RESUMO
Aim: To design and synthesize a novel series of 1-aryldonepezil analogues. Materials & methods: The 1-aryldonepezil analogues were synthesized through palladium/PCy3-catalyzed Suzuki reaction and were evaluated for cholinesterase inhibitory activities and neuroprotective effects. In silico docking of the most effective compound was conducted. Results: The 4-tert-butylphenyl analogue exhibited good inhibitory potency against acetylcholinesterase and butyrylcholinesterase and had a favorable neuroprotective effect on H2O2-induced SH-SY5Y cell injury. Conclusion: The 4-tert-butylphenyl derivative is a promising lead compound for anti-Alzheimer's disease drug development.
[Box: see text].
Assuntos
Acetilcolinesterase , Doença de Alzheimer , Butirilcolinesterase , Inibidores da Colinesterase , Desenho de Fármacos , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Humanos , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Relação Estrutura-Atividade , Piperidinas/química , Piperidinas/farmacologia , Piperidinas/síntese química , Estrutura Molecular , Linhagem Celular Tumoral , Peróxido de Hidrogênio/farmacologia , Peróxido de Hidrogênio/antagonistas & inibidores , IndóisRESUMO
Feruloylated oligosaccharides (FOs) generated by decomposing plant hemicellulose, offer a wide range of potential applications in both the food and biomedical areas. As a graminaceous plant, bamboo is rich in hemicellulose. However, the structural composition and activity studies of FOs from it were rarely reported. In this study, FOs from Phyllostachys acuta (pFOs) obtained by enzymatic hydrolysis were isolated by AmberliteXAD-2 and C18 SPE columns. Then, pFOs were qualitatively and quantitatively analyzed by UPLC-ESI-MS/MS after labeled by 3-Amino-9-ethyl-carbazole (AEC), and the chemical antioxidant activity of pFOs and effects of pFOs on H2O2-induced oxidative damage were investigated. Finally, 14 of pFOs isomers were distinguished and identified, of which 10 did not contain hexoses and 4 did, and the three most abundant pFO structures were 12 (Iso 7, F1A1X2H2-AEC, 29.04 %), 11 (Iso 6, F1A1X1H2-AEC, 17.96 %), and 4 (Iso 3-1, F1A1X3-AEC, 15.57 %). The results of antioxidant studies showed that pFOs possessed certain reducing power, scavenging DPPH radicals, scavenging superoxide anion radicals, and scavenging hydroxyl radicals. Among them, the ability to clear DPPH radicals was particularly significant. pFOs significantly reduced the viability of RAW264.7 cells after H2O2 induction, whereas pFOs had a significant protective effect (p < 0.001). pFOs increased the viability of T-AOC and SOD enzymes in oxidatively damaged cells, as well as had a significant inhibition effect on ROS elevation (p < 0.001). This study lays the foundation for the structural analysis and antioxidant activity evaluation of bamboo-derived feruloyl oligosaccharides for their application in food and pharmaceutical fields.
Assuntos
Antioxidantes , Peróxido de Hidrogênio , Oligossacarídeos , Oligossacarídeos/química , Oligossacarídeos/farmacologia , Oligossacarídeos/isolamento & purificação , Camundongos , Antioxidantes/farmacologia , Antioxidantes/química , Antioxidantes/isolamento & purificação , Animais , Células RAW 264.7 , Peróxido de Hidrogênio/farmacologia , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/química , Poaceae/química , Sobrevivência Celular/efeitos dos fármacosRESUMO
As a medicinal and edible resource, Hippophae rhamnoides Linn. subsp. sinensis Rousi is rich in bioactive secondary metabolites, including flavonoids and their derivatives, which offer protective effects against oxidative damage. This study reported the isolation of three new kaempferol derivatives from the seed residue of H. rhamnoides - Hippophandine A, B, and C (compounds 1-3). Their structures were elucidated by high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), nuclear magnetic resonance (NMR), and chemical analyses. The compounds were evaluated for their ability to mitigate hydrogen peroxide (H2O2)-induced cell death in SH-SY5Y cells. The results elucidated that Hippophandine A-C at concentrations of 1, 5, and 10â µM reduced the levels of malondialdehyde (MDA) and increased the activity of antioxidative enzymes, such as superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT). Furthermore, they significantly altered the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream heme oxygenase-1 (HO-1), which is an indicator of redox detection in H2O2-induced SH-SY5Y.
Assuntos
Hippophae , Peróxido de Hidrogênio , Quempferóis , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Regulação para Cima , Humanos , Quempferóis/farmacologia , Quempferóis/química , Quempferóis/isolamento & purificação , Peróxido de Hidrogênio/farmacologia , Peróxido de Hidrogênio/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Hippophae/química , Fator 2 Relacionado a NF-E2/metabolismo , Regulação para Cima/efeitos dos fármacos , Relação Estrutura-Atividade , Sobrevivência Celular/efeitos dos fármacos , Estrutura Molecular , Antioxidantes/farmacologia , Antioxidantes/química , Antioxidantes/isolamento & purificação , Linhagem Celular Tumoral , Relação Dose-Resposta a DrogaRESUMO
Azaphilones represent a particular group of fascinating pigments from fungal source, with easier industrialization and lower cost than the traditional plant-derived pigments, and they also display a wide range of pharmacological activities. Herein, 28 azaphilone analogs, including 12 new ones, were obtained from the fermentation culture of a marine fungus Penicillium sclerotium UJNMF 0503. Their structures were elucidated by MS, NMR and ECD analyses, together with NMR and ECD calculations and biogenetic considerations. Among them, compounds 1 and 2 feature an unusual natural benzo[d][1,3]dioxepine ring embedded with an orthoformate unit, while 3 and 4 represent the first azaphilone examples incorporating a novel rearranged 5/6 bicyclic core and a tetrahydropyran ring on the side chain, respectively. Our bioassays revealed that half of the isolates exhibited neuroprotective potential against H2O2-induced injury on RSC96 cells, while compound 13 displayed the best rescuing capacity toward the cell viability by blocking cellular apoptosis, which was likely achieved by upregulating the PI3K/Akt signaling pathway.
Assuntos
Apoptose , Benzopiranos , Relação Dose-Resposta a Droga , Peróxido de Hidrogênio , Fármacos Neuroprotetores , Penicillium , Fosfatidilinositol 3-Quinases , Pigmentos Biológicos , Proteínas Proto-Oncogênicas c-akt , Apoptose/efeitos dos fármacos , Penicillium/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/metabolismo , Pigmentos Biológicos/farmacologia , Pigmentos Biológicos/química , Pigmentos Biológicos/isolamento & purificação , Peróxido de Hidrogênio/farmacologia , Peróxido de Hidrogênio/antagonistas & inibidores , Estrutura Molecular , Benzopiranos/farmacologia , Benzopiranos/química , Benzopiranos/isolamento & purificação , Relação Estrutura-Atividade , Animais , Sobrevivência Celular/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacosRESUMO
Fungi can be used as a potent chemotherapeutic agent to treat various cancers. In current study acetone and methanol extracts of Terfezia claveryi, Terfezia boudieri, Terfezia olbiensis, Picoa lefebvrei, Picoa juniperi were used to assess total phenolic contents, antioxidant activity, ion-chelating impact, antimicrobial activity, the cytotoxic and protective effects. Both methanol and acetone extracts of T. boudieri had the highest FRAP and DPPH scavenging abilities. Dose-dependent increased ion-chelating impact of all tested truffles species was found. Extracts of T. boudieri, T. claveryi, and T. albiensis exhibited higher antimicrobial activities. T. claveryi and T. boudieri showed the highest protective effects against H2O2-induced genotoxicity (P < 0.05), in S. cerevisiae BY4741. The least protective effect was showed by the acetone extracts of T. olbiensis (144 ± 8); methanol extracts of P. lefebvrei (140 ± 8) and P. juniperi (140 ± 10). MCF 7 cells showed more sensitivity against to methanol extracts of T. boudieri at 10-100 µg/mL concentrations. HepG2 cells showed more sensitivity against the methanolic extracts of T. boudieri at both doses. Overall, P. lefebvrei and P. juniperi extracts had the least cytotoxic effects. The species of Terfezia exhibit significant protective effects against DNA damage and also have the potential of cytotoxicity effects.
Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Ascomicetos/química , Substâncias Protetoras/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antioxidantes/química , Antioxidantes/isolamento & purificação , Compostos de Bifenilo/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Ensaios de Seleção de Medicamentos Antitumorais , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Testes de Sensibilidade Microbiana , Picratos/antagonistas & inibidores , Substâncias Protetoras/química , Substâncias Protetoras/isolamento & purificação , Células Tumorais CultivadasRESUMO
A novel tumor-related biomarker, a H2O2-activatable photosensitizer 4 based on the 1,3-dicarbonyl enol moieties of hypocrellin B (3), was designed and synthesized. The photosensitizer 4 showed a blue-shifted absorption band compared with 3, and showed negligible photosensitizing ability without H2O2. However, the release of 3 from 4 by the reaction with H2O2 regenerated the photosensitizing ability. Furthermore, 4 exhibited selective and effective photo-cytotoxicity against high H2O2-expressing cancer cells upon photo-irradiation with 660 nm light, which is inside the phototherapeutic window.
