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1.
J Enzyme Inhib Med Chem ; 35(1): 85-95, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31707866

RESUMO

To develop novel anti-inflammatory agents, a series of 5-alkyl-4-oxo-4,5-dihydro-[1, 2, 4]triazolo[4,3-a]quinoxaline-1-carboxamide derivatives were designed, synthesised, and evaluated for anti-inflammatory effects using RAW264.7 cells. Structures of the synthesised compounds were determined using 1H NMR, 13 C NMR, and HRMS. All the compounds were screened for anti-inflammatory activity based on their inhibitory effects against LPS-induced NO release. Among them, 5-(3,4,5-trimethoxybenzyl)-4-oxo-4,5-dihydro-[1, 2, 4]triazolo[4,3-a]quinoxaline-1-carboxamide (6p) showed the highest anti-inflammatory activity and inhibited NO release more potently than the lead compound D1. Further studies revealed that compound 6p reduced the levels of NO, TNF-α, and IL-6, and that its anti-inflammatory activity involves the inhibition of COX-2 and iNOS and downregulation of the mitogen-activated protein kinases (MAPK) signal pathway. Notably, compound 6p displayed more prominent anti-inflammatory activity than D1 and the positive control ibuprofen in the in vivo acute inflammatory model. Overall, these findings indicate that compound 6p is a therapeutic candidate for the treatment of inflammation.


Assuntos
Amidas/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antiulcerosos/farmacologia , Descoberta de Drogas , Quinoxalinas/farmacologia , Úlcera Gástrica/tratamento farmacológico , Amidas/síntese química , Amidas/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antiulcerosos/síntese química , Antiulcerosos/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Quinoxalinas/síntese química , Quinoxalinas/química , Células RAW 264.7 , Ratos , Úlcera Gástrica/metabolismo , Relação Estrutura-Atividade
2.
Chem Pharm Bull (Tokyo) ; 67(11): 1255-1258, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31685754

RESUMO

One new 3,24-dinor-2,4-seco-ursane triterpene, rosanortriterpene C (1), together with four known compounds including 24-norursane-type nortriterpenes (2-3), 24-noroleanane-type nortriterpene (4), ursane-type triterpene (5), was isolated from the fruits of Rosa laevigata var. leiocapus. The new structure was elucidated through comprehensive spectroscopic analysis, including one dimensional (1D) and 2D NMR data, as well as electrospray ionization high resolution (HR-ESI) MS and IR spectrometry. Compounds 1-5 showed moderate anti-inflammatory activities against the production of nitric oxide (NO) in RAW264.7 cells stimulated by lipopolysaccharide (LPS) with IC50 values of 10.35 ± 0.92, 14.28 ± 1.20, 5.04 ± 1.43, 29.29 ± 3.64, and 14.37 ± 0.59 µM, respectively.


Assuntos
Anti-Inflamatórios/farmacologia , Frutas/química , Rosa/química , Triterpenos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Relação Dose-Resposta a Droga , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Conformação Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Relação Estrutura-Atividade , Triterpenos/química , Triterpenos/isolamento & purificação
3.
Phytochemistry ; 168: 112125, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31541772

RESUMO

Nine undescribed polyacetylated 18-norspirostanol saponins, trilliumosides A‒J, were obtained after a guidance based on a molecular networking strategy from the rhizomes of Trillium tschonoskii. Their structures were established by analysis of comprehensive spectroscopic data and chemical methods after their isolation in pure form. All isolated saponins were evaluated for their cytotoxicities against five selected human cancer cell lines (Huh7,A549,MCF-7,HepG2, and MOLT-4) and anti-inflammatory effects on a lipopolysaccharide (LPS)-stimulated NO production model in RAW264.7 macrophages. Trilliumoside D showed significant cytotoxicity against MOLT-4 cell lines with an IC50 value of 1.0 ±â€¯0.1 µM, whereas trilliumosides H and I displayed remarkable anti-inflammatory effects on NO production with inhibitory rates of 56.3 ±â€¯1.5 and 56.2 ±â€¯2.2% at the concentration of 1.0 µM, respectively.


Assuntos
Descoberta de Drogas , Saponinas/isolamento & purificação , Trillium/química , Acetilação , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Saponinas/química , Saponinas/farmacologia , Relação Estrutura-Atividade
4.
Phytochemistry ; 168: 112109, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31494344

