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1.
J Physiol Pharmacol ; 70(3)2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31566191

RESUMO

We hypothesized that the repolarization phase of action potentials (APs) in mammals with large body mass and high cardiac output could not be reliably controlled by only one of the delayed rectifier potassium IK current components. To test this hypothesis experimentally, we performed a comparative study of the response of AP phases to the rapid IKr channels blocker E-4031 and slow IKs blocker chromanol 293B in APs spontaneously generated in strips of sinoauricular (SA) tissue from mouse, guinea pig, and pig hearts. Application of a slow channels blocker chromanol 293B caused a decrease of Aps generation frequency in SA area strips from mouse, guinea-pig and pig by 5.3, 16, and 18% compared to the control. Treatment with the IKr blocker E-4031 caused a significant reduction of APs generation frequency in the mouse, guinea pig, and pig SA strips by 24, 26, and 36%, respectively, compared to the control values. These results suggest that the rapid IKr current is the key component responsible for AP generation in sinoauricular node cells of the pig heart.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Canais de Potássio/metabolismo , Potássio/metabolismo , Nó Sinoatrial/fisiologia , Animais , Cromanos/farmacologia , Cobaias , Masculino , Camundongos , Bloqueadores dos Canais de Potássio/farmacologia , Nó Sinoatrial/metabolismo , Sulfonamidas/farmacologia , Suínos
2.
Molecules ; 24(18)2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505754

RESUMO

Novel derivatives of some non steroidal anti-inflammatory drugs, as well as of the antioxidants α-lipoic acid, trolox and (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid with lorazepam were synthesised by a straightforward method at satisfactory to high yields (40%-93%). All the tested derivatives strongly decreased lipidemic indices in rat plasma after Triton induced hyperlipidaemia. They also reduced acute inflammation and a number of them demonstrated lipoxygenase inhibitory activity. Those compounds acquiring antioxidant moiety were inhibitors of lipid peroxidation and radical scavengers. Therefore, the synthesised compounds may add to the current knowledge about multifunctional agents acting against various disorders implicating inflammation, dyslipidaemia and oxidative stress.


Assuntos
Hiperlipidemias/tratamento farmacológico , Inflamação/tratamento farmacológico , Lorazepam/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Acrilatos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Carragenina/química , Carragenina/farmacologia , Cromanos/química , Cromanos/farmacologia , Humanos , Hiperlipidemias/patologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Inibidores de Lipoxigenase/farmacologia , Lorazepam/análogos & derivados , Ratos , Ácido Tióctico/análogos & derivados , Ácido Tióctico/farmacologia
3.
Fitoterapia ; 135: 107-113, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31048011

RESUMO

An examination of the endophytic fungus Trichoderma asperellum A-YMD-9-2 obtained from the marine red alga Gracilaria verrucosa led to the isolation of seven new chromanoid norbisabolane derivatives, trichobisabolins I-L (1-4) and trichaspsides C-E (5-7). Their structures and relative configurations were established on the basis of spectroscopic techniques, mainly including 1D/2D NMR and MS, and the absolute configuration of 1 was assigned by X-ray crystallographic analysis using Cu Kα radiation. All of these isolates feature a 1,9-epoxy ring system, and 5-7 represent the second occurrence of norbisabolane aminoglycosides. Compounds 1-7 exhibited potent inhibition of several marine phytoplankton species.


Assuntos
Aminoglicosídeos/farmacologia , Cromanos/farmacologia , Gracilaria/microbiologia , Trichoderma/química , Aminoglicosídeos/química , Aminoglicosídeos/isolamento & purificação , Cromanos/isolamento & purificação , Cristalografia por Raios X , Endófitos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Trichoderma/fisiologia
4.
Spectrochim Acta A Mol Biomol Spectrosc ; 219: 358-366, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31055242

RESUMO

Caffeic acid (CA) is a plant metabolite acting as a carcinogenic inhibitor, and exhibits a high antioxidant effect and some antimicrobial activity. Besides, this compound can be useful in the prevention of heart diseases and atherosclerosis, among others. The present study aims to determine the in vitro antioxidant activity of CA in order to increase the frequency of its use and reliability in the prevention of damage caused by free radicals and other reactive species. The tests performed were as follows: Radical anion superoxide capture; crocin bleaching assay; capturing ability of hypochlorous acid; H2O2 capture; capturing capacity of the ABTS•+/DPPH•; and SOD-like activity. The values of the CA antioxidant activity were very close to the values of standards in all tests. Besides, CA presented an antioxidant activity greater than that of ascorbic acid and trolox, and its advantages include higher stability than ascorbic acid and extraction from natural sources, as opposed to trolox.


