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1.
Int J Nanomedicine ; 14: 5215-5228, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371957

RESUMO

Background: Resveratrol (RSV) has attracted interest as an alternative drug for the treatment of acute lung injury (ALI) and other pulmonary diseases, but its poor oral bioavailability is a limitation. In this study, we employed drug delivery nanotechnology to improve the stability, lung localization and efficacy of orally administered resveratrol to control lung damage leading to ALI. Methods and materials: RSV-loaded lipid-core nanocapsules (RSV-LNCs), prepared by interfacial deposition of biodegradable polymers, were given orally to A/J mice prior to lipopolysaccharide (LPS) intranasal instillation. Inflammatory changes, oxidative stress and lung tissue elastance were assessed 24 h after LPS challenge. Results: RSV-LNCs (5 mg/kg), given 1, 4, 6 or 12 h but not 24 h before provocation, inhibited LPS-induced leukocyte accumulation in the bronchoalveolar fluid (BALF), whereas unloaded nanocapsules (ULNCs) or free RSV (5 mg/kg) were ineffective. RSV-LNCs (2.5-10 mg/kg) but not ULNCs or RSV improved lung function and prevented total leukocyte and neutrophil accumulation equally in both BALF and lung tissue when given 4 h before LPS challenge. Similar findings were seen concerning the generation of a range of pro-inflammatory cytokines such as IL-6, KC, MIP-1α, MIP-2, MCP-1 and RANTES in lung tissue. In addition, only RSV-LNCs inhibited MDA levels and SOD activity in parallel with blockade of the ERK and PI3K/Akt pathways following LPS provocation. Conclusion: Nanoformulation of RSV in biodegradable oil-core polymers is an effective strategy to improve the anti-ALI activity of RSV, suggesting that the modified-release formulation of this plant polyphenol may be of great value in clinical conditions associated with ALI and respiratory failure.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/enzimologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Nanocápsulas/química , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Resveratrol/administração & dosagem , Resveratrol/uso terapêutico , Transdução de Sinais , Lesão Pulmonar Aguda/complicações , Administração Oral , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Masculino , Camundongos Endogâmicos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Hipersensibilidade Respiratória/complicações , Hipersensibilidade Respiratória/patologia , Resveratrol/farmacologia
2.
Cancer Sci ; 110(9): 2748-2759, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31301081

RESUMO

In hepatocarcinogenesis induced by diethylnitrosamine (DEN) in B6C3F1 mice, the BrafV637E mutation, corresponding to the human BRAFV600E mutation, plays a pivotal role. The livers of transgenic mice with a hepatocyte-specific human BRAFV600E mutation weighed 4.5 times more than that of normal mice and consisted entirely of hepatocytes, resembling DEN-induced preneoplastic hepatocytes. However, these transgenic mice spontaneously died 7 wk after birth, therefore this study aimed to clarify the causes of death. In the transgenic mice, the liver showed thrombopoietin (TPO) overexpression, which is associated with eventual megakaryocytosis and thrombocytosis, and activated platelets were deposited in hepatic sinusoids. TPO was also overexpressed in the DEN-induced hepatic tumors, and sinusoidal platelet deposition was observed in the hepatic tumors of humans and mice. Podoplanin was expressed in some of the Kupffer cells in the liver of the transgenic mice, indicating that platelet activation occurred via the interaction of podoplanin with C-type lectin receptor 2 (CLEC-2) on the platelet membrane. Additionally, erythrocyte dyscrasia and glomerulonephropathy/interstitial pneumonia associated with platelet deposition were observed. In the transgenic mice, aspirin (Asp) administration prevented platelet activation, reduced the liver/body weight ratio, decreased the platelet deposition in the liver, kidney, and lung, and prevented erythrocyte dyscrasia and ameliorated the renal/pulmonary changes. Thrombopoietin overproduction by BRAFV600E-mutated hepatocytes may contribute to hepatocyte proliferation via thrombocytosis, platelet activation, and the interaction of platelets with hepatic sinusoidal cells, while hematologic, renal, and pulmonary disorders due to aberrant platelet activation may lead to spontaneous death in the transgenic mice.


