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1.
Anticancer Res ; 40(6): 3345-3354, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487630

RESUMO

BACKGROUND/AIM: In addition to its cytocidal effects as a microtubule dynamics inhibitor, eribulin mesylate (eribulin) regulates the tumour microenvironment. We examined the clinical significance of tumour infiltrating lymphocytes (TILs) and transforming growth factor-ß (TGF-ß), which are local markers of host immunity, and of the neutrophil-lymphocyte ratio (NLR) and absolute lymphocyte count (ALC), which are systemic markers. PATIENTS AND METHODS: We administered eribulin chemotherapy to 106 patients with locally advanced or metastatic breast cancer. Of these, 21 had their lesions resected. RESULTS: The response to eribulin was significantly associated with ALC (p=0.007). The expression of pSmad2 (an indicator of activation of TGF-ß downstream signaling) was significantly decreased before and after eribulin chemotherapy (p<0.001). Moreover, a baseline ALC ≥ 1,500 /µl was observed in a significantly high number of patients with pSmad2 negative conversion (p<0.001). CONCLUSION: Eribulin improved the tumour immune microenvironment by decreasing TGF-ß expression. This demonstrated that local change can be evaluated based on ALC.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Furanos/uso terapêutico , Cetonas/uso terapêutico , Neoplasias da Mama/patologia , Feminino , Furanos/farmacologia , Humanos , Cetonas/farmacologia , Reprodutibilidade dos Testes , Microambiente Tumoral
2.
Anticancer Res ; 40(5): 2475-2479, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366391

RESUMO

BACKGROUND/AIM: Matrix-producing breast carcinoma (MPBC) is a rare and usually aggressive triple-negative breast cancer (TNBC). In the present report, we determined the drug sensitivity for a triple-negative MPBC using a patient-derived orthotopic xenograft (PDOX) model. MATERIALS AND METHODS: The PDOX model was established in the left 2nd mammary by surgical orthotopic implantation (SOI). MPBC PDOX models were randomized into 4 groups (6 mice per group) when the tumor volume became 80 mm3: G1, control group; G2, cisplatinum group [intraperitoneal (i.p.) injection, weekly, for 2 weeks]; G3, paclitaxel group (i.p., weekly, for 2 weeks); G4, eribulin group [intravenous (i.v.) injection, weekly, for 2 weeks]. All mice were sacrificed on day 15. Tumor volume and body weight were measured one time per week. RESULTS: The MPBC PDOX model was resistant to cisplatinum (p=0.800). Paclitaxel suppressed tumor growth compared to the control group (p=0.009). However, only eribulin regressed the tumor (p=0.001). CONCLUSION: Eribulin has clinical potential for triple-negative MPBC patients.


Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/farmacologia , Cetonas/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Animais , Biomarcadores Tumorais , Cisplatino/uso terapêutico , Modelos Animais de Doenças , Feminino , Furanos/uso terapêutico , Humanos , Cetonas/uso terapêutico , Camundongos , Paclitaxel/farmacologia , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/etiologia , Neoplasias de Mama Triplo Negativas/metabolismo , Carga Tumoral/efeitos dos fármacos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Anticancer Res ; 40(5): 2509-2514, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366395

RESUMO

BACKGROUND/AIM: Matrix-producing breast carcinoma (MPBC) is a rare and usually aggressive triple-negative breast cancer (TNBC). In this study, we determined drug sensitivity for a triple-negative MPBC, without BRCA mutations, in a patient-derived orthotopic xenograft (PDOX) model. MATERIALS AND METHODS: The MPBC PDOX model was established in the left 2nd mammary gland of nude mouse by implantation of the patient tumor using surgical orthotopic implantation (SOI). We randomized MPBC PDOX mice into 5 groups (n=5 mice/per treatment group) when the tumor volume reached 80 mm3: G1, control-no treatment; G2, bevacizumab [intra-peritoneal (i.p.), weekly, for 2 weeks]; G3, vinorelbine (i.p., weekly, for 2 weeks); G4, olaparib (oral., daily, for 2 weeks); G5, eribulin [intravenous (i.v.), weekly, for 2 weeks]. The mice in each treatment group were sacrificed on day 15. Tumor volume and body weight were measured once/week. RESULTS: The MPBC PDOX model was resistant to olaparib (p=0.22). The MPBC PDOX model treated with bevacizumab and vinorelbine showed significantly suppressed tumor growth compared to the untreated group (p=0.005 and 0.002, respectively). However, only eribulin regressed the tumor (p=0.0001). Eribulin was more effective than olaparib (p=0.0001), bevacizumab (p=0.0025) and vinorelbine (p=0.0061). CONCLUSION: Eribulin has clinical potential as treatment for triple-negative MPBC patients that are resistant to a PARP inhibitor such as olaparib.


Assuntos
Bevacizumab/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/farmacologia , Cetonas/farmacologia , Ftalazinas/farmacologia , Piperazinas/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Vinorelbina/farmacologia , Adulto , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Nat Commun ; 11(1): 2127, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358544

RESUMO

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events in humans with type 2 diabetes (T2D); however, the underlying mechanism remains unclear. Activation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome and subsequent interleukin (IL)-1ß release induces atherosclerosis and heart failure. Here we show the effect of SGLT2 inhibitor empagliflozin on NLRP3 inflammasome activity. Patients with T2D and high cardiovascular risk receive SGLT2 inhibitor or sulfonylurea for 30 days, with NLRP3 inflammasome activation analyzed in macrophages. While the SGLT2 inhibitor's glucose-lowering capacity is similar to sulfonylurea, it shows a greater reduction in IL-1ß secretion compared to sulfonylurea accompanied by increased serum ß-hydroxybutyrate (BHB) and decreased serum insulin. Ex vivo experiments with macrophages verify the inhibitory effects of high BHB and low insulin levels on NLRP3 inflammasome activation. In conclusion, SGLT2 inhibitor attenuates NLRP3 inflammasome activation, which might help to explain its cardioprotective effects.


Assuntos
Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Idoso , Animais , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucose/farmacologia , Humanos , Insulina/metabolismo , Interleucina-1beta/metabolismo , Cetonas/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Pessoa de Meia-Idade , Inibidores do Transportador 2 de Sódio-Glicose , Compostos de Sulfonilureia/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
5.
Cell Physiol Biochem ; 54(2): 195-210, 2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-32083406

RESUMO

BACKGROUND/AIMS: Idiopathic pulmonary fibrosis (IPF) is a specific form of progressive and chronic interstitial lung disease of unknown cause. IPF is characterized by excessive deposition of extracellular matrix (ECM) and destructive pathological remodeling due to epithelial-to-mesenchymal transition (EMT). Eventually, lung interstitium thickens and stiffens and breathing becomes difficult. It has been well established that the transforming growth factor-ß1 (TGF-ß1)/Smad signaling pathway plays a critical role in the pathogenesis of pulmonary fibrosis. TGF-ß1-mediated activation of mitogen activated protein kinase (MAPK) family affects Smad signaling. p90RSK is a serine/threonine kinase and is activated by the extracellular signal-regulated kinase (ERK) signaling pathway. However, the roles played by p90RSK in TGF-ß1 signaling and the pathogenesis of pulmonary fibrosis remain unknown. METHODS: We investigated whether p90RSK regulates the pathogenesis of pulmonary fibrosis using in vitro and in vivo systems and Western blotting, real-time quantitative PCR, transcriptional activity assays and immunofluorescence studies. RESULTS: Pharmacological inhibition of p90RSK by FMK or inhibition of p90RSK with adenoviral vector encoding a dominant negative form of p90RSK suppressed TGF-ß1-induced ECM accumulation and EMT in lung epithelial cells and fibroblasts. Interestingly, FMK significantly inhibited TGF-ß1-induced Smad3 nuclear translocation and smad binding element-dependent transcriptional activity, but not Smad3 phosphorylation. Furthermore, in a mouse model of bleomycin-induced lung fibrosis, FMK ameliorated pulmonary fibrosis. CONCLUSION: These findings indicate that p90RSK plays critical roles in pulmonary fibrosis, which suggests it be viewed as a novel therapeutic target for the treatment of lung fibrosis.


Assuntos
Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Proteína Smad3/metabolismo , Animais , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Matriz Extracelular/metabolismo , Humanos , Isoquinolinas/farmacologia , Cetonas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Regiões Promotoras Genéticas/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Piridinas/farmacologia , Pirróis/farmacologia , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/antagonistas & inibidores , Proteína Smad3/genética , Ativação Transcricional/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo
6.
J Med Chem ; 63(4): 1660-1670, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31990537

RESUMO

Endothelial lipase (EL) hydrolyzes phospholipids in high-density lipoprotein (HDL) resulting in reduction in plasma HDL levels. Studies with murine transgenic, KO, or loss-of-function variants strongly suggest that inhibition of EL will lead to sustained plasma high-density lipoprotein cholesterol (HDL-C) increase and, potentially, a reduced cardiovascular disease (CVD) risk. Herein, we describe the discovery of a series of oxadiazole ketones, which upon optimization, led to the identification of compound 12. Compound 12 was evaluated in a mouse pharmacodynamics (PD) model and demonstrated a 56% increase in plasma HDL-C. In a mouse reverse cholesterol transport study, compound 12 stimulated cholesterol efflux by 53% demonstrating HDL-C functionality.


Assuntos
HDL-Colesterol/metabolismo , Inibidores Enzimáticos/farmacologia , Cetonas/farmacologia , Lipase/antagonistas & inibidores , Oxidiazóis/farmacologia , Animais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Cetonas/síntese química , Cetonas/farmacocinética , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/farmacocinética , Relação Estrutura-Atividade
7.
J Mater Sci Mater Med ; 31(1): 11, 2019 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-31875263

RESUMO

Polyether-ether-ketone (PEEK) is becoming a popular component of clinical spinal and orthopedic applications, but its practical use suffers from several limitations. In this study, irregular nano-porous monolayer with differently functional groups was formed on the surface of PEEK through sulfonation and nitrification. The surface characteristics were detected by field-emission scanning electron microscopy, atomic force microscopy, energy-dispersive X-ray spectrometry, water contact angle measurements and Fourier transform infrared spectroscopy. In vitro cellular behaviors were evaluated by cell adhesion, morphological changes, proliferation, alkalinity, phosphatase activity, real-time RT-PCR and western blot analyses. In vivo osseointegration was examined through micro-CT and histological assessments. Our results reveal that the irregular nano-porous of PEEK affect the biological properties. High-temperature hydrothermal NP treatment induced early osteogenic differentiation and early osteogenesis. Modification by sulfonation and nitrification can broaden the use of PEEK in orthopedic and dental applications. This study provides a theoretical basis for the wider clinical application of PEEK. a To obtain a uniform porous structure, PEEK samples were treated by concentrated sulfuric acid and fuming nitric acid (82-80%) with magnetic stirring sequentially. b Effects of nanopores on biological behavior of bMSCS.


Assuntos
Cetonas/química , Cetonas/farmacologia , Células-Tronco Mesenquimais/fisiologia , Osteogênese/efeitos dos fármacos , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Animais , Materiais Biocompatíveis , Osso e Ossos/citologia , Adesão Celular , Proliferação de Células , Masculino , Teste de Materiais , Nitrificação , Ratos , Ratos Sprague-Dawley , Propriedades de Superfície , Engenharia Tecidual
8.
Dalton Trans ; 48(47): 17544-17555, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31748774

RESUMO

In the study presented herein, we explore the ability of copper complexes with coordinated pyridine-2-carboxaldehyde (pyca) or 2-acetylpyridine (acepy) ligands to promote the addition of amines (Schiff condensation) and other nucleophiles such as alcohols (hemiacetal formation). Distinct reactivity patterns are observed: unlike pyca complexes, acepy copper complexes can promote self-aldol addition. The introduction of a flexible chain via Schiff condensation with ß-alanine allows the possibility of chelate ring ring-opening processes mediated by pH. Further derivatization of the complex [CuCl(py-2-C(H)[double bond, length as m-dash]NCH2CH2COO)] is possible by replacing its chloride ligand with different pseudohalogens (N3-, NCO- and NCS-). In addition to the change in their magnetism, which correlates with their solid-state structures, more unexpected effects in their cytotoxicity and relaxitivities are observed, which determines their possibility to be used as MRI contrast agents. The replacement of a chloride by another pseudohalogen, although a simple strategy, can be used to critically change the cytotoxicity of the Schiff base copper(ii) complex and its selectivity towards specific cell lines.


Assuntos
Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Cobre/química , Cobre/toxicidade , Animais , Células CHO , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Cetonas/química , Cetonas/farmacologia , Ligantes , Modelos Moleculares , Estrutura Molecular , Piridinas/química , Piridinas/farmacologia , Relação Estrutura-Atividade , beta-Alanina/química , beta-Alanina/farmacologia
9.
Int J Mol Sci ; 20(22)2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31717459

RESUMO

A number of modifications have been developed in order to enhance surface cytocompatibility for prosthetic support of dental implants. Among them, ultraviolet (UV) light and non-thermal plasma (NTP) treatment are promising methods. The objective of this study was to compare the effects of UV light and NTP on machined titanium, zirconia and modified polyetheretherketone (PEEK, BioHPP) surfaces in vitro. Machined samples of titanium, zirconia and BioHPP were treated by UV light and NTP of argon or oxygen for 12 min each. Non-treated disks were set as controls. A mouse fibroblast and a human gingival fibroblast cell line were used for in vitro experiments. After 2, 24 and 48 h of incubation, the attachment, viability and cytotoxicity of cells on surfaces were assessed. Results: Titanium, zirconia and BioHPP surfaces treated by UV light and oxygen plasma were more favorable to the early attachment of soft-tissue cells than non-treated surfaces, and the number of cells on those treated surfaces was significantly increased after 2, 24 and 48 h of incubation (p < 0.05). However, the effects of argon plasma treatment on the cytocompatibility of soft tissue cells varied with the type of cells and the treated material. UV light and oxygen plasma treatments may improve the attachment of fibroblast cells on machined titanium, zirconia and PEEK surfaces, that are materials for prosthetic support of dental implants.


Assuntos
Cetonas/farmacologia , Gases em Plasma/farmacologia , Polietilenoglicóis/farmacologia , Titânio/farmacologia , Raios Ultravioleta , Zircônio/farmacologia , Animais , Adesão Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Gengiva/citologia , Humanos , Cetonas/toxicidade , Camundongos Endogâmicos C57BL , Polietilenoglicóis/toxicidade , Propriedades de Superfície , Titânio/toxicidade , Zircônio/toxicidade
10.
Molecules ; 24(20)2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31652542

RESUMO

Chagas disease and Leishmaniasis are neglected endemic protozoan diseases recognized as public health problems by the World Health Organization. These diseases affect millions of people around the world however, efficient and low-cost treatments are not available. Different steroid molecules with antimicrobial and antiparasitic activity were isolated from diverse organisms (ticks, plants, fungi). These molecules have complex structures that make de novo synthesis extremely difficult. In this work, we designed new and simpler compounds with antiparasitic potential inspired in natural steroids and synthesized a series of nineteen steroidal arylideneketones and thiazolidenehydrazines. We explored their biological activity against Leishmania infantum, Leishmania amazonensis, and Trypanosoma cruzi in vitro and in vivo. We also assayed their genotoxicity and acute toxicity in vitro and in mice. The best compound, a steroidal thiosemicarbazone compound 8 (ID_1260) was active in vitro (IC50 200 nM) and in vivo (60% infection reduction at 50 mg/kg) in Leishmania and T. cruzi. It also has low toxicity in vitro and in vivo (LD50 >2000 mg/kg) and no genotoxic effects, being a promising compound for anti-trypanosomatid drug development.


Assuntos
Doença de Chagas/tratamento farmacológico , Leishmaniose/tratamento farmacológico , Esteroides/uso terapêutico , Tiossemicarbazonas/uso terapêutico , Tripanossomicidas/química , Tripanossomicidas/uso terapêutico , Animais , Desenvolvimento de Medicamentos , Humanos , Hidrazinas/síntese química , Hidrazinas/química , Hidrazinas/farmacologia , Cetonas/síntese química , Cetonas/química , Cetonas/farmacologia , Leishmania infantum/efeitos dos fármacos , Leishmania mexicana/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Camundongos , Testes de Sensibilidade Parasitária , Esteroides/síntese química , Esteroides/química , Relação Estrutura-Atividade , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química , Tiossemicarbazonas/toxicidade , Tripanossomicidas/síntese química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos
11.
J Agric Food Chem ; 67(43): 11839-11847, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31589436

RESUMO

4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is an important target site for discovering new bleaching herbicides. To explore novel HPPD inhibitors with excellent herbicidal activity, a series of novel N-aroyl diketone/triketone derivatives were rationally designed by splicing active groups and bioisosterism. Bioassays revealed that most of these derivatives displayed preferable herbicidal activity against Echinochloa crus-galli (EC) at 0.045 mmol/m2 and Abutilon juncea (AJ) at 0.090 mmol/m2. In particular, compound I-f was more potent compared to the commercialized compound mesotrione. Molecular docking indicated that the corresponding active molecules of target compounds and mesotrione shared similar interplay with surrounding residues, which led to a perfect interaction with the active site of Arabidopsis thaliana HPPD.