Assuntos
Antioxidantes/farmacologia , Ácidos Cafeicos/farmacologia , Ácido Ascórbico/farmacologia , Benzotiazóis/metabolismo , Compostos de Bifenilo/metabolismo , Cromanos/farmacologia , Radicais Livres/metabolismo , Peróxido de Hidrogênio/metabolismo , Ácido Hipocloroso/metabolismo , Picratos/metabolismo , Ácidos Sulfônicos/metabolismo , Superóxidos/metabolismo
5.
Immunopharmacol Immunotoxicol ; 41(2): 337-348, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31056974

RESUMO

Objective: The isochroman-type fungal metabolite 3,7-dimethyl-1,8-hydroxy-6-methoxyisochroman (DMHM) was isolated from the extracts of a marine-derived fungal strain of Penicillium sp. SF-6013. In this study, we investigated the effect of DMHM on inflammatory response. Materials and methods: Anti-inflammatory effects of DMHM were examined in lipopolysaccharide (LPS)-stimulated RAW264.7 and BV2 cells. We observed their anti-inflammatory effects by ELISA, qRT-PCR, and western blot analysis. Results: DMHM revealed that it suppressed the production of prostaglandin E2 (PGE2), nitric oxide (NO), cyclooxygenase-2 (COX-2), and inducible NO synthase (iNOS) in LPS-stimulated RAW264.7 and BV2 cells. Furthermore, DMHM decreased the mRNA expression of pro-inflammatory cytokines including interleukin (IL)-1ß and IL-6. Therefore, DMHM was further investigated to elucidate the mechanisms of its anti-inflammatory properties; the results indicated that its effect was mediated by the suppression of the nuclear factor (NF)-κB and c-Jun N-terminal kinase (JNK) MAPK pathways. Furthermore, the anti-inflammatory activity of DMHM correlated with its induction of heme oxygenase-1 (HO)-1 expression via activation of the nuclear factor erythroid 2-like 2 (Nrf2) pathway. Discussion and conclusions: Collectively, the results of this study suggest that DMHM inhibited several inflammatory pathways including the NF-κB and MAPK pathways, and induced Nrf2-mediated HO-1 expression, demonstrating its potential usefulness for treating inflammatory and neuroinflammatory diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Cromanos/farmacologia , Heme Oxigenase-1/imunologia , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas de Membrana/imunologia , Fator 2 Relacionado a NF-E2/imunologia , Animais , Anti-Inflamatórios/química , Cromanos/química , Ciclo-Oxigenase 2/imunologia , Dinoprostona/imunologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Óxido Nítrico/imunologia , Penicillium/química , Células RAW 264.7
6.
Mol Med Rep ; 19(6): 5007-5014, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942406

