RESUMO
This study was conducted according to the method presented in the Republic of Korea Pharmacopoeia 11th Revision, aseptic test method to evaluate the suitability of sterilization for a sterile needle (4 Pin Multi-needle). In this study, four tests were conducted: sterility test, cytotoxicity test, acute toxicity test, skin sensitization test. First, in the aseptic test, the microorganism was not proliferated in the aseptic test of the medium. As a result of the performance test of the medium, it was confirmed that the microorganism developed within 3 days and the fungus was evident within 5 days. Based on this, it was confirmed that the medium was suitable, and as a result of the aseptic test, the development of microorganisms was not observed during the total culture period. Based on these results, tests were conducted which were confirmed to be suitable for aseptic testing because the development of bacteria on the provided samples was not recognized. For cytotoxicity tests ISO10993-5; 2009 (Biological Evaluation of Medical Devices, Part 5: Test for in vitro Cytotoxicity). As a result, the MEM eluate of the test substance caused very slight cytotoxicity to the fibroblasts of the mouse and was judged to be Grade 1 (Slightly cytotoxic) according to the judgment standard of ISO 10993-5. On the other hand, solvent control, negative control and positive control showed the expected results on the test. Acute Toxicity Test Results: It was judged that there was no systemic toxicity change when ICR mice were treated with 50 mL/kg B.W. of the eluate of sterile injectable needle for 72 hours. Skin sensitization test result: The Hartley guinea pig was evaluated as a substance which is evaluated as a substance which does not induce any skin reaction when skin sensitization is applied to the dissected material of the sterile injectable needle and is weak in skin sensitivity. Based on the above tests, we will study the stability and efficacy of more reliable medical devices based on the verification and performance of medical devices.
Assuntos
Mesoterapia/métodos , Agulhas/microbiologia , Esterilização/métodos , Animais , Dermatite Alérgica de Contato/microbiologia , Fibroblastos/microbiologia , Cobaias , Camundongos , Reprodutibilidade dos Testes , República da Coreia , Testes Cutâneos , Esterilização/normas , Testes de ToxicidadeRESUMO
Cancer stem cells, a small subpopulation of cells with stem cell-like characteristics found within most solid tumors, are widely reported to be responsible for the malignancy of aggressive cancer cells, and targeting these cells presents a sound therapeutic strategy for reducing the risk of tumor relapse. In the present study, we examined the effects of an extract of Saccharina japonica (ESJ) on glioblastoma stem cells (GSCs). Saccharina japonica is a member of the Phaeophyceae (brown algae) family, which displays biological activities, including antitumor effects. ESJ inhibited the sphere-forming ability of GSCs in vitro as evidenced by neurosphere formation and limiting dilution assays. Treatment with ESJ partially induced apoptosis, reduced cell invasiveness, and sensitized GSCs to ionizing radiation. In addition, ESJ inhibited the maintenance of stemness in GSCs by suppressing the expression of epidermal growth factor receptor (EGFR)/EGFR variant III (EGFRvIII) and Notch intracellular domain. Intriguingly, the observed ESJ-induced suppression also appeared to induce the proteasomal degradation of EGFR/EGFRvIII. Our results indicate that ESJ could be considered a potent therapeutic adjuvant that targets GSCs.
Assuntos
Receptores ErbB/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Phaeophyceae/química , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Humanos , Camundongos , Células-Tronco Neoplásicas/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We isolated the novel vasoactive marine natural products, (5E,10E)-14-hydroxy-2,6,10-trimethylpentadeca-5,10-dien-4-one (4) and sargachromenol D (5), from Sargassum siliquastrum collected from the coast of the East Sea in South Korea by using activity-guided HPLC purification. The compounds effectively dilated depolarization (50mMK+)-induced basilar artery contraction with EC50 values of 3.52±0.42 and 1.62±0.63µM, respectively, but only sargachromenol D (5) showed a vasodilatory effect on endothelin-1 (ET-1)-induced basilar artery contraction (EC50=9.8±0.6µM). These results indicated that sargachromenol D (5) could act as a dual antagonist of l-type Ca2+ channel and endothelin A/B2 receptors. Moreover, sargachromenol D (5) lowered blood pressure in spontaneous hypertensive rats (SHRs) 2h after oral treatment at a dose of 80mg/kg dose and the effect was maintained for 24h. Based on our ex vivo and in vivo experiments, we propose that sargachromenol D (5) is a strong candidate for the treatment of hypertension that is not controlled by conventional drugs, in particular, severe-, type II diabetes-, salt-sensitive, and metabolic disease-induced hypertension.