RESUMO

Eight undescribed ergostane-type steroids, (22E,24R)-ergosta-7,22-dien-3ß,5α-diol- 6,5-olide, (22E,24R)-ergosta-7,9(11),22-trien-3ß,5ß,6ß-triol, (22E,24R)-6ß-methoxy ergosta-7,9(11),22-trien-3ß,5α,14ß-triol, (22E,24R)-9α,15α-dihydroxyergosta-4,6,8 (14),22-tetraen-3-one, (22E,24R)-ergosta-5,8,22-trien-3ß,11α-dihydroxyl-7-one, (22E,24R)-ergosta-4,7,22-trien-3ß,9α,14ß-trihydroxyl-6-one, (22E,24R)-ergosta-7,22- dien-3ß,9α,14ß-trihydroxyl-6-one, and (22E,24R)-6ß-methoxyergosta-7,22-dien-3ß, 5α,9α,14ß-tetraol, and twenty-one known analogues were isolated from the fruiting bodies of Ganoderma resinaceum Boud. Their chemical structures were determined on the basis of comprehensive spectroscopic analysis and X-ray crystal diffraction, as well as empirical pyridine-induced deshielding effects. Furthermore, selected compounds were evaluated for their inhibitory effects on macrophage activation using an inhibition of nitric oxide production assay. Finally, (22E,24R)-ergosta-5,8,22- trien-3ß,11α-dihydroxyl-7-one, (22E,24R)-ergosta-4,7,22-trien-3ß,9α,14ß-tri hydroxyl-6-one, (22E,24R)-6ß-methoxyergosta-7,22-dien-3ß,5α,9α,14ß-tetraol, (22E,24R)-ergosta-6,9,22-trien-3ß,5α,8α-triol,ergost-6,22-dien-3ß,5α,8α-triol, 5α,6α-epoxy-(22E,24R)-ergosta-8,22-diene-3ß,7α-diol, 5α,6α-epoxy-(22E,24R)- ergosta-8(14),22-diene-3ß,7α-diol, 5α,6α-epoxy-(22E,24R)-ergosta-8(14),22-diene-3ß, 7ß-diol, and 22E-7α-methoxy-5α,6α-epoxyergosta-8(14),22-dien-3ß-ol showed inhibitory effects on NO production with IC50 values ranging from 3.24 ±â€¯0.02 to 35.19 ±â€¯0.41 µM compared with L-NMMA (IC50 49.86 ±â€¯2.13 µM), indicating that they have potential anti-inflammatory activity.


Assuntos
Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Carpóforos/química , Ganoderma/química , Esteroides/isolamento & purificação , Esteroides/farmacologia , Animais , Anti-Inflamatórios/química , Relação Dose-Resposta a Droga , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Conformação Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Esteroides/química
5.
Molecules ; 24(17)2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31470525

RESUMO

Five pairs of alkaloid enantiomers (1a/1b-5a/5b) were obtained from Isatis indigotica (I. indigotica) roots. Among them, 1a/1b, 2a/2b and 3a/3b were determined as three pairs of new alkaloid enantiomers. Their structures were elucidated by physicochemical properties and spectroscopic methods. The absolute configurations were deduced by comparison of their experimental circular dichroism (CD) and calculated electronic circular dichroism (ECD) spectra, as well as by single-crystal X-ray crystallography using anomalous scattering of Cu Kα radiation. Alkaloids 1a and 1b possess an unpresented carbon skeleton and their putative biosynthetic pathways are discussed. Moreover, all of the alkaloids were tested for their nitric oxide (NO) inhibitory effects in RAW 264.7 cells, and 4a and 4b showed inhibitory effects with IC50 values of 76.97 µM and 65.88 µM, respectively.


Assuntos
Alcaloides/química , Anti-Inflamatórios/química , Isatis/química , Lipopolissacarídeos/antagonistas & inibidores , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Relação Dose-Resposta a Droga , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Extratos Vegetais/química , Raízes de Plantas/química , Células RAW 264.7 , Estereoisomerismo
6.
Infect Immun ; 87(10)2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31331956

RESUMO

To successfully colonize host tissues, bacteria must respond to and detoxify many different host-derived antimicrobial compounds, such as nitric oxide (NO). NO has direct antimicrobial activity through attack on iron-sulfur (Fe-S) cluster-containing proteins. NO detoxification plays an important role in promoting bacterial survival, but it remains unclear if repair of Fe-S clusters is also important for bacterial survival within host tissues. Here we show that the Fe-S cluster repair protein YtfE contributes to the survival of Yersinia pseudotuberculosis within the spleen following nitrosative stress. Y. pseudotuberculosis forms clustered centers of replicating bacteria within deep tissues, where peripheral bacteria express the NO-detoxifying gene hmp. ytfE expression also occurred specifically within peripheral cells at the edges of microcolonies. In the absence of ytfE, the area of microcolonies was significantly smaller than that of the wild type (WT), consistent with ytfE contributing to the survival of peripheral cells. The loss of ytfE did not alter the ability of cells to detoxify NO, which occurred within peripheral cells in both WT and ΔytfE microcolonies. In the absence of NO-detoxifying activity by hmp, NO diffused across ΔytfE microcolonies, and there was a significant decrease in the area of microcolonies lacking ytfE, indicating that ytfE also contributes to bacterial survival in the absence of NO detoxification. These results indicate a role for Fe-S cluster repair in the survival of Y. pseudotuberculosis within the spleen and suggest that extracellular bacteria may rely on this pathway for survival within host tissues.


Assuntos
Proteínas de Bactérias/genética , Proteínas com Ferro-Enxofre/genética , NADH NADPH Oxirredutases/genética , Óxido Nítrico/metabolismo , Infecções por Yersinia pseudotuberculosis/microbiologia , Yersinia pseudotuberculosis/genética , Animais , Proteínas de Bactérias/metabolismo , