTs that compared adjuvant EGFR-TKIs with a placebo, and two RCTs that compared adjuvant EGFR-TKIs with chemotherapy. For unselected intent-to-treat patients who received adjuvant EGFR-TKIs versus a placebo, the hazard ratio (HR) of disease-free survival (DFS) was 0.88 (95% confidence interval (CI): 0.59-1.32; P = 0.54). For patients with an EGFR mutation, the DFS after adjuvant EGFR-TKIs was superior to that after a placebo, with a HR of 0.59 (95% CI: 0.40-0.88; P = 0.009). For patients with an EGFR mutation, the DFS after EGFR-TKIs was greater than that after chemotherapy, with a HR of 0.42 (95% CI: 0.19-0.93; P = 0.03). For patients with wild-type EGFR, the DFS of adjuvant EGFR-TKIs was similar to the placebo, with a RR of 1.00 (95% CI: 0.62-1.60; P = 0.99). Treatment with EGFR-TKIs resulted in more adverse events compared with the placebo, with a risk ratio (RR) of 2.72, (95% CI: 2.23-3.33; P < 0.00001), but fewer adverse events compared with chemotherapy, with an RR of 0.26 (95% CI: 0.18-0.38; P < 0.00001). CONCLUSIONS: For patients with resected NSCLC harboring EGFR mutations, treatment with an adjuvant EGFR-TKI was superior to that of a placebo or chemotherapy in terms of DFS. Treatment with adjuvant EGFR-TKIs were not effective among patients with wild type EGFR NSCLC.

5.
Cell Death Dis ; 10(7): 479, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31209222

RESUMO

Cancer metastasis is the main cause of death in breast cancer (BC) patients. Therefore, prediction and treatment of metastasis is critical for enhancing the survival of BC patients. In this study, we aimed to identify biomarkers that can predict metastasis of BC and elucidate the underlying mechanism of the functional involvement of such markers in metastasis. miRNA expression profile was analyzed using a custom microarray system in 422 BC tissues. The relationship between the upregulated miR-665, metastasis and survival of BC was analyzed and verified in another set of 161 BC samples. The biological function of miR-665 in BC carcinogenesis was explored with in vitro and in vivo methods. The target gene of miR-665 and its signaling cascade were also analyzed. There are 399 differentially expressed miRNAs between BC and noncancerous tissues, of which miR-665 is the most upregulated miRNA in the BC tissues compared with non-tumor breast tissues (P < 0.001). The expression of miR-665 predicts metastasis and poor survival in 422 BC patients, which is verified in another 161 BC patients and 2323 BC cases from online databases. Ectopic miR-665 expression promotes epithelial-mesenchymal transition (EMT), proliferation, migration and invasion of BC cells, and increases tumor growth and metastasis of BC in mice. Bioinformatics, luciferase assay and other methods showed that nuclear receptor subfamily 4 group A member 3 (NR4A3) is a target of miR-665 in BC. Mechanistically, we demonstrated that miR-665 promotes EMT, invasion and metastasis of BC via inhibiting NR4A3 to activate MAPK/ERK kinase (MEK) signaling pathway. Our study demonstrates that miR-665 upregulation is associated with metastasis and poor survival in BC patients, and mechanistically, miR-665 enhances progression of BC via NR4A3/MEK signaling pathway. This study provides a new potential prognostic biomarker and therapeutic target for BC patients.

7.
Clin Rev Allergy Immunol ; 57(1): 128-143, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31243705

RESUMO

Allergen immunotherapy (AIT) for allergic rhinitis (AR), asthma, and other allergic diseases has developed quickly. House dust mite (HDM), Artemisia (wormwood), Humulus japonicus (Japanese hop), Alternaria alternata, and Cladosporium herbarum are the five most common inhalant allergens in China. AIT has been performed in China for over 60 years. With the support of the Chinese Medical Association (CMA) and the Chinese Medical Doctors Association (CMDA), the Chinese College of Allergy and Asthma (CCAA) was established in 2016 as a specialized branch of CDMA and is the main certification authority for AIT. Chinese allergists and scientists have made tremendous progress in the development of AIT. There have been many publications by Chinese allergists and scientists worldwide encompassing original research studies, systematic reviews, case studies, and clinical trials. Currently, conventional subcutaneous immunotherapy (SCIT) is the preferred AIT in China, but sublingual immunotherapy (SLIT) is beginning to gain recognition. An increasing number of clinical trials have been conducted to investigate the clinical efficacy and side effects of SLIT and SCIT. In China, HDM is the only commercial standardized allergen extracts in clinical use, whereas the others are crude allergen extracts. Besides standardized allergen extracts, other forms of hypoallergenic extracts are still being investigated and developed in China. Immunotherapy in China is similar to that in the USA in which allergen extracts can be mixed for SCIT. However, allergen extracts cannot be mixed for SCIT in Europe.


Assuntos
Dessensibilização Imunológica/efeitos adversos , Dessensibilização Imunológica/métodos , Rinite Alérgica/epidemiologia , Rinite Alérgica/terapia , Adjuvantes Imunológicos/uso terapêutico , Adolescente , Adulto , Alérgenos/imunologia , Animais , Asma/terapia , Criança , Pré-Escolar , China , Humanos , Lactente , Recém-Nascido , Exposição por Inalação , Camundongos , Prevalência , Pyroglyphidae/imunologia , Imunoterapia Sublingual/efeitos adversos , Estados Unidos , Vacinas de DNA/uso terapêutico
8.
J Neurosci ; 39(29): 5773-5793, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101759

RESUMO

Chronic pain is a serious debilitating disease for which effective treatment is still lacking. Acid-sensing ion channel 1a (ASIC1a) has been implicated in nociceptive processing at both peripheral and spinal neurons. However, whether ASIC1a also contributes to pain perception at the supraspinal level remains elusive. Here, we report that ASIC1a in ACC is required for thermal and mechanical hypersensitivity associated with chronic pain. ACC-specific genetic deletion or pharmacological blockade of ASIC1a reduced the probability of cortical LTP induction and attenuated inflammatory thermal hyperalgesia and mechanical allodynia in male mice. Using cell type-specific manipulations, we demonstrate that ASIC1a in excitatory neurons of ACC is a major player in cortical LTP and pain behavior. Mechanistically, we show that ASIC1a tuned pain-related cortical plasticity through protein kinase C λ-mediated increase of membrane trafficking of AMPAR subunit GluA1 in ACC. Importantly, postapplication of ASIC1a inhibitors in ACC reversed previously established nociceptive hypersensitivity in both chronic inflammatory pain and neuropathic pain models. These results suggest that ASIC1a critically contributes to a higher level of pain processing through synaptic potentiation in ACC, which may serve as a promising analgesic target for treatment of chronic pain.SIGNIFICANCE STATEMENT Chronic pain is a debilitating disease that still lacks effective therapy. Ion channels are good candidates for developing new analgesics. Here, we provide several lines of evidence to support an important role of cortically located ASIC1a channel in pain hypersensitivity through promoting long-term synaptic potentiation in the ACC. Our results indicate a promising translational potential of targeting ASIC1a to treat chronic pain.

9.
Cancer Cell Int ; 19: 145, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31139022

RESUMO

Background: Pancreatic cancer stem cells (CSCs), a special population of cells, renew themselves infinitely and resist to various treatment. Gramicidin A (GrA), an ionophore antibiotic derived from microorganism, can form channels across the cell membrane and disrupt cellular ionic homeostasis, leading to cell dysfunction and death. As reported, the ionophore antibiotic salinomycin (Sal) has been proved to kill CSCs effectively. Whether GrA owns the potential as a therapeutic drug for CSCs still remains unknown. This study investigated the effect of GrA on pancreatic CSCs and the mechanism. Methods: Tumorsphere formation assay was performed to assess pancreatic CSCs self-renewal potential. In vitro hemolysis assay was determined to test the borderline concentration of GrA. CCK-8 assay was used to detect pancreatic cancer cell proliferation capability. Flow cytometry was performed to detect cell apoptosis and mitochondrial membrane potential. Scanning and transmission electron microscopy was used to observe ultrastructural morphological changes on cell membrane surface and mitochondria, respectively. Western blot analysis was used to determine relative protein expression levels. Immunofluorescence staining was performed to observe CD47 re-distribution. Results: GrA at 0.05 µM caused tumorspheres disintegration and decrease in number of pancreatic cancer BxPC-3 and MIA PaCa-2 cells. GrA and Sal both inhibited cancer cell proliferation. The IC50 values of GrA and Sal for BxPC-3 cells were 0.025 µM and 0.363 µM; while for MIA PaCa-2 cells were 0.032 µM and 0.163 µM, respectively. Compared on equal concentrations, the efficacy of GrA was stronger than that of Sal. GrA at 0.1 µM or lower did not cause hemolysis. GrA induced ultrastructural changes, such as the decrease of microvilli-like protrusions on cell surface membrane and the swelling of mitochondria. GrA down-regulated the expression levels of CD133, CD44, and CD47; in addition, CD47 re-distribution was observed on cell surface. Moreover, GrA showed synergism with gemcitabine in suppressing cancer cell proliferation. Conclusions: The study found that GrA was highly active against pancreatic CSCs. It indicates that GrA exerts inhibitory effects against pancreatic CSCs associated with CD47 down-regulation, implying that GrA might play a positive role in modulating the interaction between macrophages and tumor cells.

10.
Int J Mol Med ; 43(3): 1531-1541, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30664181

RESUMO

Dogs are a major source of indoor allergens. However, the prevalence of dog allergies in China remains unclear, especially in children. In the present study, Can f 7, a canine allergen belonging to the Niemann pick type C2 protein family, was selected to study its sensitization rate in Chinese children with dog allergies. The Can f 7 gene was subcloned into a pET­28a vector and expressed in Escherichia coli BL21 (DE3) cells. Recombinant Can f 7 was purified by nickel affinity chromatography, identified by SDS­PAGE electrophoresis, and had its allergenicity assessed by western blot, ELISA and basophil activation tests. Through a series of bioinformatical approaches, B­cell epitopes, secondary structures, and 3 dimensional (3D) homology modeling of Can f 7 were predicted. The activity of the B cell epitopes was verified by ELISA. The recombinant Can f 7 showed a distinct band with a molecular weight of 14 kDa. Six of 20 sera from dog­allergic children reacted positively to the Can f 7. Can f 7 induced an ~4.0­fold increase in cluster of differentiation 63 and C­C motif chemokine receptor R3 expression in basophils sensitized with the serum of dog­allergic children compared with those of non­allergic controls. The secondary structure analysis showed that Can f 7 contains 6 ß­sheets. Five B cell epitopes of Can f 7 were predicted, and two of these were confirmed by ELISA. These results indicate that Can f 7 is an important canine allergen in Chinese children and provide novel data for further research concerning the use of Can f 7 in the diagnosis and treatment of Chinese children with canine allergy symptoms.


Assuntos
Alérgenos/genética , Alérgenos/imunologia , Epitopos de Linfócito B/genética , Epitopos de Linfócito B/imunologia , Expressão Gênica , Lipocalinas/genética , Lipocalinas/imunologia , Adolescente , Alérgenos/química , Alérgenos/isolamento & purificação , Sequência de Aminoácidos , Animais , Criança , Pré-Escolar , Códon , Cães , Ensaio de Imunoadsorção Enzimática , Epitopos de Linfócito B/química , Feminino , Humanos , Hipersensibilidade/imunologia , Imunoglobulina E/imunologia , Lactente , Lipocalinas/química , Lipocalinas/isolamento & purificação , Masculino , Modelos Moleculares , Conformação Proteica , Proteínas Recombinantes
11.
Food Sci Biotechnol ; 27(6): 1667-1673, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30483430

RESUMO

Fourier transform infrared spectroscopy was used to analyze the changes of secondary structure of myofibrillar proteins in short-term storage of battered and deep-fried pork slices. These changes were combined with low-field NMR analysis results to analyze the correlation between secondary structure and dynamic changes of water content. The results showed that the number of α-helix and ß-sheet decreased by 22.90 and 16.54% respectively, and the orderly structure changed to the disorder structure. The correlation results show that NMR spin-spin relaxation time (T21) has a high negative correlation with α-helix, ß-sheet, and has a high positive correlation with irregular curl and ß-turn. The population of immobile water (P22) has a very high positive correlation with α-helix, ß-sheet, and has a relatively high negative correlation with irregular curl and ß-turn. The immobilized water plays an important role in maintaining the secondary structure.

12.
Eur J Pharmacol ; 815: 501-511, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-29031898

RESUMO

Conflicting data exist on the effect of ginsenosides on transactivation of human glucocorticoid receptor α (herein referred to as glucocorticoid receptor), and relatively little is known regarding the effect of these chemicals on transrepression of this receptor. We investigated the effect of 20(S)-protopanaxadiol (PPD), PPD-type ginsenosides (Rb1, Rb2, Rc, Rd, Rh2, and Compound K), 20(S)-protopanaxatriol (PPT), and PPT-type ginsenosides (Re, Rf, Rg1, and Rh1) on glucocorticoid receptor binding, transactivation, and transrepression. Each ginsenoside was less efficacious than dexamethasone (positive control) in binding to the ligand-binding domain of glucocorticoid receptor. Among the ginsenosides investigated, Rh2 had the smallest IC50 value (15 ± 1µM), whereas it was 0.02 ± 0.01µM for dexamethasone. In contrast to dexamethasone, none of the ginsenosides influenced glucocorticoid receptor transactivation or transrepression in LS180 human colorectal adenocarcinoma cells, as assessed in a dual-luciferase reporter gene assay. Rh2 did not affect the endogenous mRNA level of tyrosine aminotransferase (marker for glucocorticoid receptor transactivation) or corticosteroid-binding globulin (marker for glucocorticoid receptor transrepression) in HepG2 human hepatocellular carcinoma cells. This chemical also did not alter the response by a glucocorticoid receptor agonist (dexamethasone or Compound A) in the dual-luciferase reporter gene assay or target gene expression assay. In conclusion, ginsenosides were less efficacious and less potent than dexamethasone in binding to the ligand-binding domain of glucocorticoid receptor. The number of glycosylated groups was associated with a decrease in receptor binding potency. PPD-type and PPT-type ginsenosides are not modulators of glucocorticoid receptor transactivation or transrepression in LS180 and HepG2 cells.


Assuntos
Ginsenosídeos/metabolismo , Ginsenosídeos/farmacologia , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Ativação Transcricional/efeitos dos fármacos , Células Hep G2 , Humanos , Ligantes , Ligação Proteica , Domínios Proteicos , Receptores de Glucocorticoides/química
13.
Int J Nanomedicine ; 12: 5255-5269, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28769562

RESUMO

Previous studies have shown that mithramycin A (MIT) is a promising candidate for the treatment of pancreatic carcinoma through inhibiting transcription factor Sp1. However, systemic toxicities may limit its clinical application. Here, we report a rationally designed formulation of MIT-loaded nanoparticles (MIT-NPs) with a small size and sustained release for improved passive targeting and enhanced therapeutic efficacy. Nearly spherical MIT-NPs with a mean particle size of 25.0±4.6 nm were prepared by encapsulating MIT into methoxy poly(ethylene glycol)-block-poly(d,l-lactic-co-glycolic acid) (mPEG-PLGA) nanoparticles (NPs) with drug loading of 2.11%±0.51%. The in vitro release of the MIT-NPs lasted for >48 h with a sustained-release pattern. The cytotoxicity of MIT-NPs to human pancreatic cancer BxPC-3 and MIA Paca-2 cells was comparable to that of free MIT. Determined by flow cytometry and confocal microscopy, the NPs internalized into the cells quickly and efficiently, reaching the peak level at 1-2 h. In vivo fluorescence imaging showed that the prepared NPs were gradually accumulated in BxPC-3 and MIA Paca-2 xenografts and retained for 168 h. The fluorescence intensity in both BxPC-3 and MIA Paca-2 tumors was much stronger than that of various tested organs. Therapeutic efficacy was evaluated with the poorly permeable BxPC-3 pancreatic carcinoma xenograft model. At a well-tolerated dose of 2 mg/kg, MIT-NPs suppressed BxPC-3 tumor growth by 96%. Compared at an equivalent dose, MIT-NPs exerted significantly higher therapeutic effect than free MIT (86% versus 51%, P<0.01). Moreover, the treatment of MIT and MIT-NPs reduced the expression level of oncogene c-Myc regulated by Sp1, and notably, both of them decreased the protein level of CD47. In summary, the novel formulation of MIT-NPs shows highly therapeutic efficacy against pancreatic carcinoma xenograft. In addition, MIT-NPs can downregulate CD47 expression, implying that it might play a positive role in cancer immunotherapy.


Assuntos
Nanopartículas/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Plicamicina/administração & dosagem , Poliésteres/química , Polietilenoglicóis/química , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Feminino , Humanos , Camundongos Endogâmicos BALB C , Microscopia Confocal , Nanopartículas/química , Tamanho da Partícula , Plicamicina/farmacocinética , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Pharmacol Res ; 126: 66-76, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28392461

RESUMO

Overexpression of EGFR and MMP-2 plays an essential role in the initiation and progression of non-small-cell lung carcinoma (NSCLC). In this study, a novel format of EGFR/MMP-2 bi-targeted fusion protein Ec-LDP-TIMP2 and its enediyne-integrated analogue Ec-LDP(AE)-TIMP2 have been prepared by genetic engineering and molecular reconstitution. The Ec-LDP(AE)-TIMP2 comprises endogenous inhibitor of matrix metalloproteinase 2 (TIMP2), EGF-derived oligopeptide (Ec), lidamycin apoprotein (LDP), and the extremely potent cytotoxic enediyne (AE). By tissue microarray, Ec-LDP-TIMP2 showed high binding intensity and selectivity to human NSCLC specimens as compared with the matched non-cancerous tissues. By in vivo imaging, Ec-LDP-TIMP2 displayed prominent tumor-specific distribution in human NSCLC H460 xenograft. Particularly, Ec-LDP(AE)-TIMP2 inhibited tumor growth of H460 xenograft in athymic mice more striking. At doses of 0.2 and 0.4mg/kg, Ec-LDP(AE)-TIMP2 suppressed tumor growth by 74% and 89%, respectively. No histopathological changes were found in various organs of treated animals, suggesting that the effective dosage was tolerated. In summary, the ligand-based and enediyne-integrated fusion protein displaying extremely potent cytotoxicity might be highly effective for NSCLC therapy and useful as a carrier for drug delivery.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Metaloproteinase 2 da Matriz/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Inibidor Tecidual de Metaloproteinase-2/farmacologia , Células A549 , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Ligantes , Neoplasias Pulmonares/metabolismo , Inibidores de Metaloproteinases de Matriz/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oligopeptídeos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
15.
Artigo em Inglês | MEDLINE | ID: mdl-28223385

RESUMO

Co-trimoxazole, a fixed-dose combination of sulfamethoxazole (SMX) and trimethoprim (TMP), has been used for the treatment of bacterial infections since the 1960s. Since it has long been assumed that the synergistic effects between SMX and TMP are the consequence of targeting 2 different enzymes of bacterial folate biosynthesis, 2 genes (pabB and nudB) involved in the folate biosynthesis of Escherichia coli were deleted, and their effects on the susceptibility to antifolates were tested. The results showed that the deletion of nudB resulted in a lag of growth in minimal medium and increased susceptibility to both SMX and TMP. Moreover, deletion of nudB also greatly enhanced the bactericidal effect of TMP. To elucidate the mechanism of how the deletion of nudB affects the bacterial growth and susceptibility to antifolates, 7,8-dihydroneopterin and 7,8-dihydropteroate were supplemented into the growth medium. Although those metabolites could restore bacterial growth, they had no effect on susceptibilities to the antifolates. Reverse mutants of the nudB deletion strain were isolated to further study the mechanism of how the deletion of nudB affects susceptibility to antifolates. Targeted sequencing and subsequent genetic studies revealed that the disruption of the tetrahydromonapterin biosynthesis pathway could reverse the phenotype caused by the nudB deletion. Meanwhile, overexpression of folM could also lead to increased susceptibility to both SMX and TMP. These data suggested that the deletion of nudB resulted in the excess production of tetrahydromonapterin, which then caused the increased susceptibility to antifolates. In addition, we found that the deletion of nudB also resulted in increased susceptibility to both SMX and TMP in Salmonella enterica Since dihydroneopterin triphosphate hydrolase is an important component of bacterial folate biosynthesis and the tetrahydromonapterin biosynthesis pathway also exists in a variety of bacteria, it will be interesting to design new compounds targeting dihydroneopterin triphosphate hydrolase, which may inhibit bacterial growth and simultaneously potentiate the antimicrobial activities of antifolates targeting other components of folate biosynthesis.


Assuntos
Antibacterianos/farmacologia , Proteínas de Escherichia coli/genética , Escherichia coli/efeitos dos fármacos , Antagonistas do Ácido Fólico/farmacologia , Pirofosfatases/genética , Salmonella enterica/efeitos dos fármacos , Combinação Trimetoprima e Sulfametoxazol/farmacologia , Escherichia coli/genética , Escherichia coli/crescimento & desenvolvimento , Proteínas de Escherichia coli/metabolismo , Deleção de Genes , Testes de Sensibilidade Microbiana , Neopterina/análogos & derivados , Neopterina/farmacologia , Pterinas/farmacologia , Pirofosfatases/antagonistas & inibidores , Salmonella enterica/genética , Salmonella enterica/crescimento & desenvolvimento , Tetra-Hidrofolato Desidrogenase/metabolismo
16.
Pharm Biol ; 54(1): 18-24, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-25857808

RESUMO

CONTEXT: Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects millions of elderly people worldwide. However, no efficient therapeutic method for AD has yet been developed. Recently, Salvia miltiorrhiza Bunge (Lamiaceae), a well-known traditional Chinese medicine which is widely used for treating cardio-cerebrovascular, exerts multiple neuroprotective effects and is attracting increased attention for the treatment of AD. OBJECTIVE: The objective of this study is to discuss the neuroprotective effects and neurogenesis-inducing activities of S. miltiorrhiza components. METHODS: A detailed search using major electronic search engines (such as Pubmed, ScienceDirect, and Google Scholar) was undertaken with the search terms: Salvia miltiorrhiza, the components of S. miltiorrhiza such as salvianolic acid B, salvianolic acid A, danshensu, tanshinone I, tanshinone IIA, cryptotanshinone, dihydrotanshinone, and neuroprotection. RESULTS: Salvia miltiorrhiza components exert multiple neuroprotective potentials relevant to AD, such as anti-amyloid-ß, antioxidant, anti-apoptosis, acetylcholinesterase inhibition, and anti-inflammation. Moreover, S. miltiorrhiza promotes neurogenesis of neural progenitor cells/stem cells in vitro and in vivo. CONCLUSIONS: The properties of S. miltiorrhiza indicate their therapeutic potential in AD via multiple mechanisms. In addition, S. miltiorrhiza provides lead compounds for developing new drugs against AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Salvia miltiorrhiza/química , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Fitoterapia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Plantas Medicinais , Placa Amiloide , Relação Estrutura-Atividade
17.
Guang Pu Xue Yu Guang Pu Fen Xi ; 35(5): 1187-92, 2015 May.
Artigo em Chinês | MEDLINE | ID: mdl-26415425

RESUMO

In the present paper, support vector machine (SVM) based on convex combination kernel function will be used for classification of THz pulse transmission spectra. Wavelet transform is used in data pre-processing. Peaks and valleys are regarded as location features of THz pulse transmission spectra, which are injected into maximum interval features of term frequency-inverse document frequency (TF-IDF). We can conclude weight of each sampling point from the information theory. The weight represents the possibility that sampling point becomes feature. According to the situation that different terahertz-transmission spectra are lack of obvious features, we composed a SVM classification model based on convex combination kernel function. Evaluation function should be used as an evaluation method for obtaining the parameters of optimal convex combination to achieve a better accuracy. When the optimal parameter of kenal founction was determined, we should compose the model for process of classification and prediction. Compared with the single kernel function, the method can be combined with transmission spectroscopic features with classification model iteratively. Thanks to the dimensional mapping process, outstanding margin of features can be gained for the samples of different terahertz transmission spectrum. We carried out experiments using different samples The results demonstrated that the new approach is on par or superior in terms of accuracy and much better in feature fusion than SVM with single kernel function.

18.
Biomed Pharmacother ; 69: 255-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25661367

RESUMO

HL-40, N-(4-(1-(4-chlorine indazole)) phenyl)-N-(4-chloro-3-three fluorine methyl phenyl) urea, is a novel diarylurea derivative. In this study, we investigated the kinases activities and binding constants, pharmacokinetics of HL-40, and then evaluated its anticancer efficacy by both in vitro and in vivo methods. Enzyme activities assays in vitro were employed to identify eight candidate kinase targets. The competition binding assays against eight candidate kinases suggested that HL-40 showed strong affinity to c-Kit, PDGFRß and FLT3. The pharmacokinetic studies in Wistar rats showed that HL-40 could maintain high compound concentration and long residence time in the blood circulation. HL-40 possessed strong inhibition activities against 12 human cancer cells. Meanwhile, HL-40 effectively delayed the growth of cancer xenografts without significant toxicity to mice. Based on these in vitro and in vivo results, we suggested that HL-40 might be developed as a potential multi-kinases inhibitor for cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Indazóis/farmacologia , Indazóis/farmacocinética , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Ureia/farmacologia , Ureia/farmacocinética , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios Enzimáticos , Humanos , Indazóis/administração & dosagem , Indazóis/química , Concentração Inibidora 50 , Masculino , Camundongos , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/química , Ratos Wistar , Ureia/administração & dosagem , Ureia/química , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Guang Pu Xue Yu Guang Pu Fen Xi ; 35(12): 3325-9, 2015 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-26964203

RESUMO

Feature extraction and classification are the key issues of terahertz spectroscopy identification. Because many materials have no apparent absorption peaks in the terahertz band, it is difficult to extract theirs terahertz spectroscopy feature and identify. To this end, a novel of identify terahertz spectroscopy approach with Deep Belief Network (DBN) was studied in this paper, which combines the advantages of DBN and K-Nearest Neighbors (KNN) classifier. Firstly, cubic spline interpolation and S-G filter were used to normalize the eight kinds of substances (ATP, Acetylcholine Bromide, Bifenthrin, Buprofezin, Carbazole, Bleomycin, Buckminster and Cylotriphosphazene) terahertz transmission spectra in the range of 0.9-6 THz. Secondly, the DBN model was built by two restricted Boltzmann machine (RBM) and then trained layer by layer using unsupervised approach. Instead of using handmade features, the DBN was employed to learn suitable features automatically with raw input data. Finally, a KNN classifier was applied to identify the terahertz spectrum. Experimental results show that using the feature learned by DBN can identify the terahertz spectrum of different substances with the recognition rate of over 90%, which demonstrates that the proposed method can automatically extract the effective features of terahertz spectrum. Furthermore, this KNN classifier was compared with others (BP neural network, SOM neural network and RBF neural network). Comparisons showed that the recognition rate of KNN classifier is better than the other three classifiers. Using the approach that automatic extract terahertz spectrum features by DBN can greatly reduce the workload of feature extraction. This proposed method shows a promising future in the application of identifying the mass terahertz spectroscopy.

20.
Biomed Pharmacother ; 68(3): 335-41, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24581722

RESUMO

PURPOSE: 1082-39, an analogue of sorafenib, is a derivative of indazole diarylurea. We evaluated the activity of 1082-39 against human cancer cell growth. Its effects and mechanisms of action were then compared with those of sorafenib. The experiments were performed in human melanoma M21 cells. METHODS: Cell viability was estimated by using the colorimetric assay. Annexin V-FITC/PI staining assay was used to recognize the apoptotic cells. Further analysis of the mitochondria membrane potential (MMP) was performed by the JC-1 fluorescence probe staining. The levels of apoptotic proteins and kinases related to cancer proliferation were determined by western blotting assay. RESULTS: 1082-39 possessed the activity against cancer cell proliferation with time- and dose-dependent manner. 1082-39 induced M21 cell to apoptosis, showing the increase of annexin V-FITC/PI staining cells, the MMP collapse and releasing cytochrome c from mitochondria. Western blotting analysis showed the activation of the mitochondria-mediated intrinsic pathway, showing the increase of cleaved caspase-9, cleaved caspase-3 and cleaved PARP. Statistical analysis suggested that 1082-39 possessed greater activities than sorafenib in the inhibition of M21 proliferation and induction of apoptosis. These effects of 1082-39 might arise from its activity of regulation the PI3K/Akt and Wnt/ß-catenin signaling pathways. CONCLUSIONS: 1082-39 is a promising candidate compound which could develop as a potent anticancer agent.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Niacinamida/análogos & derivados , Compostos de Fenilureia/farmacologia , Antineoplásicos/química , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Citosol/efeitos dos fármacos , Citosol/metabolismo , Relação Dose-Resposta a Droga , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estrutura Molecular , Niacinamida/química , Niacinamida/farmacologia , Compostos de Fenilureia/química , Proteínas Tirosina Quinases/metabolismo , Sorafenibe , Relação Estrutura-Atividade
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