Assuntos
4-Hidroxifenilpiruvato Dioxigenase/antagonistas & inibidores , Inibidores Enzimáticos/química , Herbicidas/química , Cetonas/química , Proteínas de Plantas/antagonistas & inibidores , 4-Hidroxifenilpiruvato Dioxigenase/química , 4-Hidroxifenilpiruvato Dioxigenase/metabolismo , Domínio Catalítico , Echinochloa/efeitos dos fármacos , Echinochloa/enzimologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Herbicidas/síntese química , Herbicidas/farmacologia , Cetonas/farmacologia , Malvaceae/efeitos dos fármacos , Malvaceae/enzimologia , Simulação de Acoplamento Molecular , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Plantas Daninhas/efeitos dos fármacos , Plantas Daninhas/enzimologia , Relação Estrutura-Atividade
12.
PLoS One ; 14(9): e0222024, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31483849

RESUMO

The identification of biomarkers for predicting the responsiveness to eribulin in patients with metastatic breast cancer pretreated with an anthracycline and a taxane remains an unmet need. Here, we established a serum microRNA (miRNA)-based prediction model for the emergence of new distant metastases after eribulin treatment. Serum samples were collected from metastatic breast cancer patients prior to eribulin treatment and comprehensively evaluated by miRNA microarray. The prediction model for estimating eribulin efficacy was established using the logistic LASSO regression model. Serum samples were collected from 147 patients, of which 52 developed at least one new distant metastasis after eribulin monotherapy and 95 did not develop new distant metastases. A combination of eight serum miRNAs (miR-4483, miR-8089, miR-4755-3p, miR-296-3p, miR-575, miR-4710, miR-5698 and miR-3160-5p) predicted the appearance of new distant metastases with an area under the curve of 0.79, sensitivity of 0.69 and specificity of 0.82. The serum levels of miR-8089 and miR-5698 were significantly associated with overall survival after the initiation of eribulin treatment. The present study provides evidence that serum miRNA profiling may serve as a biomarker for the responsiveness to eribulin and for predicting the development of new distant metastases in metastatic breast cancer.


Assuntos
Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Furanos/farmacologia , Cetonas/farmacologia , MicroRNAs/sangue , Adulto , Idoso , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Feminino , Furanos/uso terapêutico , Humanos , Cetonas/uso terapêutico , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Resultado do Tratamento
13.
Eur J Med Chem ; 183: 111687, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31539776

RESUMO

Conjugated α,ß-unsaturated ketones are very useful compounds associated with diverse medicinal properties. This review outlines α,ß-unsaturated ketones as candidate cytotoxic agents which affect mitochondrial function. Both naturally occurring compounds and synthetic chemicals have been discussed which exert their cytotoxic effects, at least in part, by acting on mitochondria. Biochemical differences between tumour mitochondria and this organelle in non-malignant cells have been exploited to investigate various compounds that can cause greater toxicity to neoplasms than normal cells. On a number of instances, correlations between the structures of various α,ß-unsaturated ketones and cytotoxic potencies have been observed. The aspiration is that this review will assist drug designers to create compounds which are significantly more toxic to neoplasms than normal tissues.


Assuntos
Cetonas/farmacologia , Mitocôndrias/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Humanos , Cetonas/química , Mitocôndrias/metabolismo , Neoplasias/metabolismo
14.
Pharmacol Res Perspect ; 7(5): e00524, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31523435

