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1.
Artigo em Inglês | MEDLINE | ID: mdl-32401490

RESUMO

Hierarchically porous carbons (HPCs) with multimodal pore systems exhibit great technological potentials, especially in the fields of heterogeneous catalysis, energy storage, and conversion. Here, we establish a simple and general approach to HPCs by carbonization of nonporous coordination polymers that are produced by mixing metal salts with polytopic ligands in alkaline aqueous solutions at room temperature. The proposed approach is applicable to a wide scope of ligand molecules (18 examples), thus affording the synthesized HPCs with high diversity in porosity, morphology, and composition. In particular, the prepared HPCs exhibit high specific surface areas (up to 2647 m2 g-1) and large pore volumes (up to 2.39 cm3 g-1). The HPCs-supported atomically dispersed Fe-Nx catalysts show much-improved fuel cell cathode performance over the micropore-dominated carbon black-supported catalysts, demonstrating the structural superiority of the HPCs for enhancing the mass transport properties.

2.
Bioorg Med Chem Lett ; 30(7): 126969, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32014384

RESUMO

In this work, according to the 'me-too me-better' design strategy, a peculiar side chain different from lefamulin at C14 position of pleuromutilin was introduced. A series of novel thioether pleuromutilin derivatives containing cyclohexane in the C14 chain was synthesized by ten-step synthesis reaction. All derivatives were characterized by Nuclear Magnetic Resonance (NMR) and High Resolution Mass Spectrometer (HRMS). Furthermore, majority of derivatives displayed moderate antibacterial activity in vitro. However, the compound 2C and 2J exhibited comparable or superior antibacterial activity to lefamulin. The summarized structure-activity relationship not only made the variety of pleuromutilin derivatives more diverse, but also provided new ideas for its design and development.

3.
Bioorg Med Chem Lett ; 30(7): 127019, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32057582

RESUMO

A series of novel HIV-1 protease inhibitors has been designed and synthesized, which contained morpholine derivatives as the P2 ligands and hydrophobic cyclopropyl as the P1' ligand at the meantime in this study, with the aim of improving the interactions between the active sites of HIV-1 protease and the inhibitors. Twenty-eight compounds were synthesized and assessed, among which inhibitors m18 and m1 exhibited excellent inhibitory effect on the activity of HIV-1 protease with IC50 value of 47 nM and 53 nM, respectively. The molecular modeling of m1 revealed possible hydrogen bondings or van der Waals between the inhibitor and the protease, worthy of in-depth study.

4.
Acta Pharmacol Sin ; 41(5): 661-669, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31932644

RESUMO

Chronic tissue injury with fibrosis results in the disruption of tissue architecture, organ dysfunction, and eventual organ failure. Therefore, the development of effective antifibrotic drugs is urgently required. IMB-S7 is novel biphenyl compound derived from bifendate (biphenyldicarboxylate) that is used for the treatment of chronic hepatitis in China. In the current study we investigated the potential of IMB-S7 as an antihepatic fibrosis agent. In bile duct ligation (BDL) rat model, oral administration of IMB-S7 (400 mg· kg-1· d-1, for 14 days) significantly ameliorated BDL-induced liver necrosis, bile duct proliferation, and collagen accumulation. We then showed that IMB-S7 treatment markedly suppressed the TGF-ß/Smad pathway in human hepatic stellate cell line LX2 and mouse primary HSCs, as well as in liver samples of BDL rats, thus inhibiting the transcription of most fibrogenesis-associated genes, including TGF-ß1, COL1A1, and ACTA2. Furthermore, IMB-S7 treatment significantly suppressed the expression of integrin αv at the mRNA and protein levels in TGF-ß-treated LX2 cells and liver samples of BDL rats. Using integrin αv overexpression and silencing, we demonstrated that integrin αv activity correlated positively with the activation of TGF-ß/Smad pathway. Based on dual luciferase assay and DNA affinity precipitation assay, we revealed that IMB-S7 inactivated integrin αv through competitively inhibiting the binding of Sp1, a transcription factor, to the integrin αv (ITGAV) promoter (-173/-163 bp). These results suggest that IMB-S7 inhibits HSCs activation and liver fibrosis through Sp1-integrin αv signaling, and IMB-S7 may be a promising candidate to combat hepatic fibrosis in the future.