RESUMO

Myocardial infarction (MI) is associated with a high risk of mortality and is a major global health concern. The present study aimed to investigate the protective effects of (3R)­5,6,7­trihydroxy­3­isopropyl­3­methylisochroman­1­one (TIM) against MI induced by isoproterenol (ISO) in a rat model and the underlying mechanisms. Wistar rats were assigned to 4 groups (n=10): The control group received saline treatment; the ISO group received an intraperitoneal injection of ISO (100 mg/kg); and the TIM (low) and TIM (high) groups received an intraperitoneal injection of ISO, plus a 1 and 2 mg/kg dose of TIM orally, respectively. TIM rats were treated with TIM daily for 12 days and received ISO injections on the final 2 days to induce MI. Cardiac function, apoptosis index and protein expression were subsequently determined. The levels of oxidative stress markers were determined by ELISAs, whereas DNA damage was detected using a Cell Death Detection ELISA kit. Gene and protein expression were determined via reverse transcription­quantitative polymerase chain reaction and western blot analyses, respectively. Following treatment with ISO, the maximum left ventricular contraction/relaxation velocity and left ventricular systolic pressure were significantly decreased, whereas the left ventricular end­diastolic pressure was increased; however, treatment with TIM significantly ameliorated ISO­induced cardiac dysfunction. Additionally, TIM treatment significantly decreased oxidative stress and inhibited the apoptosis of cardiomyocytes, as determined by a decrease in caspase activities, increased expression of B­cell lymphoma 2 (Bcl­2) and reduced expression of cleaved caspase­3, cleaved caspase­9 and Bcl­2­associated X. Furthermore, treatment with TIM upregulated the levels of apelin in the plasma and myocardium of ISO­treated rats. The results indicated that TIM protected cardiomyocytes against ISO­induced MI, potentially via the apelin/apelin receptor signaling pathway. The results of the present study suggested that TIM may be a potential novel therapy for the treatment of MI.


Assuntos
Receptores de Apelina/metabolismo , Apelina/metabolismo , Cromanos/farmacologia , Coração/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Caspase 3/genética , Caspase 3/metabolismo , Cromanos/química , Cromanos/uso terapêutico , Isoproterenol/toxicidade , Masculino , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
7.
Int J Oncol ; 54(4): 1295-1305, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30968157

RESUMO

The mechanisms through which cancer­upregulated gene 2 (CUG2), a novel oncogene, affects Wnt/ß­catenin signaling, essential for tumorigenesis, are unclear. In this study, we aimed to elucidate some of these mechanisms in A549 lung cancer cells. Under the overexpression of CUG2, the protein levels and activity of ß­catenin were evaluated by western blot analysis and luciferase assay. To examine a biological consequence of ß­catenin under CUG2 overexpression, cell migration, invasion and sphere formation assay were performed. The upregulation of ß­catenin induced by CUG2 overexpression was also accessed by xenotransplantation in mice. We first found that CUG2 overexpression increased ß­catenin expression and activity. The suppression of ß­catenin decreased cancer stem cell (CSC)­like phenotypes, indicating that ß­catenin is involved in CUG2­mediated CSC­like phenotypes. Notably, CUG2 overexpression increased the phosphorylation of ß­catenin at Ser33/Ser37, which is known to recruit E3 ligase for ß­catenin degradation. Moreover, CUG2 interacted with and enhanced the expression and kinase activity of never in mitosis gene A­related kinase 2 (NEK2). Recombinant NEK2 phosphorylated ß­catenin at Ser33/Ser37, while NEK2 knockdown decreased the phosphorylation of ß­catenin, suggesting that NEK2 is involved in the phosphorylation of ß­catenin at Ser33/Ser37. Treatment with CGK062, a small chemical molecule, which promotes the phosphorylation of ß­catenin at Ser33/Ser37 through protein kinase C (PKC)α to induce its degradation, reduced ß­catenin levels and inhibited the CUG2­induced features of malignant tumors, including increased cell migration, invasion and sphere formation. Furthermore, CGK062 treatment suppressed CUG2­mediated tumor formation in nude mice. Taken together, the findings of this study suggest that CUG2 enhances the phosphorylation of ß­catenin at Ser33/Ser37 by activating NEK2, thus stabilizing ß­catenin. CGK062 may thus have potential for use as a therapeutic drug against CUG2­overexpressing lung cancer cells.


Assuntos
Carcinogênese/efeitos dos fármacos , Proteínas Cromossômicas não Histona/metabolismo , Quinases Relacionadas a NIMA/metabolismo , Neoplasias/tratamento farmacológico , beta Catenina/metabolismo , Células A549 , Acrilatos/farmacologia , Acrilatos/uso terapêutico , Animais , Carcinogênese/patologia , Cromanos/farmacologia , Cromanos/uso terapêutico , Feminino , Humanos , Masculino , Camundongos , Camundongos Nus , Quinases Relacionadas a NIMA/genética , Neoplasias/patologia , Fosforilação/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/genética
8.
Eur J Med Chem ; 170: 16-27, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30878829

RESUMO

A series of Flexible Heteroarotinoid (Flex-Het) analogs was synthesized and their biological activities were evaluated against the A2780 ovarian cancer cell line. The objective of this study was to establish structure-activity relationships (SARs) for new Flex-Het derivatives, which were previously inaccessible due to the limited availability of aryl isothiocyanate precursors. The current work developed a synthesis of isothiocyanate 13 and used it to prepare 14 diverse thiourea analogs of the lead compound SHetA2 (1, NSC-721689) from a range of commercial amines. Additionally, five new ureas were prepared along with nine N-benzylthioureas, five derivatives incorporating hydrazine or hydrazide linkers and four desmethyl compounds. Potencies and efficacies were determined for each derivative. Some of the new Flex-Hets displayed high activity with IC50 values ranging from 1.86 to 4.70 µM and 85.6-95.9% efficacies, which are comparable to or better than the lead compound (IC50 3.17 µM, 84.3% efficacy). Although SHetA2 is scheduled to enter clinical trials in the near future, alternative backup drug candidates have been identified in this work. The new agents possess similar pharmacological properties and retain selective activity against A2780 ovarian cancer cells. Although a mixed SAR was obtained for these analogs, diversified, highly potent molecules were identified for further investigation. In particular, agents 2c-d and 3e-f, which incorporated CF3 and OCF3 groups in place of NO2 on the pendent aryl ring, displayed high activity and excellent differentiation between normal and cancerous cells.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Cromanos/química , Cromanos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Tionas/química , Tionas/farmacologia , Tioureia/análogos & derivados , Tioureia/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromanos/síntese química , Feminino , Humanos , Neoplasias Ovarianas/patologia , Relação Estrutura-Atividade , Tionas/síntese química , Tioureia/síntese química
9.
Bioorg Med Chem ; 27(7): 1382-1390, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30819619

RESUMO

ROCK1 and ROCK2 are highly homologous isoforms. Accumulated studies indicate that they have distinct different functions, and the development of isoform selective ROCK inhibitors will pave new roads for the treatment of various diseases. In this work, a series of amide-chroman derivatives were synthesized and biologically evaluated in order to develop potent and isoform selective ROCK2 inhibitors. Remarkably, (S)-6-methoxy-chroman-3-carboxylic acid (4-pyridin-4-yl-phenyl)-amide ((S)-7c) possessed ROCK2 inhibitory activity with an IC50 value of 3 nM and 22.7-fold isoform selectivity (vs. ROCK1). Molecular docking indicated that hydrophobic interactions were the key element for the high potency and isoform selectivity of (S)-7c. The binding free energies predicted by MM/GBSA were in good agreement with the experimental bioactivities, and the analysis of individual energy terms suggested that residue Lys105 in ROCK1 or Lys121 in ROCK2 was the key residue for the isoform selectivity of (S)-7c.


Assuntos
Cromanos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Cromanos/síntese química , Cromanos/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Quinases Associadas a rho/metabolismo
10.
Mil Med ; 184(Suppl 1): 644-651, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30901461

RESUMO

Ionizing radiation exposure is a major concern for active military service members, as well as civilian population. Considering that the exposure is not predictable, it is imperative that strategies to counteract radiation damage must be discovered. Recent in vitro studies performed in our laboratory demonstrated that the vitamin E analog gamma-tocotrienol (GT3) in combination with cholesterol-lowering drugs (Statins), synergistically induced endothelial thrombomodulin, an anticoagulant with radio-protective efficacy. It was hypothesized that the combination of treatment with both GT3 along with Statins would provide better radiation protection in vivo than each drug individually. CD2F1 mice were injected subcutaneously with either vehicle or single dose of GT3 (200 mg/kg body weight) 24 hours before irradiation followed by oral or subcutaneous administration of various doses of simvastatin (25, 50, and 100 mg/kg body weight) before exposure to lethal doses (11.5 and 12 Gy) of Cobalt-60 (60Co) gamma-irradiation. The combined treatment group exhibited enhanced radiation lethality protection substantially, accelerated white blood cell recovery, and augmented restoration of bone marrow cellularity when compared to the animals treated with either drug exclusively. This information clearly suggests that combined treatment could be used as a safeguard for military personnel from exposure to harmful ionizing radiation.


Assuntos
Cromanos/farmacologia , Quimioterapia Combinada/normas , Sinvastatina/farmacologia , Vitamina E/análogos & derivados , Animais , Cromanos/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Quimioterapia Combinada/métodos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Camundongos , Exposição Ocupacional/efeitos adversos , Radiação Ionizante , Sinvastatina/uso terapêutico , Análise de Sobrevida , Vitamina E/farmacologia , Vitamina E/uso terapêutico
11.
Int J Mol Sci ; 20(5)2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30866453

RESUMO

Emerging evidence suggests that gamma-tocotrienol (γ-T3), a vitamin E isomer, has potent anti-cancer properties against a wide-range of cancers. γ-T3 not only inhibited the growth and survival of cancer cells in vitro, but also suppressed angiogenesis and tumour metastasis under in vivo conditions. Recently, γ-T3 was found to target cancer stem cells (CSCs), leading to suppression of tumour formation and chemosensitisation. Despite its promising anti-cancer potential, the exact mechanisms responsible for the effects of γ-T3 are still largely unknown. Here, we report the identification of Ang-1 (Angiopoietin-1)/Tie-2 as a novel γ-T3 downstream target. In prostate cancer cells, γ-T3 treatment leads to the suppression of Ang-1 at both the mRNA transcript and protein levels. Supplementing the cells with Ang-1 was found to protect them against the anti-CSC effect of γ-T3. Intriguingly, inactivation of Tie-2, a member receptor that mediates the effect of Ang-1, was found to significantly enhance the cytotoxic effect of γ-T3 through activation of AMP-activated protein kinase (AMPK) and subsequent interruption of autophagy. Our results highlighted the therapeutic potential of using γ-T3 in combination with a Tie-2 inhibitor to treat advanced prostate cancer.


Assuntos
Cromanos/farmacologia , Neoplasias da Próstata/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vitamina E/análogos & derivados , Angiopoietina-1/genética , Angiopoietina-1/metabolismo , Autofagia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Receptor TIE-2/genética , Receptor TIE-2/metabolismo , Vitamina E/farmacologia
12.
Oxid Med Cell Longev ; 2019: 2069250, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30906500

RESUMO

The newly synthesized coumarin derivative with dopamine, 3-(1-((3,4-dihydroxyphenethyl)amino)ethylidene)-chroman-2,4-dione, was completely structurally characterized by X-ray crystallography. It was shown that several types of hydrogen bonds are present, which additionally stabilize the structure. The compound was tested in vitro against different cell lines, healthy human keratinocyte HaCaT, cervical squamous cell carcinoma SiHa, breast carcinoma MCF7, and hepatocellular carcinoma HepG2. Compared to control, the new derivate showed a stronger effect on both healthy and carcinoma cell lines, with the most prominent effect on the breast carcinoma MCF7 cell line. The molecular docking study, obtained for ten different conformations of the new compound, showed its inhibitory nature against CDKS protein. Lower inhibition constant, relative to one of 4-OH-coumarine, proved stronger and more numerous interactions with CDKS protein. These interactions were carefully examined for both parent molecule and derivative and explained from a structural point of view.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Cromanos/síntese química , Cromanos/farmacologia , Antineoplásicos/química , Sobrevivência Celular/efeitos dos fármacos , Cromanos/química , Cristalografia por Raios X , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular
13.
Chem Biol Interact ; 302: 22-27, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30707977

RESUMO

In this work, we determined whether oxidative stress contributed to the activation of the kynurenine pathway by AgNPs. Male Wistar rats weighing between 130 and 146 g were randomly assigned into six groups. Animals in the negative control group were orally administered distilled water while, the other treatment groups were respectively given AgNPs (25 and 50 mg/kg bw) alone or in combination with Trolox (100 mg/kg bw). Results showed that treatments with AgNPs significantly raised protein carbonyl level in rat liver, but the co-treatment with Trolox attenuated the elevation. Conversely, AgNPs raised the level of reduced glutathione (GSH) in rat plasma and tissues compared to the negative control. Further, oral exposure to AgNPs (50 mg/kg bw) significantly elevated rat plasma and brain kynurenine levels compared to the negative control. Meantime, the co-treatment with Trolox appreciably restored kynurenine level in rat plasma, but not in the rat brain. Taken together, findings indicate that the oral administration of AgNPs alone at the doses used in this study, might not have caused oxidative stress. However, the co-treatment with Trolox appears to potentiate oxidative stress in rats following exposure to AgNPs. Furthermore, data support that the activation of the kynurenine pathway in the rat brain by AgNPs might be independent of oxidative stress. The findings are new and contribute to deepen our understanding of the cellular interaction by nanoparticles.


Assuntos
Encéfalo/efeitos dos fármacos , Cinurenina/metabolismo , Nanopartículas Metálicas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Administração Oral , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Cromanos/farmacologia , Glutationa/sangue , Glutationa/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Nanopartículas Metálicas/química , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Prata/química
14.
Toxicology ; 417: 42-53, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30769052

RESUMO

Tocotrienols (T3s) are a subgroup of vitamin E and they have been widely tested to inhibit cell growth in various tumor types. Previous studies have shown that T3s inhibit cancer cell growth by targeting multiple signaling transduction and cellular processes. However, the role of T3s in the regulation of cellular bioenergetic processes remains unclear. In this study, we found that γ-T3 interacts with mitochondrial electron transfer chain NDUFB8 (a subunit of complex I) and SDHB (a subunit of complex II) and inhibits oxidative phosphorylation (OXPHOS), and triggers the production of reactive oxygen species (ROS). In addition, we observed that γ-T3 upregulates the glycolytic capacity in cells, but it did not compensate for cellular ATP generation and decreased the ATP levels in cells. Furthermore, we performed western blots and RT-PCR to measure the mRNA and protein levels of mitochondrial electron transfer chain (ETC) proteins and complex V (ATP synthase), where the results indicated that γ-T3 specifically inhibited the levels of NDUFB8 and SDHB, whereas it had little effect on UQCRC2 (a subunit of complex III), COX4I1 (a subunit of complex IV), and ATP5F1A (a subunit of complex V). The inhibition of NDUFB8 and SDHB by γ-T3 led to the overproduction of ROS and the depletion of ATP, which may be responsible for inducing apoptosis in cancer cells. Our results suggest that mitochondrial respiration may be an effective target for anticancer treatments based on γ-T3.


Assuntos
Apoptose/efeitos dos fármacos , Cromanos/farmacologia , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Fosforilação Oxidativa/efeitos dos fármacos , Succinato Desidrogenase/antagonistas & inibidores , Vitamina E/análogos & derivados , Apoptose/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Complexo I de Transporte de Elétrons/metabolismo , Humanos , Succinato Desidrogenase/metabolismo , Vitamina E/farmacologia
15.
Sci Rep ; 9(1): 13, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30626882

RESUMO

SUL-compounds are protectants from cold-induced ischemia and mitochondrial dysfunction. We discovered that adding SUL-121 to renal grafts during warm machine reperfusion elicits a rapid improvement in perfusion parameters. Therefore, we investigate the molecular mechanisms of action in porcine intrarenal arteries (PIRA). Porcine kidneys were stored on ice overnight and perfusion parameters were recorded during treatment with SUL-compounds. Agonist-induced vasoconstriction was measured in isolated PIRA after pre-incubation with SUL-compounds. Receptor binding and calcium transients were assessed in α1-adrenoceptor (α1-AR) transgenic CHO cells. Molecular docking simulation was performed using Schrödinger software. Renal pressure during warm reperfusion was reduced by SUL-121 (-11.9 ± 2.50 mmHg) and its (R)-enantiomer SUL-150 (-13.2 ± 2.77 mmHg), but not by the (S)-enantiomer SUL-151 (-1.33 ± 1.26 mmHg). Additionally, SUL-150 improved renal flow (16.21 ± 1.71 mL/min to 21.94 ± 1.38 mL/min). SUL-121 and SUL-150 competitively inhibited PIRA contraction responses to phenylephrine, while other 6-chromanols were without effect. SUL-150 similarly inhibited phenylephrine-induced calcium influx and effectively displaced [7-Methoxy-3H]-prazosin in CHO cells. Docking simulation to the α1-AR revealed shared binding characteristics between prazosin and SUL-150. SUL-150 is a novel α1-AR antagonist with the potential to improve renal graft perfusion after hypothermic storage. In combination with previously reported protective effects, SUL-150 emerges as a novel protectant in organ transplantation.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Cromanos/farmacologia , Rim/irrigação sanguínea , Piperazinas/farmacologia , Receptores Adrenérgicos alfa 1/metabolismo , Vasoconstrição/efeitos dos fármacos , Animais , Células CHO , Cricetulus , Reperfusão/métodos , Suínos
16.
J Photochem Photobiol B ; 191: 116-122, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30605891

RESUMO

Riboflavin (RF), a water-soluble vitamin B2, is an endogenous singlet oxygen photosensitizer in human skin and eye. Time profiles of the near-infrared phosphorescence of singlet oxygen generated by RF have been measured in the absence and presence of l-ascorbic acid (AA, vitamin C), 3-O-ethyl-l-ascorbic acid (3-EtAA) and Trolox (TX, a water-soluble analogue of vitamin E) in phosphate buffer (pH 6.8). These substances suppress the RF-photosensitized singlet oxygen generation. For example, the quantum yield of singlet oxygen generation is decreased to a third by adding 0.4 mmol dm-3 AA or TX (the concentration of dissolved oxygen in air-saturated water is 0.27 mmol dm-3). AA and TX are more efficient suppressors of RF-photosensitized singlet oxygen generation than 3-EtAA. The bimolecular rate constants for quenching of the excited singlet and triplet states of RF by AA, 3-EtAA and TX have been determined through measurements of fluorescence and transient absorption. These measurements suggest that the observed suppression is due to the quenching of the excited singlet and triplet states of RF by AA, 3-EtAA and TX. The bimolecular rate constants for quenching of singlet oxygen by AA, 3-EtAA and TX were determined to be 1.8 × 108, 0.27 × 108, and 4.4 × 108 mol-1 dm3 s-1, respectively.


Assuntos
Antioxidantes/farmacologia , Riboflavina/química , Oxigênio Singlete/química , Ácido Ascórbico/análogos & derivados , Ácido Ascórbico/farmacologia , Cromanos/farmacologia , Humanos , Cinética , Oxigênio/química , Fármacos Fotossensibilizantes/química , Análise Espectral/métodos
17.
Nat Prod Res ; 33(13): 1870-1875, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29792356

RESUMO

Four previously undescribed isochromanes were isolated from the fermentation broth of an endophytic fungus Aspergillus fumigatus, which was obtained from the fruiting body of Cordyceps sinensis. Their structures were elucidated through extensive spectroscopic analyses. One racemic isochromane was further purified by chiral HPLC to yield a pair of enantiomers and their absolute configurations were determined by quantum chemical ECD calculations. These isolated compounds were evaluated for cytotoxicity against two cell lines (MV4-11 and MDA-ME-231) and the result showed that compounds 1a and 2 exhibited moderate growth inhibition against MV4-11 cell line.


Assuntos
Aspergillus fumigatus/química , Cromanos/isolamento & purificação , Cordyceps , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cromanos/química , Cromanos/farmacologia , Citotoxinas/isolamento & purificação , Inibidores do Crescimento/isolamento & purificação , Humanos , Estrutura Molecular , Análise Espectral , Estereoisomerismo
18.
Chem Biol Drug Des ; 93(3): 254-261, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30264436

RESUMO

Sulfone/sulfoxide-containing carbohydrate derived thiochromans were found to be highly active antiplasmodial agents. However, the inability of the sulfone/sulfoxide functional groups for further derivatization and manipulation limited the potential for further exploration. In this study, based on the interesting and important physicochemical properties, as well as amenability of sulfoximines (isosters of sulfones) for further derivatization, a series of novel sulfoximine-type carbohydrate-derived thiochroman derivatives have been successfully synthesized, characterized, and evaluated for their antiplasmodial activity. Although the replacement of the sulfone functional group with a sulfoximine unit improved the antiplasmodial activity of the scaffolds, the activity was highly dependent on the configuration of the stereogenic centre at the sulfur atom. Moreover, analysis of the crystal structures of the sulfoximine analogues revealed that the bond between the sulfur and nitrogen atoms of the sulfoximine functional group is not a true double bond but rather a polarized single bond.


Assuntos
Antimaláricos/síntese química , Cromanos/química , Desenho de Drogas , Safrol/análogos & derivados , Sulfonas/química , Alquilação , Antimaláricos/química , Antimaláricos/farmacologia , Carboidratos/química , Sobrevivência Celular/efeitos dos fármacos , Cromanos/síntese química , Cromanos/farmacologia , Células HeLa , Humanos , Plasmodium falciparum/efeitos dos fármacos , Safrol/síntese química , Safrol/química , Safrol/farmacologia , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/farmacologia
19.
Bioorg Chem ; 83: 468-476, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30448725

RESUMO

Medicago sativa L. is a forage legume plant widely distributed in all continents. Six new triterpenoid saponins, Medicagosides A-F (1-6) and five known ones (7-11) were isolated from M. sativa. Their structures were determined via HRESIMS, 1D and 2D NMR analysis. Biologically, all the isolates displayed neuroprotective activities against H2O2-induced damage in SH-SY5Y cells. Among them, compounds 1, 3-5 and 10 exhibited striking neuroprotective activities at 100 µM, restoring cell viability range from 79.66% to 89.03%, relative to 79.46% (100 µM) of Trolox used as the positive control.


Assuntos
Medicago sativa/química , Fármacos Neuroprotetores/farmacologia , Saponinas/farmacologia , Triterpenos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromanos/farmacologia , Humanos , Peróxido de Hidrogênio/farmacologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Estresse Oxidativo/efeitos dos fármacos , Saponinas/química , Saponinas/isolamento & purificação , Triterpenos/química , Triterpenos/isolamento & purificação
20.
Food Chem ; 277: 353-361, 2019 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-30502157

RESUMO

The non-isothermal autohydrolysis temperature impact of edible brown seaweed Laminaria ochroleuca was studied to recover high valuable compounds. Extraction yield was determined, above 80% was obtained at 220 °C. The maximal fucose content (17% d.b.) was attained at 180 °C, whereas the maximal sulphate was achieved at 160 °C, and phenolic and protein content at 220 °C. The maximum sulphated fucoidan content (41.38 g fucoidan/100 g extract) was obtained at 160 °C, whereas the maximum fucose oligosaccharides was obtained at 180 °C. The antioxidant capacity was equivalent to 32 mg Trolox/g dry extract produced at 220 °C. The milder processing condition was selected to study the potentiality of the precipitated alginate in terms of viscoelastic properties determined by rheology. Alginate extraction (14.94 g/100 g extract) was determined at 160 °C. The crude fucoidan fractions were tested at 25-500 µg/mL, showed up to 50% cell growth inhibition in four selected tumoral cell lines.


Assuntos
Géis/química , Laminaria/química , Alga Marinha/química , Células A549 , Alginatos/análise , Alginatos/farmacologia , Antineoplásicos Fitogênicos/análise , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/análise , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Fenômenos Químicos , Cromanos/análise , Cromanos/farmacologia , Inibidores do Crescimento/análise , Inibidores do Crescimento/farmacologia , Células HCT116 , Temperatura Alta , Humanos , Hidrólise , Peso Molecular , Polissacarídeos/farmacologia , Reologia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectroscopia de Infravermelho com Transformada de Fourier
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