RESUMO

5-lipoxygenase (5-LO) catalyzes the biosynthesis of leukotrienes, potent lipid mediators involved in inflammatory diseases, and both 5-LO and the leukotrienes are validated therapeutic targets. Caffeic acid phenethyl ester (CAPE) is an effective inhibitor of 5-LO and leukotriene biosynthesis but is susceptible to hydrolysis by esterases. In this study a number of CAPE analogues were synthesized with modifications to the caffeoyl moiety and the replacement of the ester linkage with a ketone. Several new molecules showed better inhibition of leukotriene biosynthesis than CAPE in isolated human neutrophils and in whole blood with IC50 values in the nanomolar (290-520 nmol/L) and low micromolar (1.0-2.3 µmol/L) ranges, respectively. Sinapic acid and 2,5-dihydroxy derivatives were more stable than CAPE in whole blood, and ketone analogues were degraded more slowly in HepaRG hepatocyte cultures than esters. All compounds underwent modification consistent with glucuronidation in HepaRG cultures as determined using LC-MS/MS analysis, though the modified sinapoyl ketone (10) retained 50% of its inhibitory activity after up to one hour of incubation. This study has identified at least one CAPE analogue, compound 10, that shows favorable properties that warrant further in vivo investigation as an antiinflammatory compound.


Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Hidroxibenzoatos/síntese química , Cetonas/síntese química , Inibidores de Lipoxigenase/síntese química , Análise Química do Sangue , Ácidos Cafeicos/química , Linhagem Celular , Estabilidade de Medicamentos , Ésteres/química , Células HEK293 , Humanos , Hidroxibenzoatos/química , Hidroxibenzoatos/farmacologia , Concentração Inibidora 50 , Cetonas/química , Cetonas/farmacologia , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacologia , Simulação de Acoplamento Molecular , Neutrófilos/química , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/química
15.
Anticancer Res ; 39(9): 4775-4779, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519578

RESUMO

BACKGROUND: Osteosarcoma is a recalcitrant disease treated with surgery and intensive chemotherapy as standard. The 5-year survival rate of patients with relapsed and lung metastatic osteosarcoma is as low as 20%. MATERIALS AND METHODS: A 16-year-old patient developed left distal femoral high-grade osteosarcoma and underwent cisplatinum-based neoadjuvant chemotherapy and surgery. From the resected tumor, a patient-derived orthotopic xenograft (PDOX) model was established in the femur of nude mice. PDOX models were randomized into the following groups: untreated control, or treatment with doxorubicin (3 mg/kg, i.p., weekly for 14 days), sunitinib (40 mg/kg, oral gavage, daily for 14 days), pazopanib (100 mg/kg, oral gavage, daily for 14 days), temozolomide(25 mg/kg, oral gavage, daily for 14 days), and eribulin (1.5 mg/kg, i.p., daily for 14 days). Tumor volume and body weight were monitored twice a week. RESULTS: The osteosarcoma PDOX was resistant to doxorubicin, sunitinib, and pazopanib. In contrast, eribulin and temozolomide arrested tumor growth. CONCLUSION: This study demonstrated the utility of the PDOX model in allowing effective from non-effective drugs to be distinguished in a model in which the tumor was growing on the organ corresponding to that of the patient.


Assuntos
Cisplatino/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/farmacologia , Cetonas/farmacologia , Neoplasias Pulmonares/secundário , Osteossarcoma/patologia , Adolescente , Animais , Modelos Animais de Doenças , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos , Osteossarcoma/tratamento farmacológico , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Eur J Med Chem ; 182: 111669, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31494473

RESUMO

A series of 2,8-diazaspiro[4.5]decan-1-one derivatives were designed, synthesized and screened for their inhibition activities against chitin synthase (CHS) and antimicrobial activities in vitro. The biological assays revealed that compounds 4a, 4e, 4h, 4j, 4o, 4q and 4r exhibited moderated to excellent potency against CHS with IC50 values ranging from 0.12 to 0.29 mM. Compounds 4e, 4j with IC50 value of 0.13 mM, 0.12 mM respectively, showed excellent inhibition potency among these compounds, which were similar to that of polyoxin B whose IC50 value was 0.08 mM. Meanwhile, the screening of the antifungal activity showed that compounds 4j and 4r had the same potency of inhibiting the growth of A. fumigatus with MIC value of 0.08 mmol/L. Compound 4d displayed excellent activity against C. albicans (ATCC 90023) with MIC value of 0.04 mmol/L, which was superior to fluconazole (0.104 mmol/L) and polyoxin B (0.129 mmol/L). The result of antibacterial assay showed that these compounds had little potency against those selected bacteria strains including three Gram-positive bacteria and three Gram-negative bacteria. Furthermore, the combination use of 4c-fluconazole, 4i-fluconazole, 4j-fluconazole, and 4o-fluconazole against C. albicans,A. fumigatus and A. flavus showed additive or synergistic effects. These results indicated that the designed compounds serve as potential chitin synthase inhibitors and have selectively antifungal activities.