5.
Chem Sci ; 10(35): 8236-8240, 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31673323

RESUMO

The development of high-performance non-platinum group metal (non-PGM) catalysts for the oxygen reduction reaction (ORR) is still of significance in promoting the commercialization of proton exchange membrane fuel cells (PEMFCs). In this work, a "hierarchically porous carbon (HPC)-supporting" approach was developed to synthesize highly ORR active Fe-phenanthroline (Fe-phen) derived Fe-N x -C catalysts. Compared to commercial carbon black supports, utilizing HPCs as carbon supports can not only prevent the formation of inactive iron nanoparticles during pyrolysis but also optimize the porous morphology of the catalysts, which eventually increases the amount of reactant-accessible and atomically dispersed Fe-N x active sites. The prepared catalyst therefore exhibits a remarkable ORR activity in both half-cells (half-wave potential of 0.80 V in 0.5 M H2SO4) and H2-air PEMFCs (442 mA cm-2 at a working voltage of 0.6 V), making it among the best non-PGM catalysts for PEMFCs.

6.
Healthcare (Basel) ; 7(3)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31500204

RESUMO

Three-dimensional (3D) printing has great potential for establishing a ubiquitous service in the medical industry. However, the planning, optimization, and control of a ubiquitous 3D printing network have not been sufficiently discussed. Therefore, this study established a collaborative and ubiquitous system for making dental parts using 3D printing. The collaborative and ubiquitous system split an order for the 3D printing facilities to fulfill the order collaboratively and forms a delivery plan to pick up the 3D objects. To optimize the performance of the two tasks, a mixed-integer linear programming (MILP) model and a mixed-integer quadratic programming (MIQP) model are proposed, respectively. In addition, slack information is derived and provided to each 3D printing facility so that it can determine the feasibility of resuming the same 3D printing process locally from the beginning without violating the optimality of the original printing and delivery plan. Further, more slack is gained by considering the chain effect between two successive 3D printing facilities. The effectiveness of the collaborative and ubiquitous system was validated using a regional experiment in Taichung City, Taiwan. Compared with two existing methods, the collaborative and ubiquitous 3D printing network reduced the manufacturing lead time by 45% on average. Furthermore, with the slack information, a 3D printing facility could make an independent decision about the feasibility of resuming the same 3D printing process locally from the beginning.

7.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 37(3): 265-269, 2019 Jun 01.
Artigo em Chinês | MEDLINE | ID: mdl-31218859

RESUMO

OBJECTIVE: This study applied the direct orthodontic force system to explore the applicability of the finite element method in the simulation of alveolar bone absorption and analyze periodontal stress distribution and the overall displacement trend. METHODS: The horizontal balanced alveolar bones of model 2, 3 and 4 were reduced by 2, 4, and 6 mm by deleting elements in reference to the established height of the normal alveolar bone model 1. Then, stress distribution on the posterior set of teeth and initial total tooth displacement under the simulated load of 1.47 N of orthodontic force were investigated. RESULTS: The total displacement of posterior teeth increased and parodontium Von Mises stress gradually increased as the alveolar bone height decreased. The total displacement trend and parodontium stress drastically increased when alveolar bone absorp-tion reached the height of 4 mm. CONCLUSIONS: When treating patients with alveolar bone loss, stress should be avoided or drasti-cally reduced to prevent irreversible damage to periodontal tissue and to improve the quality of medical treatment.


Assuntos
Dente Canino , Técnicas de Movimentação Dentária , Simulação por Computador , Análise de Elementos Finitos , Humanos , Maxila , Ligamento Periodontal
8.
Oncol Rep ; 42(2): 697-707, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31233205

RESUMO

Human non­small cell lung cancer (NSCLC) is associated with an extremely poor prognosis especially for the 40% of patients who develop brain metastasis, and few treatment strategies exist. Cucurbitacin E (CuE), an oxygenated tetracyclic triterpenoid isolated from plants particularly of the family Cucurbitaceae, has shown anti­tumorigenic properties in several types of cancer, yet the mechanism remains unclear. Yes­associated protein (YAP), a main mediator of the Hippo signaling pathway, promotes tumorigenesis, drug resistance and metastasis in human NSCLC. The present study was designed to ascertain whether CuE inhibits YAP and its downstream gene expression in the human NSCLC cell lines H2030­BrM3 (K­rasG12C mutation) and PC9­BrM3 (EGFRΔexon19 mutation), which have high potential for brain metastasis. The efficacy of CuE in suppressing brain metastasis of H2030­BrM3 cells in a murine model was also investigated. It was found that after CuE treatment in H2030­BrM3 and PC9­BrM3 cells, YAP protein expression was decreased, and YAP signaling GTIIC reporter activity and expression of the downstream genes CTGF and CYR61 were significantly (P<0.01) decreased. CuE treatment also reduced the migration and invasion abilities of the H2030­BrM3 and PC9­BrM3 cells. Finally, our in vivo study showed that CuE treatment (0.2 mg/kg) suppressed H2030­BrM3 cell brain metastasis and that mice treated with CuE survived longer than the control mice treated with 10% DMSO (P=0.02). The present study is the first to demonstrate that CuE treatment inhibits YAP and the signaling downstream gene expression in human NSCLC in vitro, and suppresses brain metastasis of NSCLC in a murine model. More studies to verify the promising efficacy of CuE in inhibiting brain metastasis of NSCLC and various other cancers may be warranted.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/antagonistas & inibidores , Triterpenos/farmacologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Movimento Celular , Proliferação de Células , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Bioorg Med Chem Lett ; 29(12): 1541-1545, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31014912

RESUMO

Introducing purine bases to P2-ligands might enhance the potency of Human Immunodeficiency Virus-1 (HIV-1) protease inhibitory because of the carbonyl and NH groups promoting the formation of extensive H-bonding interactions. In this work, thirty-three compounds are synthesized and evaluated, among which inhibitors 16a, 16f and 16j containing N-2-(6-substituted-9H-purin-9-yl)acetamide as the P2-ligands along with 4-methoxylphenylsulfonamide as the P2'-ligand, display potent inhibitory effect on the activity of HIV-1 protease with IC50 43 nM, 42 nM and 68 nM in vitro, respectively.

10.
Int J Mol Sci ; 20(5)2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30866467

RESUMO

MYB proteins play important roles in the regulation of plant growth, development, and stress responses. Overexpression of BplMYB46 from Betula platyphylla improved plant salt and osmotic tolerances. In the present study, the interaction of eight avian myeloblastosis viral oncogene homolog (MYB) transcription factors with BplMYB46 was investigated using the yeast two-hybrid system, which showed that BplMYB46 could form homodimers and heterodimers with BplMYB6, BplMYB8, BplMYB11, BplMYB12, and BplMYB13. Relative beta-glucuronidase activity and chromatin immunoprecipitation assays showed that the interaction between BplMYB46 and the five MYBs increased the binding of BplMYB46 to the MYBCORE motif. A subcellular localization study showed that these MYBs were all located in the nucleus. Real-time fluorescence quantitative PCR results indicated that the expressions of BplMYB46 and the five MYB genes could be induced by salt and osmotic stress, and the BplMYB46 and BplMYB13 exhibited the most similar expression patterns. BplMYB46 and BplMYB13 co-overexpression in tobacco using transient transformation technology improved tobacco's tolerance to salt and osmotic stresses compared with overexpressing BplMYB13 or BplMYB46 alone. Taken together, these results demonstrated that BplMYB46 could interact with five other MYBs to form heterodimers that activate the transcription of target genes via an enhanced binding ability to the MYBCORE motif to mediate reactive oxygen species scavenging in response to salt and osmotic stresses.


Assuntos
Betula/crescimento & desenvolvimento , Fatores de Transcrição/química , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Motivos de Aminoácidos , Betula/química , Betula/genética , Betula/metabolismo , Sítios de Ligação , Núcleo Celular/metabolismo , Evolução Molecular , Regulação da Expressão Gênica de Plantas , Pressão Osmótica , Proteínas de Plantas/química , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Ligação Proteica , Multimerização Proteica , Estresse Salino , Técnicas do Sistema de Duplo-Híbrido
11.
Acta Biomater ; 86: 280-290, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30616077

RESUMO

Recently, novel approaches for the delivery of therapeutic antibodies have attracted much attention, especially sustained release formulations. However, sustained release formulations capable of carrying a high antibody load remain a challenge for practical use. In this study, a novel injectable hydrogel composed of maleimide-modified γ-polyglutamic acid (γ-PGA-MA) and thiol end-functionalized 4-arm poly(ethylene glycol) (4-arm PEG-SH) was developed for the subcutaneous delivery of trastuzumab. γ-PGA-MA and 4-arm PEG-SH formed a hydrogel through thiol-maleimide reactions, which had shear-thinning properties and reversible rheological behaviors. Moreover, a high content of trastuzumab (>100 mg/mL) could be loaded into this hydrogel, and trastuzumab demonstrated a sustained release over several weeks through electrostatic attraction. In addition, trastuzumab released from the hydrogel had adequate stability in terms of its structural integrity, binding bioactivity, and antiproliferative effect on BT-474 cells. Pharmacokinetic studies demonstrated that trastuzumab-loaded hydrogel (Her-hydrogel-10, composed of 1.5% γ-PGA-MA, 1.5% 4-arm PEG-SH, and 10 mg/mL trastuzumab) and trastuzumab/Zn-loaded hydrogel (Her/Zn-hydrogel-10, composed of 1.5% γ-PGA-MA, 1.5% 4-arm PEG-SH, 5 mM ZnCl2, and 10 mg/mL trastuzumab) could lower the maximum plasma concentration (Cmax) than the trastuzumab solution. Furthermore, Her/Zn-hydrogel-10 was better able to release trastuzumab in a controlled manner, which was ascribed to electrostatic attraction and formation of trastuzumab/Zn nanocomplexes. In a BT-474 xenograft tumor model, Her-hydrogel-10 had a similar tumor growth-inhibitory effect as that of the trastuzumab solution. By contrast, Her/Zn-hydrogel-10 exhibited a superior tumor growth-inhibitory capability due to the functionality of Zn. This study demonstrated that this hydrogel has potential as a carrier for the local and systemic delivery of proteins and antibodies. STATEMENT OF SIGNIFICANCE: Recently, novel sustained-release formulations of therapeutic antibodies have attracted much attention. However, these formulations should be able to carry a high antibody load owing to the required high dose, and these formulations remain a challenge for practical use. In this study, a novel injectable chemically cross-linked hydrogel was developed for the subcutaneous delivery of trastuzumab. This novel hydrogel possessed ideal characteristics of loading high content of trastuzumab (>100 mg/mL), sustained release of trastuzumab over several weeks, and maintaining adequate stability of trastuzumab. In vivo studies demonstrated that a trastuzumab-loaded hydrogel possessed the ability of controlled release of trastuzumab and maintained antitumor efficacy same as that of trastuzumab. These results implied that a γ-PGA-MA and 4-arm PEG-SH-based hydrogel has great potential in serving as a carrier for the local or systemic delivery of therapeutic proteins or antibodies.

12.
Chem Biodivers ; 16(2): e1800560, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30467968

RESUMO

A series of novel thioether or sulfoxide-type pleuromutilin derivatives containing heteroaromatic substituents at the end of C14 side chain were designed and synthesized. All of the derivatives were evaluated for their in vitro antibacterial activity. Some of them showed good to excellent antibacterial activity comparable to retapamulin and azamulin in most of the tested Gram-positive pathogens. In this work, a five-membered heterocyclic moiety, a pyrimidine-heterocyclic moiety, or a benzoheterocyclic moiety was introduced in the C14 side chain to increase the structural diversity of the pleuromutilin derivatives. The antibacterial results reveal that the thioether-containing pleuromutilin derivatives exert a more potency activity than the sulfoxide-type derivatives against Gram-positive pathogens. The structure-activity relationship summarized in this work may provide with some interesting clues as to which functionalities are beneficial for high antimicrobial activity of the pleuromutilin derivatives.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Diterpenos/química , Diterpenos/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Compostos Policíclicos , Relação Estrutura-Atividade , Sulfetos , Sulfóxidos
13.
Bioorg Med Chem Lett ; 29(3): 357-361, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30580917

RESUMO

The design, synthesis and SAR study of a new series of HIV-1 protease inhibitors with pentacyclic triterpenoids as P2 ligands and phenylsulfonamide as P2' ligands were discussed. These compounds exhibited micromolar inhibitory potency, among which compound T1c displayed HIV-1 protease inhibition with IC50 values of 0.12 µM, which was 67 times the inhibitory activity of its raw material Ursolic acid (8.0 µM).


Assuntos
Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , Triterpenos Pentacíclicos/farmacologia , Sulfonamidas/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/química , HIV-1/efeitos dos fármacos , Humanos , Ligantes , Testes de Sensibilidade Microbiana , Estrutura Molecular , Triterpenos Pentacíclicos/síntese química , Triterpenos Pentacíclicos/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
14.
Mol Oncol ; 13(2): 246-263, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30372581

RESUMO

Epidermal growth factor receptor (EGFR) is a rational target for cancer therapy, because its overexpression plays an important oncogenic role in a variety of solid tumors; however, EGFR-targeted antibody-drug conjugate (ADC) therapy for esophageal squamous cell carcinoma (ESCC) is exceedingly rare. LR004 is a novel anti-EGFR antibody with the advantages of improved safety and fewer hypersensitivity reactions. It may be of great value as a carrier in ADCs with high binding affinity and internalization ability. Here, we prepared an EGFR-targeting ADC, LR004-VC-MMAE, and evaluated its antitumor activities against ESCC and EGFR-positive cells. LR004 was covalently conjugated with monomethyl auristatin E (MMAE) via a VC linker by antibody interchain disulfide bond reduction. VC-MMAE was conjugated with LR004 with approximately 4.0 MMAE molecules per ADC. LR004-VC-MMAE showed a potent antitumor effect against ESCC and other EGFR-positive cells with IC50 values of nM concentrations in vitro. The in vivo antitumor effects of LR004-VC-MMAE were investigated in ESCC KYSE520 and A431 xenograft nude mice models. Significant activity was seen at 5 mg·kg-1 , and complete tumor regression was observed at 15 mg·kg-1 in the KYSE520 xenograft nude mice after four injections, while the naked antibody LR004 had little effect on inhibiting tumor growth. Similar promising results were obtained in the A431 models. In addition, the tumors also remained responsive to LR004-VC-MMAE for large tumor experiments (tumor volume 400-500 mm3 ). The study results demonstrated that LR004-VC-MMAE could be a potential therapeutic agent for ESCC and other EGFR-expressing malignancies. We also evaluated PK profile of LR004-VC-MMAE ADC in the mice model, which would provide qualitative guiding significance for the further research.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Receptores ErbB/metabolismo , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Imunoconjugados/uso terapêutico , Oligopeptídeos/uso terapêutico , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Endocitose/efeitos dos fármacos , Feminino , Humanos , Imunoconjugados/química , Imunoconjugados/farmacocinética , Imunoconjugados/farmacologia , Concentração Inibidora 50 , Camundongos Endogâmicos BALB C , Camundongos Nus , Oligopeptídeos/química , Oligopeptídeos/farmacocinética , Oligopeptídeos/farmacologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Acta Pharmacol Sin ; 40(7): 895-907, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30573812

RESUMO

The manipulation of bile acid (BA) homeostasis by blocking the ileal apical Na+-dependent bile salt transporter (ASBT/SLC10A2) may have therapeutic effects in nonalcoholic fatty liver disease. We developed a novel ASBT inhibitor, an N-(3,4-o-dichlorophenyl)-2-(3-trifluoromethoxy) benzamide derivative referred to as IMB17-15, and investigated its therapeutic effects and the molecular mechanisms underlying the effects. Syrian golden hamsters were challenged with high-fat diet (HFD) to induce NAFLD and were subsequently administered 400 mg/kg IMB17-15 by gavage daily for 21 days. Serum, liver, and fecal samples were collected for further analysis. Plasma concentration-time profiles of IMB17-15 were also constructed. The human hepatocyte cell line HL-7702 was treated with Oleic acid (OA) with or without IMB17-15. Western blotting and real-time PCR were used to study the molecular mechanisms of IMB17-15. We found that IMB17-15 inhibited ASBT and subsequently suppressed ileal farnesoid X receptor (FXR) and FXR-activated fibroblast growth factor15/19 (FGF15/19) expression, which reduced the hepatic phosphorylated extracellular regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) levels and upregulated the cholesterol 7α-hydroxylase (CYP7A1) activity. Additionally, IMB17-15 stimulated adenosine monophosphate (AMP)-activated protein kinase (AMPKα) phosphorylation and enhanced peroxisome proliferator activated receptor α (PPARα) expression and thus promoted triglyceride (TG) oxidation and high-density lipoprotein cholesterol (HDL-c) metabolism through an ASBT-independent mechanism. In conclusion, a novel ASBT inhibitor known as IMB17-15 protected hamsters against HFD-induced NFALD by manipulating BA and lipid homeostasis. IMB17-15 also reduced lipid deposition in human hepatic cell lines, indicating that it may be useful as a therapy for NAFLD patients.