Assuntos
Carcinogênese/genética , Neoplasias Hepáticas Experimentais/patologia , Fígado/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Trombopoetina/metabolismo , Animais , Biópsia , Plaquetas/patologia , Medula Óssea/patologia , Capilares/patologia , Carcinógenos/administração & dosagem , Carcinógenos/toxicidade , Proliferação de Células/genética , Dietilnitrosamina/administração & dosagem , Dietilnitrosamina/toxicidade , Feminino , Regulação Neoplásica da Expressão Gênica , Hepatectomia , Hepatócitos/patologia , Humanos , Fígado/irrigação sanguínea , Fígado/citologia , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Transgênicos , Ativação Plaquetária/genética , Cultura Primária de Células , Proteínas Proto-Oncogênicas B-raf/metabolismo , Células Tumorais Cultivadas
3.
Eur J Med Chem ; 178: 401-416, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202128

RESUMO

This work mainly introduces the synthesis and characterization of three iridium(III) complexes [Ir(ppy)2(adppz)](PF6) (Ir-1), [Ir(bzq)2(addpz)](PF6) (Ir-2) and [Ir(piq)2(adppz)](PF6) (Ir-3). The complexes are more cytotoxic than cisplatin against tumor cell lines such as SGC-7901, A549, HeLa, Eca-109, HepG2 and BEL-7402. The toxicity test results indicated that complexes Ir-1, Ir-2 and Ir-3 can effectively inhibit the cell growth of SGC-7901 cells, and the measured IC50 values are 1.8 ±â€¯0.4, 1.6 ±â€¯0.3 and 0.8 ±â€¯0.1 µM, respectively. AO/EB staining and flow apoptosis confirmed that SGC-7901 cells were caused apoptosis after being treated with the complexes. Along with the increase of endogenous ROS and Ca2+ levels, mitochondrial membrane potential collapse and massive release of cytochrome c, it is fully demonstrated that these complexes induce apoptosis through ROS-mediated mitochondrial pathway. At the same time, the complex Ir-3 is outstanding in the inhibition of tumor growth in vivo. Combined with the above results, it provides a favorable foundation for the future development of more effective anti-tumor drugs.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Irídio/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Irídio/química , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Neoplasias Gástricas/patologia , Relação Estrutura-Atividade
4.
Eur J Med Chem ; 178: 433-445, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202991

RESUMO

Reported herein is the design, synthesis, and pharmacologic evaluation of a class of TRPV1 antagonists constructed on 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as A-region and triazole as B-region. The SAR analysis indicated that 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole analogues displayed excellent antagonism of hTRPV1 activation by capsaicin and showed better potency compared to the corresponding dihydroindole analogues. Optimization of this design led to the eventual identification of 2-((1-(2-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (6g), a potent TRPV1 antagonist. In vitro, using cells expressing recombinant human TRPV1 channels, 6g displayed potent antagonism activated by capsaicin (IC50 = 0.075 µM) and only partially blocked acid activation of TRPV1. In vivo, 6g exhibited good efficacy in capsaicin-induced and heat-induced pain models and had almost no hyperthermia side-effect. Furthermore, pharmacokinetic studies revealed that compound 6g had a superior oral exposure after oral administration in rats. To understand its binding interactions with the receptor, the docking study of 6g was performed in rTRPV1 model and showed an excellent fit to the binding site. On the basis of its superior profiles, 6g could be considered as the lead candidate for the further development of antinociceptive drugs.


Assuntos
Desenho de Drogas , Indóis/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Triazóis/farmacologia , Animais , Relação Dose-Resposta a Droga , Indóis/administração & dosagem , Indóis/química , Masculino , Camundongos , Camundongos Endogâmicos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismo , Triazóis/administração & dosagem , Triazóis/química
5.
Eur J Med Chem ; 178: 726-739, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31229875

RESUMO

To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a series of chalcone-O-carbamate derivatives was designed and synthesized based on the multitarget-directed ligands strategy. The in vitro biological activities were evaluated including AChE/BChE inhibition, MAO-A/MAO-B inhibition, antioxidant activities, Aß1-42 aggregation inhibition, metal-chelating properties and neuroprotective effects against H2O2-induced PC12 cell injury. The results showed compounds 5b and 5h indicated highly selective BChE inhibitory activity with IC50 values of 3.1 µM and 1.2 µM, respectively and showed highly selective MAO-B inhibitory potency with IC50 values of 1.3 µM and 3.7 µM, respectively. In addition, compounds 5b and 5h could inhibit self-induced Aß1-42 aggregation with 63.9% and 53.1% inhibition percent rate, respectively. Particularly, compound 5b was a potent antioxidant agent and neuroprotectant, as well as a selective metal chelator by chelating Cu2+ and Al3+. Moreover, compound 5b could inhibit and disaggregate Cu2+-induced Aß1-42 aggregation, which was further supported by the TEM images. Furthermore, compounds 5b and 5h could cross the blood-brain barrier (BBB) in vitro and conformed to the Lipinski's rule of five. Finally, the in vivo assay exhibited that compound 5b could improve scopolamine-induced cognitive impairment. Taken together, these results revealed that compound 5b might be a potential multifunctional agent for the treatment of AD, and deserved to do further structure optimization.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Chalconas/farmacologia , Inibidores da Colinesterase/farmacologia , Desenho de Drogas , Inibidores da Monoaminoxidase/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Butirilcolinesterase/metabolismo , Chalconas/síntese química , Chalconas/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Enguias , Feminino , Cavalos , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Modelos Moleculares , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fragmentos de Peptídeos/antagonistas & inibidores , Agregados Proteicos/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
6.
Planta Med ; 85(9-10): 766-773, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31167297