Assuntos
Antifúngicos/farmacologia , Aspergillus flavus/efeitos dos fármacos , Aspergillus fumigatus/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Quitina Sintase/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Compostos Aza/síntese química , Compostos Aza/química , Compostos Aza/farmacologia , Quitina Sintase/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Cetonas/síntese química , Cetonas/química , Cetonas/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade
17.
Parasit Vectors ; 12(1): 382, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362759

RESUMO

BACKGROUND: The Asian tiger mosquito, Aedes albopictus, an increasingly relevant arboviral vector, has spread worldwide. However, currently available tools are limited in terms of effective monitoring of vector populations and accurate determination of the extent of viral transmission, especially before and during outbreaks. Therefore, it is essential to develop novel monitoring and surveillance tools, particularly those that target adult mosquitoes and enhance the trapping efficiency for Ae. albopictus. METHODS: A variety of human body odorants associated with different types of mosquito olfactory receptors were selected, and their attractiveness to Ae. albopictus was tested by a four-arm olfactometer. The optimal compatibility and proportion of the odorants, Mix-5, was observed via orthogonal design analyses. The attractiveness of Mix-5 to Ae. albopictus in the laboratory was assessed using Mosq-ovitraps and Electric Mosquito Killers. In the field, the effectiveness of generic BG-Lure, Mix-5 and a control treatment was compared with a baited Biogents Sentinel trap (BGS-trap) using a Latin square design. RESULTS: In the olfactometer experiments, the attractiveness of the selected candidate compounds at varying dilutions was poor when the individual compounds were used alone. The optimal combination, Mix-5, was generated based on orthogonal design analyses. In the laboratory, the average numbers of female Ae. albopictus mosquitoes attracted by the synthetic odorant blend Mix-5 were 27.00 and 27.50, compared with 12.00 and 14.83 for the control, when using Mosq-ovitraps and Electric Mosquito Killers, respectively. In the field, the average number of Ae. albopictus female mosquitoes trapped by Mix-5 was 9.67 females/trap, whereas the average numbers for BG-Lure and the control were 7.78 and 4.47, respectively. The lure also played an important role in attracting Culex quinquefasciatus mosquitoes, and the average numbers of Cx. quinquefasciatus female mosquitoes attracted by Mix-5, BG-Lure and the control were 18.78, 25.11 and 12.22, respectively. CONCLUSIONS: A human odor-based bait blend was developed and exhibited enhanced effectiveness at attracting Ae. albopictus This blend can be used to monitor and trap dengue vector mosquitoes in Chinese cities.


Assuntos
Aedes/efeitos dos fármacos , Aedes/fisiologia , Comportamento Animal/efeitos dos fármacos , Odorantes/análise , Feromônios Humano/farmacologia , Feromônios/farmacologia , Animais , Feminino , Humanos , Cetonas/síntese química , Cetonas/farmacologia , Controle de Mosquitos , Mosquitos Vetores , Feromônios/síntese química , Feromônios Humano/síntese química , Receptores Odorantes/efeitos dos fármacos
18.
Int J Nanomedicine ; 14: 4975-4989, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371942

RESUMO

The porous surface of a polyetheretherketone (PK)-nanoporous lithium-doped magnesium silicate (NLS) blend (PKNLS) was fabricated on a PK surface by layer-by-layer pressuring, sintering, and salt-leaching. As controls, porous surfaces of a PK/lithium-doped magnesium silicate blend (PKLS) and PK were fabricated using the same method. The results revealed that porosity, water absorption, and protein absorption of the porous surface of PKNLS containing macropores and nanopores were obviously enhanced compared to PKLS and PK containing macropores without nanopores. In addition, PKNLS, with both macroporostiy and nanoporosity, displayed the highest ability of apatite mineralization in simulated body liquid, indicating excellent bioactivity. In vitro responses (including adhesion, proliferation, and differentiation) of MC3T3E1 cells to PKNLS were significantly enhanced compared to PKLS and PK. In vivo implantation results showed that new bone grew into the macroporous surface of PKNLS, and the amount of new bone for PKNLS was the highest. In short, PKNLS integration with PK significantly promoted cells/bone-tissue responses and exhibited excellent osteogenesis in vivo, which might have great potential for bone repair.