Assuntos
Antineoplásicos/farmacologia , Peróxido de Hidrogênio/antagonistas & inibidores , Perileno/análogos & derivados , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Quinonas/farmacologia , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Peróxido de Hidrogênio/farmacologia , Estrutura Molecular , Perileno/química , Perileno/farmacologia , Fármacos Fotossensibilizantes/química , Quinonas/química , Espectrofotometria UltravioletaRESUMO
Pistacia lentiscus L. is a sclerophyllous shrub capable of growing under harsh climatic conditions especially in the Mediterranean Basin. Different products can be obtained from this plant, such as essential oil, mastic gum or even fixed oil. The last is well known for its flavor which is mainly exploited in the food industry. Additionally, it has been traditionally used in the treatment of skin diseases, but, at the moment, any suitable formulation for skin delivery has been formulated and its biological effects was not deeply confirmed. Given that, in the present study, the lentisk oil has been formulated in liposomes at different concentrations (10, 20, 30â¯mg/ml) and their physicochemical, technological and main biological properties have been evaluated. Vesicles were prepared by using natural soy lecithin and a green and organic solvent free method, thus obtaining spherical, small (~ 118â¯nm), homogeneously dispersed (0.27) and highly negatively charged (~ -62â¯mV) vesicles. The used amount of oil loaded in liposomes (10, 20, 30â¯mg/ml) modulated the penetration ability of vesicles in the skin, favoring the deposition of the payload in the deeper strata. The loading in the vesicles potentiated the ability of oil to counteract the damaging effects caused by hydrogen peroxide in keratinocytes and fibroblasts and facilitate their migration in a cell monolayer lesion. Overall findings suggested that the incorporation of lentisk oil in liposomes made from soy lecithin can be an alternative and natural approach to exploit it in pharmaceutical ad cosmetical applications and manufacturing natural products suitable for the treatment of skin lesions.
Assuntos
Movimento Celular/efeitos dos fármacos , Lipossomos/química , Óleos Voláteis/administração & dosagem , Óleos Voláteis/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Pistacia/química , Administração Tópica , Animais , Linhagem Celular , Composição de Medicamentos , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/toxicidade , Queratinócitos/efeitos dos fármacos , Lecitinas/química , Teste de Materiais , Camundongos , Oxidantes/antagonistas & inibidores , Oxidantes/toxicidade , Tamanho da Partícula , Glycine max/química , SuínosRESUMO
Transient receptor potential melastatin 2 (TRPM2) channel is associated with ischemia/reperfusion injury, inflammation, cancer and neurodegenerative diseases. However, the lack of specific inhibitors impedes the development of TRPM2 targeted therapeutic agents. To develop a selective TRPM2 inhibitor, three-dimensional similarity-based screening strategy was employed using the energy-minimized conformation of non-selective TRPM2 inhibitor 2-APB as the query structure, which resulted in the discovery of a novel tricyclic TRPM2 inhibitor Z-4 with benzo[d]imidazo[1,2-a]imidazole skeleton. A series of Z-4 derivatives were subsequently synthesized and evaluated using calcium imaging and electrophysiology approaches. Among them, preferred compounds ZA10 and ZA18 inhibited the TRPM2 channel with micromolar half-maximal inhibitory concentration values and exhibited TRPM2 selectivity over the TRPM8 channel, TRPV1 channel, InsP3 receptor and Orai channel. The analysis of structure-activity relationship provides valuable insights for further development of selective TRPM2 inhibitors. Neuroprotection assay showed that ZA10 and ZA18 could effectively reduce the mortality of SH-SY5Y cells induced by H2O2. These findings enrich the structure types of existing TRPM2 inhibitors and might provide a new tool for the study of TRPM2 function in Reactive oxygen species (ROS) -related diseases.
Assuntos
Desenho de Fármacos , Imidazóis/farmacologia , Fármacos Neuroprotetores/farmacologia , Canais de Cátion TRPM/antagonistas & inibidores , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Imidazóis/síntese química , Imidazóis/química , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Relação Estrutura-Atividade , Canais de Cátion TRPM/metabolismoRESUMO
Neurodegenerative diseases have a complex nature which highlights the need for multitarget ligands to address the complementary pathways involved in these diseases. Over the last decade, many innovative curcumin-based compounds have been designed and synthesized, searching for new derivatives having anti-amyloidogenic, inhibitory of tau formation, as well as anti-neuroinflammation, antioxidative, and AChE inhibitory activities. Regarding our experience studying 3-substituted coumarins with interesting properties for neurodegenerative diseases, our aim was to synthesize a new series of curcumin-coumarin hybrid analogues and evaluate their activity. Most of the 3-(7-phenyl-3,5-dioxohepta-1,6-dien-1-yl)coumarin derivatives 11-18 resulted in moderated inhibitors of hMAO isoforms and AChE and BuChE activity. Some of them are also capable of scavenger the free radical DPPH. Furthermore, compounds 14 and 16 showed neuroprotective activity against H2O2 in SH-SY5Y cell line. Nanoparticles formulation of these derivatives improved this property increasing the neuroprotective activity to the nanomolar range. Results suggest that by modulating the substitution pattern on both coumarin moiety and phenyl ring, ChE and MAO-targeted derivatives or derivatives with activity in cell-based phenotypic assays can be obtained.
Assuntos
Antioxidantes/síntese química , Inibidores da Colinesterase/síntese química , Cumarínicos/síntese química , Curcumina/análogos & derivados , Inibidores da Monoaminoxidase/síntese química , Fármacos Neuroprotetores/síntese química , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/farmacologia , Compostos de Bifenilo/antagonistas & inibidores , Butirilcolinesterase/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Cumarínicos/farmacologia , Curcumina/farmacologia , Proteínas Ligadas por GPI/metabolismo , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Córtex Motor/citologia , Córtex Motor/enzimologia , Nanopartículas/química , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Fármacos Neuroprotetores/farmacologia , Picratos/antagonistas & inibidores , Cultura Primária de Células , Ratos , Relação Estrutura-AtividadeRESUMO
Silver birch, Betula pendula Roth, is one of the most common trees in Europe. Due to its content of many biologically active substances, it has long been used in medicine and cosmetics, unlike the rare black birch, Betula obscura Kotula. The aim of the study was therefore to compare the antioxidant properties of extracts from the inner and outer bark layers of both birch trees towards the L929 line treated with acetaldehyde. Based on the lactate dehydrogenase test and the MTT test, 10 and 25% concentrations of extracts were selected for the antioxidant evaluation. All extracts at tested concentrations reduced the production of hydrogen peroxide, superoxide anion radical, and 25% extract decreased malonic aldehyde formation in acetaldehyde-treated cells. The chemical composition of bark extracts was accessed by IR and HPLC-PDA methods and surprisingly, revealed a high content of betulin and lupeol in the inner bark extract of B. obscura. Furthermore, IR analysis revealed differences in the chemical composition of the outer bark between black and silver birch extracts, indicating that black birch may be a valuable source of numerous biologically active substances. Further experiments are required to evaluate their potential against neuroinflammation, cancer, viral infections, as well as their usefulness in cosmetology.
Assuntos
Antioxidantes/farmacologia , Betula/química , Casca de Planta/química , Extratos Vegetais/farmacologia , Acetaldeído/antagonistas & inibidores , Acetaldeído/farmacologia , Animais , Antioxidantes/química , Antioxidantes/isolamento & purificação , Betula/classificação , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Malondialdeído/antagonistas & inibidores , Camundongos , Oxidantes/antagonistas & inibidores , Oxidantes/farmacologia , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/isolamento & purificação , Casca de Planta/classificação , Extratos Vegetais/química , Polônia , Superóxidos/antagonistas & inibidores , Triterpenos/química , Triterpenos/isolamento & purificaçãoRESUMO
Heat shock protein 90 (Hsp90) plays an important role in cancer cell proliferation, survival, and migration by regulating the maturation and stabilization of numerous oncoproteins. Despite significant efforts in developing Hsp90 inhibitors, none of these have been approved for clinical use, mostly due to toxicity, such as liver, cardiac, and retinal toxicity. To avoid undesirable toxicity, we herein report a hydrogen peroxide-activated Hsp90 inhibitor, Boro-BZide (3), which is capable of selectively targeting cancer cells over normal cells. Boro-BZide (3) can be activated by high levels of hydrogen peroxide, releasing its parent active Hsp90 inhibitor. The mechanism of action was determined by a series of experiments including fluorescence polarization assay, cell viability assay, western blotting, high-pressure liquid chromatography (HPLC), and fluorescence-activated cell sorting (FACS) analysis. These efforts ultimately led to the identification of a novel hydrogen peroxide-activated Hsp90 prodrug with improved therapeutic index, which was less prone to furnish unwanted adverse effects. This hydrogen peroxide-responsive prodrug strategy will be beneficial for overcoming the toxicity hurdles of Hsp90 inhibitors for clinical application.