Assuntos
Anti-Hipertensivos/química , Benzopiranos/química , Bloqueadores dos Canais de Cálcio/química , Antagonistas do Receptor de Endotelina A/química , Antagonistas do Receptor de Endotelina B/química , Phaeophyceae/química , Administração Oral , Animais , Anti-Hipertensivos/isolamento & purificação , Anti-Hipertensivos/farmacologia , Artéria Basilar/efeitos dos fármacos , Artéria Basilar/fisiologia , Benzopiranos/isolamento & purificação , Benzopiranos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/isolamento & purificação , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/química , Canais de Cálcio Tipo L/metabolismo , Antagonistas do Receptor de Endotelina A/isolamento & purificação , Antagonistas do Receptor de Endotelina A/farmacologia , Antagonistas do Receptor de Endotelina B/isolamento & purificação , Antagonistas do Receptor de Endotelina B/farmacologia , Masculino , Phaeophyceae/metabolismo , Coelhos , Ratos , Ratos Endogâmicos SHR , Receptor de Endotelina A/química , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/química , Receptor de Endotelina B/metabolismoRESUMO
Hyaluronan has diverse biological activities depending on its molecular size. The hyaluronan fragments (50 kDa) can decrease adipogenic differentiation in vitro. However, in vivo anti-obesitic effects of hyaluronan fragments have not been elucidated. Therefore, we examined the anti-obesity effects of hyaluronan fragments on high-fat diet induced obesity in C57BL/6 mice. Oral administration of hyaluronan fragments (200 mg/kg for 8 weeks) decreased body weight, adipose tissues, serum lipid (low-density lipoprotein cholesterol, triglyceride), and leptin level. Hyaluronan fragments decreased the hypertrophy of adipose tissue and ameliorated liver steatosis. The mRNA expression of leptin was reduced in adipocyte by treatment with hyaluronan fragments. Additionally, hyaluronan fragments enhanced the mRNA expression of PPAR-α and its target genes UCP-2 and decreased mRNA expression of PPAR- γ and fatty acid synthase in liver. In conclusions, hyaluronan fragments had marked effects on inhibiting the development of obesity in obese mice fed the high-fat diet. It suggested that enhancing PPAR-α and suppressing PPAR-γ expression are two possible mechanisms for the anti-obesitic effect of hyaluronan fragments.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Ácido Hialurônico/farmacologia , Obesidade/terapia , Adipócitos/metabolismo , Adiponectina/sangue , Animais , Peso Corporal , Fígado Gorduroso/patologia , Hiperlipidemias/metabolismo , Leptina/sangue , Leptina/metabolismo , Metabolismo dos Lipídeos , Lipídeos/sangue , Lipoproteínas LDL/sangue , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Peso Molecular , Obesidade/fisiopatologia , PPAR alfa/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Triglicerídeos/sangueRESUMO
Hyaluronan has diverse biological activities depending on its molecular size. High molecular weight hyaluronan (2000 kDa) is a major component of extracellular matrix, and has been used in wounding healing, extracellular matrix regeneration, and in the treatment of osteoarthritis. Hyaluronan fragments can stimulate inflammation or induce loss of extracellular matrix. Hyaluronan is expressed during adipocyte differentiation, and down regulation of hyaluronan synthesis can reduce adipogenic differentiation. However, the direct effects of hyaluronan fragments on adipocyte differentiation have not been elucidated. Therefore, we prepared hyaluronan fragments by enzymatic digestion, and examined the inhibitory effects of these hyaluronan fragments on the accumulation of lipid droplets and on adipogenic gene mRNA expression in differentiating 3T3-L1 pre-adipocytes. Medium sized hyaluronan fragments (50 kDa) decreased lipid droplet accumulation in a dose-dependent manner. However, high molecular weight hyaluronan did not inhibit lipid droplet accumulation when used at a concentration of 600 µg/ml. Two or 4 day treatments with medium molecular weight of hyaluronan resulted in similar inhibitory levels of lipid accumulation as did treatment for 8 days. Medium sized hyaluronan inhibited the differentiation of 3T3-L1 pre-adipocytes during the early stages of adipogenesis. When 3T3-L1 cells were treated with 180 µg/ml of medium sized hyaluronan, the mRNAs for the master adipogenic transcription factors PPAR-γ and C/EBP-α were inhibited. Additionally, medium molecular weight hyaluronan suppressed mRNA expression of PPAR-γ target genes, including aP2 and FAS. This study is the first to report that medium molecular weight hyaluronan fragments can inhibit adipocyte differentiation.