Assuntos
Osso e Ossos/fisiologia , Cetonas/farmacologia , Lítio/farmacologia , Silicatos de Magnésio/farmacologia , Nanoporos , Osteoblastos/citologia , Polietilenoglicóis/farmacologia , Adsorção , Fosfatase Alcalina/metabolismo , Animais , Apatitas/química , Osso e Ossos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Imageamento Tridimensional , Masculino , Camundongos , Nanoporos/ultraestrutura , Osteoblastos/efeitos dos fármacos , Osteoblastos/ultraestrutura , Osteogênese/efeitos dos fármacos , Porosidade , Coelhos , Água/química , Difração de Raios X
19.
Int J Mol Sci ; 20(15)2019 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-31382697

RESUMO

Polyether-ether-ketone (peek) is one of the most common materials used for load-bearing orthopedic devices owing to its radiolucency and favorable mechanical properties. However, current smooth-surfaced peek implants can lead to fibrous capsule formation. To overcome this issue, here, peek specimens with well-defined internal cross-linked structures (macropore diameters of 1.0-2.0 mm) were fabricated using a three-dimensional (3D) printer, and an acid-etched microporous surface was achieved using injection-molding technology. The cell adhesion properties of smooth and microporous peek specimens was compared in vitro through a scanning electron microscope (SEM), and the soft tissue responses to the both microporous and cross-linked structure of different groups were determined in vivo using a New Zealand white rabbit model, and examined through histologic staining and separating test. The results showed that the acid-etched microporous surface promoted human skin fibroblasts (HSF) adherence, while internal cross-linked structure improved the ability of the peek specimen to form a mechanical combination with soft tissue, especially with the 1.5 mm porous specimen. The peek specimens with both the internal cross-linked structure and external acid-etched microporous surface could effectively promote the close integration of soft tissue and prevent formation of fibrous capsules, demonstrating the potential for clinical application in surgical repair.


Assuntos
Materiais Biocompatíveis/farmacologia , Adesão Celular/efeitos dos fármacos , Impressão Tridimensional , Próteses e Implantes/efeitos adversos , Animais , Materiais Biocompatíveis/química , Éter/química , Éter/farmacologia , Humanos , Cetonas/química , Cetonas/farmacologia , Polietilenoglicóis/química , Porosidade , Coelhos , Propriedades de Superfície
20.
Biofabrication ; 11(4): 045014, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31365916

RESUMO

Polyetheretherketone (PEEK), one of the potential alternatives to metallic materials for implants, necessarily involves high temperature process conditions to be three-dimensionally (3D) printed. We developed a 3D printing setup equipped with thermally stabilized modules of the printing nozzle and building chamber, by which the PEEK implants could be successfully manufactured. Under optimized printing conditions, the maximal mechanical strength of the 3D printed sample attained over 80% of the original bulk property of PEEK. To enhance the interfacial biocompatibility, the as-printed implants were postprocessed with titanium (Ti) sputtering. The Ti-coated surfaces were evaluated through characterization studies of x-ray diffraction spectra, microscopic topographies, and wetting properties. For the in vitro tests, preosteoblasts were cultured on the developed PEEK-Ti structures and evaluated in terms of cell adhesion, proliferation, and osteogenic differentiation. In addition, the bone regeneration capability of the PEEK-Ti implants was confirmed by animal experiments using a rabbit tibia defect model for a period of 12 weeks. In the overall in vitro and in vivo tests, we confirmed the superior bioactivities of the Ti-modified and 3D printed interface by comparisons between the samples of machined and printed samples with or without Ti coating. Taken together, the comprehensive manufacturing approaches that involve 3D printing and biocompatible postprocessing are expected to have universal applicability in a wide range of bone tissue engineering.


Assuntos
Materiais Biocompatíveis/farmacologia , Materiais Revestidos Biocompatíveis/farmacologia , Temperatura Alta , Cetonas/farmacologia , Polietilenoglicóis/farmacologia , Impressão Tridimensional , Próteses e Implantes , Titânio/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Regeneração Óssea/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Fêmur/diagnóstico por imagem , Fêmur/efeitos dos fármacos , Imageamento Tridimensional , Masculino , Camundongos , Imagem Óptica , Coelhos , Propriedades de Superfície , Resistência à Tração , Difração de Raios X , Microtomografia por Raio-X
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