Assuntos
Antineoplásicos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Peróxido de Hidrogênio/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Peróxido de Hidrogênio/farmacologia , Células MCF-7 , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A novel series of tacrine based cyclopentapyranopyridine- and tetrahydropyranoquinoline-kojic acid derivatives were designed, synthesized, and evaluated as anti-cholinesterase agents. The chemical structures of all target compounds were characterized by 1 H-NMR, 13 C-NMR, and elemental analyses. The synthesized compounds mostly inhibited acetylcholinesterase enzyme (AChE) with IC50 values of 4.18-48.71â µM rather than butyrylcholinesterase enzyme (BChE) with IC50 values of >100â µM. Among them, cyclopentapyranopyridine-kojic acid derivatives showed slightly better AChE inhibitory activity compared to tetrahydropyranoquinoline-kojic acid. The compound 10-amino-2-(hydroxymethyl)-11-(4-isopropylphenyl)-7,8,9,11-tetrahydro-4H-cyclopenta[b]pyrano[2',3' : 5,6]pyrano[3,2-e]pyridin-4-one (6f) bearing 4-isopropylphenyl moiety and cyclopentane ring exhibited the highest anti-AChE activity with IC50 value of 4.18â µM. The kinetic study indicated that the compound 6f acts as a mixed inhibitor and the molecular docking studies also illustrated that the compound 6f binds to both the catalytic site (CS) and peripheral anionic site (PAS) of AChE. The compound 6f showed moderate neuroprotective properties against H2 O2 -induced cytotoxicity in PC12 cells. The theoretical ADME study also predicted good drug-likeness for the compound 6f. Based on these results, the compound 6f seems to be a very promising AChE inhibitor for the treatment of Alzheimer's disease.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Fármacos Neuroprotetores/farmacologia , Tacrina/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Electrophorus , Cavalos , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Células PC12 , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Pironas/síntese química , Pironas/química , Pironas/farmacologia , Quinolinas/síntese química , Quinolinas/química , Quinolinas/farmacologia , Ratos , Tacrina/análogos & derivados , Tacrina/químicaRESUMO
BACKGROUND: Polygonum cuspidatum is a Chinese medicine commonly used to treat phlegm-heat asthma. However, its anti-asthmatic active ingredients and mechanism are still unknown. The aim of this study was to predict the active ingredients and pathways of Polygonum cuspidatum and to further explore the potential molecular mechanism in asthma by using network pharmacology. METHODS: The active ingredients and their targets related to Polygonum cuspidatum were seeked out with the TCM systematic pharmacology analysis platform (TCMSP), and the ingredient-target network was constructed. The GeneCards, DrugBank and OMIM databases were used to collect and screen asthma targets, and then the drug-target-disease interaction network was constructed with Cytoscape software. A target protein-protein interaction (PPI) network was constructed using the STRING database to screen key targets. Finally, GO and KEGG analyses were used to identify biological processes and signaling pathways. The anti-asthmatic effects of Polygonum cuspidatum and its active ingredients were tested in vitro for regulating airway smooth muscle (ASM) cells proliferation and MUC5AC expression, two main symptoms of asthma, by using Real-time PCR, Western blotting, CCK-8 assays and annexin V-FITC staining. RESULTS: Twelve active ingredients in Polygonum cuspidatum and 479 related target proteins were screened in the relevant databases. Among these target proteins, 191 genes had been found to be differentially expressed in asthma. PPI network analysis and KEGG pathway enrichment analysis predicted that the Polygonum cuspidatum could regulate the AKT, MAPK and apoptosis signaling pathways. Consistently, further in vitro experiments demonstrated that Polygonum cuspidatum and resveratrol (one active ingredient of Polygonum cuspidatum) were shown to inhibit ASM cells proliferation and promoted apoptosis of ASM cells. Furthermore, Polygonum cuspidatum and resveratrol inhibited PDGF-induced AKT/mTOR activation in ASM cells. In addition, Polygonum cuspidatum decreased H2O2 induced MUC5AC overexpression in airway epithelial NCI-H292 cells. CONCLUSION: Polygonum cuspidatum could alleviate the symptoms of asthma including ASM cells proliferation and MUC5AC expression through the mechanisms predicted by network pharmacology, which provides a basis for further understanding of Polygonum cuspidatum in the treatment of asthma.