RESUMO

Osteoporosis is a clinical condition characterized by low bone strength that leads to an increased risk of fracture. Strategies for the treatment of osteoporosis involve inhibition of bone resorption by osteoclasts and an increase of bone formation by osteoblasts. Here, we identified the extract derived from the stem part of Edgeworthia papyrifera that enhanced differentiation of MC3T3-E1 cells to osteoblast-like cells and inhibited osteoclast differentiation of RAW 264.7 cells in vitro. In support of our observation, rutin and daphnoretin, which were previously reported to inhibit osteoclast differentiation, were identified in E. papyrifera extract. In an animal model of osteoporosis, the ovariectomy-induced increases in bone resorption biomarkers such as pyridinoline and tartrate-resistant acid phosphatase were significantly reduced by E. papyrifera extract administration at 25.6 and 48.1%, respectively. Furthermore, the ovariectomy-induced bone loss in animal models of osteoporosis was significantly prevented by the administration of E. papyrifera in our study. Taking these observations into account, we suggest that E. papyrifera is an interesting candidate for further exploration as an anti-osteoporotic agent.


Assuntos
Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Extratos Vegetais/farmacologia , Thymelaeaceae/química , Fosfatase Alcalina/metabolismo , Aminoácidos/urina , Animais , Biomarcadores/sangue , Biomarcadores/urina , Reabsorção Óssea/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Camundongos , Camundongos Endogâmicos , Modelos Animais , Osteoporose/etiologia , Extratos Vegetais/análise , Células RAW 264.7 , Ratos Sprague-Dawley
7.
Phytochemistry ; 164: 228-235, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31181354

RESUMO

Terminthia paniculata (Sanyeqi) is widely used for treating inflammation and rheumatic arthritis in the folk areas of Yunnan province, China. Its total extract was first revealed with xanthine oxidase (XO) inhibitory activity in vitro and anti-hyperuricemic effect in vivo. Bioassay-guided separation on Fr. A5 yielded six chalcone-flavonone heterodimers, termipaniculatones A-F. Their structures were elucidated based on extensive spectroscopic analyses involving HRESIMS, 1D and 2D NMR, UV, IR and [α]D, and the absolute configuration of termipaniculatone F was verified by ECD calculation. Termipaniculatones A and E showed obvious XO inhibitory activity with IC50 values of 55.6 and 89.5 µM, respectively, which took effects via a mix-type mode. A molecular modeling study revealed that termipaniculatone A was well located into the active site of XO by interacting with Glu802, Arg880, Thr1010 and Val1011 residues. Termipaniculatone A showed anti-hyperuricemic effects by decreasing serum uric acid levels and inhibiting XO activity in both serum and liver on potassium oxonate (PO)-induced hyperuricemia mice, and anti-inflammatory activity through alleviating paw swelling on monosodium urate (MSU)-induced mice, at the concentration of 20 mg/kg. This is the first time to reveal the anti-hyperuricemic and anti-acute gouty arthritis potency of T. paniculata and the characteristic biflavonoids as active constituents, which provides valuable information for searching new XO inhibitors from natural sources.


Assuntos
Anacardiaceae/química , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Gotosa/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Hiperuricemia/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/metabolismo , Chalcona/química , Chalcona/isolamento & purificação , Chalcona/farmacologia , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Flavanonas/química , Flavanonas/isolamento & purificação , Flavanonas/farmacologia , Hiperuricemia/induzido quimicamente , Hiperuricemia/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Ácido Oxônico/antagonistas & inibidores , Relação Estrutura-Atividade , Ácido Úrico/antagonistas & inibidores , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/metabolismo
8.
Adv Gerontol ; 32(1-2): 66-75, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31228370

RESUMO

Melatonin was administered at the dose of 1,2 mcg per capita (an equivalent to pediatric dosages) at days 1, 3 and 5 postpartum to 129/Sv mice, which were followed thereafter till their natural deaths. In adult males, findings included a decrease in body weight and an increase in the contribution of pulmonary lesions, which were revealed upon postmortem examinations, to the overall mortality. In adult females, no changes in body weight occurred, the proportion of middle- and late-age mice having irregular estrous cycles increased, and mortality associated with uterine hemangiomas was accelerated. Trends in malignant tumor yields were different: a decrease in males and an increase in females. Tends in survival patterns were expressed as significant increases or decreases in the lifespans of the last 25% and 10% of male or female survivors respectively. An analysis of the complete survivorships curves in terms of the Gompertz model showed that changes in the initial mortality and aging rate were within the limits determined by the artifactual component of the Strehler-Mildvan correlation between these parameters. On a whole, the trends found in the present work were opposite in males and females being mostly favorable for the former and adverse for the latter. Gender specificity should be kept in mind upon considering the use of melatonin by children and their mothers.


Assuntos
Antioxidantes , Longevidade , Melatonina , Animais , Antioxidantes/farmacologia , Peso Corporal , Criança , Feminino , Humanos , Recém-Nascido , Masculino , Melatonina/farmacologia , Camundongos , Camundongos Endogâmicos , Fatores Sexuais
9.
Chemosphere ; 230: 432-439, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31121507

RESUMO

This study was conducted to investigate the effects of maternal exposure to BPA on testicular development in offspring males. Pregnant Kunming mice were randomly divided into 7 groups with 20 mice in each group. Group A was the control group and the mice were given distilled water orally. Mice in groups B, C, D, E, F, G received BPA orally at a dose of 0.05 mg/kg/d, 0.5 mg/kg/d, 5 mg/kg/d, 10 mg/kg/d, 20 mg/kg/d, 50 mg/kg/d, respectively. F0 mice were exposed to BPA for 40 days from gestation day 0 to lactation day 21. F1 male mice were sacrificed at weaning (postnatal day 21). Histological observations revealed architectural damages in testis in BPA exposed groups. The testicular organ index increased significantly when the BPA oral exposure dose was above 20 mg/kg/d (P < 0.05). BPA contents in serum of F1 male mice increased significantly when BPA was above 5 mg/kg/d (P < 0.05), while the contents significant increased in maternal serum when BPA was higher than 0.5 mg/kg/d. The damage of cell nuclear DNA of testis was significantly aggravated when BPA was above 5 mg/kg/d. The expression of AR in the testis was significantly increased when BPA was above 20 mg/kg/d (P < 0.05). Transcriptome sequencing showed that the Snrnp 40 which encoding U5 snRNA subunit was significantly up-regulated in spliceosome pathway, and the Hnrnpu which encoding splicing universal protein component was significantly down-regulated. The blockage of spliceosome might be one of the reasons why BPA affects testicular development.


Assuntos
Compostos Benzidrílicos/toxicidade , Poluentes Ambientais/toxicidade , Exposição Materna/efeitos adversos , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Processamento de RNA/efeitos dos fármacos , Testículo/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Feminino , Perfilação da Expressão Gênica , Lactação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Testículo/embriologia , Testículo/crescimento & desenvolvimento , Testículo/metabolismo , Transcriptoma/efeitos dos fármacos
10.
J Oleo Sci ; 68(6): 591-598, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31092795

RESUMO

Fatty acids in triacylglycerol (TAG) are catabolized after digestion. However, the catabolic rates of several fatty acids bound to the α (sn-1, 3) or ß (sn-2) position of TAG have not been thoroughly compared. In this study, the catabolic rates of 13C-labeled palmitic acid, oleic acid, linoleic acid, α-linolenic acid, eicosapentaenoic acid (EPA), or docosahexaenoic acid (DHA) bound to the α and ß position of TAG were compared using isotope ratio mass spectrometry. The catabolic rates of the studied fatty acids were evaluated using the ratio of 13C and 12C in carbon dioxide expired from mice. The results indicated that palmitic acid, oleic acid, or α-linolenic acid bound to the ß position was slowly catabolized for a long duration compared to that when bound to the α position. In contrast, EPA bound to the ß position was quickly catabolized, and EPA bound to the α position was slowly catabolized for a long time. For linoleic acid or DHA, no difference in the catabolic rates was detected between the binding positions in TAG. Furthermore, EPA and DHA were less catabolized than the other fatty acids. These results indicate that the catabolic rates of fatty acids are influenced by their binding positions in TAG and that this influence on the catabolic rate differed depending on the fatty acid species.


Assuntos
Testes Respiratórios , Dióxido de Carbono/metabolismo , Isótopos de Carbono , Ácidos Graxos/metabolismo , Marcação por Isótopo , Triglicerídeos/química , Triglicerídeos/metabolismo , Animais , Masculino , Camundongos Endogâmicos
11.
Nat Mater ; 18(6): 627-637, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31114073

RESUMO

Cells are transplanted to regenerate an organs' parenchyma, but how transplanted parenchymal cells induce stromal regeneration is elusive. Despite the common use of a decellularized matrix, little is known as to the pivotal signals that must be restored for tissue or organ regeneration. We report that Alx3, a developmentally important gene, orchestrated adult parenchymal and stromal regeneration by directly transactivating Wnt3a and vascular endothelial growth factor. In contrast to the modest parenchyma formed by native adult progenitors, Alx3-restored cells in decellularized scaffolds not only produced vascularized stroma that involved vascular endothelial growth factor signalling, but also parenchymal dentin via the Wnt/ß-catenin pathway. In an orthotopic large-animal model following parenchyma and stroma ablation, Wnt3a-recruited endogenous cells regenerated neurovascular stroma and differentiated into parenchymal odontoblast-like cells that extended the processes into newly formed dentin with a structure-mechanical equivalency to native dentin. Thus, the Alx3-Wnt3a axis enables postnatal progenitors with a modest innate regenerative capacity to regenerate adult tissues. Depleted signals in the decellularized matrix may be reinstated by a developmentally pivotal gene or corresponding protein.


Assuntos
Proteínas de Homeodomínio/metabolismo , Tecido Parenquimatoso/fisiologia , Dente/citologia , Dente/embriologia , Adolescente , Animais , Feminino , Proteínas de Homeodomínio/genética , Humanos , Incisivo/citologia , Incisivo/embriologia , Camundongos Endogâmicos , Dente Serotino/citologia , Técnicas de Cultura de Órgãos , Tecido Parenquimatoso/citologia , Gravidez , Regiões Promotoras Genéticas , Regeneração , Células Estromais/fisiologia , Suínos , Fator A de Crescimento do Endotélio Vascular/genética , Proteína Wnt3A/genética , Proteína Wnt3A/metabolismo
12.
Curr Top Med Chem ; 19(11): 927-930, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31072292

RESUMO

BACKGROUND: Quillaja saponaria Mol. bark contains a high concentration of triterpene saponins that have been used for centuries as a cleansing, antiinflammatory and analgesic agent in Chilean folk medicine. In earlier studies, in mice, both the anti-inflammatory as well as the antinociceptive effect of the major sapogenin, quillaic acid have been demonstrated (QA). OBJECTIVE: To determine the antihyperalgesic effect of QA one and seven days after itpl administration of complete Freund's adjuvant (CFA) in male mice using the hot plate test in the presence of complete Freund's adjuvant (HP/CFA) as an acute and chronic skeletal muscle pain model. METHODS: The present study evaluated the antihyperalgesic activity of QA against acute and chronic skeletal muscle pain models in mice using the hot plate test in the presence of complete Freund's adjuvant (HP/CFA), at 24 h (acute assay) and 7 days (chronic assay) , with dexketoprofen (DEX) as the reference drug. RESULTS: In acute and chronic skeletal muscle pain assays, QA at 30 mg/kg ip elicited its maximal antihyperalgesic effects (65.0% and 53.4%) at 24 h and 7 days, respectively. The maximal effect of DEX (99.0 and 94.1 at 24 h and 7 days, respectively) was induced at 100 mg/kg. CONCLUSION: QA and DEX elicit dose-dependent antihyperalgesic effects against acute and chronic skeletal muscle pain, but QA is more potent than DEX in the early and late periods of inflammatory pain induced by CFA.


Assuntos
Músculos Abdominais/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Ácido Oleanólico/análogos & derivados , Dor/tratamento farmacológico , Quillaja/química , Animais , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Masculino , Camundongos , Camundongos Endogâmicos , Conformação Molecular , Ácido Oleanólico/química , Ácido Oleanólico/isolamento & purificação , Ácido Oleanólico/farmacologia
13.
Bull Exp Biol Med ; 166(6): 797-801, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31028589

RESUMO

We studied the intensity of age-specific changes in the dermis (number and proliferative activity of fibroblasts) in mice with normal and experimentally changed level of thyroid hormones. Receptors of thyroid hormones, TR-α and TR-ß, in mouse dermal fibroblasts were identified by immunohistochemical methods. The relative expression of Thra, Thrb, and Dio2 genes was assessed by real-time PCR analysis. From the second to fifth month of life, the number of fibroblasts in the connective tissue layer of mouse skin decreased by 42.3%. The number of fibroblasts in the dermis of 5-month-old mice treated with Thyrozol significantly decreases by 25.9% (p<0.05), and vice versa, in mice receiving thyroxin this parameter increased by 4.7% in comparison with the control (p>0.05). TR-α and TR-ß were identified in dermal fibroblasts in all groups of mice. No differences in the content TR-α and Thra gene expression in 2- and 5-month-old mice of the control and experimental were revealed. TR-ß content in dermal fibroblasts of 2-month-old animals was maximum and exceeded this value in 5-month-old control mice by 25%. The number of these receptors decreased by 33.3% in mice treated with Thyrozol and increased by 25% in animals receiving thyroxin injection in comparison with the control. Relative expression of Thrb gene significantly increased only in mice treated with thyroxin. Comparative analysis of the relative expression of Dio2 gene revealed no differences between the experimental and control groups. Changes in the level of thyroid hormones, content of TR-ß, and relative Thrb gene expression contribute to agerelated shifts in the number and proliferative activity of mouse dermal fibroblasts.


Assuntos
Envelhecimento/genética , Fibroblastos/metabolismo , Iodeto Peroxidase/genética , Glândula Tireoide/metabolismo , Receptores alfa dos Hormônios Tireóideos/genética , Receptores beta dos Hormônios Tireóideos/genética , Envelhecimento/metabolismo , Animais , Antitireóideos/farmacologia , Proliferação de Células , Derme/citologia , Derme/efeitos dos fármacos , Derme/metabolismo , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Expressão Gênica , Iodeto Peroxidase/metabolismo , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Metimazol/farmacologia , Camundongos , Camundongos Endogâmicos , Glândula Tireoide/citologia , Glândula Tireoide/efeitos dos fármacos , Receptores alfa dos Hormônios Tireóideos/metabolismo , Receptores beta dos Hormônios Tireóideos/metabolismo , Tiroxina/farmacologia
14.
Biomed Pharmacother ; 112: 108717, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30970516

RESUMO

The purpose of this study was to explore the possible interaction between ketamine and cannabinoid system in the modulation of depression-related responses using the forced swimming test (FST), tail suspension test (TST) and open-field test (OFT) in mice. Our results revealed that intra-peritoneal (i.p.) injection of ketamine (5 and 10 mg/kg), a non-competitive NMDA antagonist, dose-dependently produced antidepressant-like effect in the FST. Moreover, i.p. administration of both CB1 and CB2 receptor drugs: ACPA (1 mg/kg; CB1 receptor agonist), AM251 (1 mg/kg; CB1 receptor antagonist), GP1a (2 mg/kg; CB2 receptor agonist) and AM630 (0.5 mg/kg; CB2 receptor antagonist) exhibited antidepressant action. Interestingly, the concomitant administration of ineffective doses of ketamine and cannabinoid receptor antagonists provoked the antidepressant-like effects as compared to control group. It should be considered, all above mentioned doses of drugs could not change locomotor activity in the OFT. It seems that possible interaction between ketamine and cannabinoid system may modulate depression-related behavior.


Assuntos
Antidepressivos/uso terapêutico , Agonistas de Receptores de Canabinoides/uso terapêutico , Antagonistas de Receptores de Canabinoides/uso terapêutico , Depressão/tratamento farmacológico , Ketamina/uso terapêutico , Animais , Antidepressivos/administração & dosagem , Antidepressivos/farmacologia , Agonistas de Receptores de Canabinoides/administração & dosagem , Agonistas de Receptores de Canabinoides/farmacologia , Antagonistas de Receptores de Canabinoides/administração & dosagem , Antagonistas de Receptores de Canabinoides/farmacologia , Depressão/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Elevação dos Membros Posteriores , Ketamina/administração & dosagem , Ketamina/farmacologia , Masculino , Camundongos Endogâmicos , Atividade Motora/efeitos dos fármacos , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Natação
15.
Biomed Pharmacother ; 112: 108741, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30970528

RESUMO

Seaweeds are excellent source of bioactive compounds and seaweed-derived polysaccharides have demonstrated an array of biological effects. Here, we investigated the effect of polysaccharide of Sargassum weizhouense (PSW) on the inflammatory response in porcine circovirus type 2 (PCV2) infected mice and the underlying mechanism was studied according to the histone acetylation. After PCV2 infection, the levels of TNF-α, IL-1ß, IL-6, IL-8, IL-10, MCP-1, COX-1, COX-2 and HAT in both serum and spleen were significantly increased (P <0.05). The mRNA expression of TNF-α, IL-6, IL-10 and NF-κB p65 were elevated in PCV2 infected mice (P <0.05). The HDAC content in both serum and spleen as well the mRNA expression of HDAC1 were greatly decreased (P <0.05). PSW treatment dramatically inhibited the secretions of inflammatory cytokines and HATs, reduced mRNA expression of TNF-α, IL-6, IL-10 and NF-κB p65, but promoted HDAC secretion and mRNA expression of HDAC1 in PCV2-infected mice. The acetylation of both H3 and H4 was significantly up-regulated in PCV2-infected mice, and strongly inhibited by PSW treatment (P <0.01). These results suggested that PCV2 mediate the equilibrium between HATs and HDACs, alternate the histone acetylation and thus DNA packaging, and then activate the transcription of inflammatory cytokines. PSW could inhibit the histone acetylation and the production of inflammatory cytokines, showing excellent potentials in improving the resistance of host against PCV2 infection.