Assuntos
Adipócitos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Ácido Hialurônico/farmacologia , Células 3T3-L1 , Adipócitos/citologia , Animais , Ácido Hialurônico/química , Camundongos , Peso MolecularRESUMO
We synthesized a library of curcumin mimics with diverse alkylsulfonyl and substituted benzenesulfonyl modifications through a simple addition reaction of important intermediate, 1-(3-Amino-phenyl)-3-(4-hydroxy-3-methoxy-phenyl)-propenone (10), with various sulfonyl chloride reactants and then tested their vasodilatation effect on depolarization (50 mM K(+))- and endothelin-1 (ET-1)-induced basilar artery contraction. Generally, curcumin mimics with aromatic sulfonyl groups showed stronger vasodilation effect than alkyl sulfonylated curcumin mimics. Among the tested compounds, six curcumin mimics (11g, 11h, 11i, 11j, 11l, and 11s) in a depolarization-induced vasoconstriction and seven compounds (11g, 11h, 11i, 11j, 11l, 11p, and 11s) in an ET-1-induced vasoconstriction showed strong vasodilation effect. Based on their biological properties, synthetic curcumin mimics can act as dual antagonist scaffold of L-type Ca(2+) channel and endothelin A/B2 receptor in vascular smooth muscle cells. In particular, compounds 11g and 11s are promising novel drug candidates to treat hypertension related to the overexpression of L-type Ca(2+) channels and ET peptides/receptors-mediated cardiovascular diseases.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Curcumina/farmacologia , Antagonistas do Receptor de Endotelina A/farmacologia , Antagonistas do Receptor de Endotelina B/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/química , Canais de Cálcio Tipo L/metabolismo , Curcumina/síntese química , Curcumina/química , Relação Dose-Resposta a Droga , Antagonistas do Receptor de Endotelina A/síntese química , Antagonistas do Receptor de Endotelina A/química , Antagonistas do Receptor de Endotelina B/síntese química , Antagonistas do Receptor de Endotelina B/química , Masculino , Estrutura Molecular , Coelhos , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , Relação Estrutura-AtividadeRESUMO
A newly designed curcumin mimic library (11a-11k) with 2-ethylamino groups in a chalcone structure and variously substituted triazole groups as side chains was synthesized using the Huisgen 1,3-cycloaddition reaction between various alkynes (a-k) and an intermediate (10), with CuSO4 and sodium ascorbate in a solution mixture of chloroform, ethanol, and water (5:3:1) at room temperature for 5h. In the lactate dehydrogenase (LDH) release assay involving co-treatment with tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and/or synthetic curcumin derivatives using TRAIL-resistant human CRT-MG astroglioma cells, the novel curcumin mimic library was found to effectively stimulate the cytotoxicity of TRAIL, causing mild cytotoxicity when administered alone. In particular, 11a and 11j are promising candidates for TRAIL-sensitizers with potential use in combination chemotherapy for brain tumors.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Curcumina/química , Dietilaminas/química , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Triazóis/química , Protocolos de Quimioterapia Combinada Antineoplásica/síntese química , Protocolos de Quimioterapia Combinada Antineoplásica/química , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Ligante Indutor de Apoptose Relacionado a TNF/síntese química , Ligante Indutor de Apoptose Relacionado a TNF/químicaRESUMO
The chlorophyll-related compound pheophorbide a (Pa) was successively purified from an edible red seaweed, Grateloupia elliptica, using silica, octadecyl silica column chromatography and reversed phase-high-performance liquid chromatography, as well as the cell cycle inhibitory and apoptotic effects of Pa being investigated in U87MG glioblastoma cells. The Pa exhibited strong anticancer effects in the absence of direct photo-irradiation against various cancer cell lines, including U87MG, SK-OV-3, and HeLa cells. Among the cancer cells, the strongest anticancer activity of Pa exhibited on U87MG cells with IC50 values of 2.8 µg/ml. In addition, Pa specifically had cytostatic activity on glioblastoma cells rather than human umbilical vein endothelial cells. Analysis of the cell cycle distribution showed that Pa induced G0/G1 arrest of U87 MG cells. In addition, arrested cells induced late apoptosis and DNA degradation under dark condition. These results suggest that Pa isolated from G. elliptica is a potential glioblastoma-specific anticancer agent without side effects on normal cells.
Assuntos
Antineoplásicos/farmacologia , Clorofila/análogos & derivados , Citostáticos/farmacologia , Neurônios/efeitos dos fármacos , Rodófitas/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/toxicidade , Apoptose , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Clorofila/isolamento & purificação , Clorofila/farmacologia , Citostáticos/isolamento & purificação , Citostáticos/toxicidade , Fragmentação do DNA , Células Endoteliais/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Humanos , Concentração Inibidora 50RESUMO
A specific blocker of L-type Ca(2+) channels may be useful in decreasing arterial tone by reducing the open-state probability of L-type Ca(2+) channels. The aim of the present study was to evaluate the farnesylacetones, which are major active constituents of Sargassum siliquastrum, regarding their vasodilatation efficacies, selectivities toward L-type Ca(2+) channels, and in vivo antihypertensive activities. The application of 5E-(farnesylacetone 311) or 5Z-farnesylacetone (farnesylacetone 312) induced concentration-dependent vasodilatation effects on the basilar artery that was pre-contracted with depolarization and showed an ignorable potential role of endothelial-derived nitric oxide. We also tested farnesylacetone 311 or 312 to determine their pharmacological profiles for the blockade of native L-type Ca(2+) channels in basilar arterial smooth muscle cells (BASMCs) and ventricular myocytes (VMCs), cloned L- (α1C/ß2a/α2δ), N- (α1B/ß1b/α2δ), and T-type Ca(2+) channels (α1G, α1H, and α1I). Farnesylacetone 311 or 312 showed greater selectivity toward the L-type Ca(2+) channels among the tested voltage-gated Ca(2+) channels. The ranked order of the potency for farnesylacetone 311 was cloned α1CâL-type (BASMC)âL-type (VMCs)>α1B>α1H>α1I>α1G and that for farnesylacetone 312 was cloned α1CâL-type (BASMCs)âL-type (VMCs)>α1H>α1G>α1B>α1I. The oral administration of the farnesylacetone 311 (80mg/kg) conferred potent, long-lasting antihypertensive activity in spontaneous hypertensive rats, but it did not alter the heart rate.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/efeitos dos fármacos , Sargassum/química , Terpenos/farmacologia , Administração Oral , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/isolamento & purificação , Anti-Hipertensivos/farmacologia , Artéria Basilar/efeitos dos fármacos , Artéria Basilar/metabolismo , Tempo de Circulação Sanguínea , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/isolamento & purificação , Canais de Cálcio Tipo L/metabolismo , Relação Dose-Resposta a Droga , Células HEK293 , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipertensão/tratamento farmacológico , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Óxido Nítrico/metabolismo , Coelhos , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Terpenos/química , Terpenos/isolamento & purificação , Vasodilatação/efeitos dos fármacosRESUMO
This study was aimed at the synthesis and characterization of novel Titania nanorods by sol-gel electrospinning technique. The physicochemical properties of the synthesized nanorods were determined by field emission scanning electron microscopy (FE-SEM), energy dispersive X-ray spectroscopy (EDX), transmission electron microscopy (TEM), and X-ray diffraction (XRD) pattern. To examine the in vitro cytotoxicity, mouse myoblast C2C12 cells were treated with different concentrations of as prepared TiO(2) nanorods and the viability of cells was analyzed by Cell Counting Kit-8 assay at regular time intervals. The morphological features of the cells attached with nanorods were examined by Bio-SEM. Cytotoxicity experiments indicated that the mouse myoblast cells could attach to the TiO(2) nanorods after being cultured. We observed that TiO(2) nanorods could support cell adhesion and growth and guide spreading behavior of myoblasts. We conclude that the electrospun TiO(2) nanorods scaffolds with unique morphology had excellent biocompatibility. Thus, the current work demonstrates that the as-synthesized TiO(2) nanorods represent a promising biomaterial to be exploited for various tissue engineering applications.
Assuntos
Adesão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Mioblastos/efeitos dos fármacos , Titânio/química , Titânio/farmacologia , Animais , Materiais Biocompatíveis , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Indicadores e Reagentes , Camundongos , Microscopia Confocal , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Nanotubos , Alicerces Teciduais , Difração de Raios XRESUMO
An extract of the red alga, Neorhodomela aculeata, exhibited antiviral activity against human rhinoviruses. Bioassay-guided purification was performed to yield six compounds, which were subsequently identified as lanosol (1) and five polybromocatechols (2-6) by spectroscopic methods, including 1D and 2D NMR and mass spectrometric analyses. Structurally, all of these compounds, except compound 5, contain one or two 2,3-dibromo-4,5-dihydroxyphenyl moieties. In a biological activity assay, compound 1 was found to possess antiviral activity with a 50% inhibitory concentration (IC50) of 2.50 µg/mL against HRV2. Compound 3 showed anti-HRV2 activity, with an IC50 of 7.11 µg/mL, and anti-HRV3 activity, with an IC50 of 4.69 µg/mL, without demonstrable cytotoxicity at a concentration of 20 µg/mL. Collectively, the results suggest that compounds 1 and 3 are candidates for novel therapeutics against two different groups of human rhinovirus.
Assuntos
Antivirais/farmacologia , Catecóis/química , Catecóis/farmacologia , Rhinovirus/efeitos dos fármacos , Rodófitas/química , Rodófitas/metabolismo , Antivirais/química , Catecóis/metabolismo , Células HeLa , Humanos , Estrutura MolecularRESUMO
A diastereomeric and regioisomeric library of 10-substituted triazolyl artemisinin compounds (6a-6h, 7a-7h, and 8a-8h) with a potent growth inhibitory activities against various cancer cell lines was established. These compounds were synthesized by a reaction with dihydroartemisinin (2) and various substituted triazoles (5a-5h) in methylene chloride using a BF(3)Et(2)O catalyst. Most of the compounds exhibited a strong potency in the submicromolar range, and, in particular, 6f, 7f, and 8f, which have a pentylphenyltriazole moiety, proved to be promising candidates for preclinical trials.
Assuntos
Ácidos/química , Artemisininas/síntese química , Artemisininas/farmacologia , Divisão Celular/efeitos dos fármacos , Artemisininas/química , Catálise , Linhagem Celular Tumoral , Humanos , Espectroscopia de Ressonância MagnéticaRESUMO
A marine bacterium was isolated from seawater near the Korean south coast for efficient saccharification from alginate. Based on 16S rDNA sequence, the isolated strain was identified as Pseudoalteromonas agarovorans. Various environmental factors affecting saccharification of alginate using P. agarovorans CHO-12 have been investigated in flask cultures. The optimum concentration of sugar was obtained at 30 rpm and 29 degrees C. Among various NaCl concentrations, when NaCl concentration was increased from 10 to 30 g/l, the cell concentration sharply increased, while there is no increase at above 40 g/l. The maximum sugar concentration was obtained at 13.8 when 30 g/l of NaCl was used. Yeast extract and corn steep liquor were the best nitrogen source for efficient saccharification. Especially, the sugar concentration of 14.9 g/l was obtained after 3 days of culture using a mixture of 1.0 g/l of yeast extract and 1.5 g/l of corn steep liquor. Scale up was carried out at 50 l of reactor for 3 days using P. agarovorans CHO-12 and Stenotrophomonas maltophilia sp. When S. maltophilia was used, cell concentration was about twofold higher than that of P. agarovorans CHO-12. On the other hand, when P. agarovorans CHO-12 was used, the maximum saccharification rate was obtained, 7.5 g/l/day after 2 days of culture, which was about tenfold higher than that of S. maltophilia.
Assuntos
Alginatos/metabolismo , Oligossacarídeos/biossíntese , Pseudoalteromonas/classificação , Pseudoalteromonas/metabolismo , Água do Mar/microbiologia , Ácido Glucurônico/metabolismo , Ácidos Hexurônicos/metabolismo , Coreia (Geográfico) , Pseudoalteromonas/isolamento & purificação , Especificidade da EspécieRESUMO
In order to discover novel small vasodilatory molecules for potential use in the treatment of vascular disease, we tested the vasodilatation effect of two types of synthetic curcumin mimics, amide type (3) and sulfonyl amide type (4), upon the basilar artery of rabbits. In general, the sulfonyl amide type mimic (4) is more potent than the amide type (3). Curcumin (1) and compounds 12 and 20 effectively dilated the basilar artery of white rabbits.
Assuntos
Artéria Basilar/fisiologia , Curcumina/síntese química , Mimetismo Molecular , Ácidos Sulfínicos/síntese química , Vasodilatação/fisiologia , Animais , Artéria Basilar/efeitos dos fármacos , Curcumina/farmacologia , Relação Dose-Resposta a Droga , Técnicas In Vitro , Masculino , Mimetismo Molecular/fisiologia , Coelhos , Ácidos Sulfínicos/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/síntese química , Vasodilatadores/farmacologiaRESUMO
Most of the 10-substituted triazolylartemisinin synthesized via the Huisgen 1,3-dipolar cylcoaddition of diastereomeric 10-azidoartemisinin (5, 6, and 7) with various alkynes (a-h) exhibit strong growth inhibition activity, even at sub-micromolar concentrations, against various cancer cell lines such as DLD-1, U-87, Hela, SiHa, A172, and B16. In particular, 10b and 10f showed a highly strong cytotoxicity.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Artemisininas/síntese química , Artemisininas/farmacologia , Antineoplásicos/química , Artemisininas/química , Linhagem Celular Tumoral , Ciclização , Humanos , Espectroscopia de Ressonância MagnéticaRESUMO
Two farnesylacetones, 311 and 312, major active constituents of Sargassum siliquastrum collected from the coast of the East Sea in Korea, showed a moderate vasodilatation effect on the basilar arteries of rabbits. Therefore, treatment with farnesylacetones 311 and 312 may selectively accelerate cerebral blood flow through dilatation of the basilar artery.
Assuntos
Artéria Basilar/efeitos dos fármacos , Artérias Carótidas/efeitos dos fármacos , Sargassum/metabolismo , Terpenos/química , Vasodilatadores/síntese química , Vasodilatadores/farmacologia , Animais , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Circulação Cerebrovascular/efeitos dos fármacos , Química Farmacêutica/métodos , Desenho de Fármacos , Modelos Químicos , Coelhos , Vasodilatação/efeitos dos fármacosRESUMO
Hyaluronic acid (HA) has been implicated in cell adhesion, motility, and tumor progression in gliomas. We previously reported that HA stimulates secretion of matrix metalloproteinase-9 (MMP-9) and induces glioma invasion. However, the molecular mechanism of HA action and therapeutic strategies for blocking HA-induced MMP-9 secretion remain unknown. Here, we report that the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) blocks MMP-9 secretion and that HA-induced nuclear factor-kappaB (NF-kappaB) activation is mediated by IkappaB kinase, which phosphorylates the NF-kappaB inhibitor IkappaBalpha and promotes its degradation. In addition, using an RNA interference approach, we show that the focal adhesion kinase plays a critical role in mediating HA-induced NF-kappaB activation, which resulted in increased MMP-9 expression and secretion, cell migration, and invasion. Importantly, we show that 17-AAG acts by blocking focal adhesion kinase activation, thereby inhibiting IkappaB kinase-dependent IkappaBalpha phosphorylation/degradation, NF-kappaB activation, and MMP-9 expression. This leads to suppression of HA-induced cell migration and invasion. Based on our data, we propose that 17-AAG is a candidate drug for treatment of highly invasive gliomas resulting from HA-induced, NF-kappaB-mediated MMP-9 secretion.
Assuntos
Benzoquinonas/farmacologia , Glioma/metabolismo , Ácido Hialurônico/metabolismo , Lactamas Macrocíclicas/farmacologia , Metaloproteinase 9 da Matriz/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Núcleo Celular/metabolismo , Regulação para Baixo , Ativação Enzimática/efeitos dos fármacos , Matriz Extracelular/patologia , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Glioma/tratamento farmacológico , Glioma/patologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/farmacologia , Humanos , Ácido Hialurônico/farmacologia , Quinase I-kappa B/metabolismo , Proteínas I-kappa B/metabolismo , Inibidor de NF-kappaB alfa , NF-kappa B/metabolismo , Fosforilação , Interferência de RNA , Transdução de SinaisRESUMO
We screened active compounds from natural marine products able to increase PPARalpha/gamma transcriptional activity. Sargaquinoic acid (SQA) and sargahydroquinoic acid (SHQA) from Sargassum yezoense were identified as novel PPARalpha/gamma dual agonists. The binding affinity of SQA with PPARgamma was higher than that of the specific PPARgamma agonist troglitazone, leading to an activation of PPARgamma transcriptional activity. In parallel, treatment of 3T3-L1 cells with SQA and SHQA led to an increase in adipocyte differentiation and increased expression of adipogenic marker genes such as aP2, PPARgamma, resistin, adiponectin, C/EBPalpha and Glut4. Collectively, our data suggest that SQA and SHQA are novel PPARalpha/gamma dual agonists and may be beneficial for reducing insulin resistance through regulation of adipogenesis.
Assuntos
Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Alcenos/farmacologia , Benzoquinonas/farmacologia , PPAR alfa/agonistas , PPAR gama/agonistas , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/metabolismo , Adipogenia/genética , Alcenos/isolamento & purificação , Animais , Benzoquinonas/isolamento & purificação , Camundongos , PPAR alfa/metabolismo , PPAR gama/metabolismo , Sargassum/química , Transcrição Gênica/efeitos dos fármacosRESUMO
Sargahydroquinoic acid (2), a major active constituent of Sargassum micracanthum collected from the coast of the East Sea in Korea, showed a selective vasodilatation effect on the basilar arteries of rabbits. Therefore, treatment with sargahydroquinoic acid may selectively accelerate cerebral blood flow through dilatation of the basilar artery without lowering systemic blood pressure.
Assuntos
Alcenos/química , Alcenos/farmacologia , Artéria Basilar/efeitos dos fármacos , Benzoquinonas/química , Benzoquinonas/farmacologia , Animais , Estrutura Molecular , Coelhos , Sargassum/química , Vasodilatação/efeitos dos fármacosRESUMO
OBJECTIVES: To verify in vitro and in vivo activities of echinomycin against clinical isolates of Staphylococcus aureus, we compared antistaphylococcal activities of echinomycin with those of vancomycin. METHODS: In vitro activities (MICs and MBCs) of oxacillin, vancomycin and echinomycin against 18 isolates of methicillin-susceptible S. aureus (MSSA) and 118 isolates of methicillin-resistant S. aureus (MRSA) were compared. Using four representative isolates of S. aureus, time-kill assay and in vivo antistaphylococcal activities were assessed. Echinomycin and vancomycin were compared in an in vivo mouse infection model. RESULTS: Echinomycin demonstrated higher in vitro activities against MSSA and MRSA strains, exhibiting 2-fold lower MIC(90)s and 4-fold lower MBC(90)s than vancomycin. Additionally, time-kill assay indicated that echinomycin is more potent than vancomycin against MSSA and MRSA strains in the context of MICs and MBCs. Using an in vivo protection model, it was shown that the 50% effective doses of echinomycin were at least 7-fold lower than those of vancomycin. Therefore, echinomycin displayed excellent protection in mice against acute peritoneal infections caused by both MSSA and MRSA strains. CONCLUSIONS: Collectively, these data indicate that the activity of echinomycin against S. aureus strains is at least equivalent to that of vancomycin, regardless of the methicillin resistance of these strains. These promising activities of echinomycin might justify its potential use against infections with S. aureus strains resistant to vancomycin. This might be the first report to show that echinomycin possesses antipathogenic staphylococcal activity.