Assuntos
Antiasmáticos/farmacologia , Asma/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Fallopia japonica/química , Mucina-5AC/antagonistas & inibidores , Animais , Antiasmáticos/química , Asma/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/química , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Medicina Tradicional Chinesa , Estrutura Molecular , Mucina-5AC/genética , Mucina-5AC/metabolismo , Mapas de Interação de Proteínas/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Accumulating evidence has demonstrated that cellular antioxidant systems play essential roles in retarding oxidative stress-related diseases, such as Parkinson's disease. Because nuclear factor erythroid 2-related factor 2 (Nrf2) is a chief regulator of cellular antioxidant systems, small molecules with Nrf2-activating ability may be promising neuroprotective agents. Avenanthramide-2c (Aven-2c), avenanthramide-2f (Aven-2f) and avenanthramide-2p (Aven-2p) are the most abundant avenanthramides in oats, and they have been documented to possess multiple pharmacological benefits. In this work, we synthesized these three compounds and evaluated their cytoprotective effect against oxidative stress-induced PC12 cell injuries. Aven-2c displayed the best protective potency among them. Aven-2c conferred protection on PC12 cells by scavenging free radicals and activating the Nrf2-ARE signaling pathway. Pretreatment of PC12 cells with Aven-2c efficiently enhanced Nrf2 nuclear accumulation and evoked the expression of a set of cytoprotective molecules. The mechanistic study also supports that Nrf2 activation is the molecular basis for the cellular action of Aven-2c. Collectively, this study demonstrates that Aven-2c is a potent Nrf2 agonist, shedding light on the potential usage of Aven-2c in the treatment of neuroprotective diseases.
Assuntos
Elementos de Resposta Antioxidante , Antioxidantes/farmacologia , Fator 2 Relacionado a NF-E2/genética , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/genética , ortoaminobenzoatos/farmacologia , Animais , Avena/química , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase (Desciclizante)/metabolismo , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxidopamina/antagonistas & inibidores , Oxidopamina/farmacologia , Células PC12 , Extratos Vegetais/química , Ratos , Tiorredoxina Redutase 1/genética , Tiorredoxina Redutase 1/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismoRESUMO
PURPOSE: This study aimed to determine the extent of contribution of dopamine to antioxidant and anti-tyrosinase activities, by dopamine addition to vanillin. This study achieved the synthesis of dopamine-associated vanillin Mannich base derivatives prepared via a one-step reaction involving a green chemistry approach, and investigation of antioxidant and anti-tyrosinase activities. METHODS: Novel one-pot synthesis of Mannich base dopamine-connected vanillin (1a-l) derivatives can be achieved via green chemistry without using a catalyst. Newly-prepared compounds were characterised with FTIR and NMR (1H and 13C) spectra, mass spectra, and elemental analyses. In total, 12 compounds (1a-l) were synthesised and their antioxidant and anti-tyrosinase activities evaluated. Antioxidant activities of 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO), hydrogen peroxide (H2O2), and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and diammonium assays, ABTSâ¢+ radical scavenging, and linoleic acid peroxidation were used to screen all synthesised compounds (1a-l) for anti-tyrosinase activities and cytotoxicity against MCF-7 and Vero cell lines;. RESULTS: The compound 1k inhibited (IC50:11.02µg/mL) the DPPH-scavenging activity to a greater extent than the standard BHT (IC50:25.17µg/mL), and showed high activity in H2O2 and NO scavenging assays. Compound 1e was more potent (96.21%) against ABTS and compound 1k was more potent (95.28%) against 2,2'-azobis(2-amidinopropane)dihydrochloride antioxidant than the standard trolox. All synthesised compounds were screened for anti-tyrosinase inhibitory activity. Compound 1e had higher activity against tyrosinase (IC50=10.63 µg/mL), than kojic acid (IC50=21.52µg/mL), and was more cytotoxic (GI50 0.01µM) against MCF-7 cell line than the doxorubicin standard and other tested compounds. CONCLUSION: In this study, all compounds were found to possess significant antioxidant and anti-tyrosinase activities. Compounds 1e and 1k performed well, compared with other compounds, in all assays. In addition, this study successfully identified several promising molecules that exhibited antioxidant and anti-tyrosinase activities.
Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Benzaldeídos/farmacologia , Dopamina/farmacologia , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antioxidantes/síntese química , Antioxidantes/química , Benzaldeídos/química , Benzotiazóis/antagonistas & inibidores , Compostos de Bifenilo/antagonistas & inibidores , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Dopamina/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Química Verde , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Células MCF-7 , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Óxido Nítrico/antagonistas & inibidores , Picratos/antagonistas & inibidores , Ácidos Sulfônicos/antagonistas & inibidores , Células VeroRESUMO
Melanin plays an important role in determining skin colour. Apoptosis of melanocytes and defect in melanin production cause vitiligo. Various studies have been conducted to treat the disease, but its treatment is still difficult. Therefore, this study aimed to investigate the effect of spermidine, which is known as an inhibitor of ageing-related oxidized proteins, on melanogenesis. Even though spermidine above 50 µM had no effect on antioxidant activity and DOPA oxidation, it displayed tyrosinase activity. However, spermidine at 2000 µM was cytotoxic in B16F1 cells using MTT assay. Spermidine above 125 µM decreased the amount of intracellular hydrogen peroxide in a concentration-dependent manner in DCFH-DA analysis. It was also found that spermidine above 2000 µM increased melanin synthesis in living cells. However, spermidine above 1000 µM increased melanin synthesis in a concentration-dependent manner in H2 O2 -treated B16F1 cells. Furthermore, spermidine enhanced the expression of tyrosine hydroxylase via MITF transcription factor involved in melanogenesis in H2 O2 -treated B16F1 cells. Therefore, these results suggest that spermidine could be applied as a potential stimulator of melanin synthesis for the prevention of hair greying.
Assuntos
Antioxidantes/farmacologia , Melaninas/biossíntese , Fator de Transcrição Associado à Microftalmia/metabolismo , Espermidina/farmacologia , Animais , Compostos de Bifenilo/antagonistas & inibidores , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/metabolismo , Camundongos , Fator de Transcrição Associado à Microftalmia/genética , Picratos/antagonistas & inibidores , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
The aim of this study was to investigate the primary structure of an acetylated Cyclocarya paliurus polysaccharide (Ac-CPP0.1) and its protective effect on H2O2-treated dendritic cells. The backbone of Ac-CPP0.1 was â3)-ß-D-Galp-(1â, with some branches α-L-Araf-(1â residues at O-6 and O-5, ß-D-Galp-(1â and 3,5,6)-ß-D-Galf-(1 residues at O-4 and acetyl groups were substituted at the O-2 and O-6 positions of 3)-ß-D-Galp-(1 residues. The CPP0.1 and Ac-CPP0.1 significantly increased the levels of superoxide dismutase, glutathione peroxidase and catalase on H2O2-treated dendritic cells. Meanwhile, both CPP0.1 and Ac-CPP0.1 up-regulated the expression of Nrf2 (NF-E2-related factor 2) and down-regulated the Keap1 (Kelch-like ECH-associated protein-1), but Ac-CPP0.1 had a better effect on antioxidant capacity. These results indicated that potential application of Ac-CPP0.1 as an antioxidant agent.
Assuntos
Antioxidantes/farmacologia , Células Dendríticas/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Juglandaceae/química , Polissacarídeos/farmacologia , Acetilação , Animais , Antioxidantes/química , Antioxidantes/isolamento & purificação , Compostos de Bifenilo/antagonistas & inibidores , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Catalase/genética , Catalase/metabolismo , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Picratos/antagonistas & inibidores , Extratos Vegetais/química , Folhas de Planta/química , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Cultura Primária de Células , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Glutationa Peroxidase GPX1RESUMO
Polyphyllin VII, a compound extracted from the rhizomes of Paris polyphylla, has strong antitumor effects on various human tumor cell lines. However, few studies have reported the possible effect of Polyphyllin VII on human osteosarcoma (OS) cell lines. The present study revealed that Polyphyllin VII promoted OS cell apoptosis and inhibited cell proliferation via upregulating the expression of LC3II, Atg5, Atg7 and the Atg12Atg5 complex. By contrast, treatment of OS cells with Polyphyllin VII downregulated Atg12 and p62 expression. Following treatment with class III PI 3kinase inhibitor (3MA; an autophagy inhibitor), the Polyphyllin VIImediated apoptotic effect was reversed. These findings indicated that the inhibition of autophagy could attenuate U2OS cell apoptosis in cells treated with high concentrations of Polyphyllin VII. The present study also demonstrated that Polyphyllin VII upregulated the intracellular hydrogen peroxide (H2O2) levels in U2OS cells. However, treatment of U2OS cells with NacetylL cysteine (NAC) effectively reversed this effect. The western blot analysis results indicated that the cJun Nterminal kinase (JNK) signaling pathway was closely associated with Polyphyllin VIIinduced apoptosis and autophagy. In conclusion, the results of the present study demonstrated that Polyphyllin VII could effectively inhibit cell viability and promote autophagy and apoptosis in U2OS cells. In addition, the mechanism underlying these effects could be associated with the intracellular H2O2 levels and the JNK signaling pathway.
Assuntos
Autofagia/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Saponinas/farmacologia , Acetilcisteína/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Osteossarcoma/patologia , Saponinas/uso terapêuticoRESUMO
Phenolic compounds from olive oil (ArOH-EVOO) are recognized for their antioxidant and neuroprotective capacities, but are often studied individually or through a natural extract. As their reactivity towards reactive oxygen species (ROS) depends on their structure and could implicate different complementary mechanisms, we hypothesized that their effects could be enhanced by an innovative combination of some of the most abundant ArOH-EVOO. Using electrochemical methods, we have compared their reactivity towards hydrogen peroxide and the superoxide anion radical. The mixture containing oleuropein, p-coumaric acid and tyrosol (Mix1), was more efficient than the mixture containing hydroxytyrosol, the oleuropein catechol moiety, and the two monophenols (Mix2). On neuronal SK-N-SH cells challenged with H2O2 or Paraquat, low concentrations (0.1 and 1â µM) of the Mix1 improved neuronal survival. These neuroprotective effects were supported by a decrease in intracellular ROS, in the protein carbonyl levels and the prevention of the redox-sensitive factors Nrf2 and NF-κB activation. These intracellular effects were supported by the demonstration of the internalization of these ArOH-EVOO into neuronal cells, evidenced by LC-HRMS. Our results demonstrated that this combination of ArOH-EVOO could be more efficient than individual ArOH usually studied for their neuroprotective properties. These data suggest that the Mix1 could delay neuronal death in neurodegenerative diseases related to oxidative stress such as Alzheimer's (AD) and Parkinson's diseases (PD).
Assuntos
Transporte de Elétrons/efeitos dos fármacos , Azeite de Oliva/química , Fenóis/química , Fenóis/farmacologia , Disponibilidade Biológica , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ácidos Cumáricos/química , Ácidos Cumáricos/farmacologia , Sinergismo Farmacológico , Eletroquímica , Sequestradores de Radicais Livres , Peróxido de Hidrogênio/antagonistas & inibidores , Glucosídeos Iridoides/química , Glucosídeos Iridoides/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Fármacos Neuroprotetores , Fenóis/farmacocinética , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Soluções , Superóxidos/antagonistas & inibidoresRESUMO
BACKGROUND: Microglia are associated with neuroinflammation, which play a key role in the pathogenesis of neurodegenerative diseases. It has been reported that some quinazolines and quinazolinones possess anti-inflammatory properties. However, the pharmacological properties of certain quinazoline derivatives are still unknown. OBJECTIVE: The antioxidant, cytotoxic, and protective effects of a series of synthesized 2- trifluoromethylquinazolines (2, 4, and 5) and quinazolinones (6-8) in lipopolysaccharide (LPS)- murine microglia (BV2) and hydrogen peroxide (H2O2)-mouse neuroblastoma-2a (N2a) cells were investigated. METHOD: The antioxidant activity of synthesized compounds was evaluated with ABTS and DPPH assays. The cytotoxic activities were determined by MTS assay in BV2 and N2a cells. The production of nitric oxide (NO) in LPS-induced BV2 microglia cells was quantified. RESULTS: The highest ABTS and DPPH scavenging activities were observed for compound 8 with 87.7% of ABTS scavenge percentage and 54.2% DPPH inhibition. All compounds were noncytotoxic in BV2 and N2a cells at 5 and 50 µg/mL. The compounds which showed the highest protective effects in LPS-induced BV2 and H2O2-induced N2a cells were 5 and 7. All tested compounds, except 4, also reduced NO production at concentrations of 50 µg/mL. The quinazolinone series 6-8 exhibited the highest percentage of NO reduction, ranging from 38 to 60%. Compounds 5 and 8 possess balanced antioxidant and protective properties against LPS- and H2O2-induced cell death, thus showing great potential to be developed into anti-inflammatory and neuroprotective agents. CONCLUSION: Compounds 5 and 7 were able to protect the BV2 and N2a cells against LPS and H2O2 toxicity, respectively, at a low concentration (5 µg/mL). Compounds 6-8 showed potent reduction of NO production in BV2 cells.