Assuntos
Antivirais/uso terapêutico , Infecções por Circoviridae/tratamento farmacológico , Histonas/metabolismo , Polissacarídeos/uso terapêutico , Sargassum/química , Acetilação , Animais , Antivirais/isolamento & purificação , Infecções por Circoviridae/imunologia , Citocinas/sangue , Feminino , Histona Acetiltransferases/metabolismo , Histona Desacetilases/metabolismo , Inflamação , Masculino , Camundongos Endogâmicos , Polissacarídeos/isolamento & purificação , Baço/imunologia
16.
Vet Parasitol ; 268: 32-35, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30981303

RESUMO

This study developed and evaluated Giardia duodenalis cyst propagation using a dexamethasone immunosuppressed CF-1 mouse model as an alternative to a previously described Mongolian gerbil model. The CF-1 mouse model shed significantly more cysts per animal during a 16-18 h collection period compared to the gerbil (averages: 7.8 × 106 cysts/CF-1 mouse and 2.5 × 106 cysts/gerbil). In addition, the patency period for this model differed from both G. muris in mice and G. duodenalis in gerbils in that cysts were shed continuously for over 20 days. Results further showed that the ß-giardin gene sequences from gerbil derived and mouse derived G. duodenalis were identical, after 34 serial passages through the CF-1 mouse model. Overall, the CF-1 mouse model produced higher concentrations of cysts per animal, and were genetically and phenotypically stable based on ß-giardin gene sequences.


Assuntos
Cistos/parasitologia , Modelos Animais de Doenças , Giardia lamblia/crescimento & desenvolvimento , Hospedeiro Imunocomprometido , Animais , Anti-Inflamatórios/administração & dosagem , Proteínas do Citoesqueleto/genética , Dexametasona/administração & dosagem , Fezes/parasitologia , Feminino , Genótipo , Giardia lamblia/genética , Giardíase/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos , Proteínas de Protozoários/genética , Reprodução
17.
Environ Toxicol ; 34(7): 836-843, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30953400

RESUMO

The synergic allergic inflammatory effects of particulate matter (PM) 2.5 and human albumin were investigated in NC/Nga mice, which are hypersensitive to mite allergens. PM2.5 or PM2.5 plus human albumin with aluminum oxide was injected twice intraperitoneally for sensitization. After 7 days, PM2.5 or PM2.5 plus human albumin was administered five times intranasally to mice for further sensitization. Subsequently, PM2.5 was administered as a challenge on the 11th day. On the 12th day, mice were examined for airway hyperresponsiveness (AHR), bronchoalveolar lavage fluid (BALF) cell count, mRNA expression of Th1 , Th2 cytokines, chemokines, and mucus proteins (MUC5AC and MUC5B) in the lung tissue and histopathology. Although PM2.5 or human albumin alone did not induce allergic airway inflammation, simultaneous inoculation of PM2.5 and human albumin-induced airway inflammation showing increase in AHR, total BALF cell numbers, mRNA levels of IL-13, eotaxin 1, eotaxin 2, and MUC5AC, and anti-IG against human serum albumin. Inflammation was observed around the bronchus in PM2.5 plus human albumin-induced lungs. These results demonstrate that PM2.5 can induce allergic airway inflammation through the synergistic action with human albumin in NC/Nga mice.


Assuntos
Hiper-Reatividade Brônquica/induzido quimicamente , Material Particulado/toxicidade , Pneumonia/induzido quimicamente , Albumina Sérica Humana/farmacologia , Animais , Hiper-Reatividade Brônquica/patologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Progressão da Doença , Humanos , Inflamação/induzido quimicamente , Inflamação/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos , Tamanho da Partícula , Pneumonia/patologia , Organismos Livres de Patógenos Específicos
18.
J Nat Med ; 73(3): 584-588, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31028661

RESUMO

The antidiabetic effects of a hot water extract of the stems of Salacia chinensis (SCE) were evaluated in vivo in ob/ob mice (genetically obese hyperglycemic mice). Administration of dietary feed containing 0.20 and 0.50% of SCE for 23 days to ob/ob mice significantly suppressed the elevation of both blood glucose and HbA1c levels, without significantly changing body weight and food intake. To characterize the antidiabetic effects of the thiosugar sulfonium constituent neokotalanol (1), which has potent α-glucosidase inhibitory activity, we performed a similar in vivo study. HbA1c levels were significantly suppressed in ob/ob mice after the administration of dietary feed containing 0.0003% of neokotalanol (1) for 20 days. These results indicate that SCE and neokotalanol (1) are potential leads for the development of novel antidiabetic agents.