Assuntos
Benzamidas/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Simportadores/antagonistas & inibidores , Animais , Benzamidas/farmacocinética , Benzamidas/toxicidade , Linhagem Celular , Citocinas/metabolismo , Dieta Hiperlipídica , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fígado/patologia , Masculino , Mesocricetus , Camundongos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Sulfonamidas/farmacocinética , Sulfonamidas/toxicidade
16.
Zhongguo Zhong Yao Za Zhi ; 43(10): 2147-2152, 2018 May.
Artigo em Chinês | MEDLINE | ID: mdl-29933685

RESUMO

Alisol A 24-acetate, a triterpenoid extracted from Alisma orientale, has shown anti-atherosclerotic actions and many studies have proved that oxidized low density lipoprotein (Ox-LDL) could promote proliferation of aorta smooth muscle cells (VSMCs) which are closely related to atherosclerosis (AS). The purpose of this study was to evaluate the effect of alisol A 24-acetate on the proliferation of VSMCs isolated from the thoracic aorta of rats induced by ox-LDL. VSMCs were induced by ox-LDL(50 mg·L⁻¹) to establish the proliferation model and intervened by alisol A 24-acetate (5, 10, 20 mg·L⁻¹) for 12, 24 and 48 h. Then the proliferation of VSMCs was detected by MTT assay; protein expression levels of VSMCs PCNA, cyclinD1, cyclinE, p21, p27 and VSMCs PCNA, p21and p27 mRNA expression levels were detected by Western blot and Real-time polymerase chain reaction (RT-PCR) respectively. The results showed that ox-LDL could induce the proliferation of VSMCs (P<0.05), increase the protein expression levels of PCNA, cyclinD1 and cyclinE in the VSMCs (P<0.05) and inhibit the protein and mRNA expression levels of p21 and p27 (P<0.05). As compared with the model group, alisol A 24-acetate inhibited the proliferation of VSMCs in rats induced by ox-LDL and inhibited the protein expression of VSMCs PCNA, cyclinD1, cyclinE and enhanced the protein and mRNA p21 and p27 expression levels (P<0.05). The effect was more obvious with the increase of concentration of alisol A 24-acetate. These data indicate that alisol A 24-acetate can inhibit the proliferation of VSMCs induced by ox-LDL and the mechanism may be associated with inhibiting expression of cyclin protein, including cyclinD1, cyclinE, p21, p27 and so on.


Assuntos
Proliferação de Células/efeitos dos fármacos , Colestenonas/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Animais , Aorta/citologia , Células Cultivadas , Lipoproteínas LDL , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/citologia , Ratos
17.
PLoS Biol ; 16(5): e2004225, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29750781

RESUMO

p38 has long been known as a central mediator of protein kinase A (PKA) signaling in brown adipocytes, which positively regulate the transcription of uncoupling protein 1 (UCP-1). However, the physiological role of p38 in adipose tissues, especially the white adipose tissue (WAT), is largely unknown. Here, we show that mice lacking p38α in adipose tissues display a lean phenotype, improved metabolism, and resistance to diet-induced obesity. Surprisingly, ablation of p38α causes minimal effects on brown adipose tissue (BAT) in adult mice, as evident from undetectable changes in UCP-1 expression, mitochondrial function, body temperature (BT), and energy expenditure. In contrast, genetic ablation of p38α in adipose tissues not only markedly facilitates the browning in WAT upon cold stress but also prevents diet-induced obesity. Consistently, pharmaceutical inhibition of p38α remarkably enhances the browning of WAT and has metabolic benefits. Furthermore, our data suggest that p38α deficiency promotes white-to-beige adipocyte reprogramming in a cell-autonomous manner. Mechanistically, inhibition of p38α stimulates the UCP-1 transcription through PKA and its downstream cAMP-response element binding protein (CREB), which form a positive feedback loop that functions to reinforce the white-to-beige phenotypic switch during cold exposure. Together, our study reveals that inhibition of p38α is able to promote WAT browning and confer metabolic benefits. Our study also indicates that p38α in WAT represents an exciting pharmacological target to combat obesity and metabolic diseases.


Assuntos
Tecido Adiposo/metabolismo , Imidazóis/uso terapêutico , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Obesidade/metabolismo , Piridinas/uso terapêutico , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Animais , Reprogramação Celular , Temperatura Baixa , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dieta Hiperlipídica , Avaliação Pré-Clínica de Medicamentos , Imidazóis/farmacologia , Camundongos , Camundongos Knockout , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 14 Ativada por Mitógeno/genética , Obesidade/prevenção & controle , Fenótipo , Piridinas/farmacologia , Termogênese
18.
ACS Appl Mater Interfaces ; 10(19): 16596-16604, 2018 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-29687705

RESUMO

We report a facile transfer method to fabricate flexible photodetectors directly on tape, wherein the films formed by different processes were integrated together. The tape-based photodetectors with CdS nanowire (NW) active layers exhibited good performances as those fabricated by conventional processes. The obvious persistent photocurrent in our device was eliminated by introducing a conductive polymer poly(3,4-ethylenedioxythiophene)polystyrene sulfonate (PEDOT:PSS) onto the CdS NW layer. By adjusting the concentration of the PEDOT:PSS aqueous solution, a device with a fast response, ultrashort decay time, and relatively large photocurrent was obtained. The decay times were 11.59 and 6.64 ms for devices using electrodes of silver NWs and gold, respectively. These values are much shorter than the shortest decay times (on the order of hundreds of milliseconds) reported previously.

19.
J Cell Mol Med ; 22(6): 3139-3148, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29575535

RESUMO

Although tumour PD-L1 (CD274) expression had been used as a predictive biomarker in checkpoint immunotherapy targeting the PD1/PD-L1 axis in various cancers, the regulation of PD-L1 (CD274) expression is unclear. Yes-associated protein (YAP), an important oncogenic protein in Hippo signalling pathway, reportedly promotes cancer development. We investigated whether inhibition of YAP down-regulates PD-L1 (CD274) in human malignant pleural mesothelioma (MPM). Western blotting showed that 2 human MPM cell lines (H2052 and 211H) had increased PD-L1 protein expression compared to H290, MS-1 and H28 cells. In H2052 and 211H cells, PD-L1 mRNA expression was significantly increased compared to other MPM cell lines; YAP knockdown by small interfering RNA decreased PD-L1 protein and mRNA expression. Forced overexpression of the YAP gene increased PD-L1 protein expression in H2452 cells. Chromatin immunoprecipitation (ChIP) assay showed the precipitation of PD-L1 enhancer region encompassing 2 putative YAP-TEAD-binding sites in H2052 cells. We found that, in human MPM tissue microarray samples, YAP and PD-L1 concurrently expressed in immunohistochemistry stain (n = 70, P < .05, chi-square). We conclude that PD-L1 is correlated with YAP expression, and inhibition of YAP down-regulates PD-L1 expression in human MPM. Further study of how YAP regulates PD-L1 in MPM is warranted.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Antígeno B7-H1/genética , Neoplasias Pulmonares/genética , Mesotelioma/genética , Fosfoproteínas/genética , Neoplasias Pleurais/genética , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Mesotelioma/patologia , Fosfoproteínas/antagonistas & inibidores , Neoplasias Pleurais/patologia , Transdução de Sinais/genética , Fatores de Transcrição
20.
ACS Appl Mater Interfaces ; 10(17): 14602-14613, 2018 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-29565123

RESUMO

Reasonable design and synthesis of Fe/N/C-based catalysts is one of the most promising way for developing precious metal-free oxygen reduction reaction (ORR) catalysts in acidic mediums. Herein, we developed a highly active metal-organic framework-derived S-doped Fe/N/C catalyst [S-Fe/Z8/2-aminothiazole (2-AT)] prepared by thermal treatment. The S-Fe/Z8/2-AT catalyst with uniform S-doping possesses a three-dimensional macro-meso-micro hierarchically porous structure. Moreover, the chemical composition and structural features have been well-optimized and characterized for such S-Fe/Z8/2-AT catalysts; and their formation mechanism was also revealed. Significantly, applying the optimal S-Fe/Z8/2-AT catalysts into electrocatalytic test exhibits remarkable ORR catalytic activity with a half-wave potential of 0.82 V (vs reversible hydrogen electrode) and a mass activity of 18.3 A g-1 at 0.8 V in 0.1 M H2SO4 solution; the polymer electrolyte membrane fuel cell test also confirmed their excellent catalytic activity, which gives a maximal power density as high as 800 mW cm-2 at 1 bar. A series of designed experiments disclosed that the favorable structural merits and desirable chemical compositions of S-Fe/Z8/2-AT catalysts are critical factors for efficient electrocatalytic performance. The work provides a new approach to open an avenue for accurately controlling the composition and structure of Fe/N/C catalysts with highly activity for ORR.

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