Assuntos
Hemoglobina A Glicada/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Extratos Vegetais/farmacologia , Salacia/química , Tioaçúcares/farmacologia , Animais , Glicemia/análise , Glicemia/efeitos dos fármacos , Peso Corporal , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Obesos , Obesidade , Tioaçúcares/química
19.
J Toxicol Sci ; 44(4): 299-307, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30944282

RESUMO

Methicillin-resistant Staphylococcus aureus (MRSA) leads to serious infections, but it is not known whether it changes the expression of kidney drug metabolizing enzymes during infection. The mice were infected with different doses of MRSA and the oxidative stress and inflammation levels in the kidney were examined. The mRNA expression and activity of cytochrome P450 enzyme was analysed. Mice infected with high levels of MRSA showed a decrease in renal antioxidant capability and an elevated level of oxidative metabolites, which was accompanied by the release of inflammatory cytokines. The levels of interleukin 1ß, tumour necrosis factor alpha, and macrophage inflammatory protein-1α were significantly increased along with the levels of nitric oxide and malondialdehyde. On day 7, mRNA expression of Cyp1a2, 2d22, and 3a11 were decreased by the high level of MRSA, but the low level of MRSA increased their expressions. Cyp2e1 mRNA expression was increased by MRSA in the kidney of mice. High dose of MRSA infection increased the oxidative stress and inflammatory response in mouse kidney, leading to the decrease in the expression of renal drug-metabolizing enzymes and no recovery within 7 days.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Expressão Gênica , Rim/enzimologia , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas/enzimologia , Infecções Estafilocócicas/genética , Animais , Citocinas/metabolismo , Inflamação , Mediadores da Inflamação/metabolismo , Rim/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos Endogâmicos , Óxido Nítrico/metabolismo , Estresse Oxidativo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
20.
J Dairy Sci ; 102(6): 4816-4831, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30981495

RESUMO

Dynamic interactions between lipid metabolism, gut permeability, and systemic inflammation remain unclear in the context of obesity. Milk polar lipids, lipids derived from the milk fat globule membrane, could positively affect the aforementioned obesity-related endpoints. This study aimed to test the hypotheses that milk polar lipids will reduce gut permeability, systemic inflammation, and liver lipid levels, and differentially affect the hepatic expression of genes associated with fatty acid synthesis and cholesterol regulation in preexisting obesity. We fed 3 groups of C57BL/6J ob/ob mice (n = 6 per group) for 2 wk: (1) a modified AIN-93G diet (CO) with 34% fat by energy; (2) CO with milk gangliosides (GG) at 0.2 g/kg of diet; and (3) CO with milk phospholipids (PL) at 10 g/kg of diet. The GG and PL were provided as semi-purified concentrates and replaced 2.0% and 7.2% of dietary fat by energy. The GG and PL did not affect total food intake, weight gain, fasting glucose, or gut permeability. The PL decreased liver mass and the mesenteric fat depot compared with the CO. The GG increased tight junction protein occludin in colon mucosa compared with the CO. The GG and PL decreased tight junction protein zonula occludens-1 in jejunum mucosa compared with the CO. Plasma endotoxin increased during the study but was unaffected by the treatments. Compared with the CO and GG, the PL increased plasma sphingomyelin and plasma IL-6. The GG and PL differentially regulated genes associated with lipid metabolism in the liver compared with the CO. Regarding general effects on lipid metabolism, the GG and PL decreased lipid levels in the liver and the mesenteric depot, and increased lipid levels in the plasma. Diet consumption decreased significantly when the ob/ob mice were kept in metabolic cages, which were not big enough and resulted in unwanted animal deaths. Future studies may keep this in mind and use better metabolic equipment for ob/ob mice. In conclusion, dietary milk polar lipids may have limited beneficial effects on gut barrier integrity, systemic inflammation, and lipid metabolism in the context of severe obesity.


Assuntos
Inflamação/metabolismo , Mucosa Intestinal/metabolismo , Metabolismo dos Lipídeos , Leite/metabolismo , Obesidade Mórbida/metabolismo , Adipogenia , Animais , Dieta , Gorduras na Dieta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Permeabilidade , Fosfolipídeos/metabolismo , Ganho de Peso
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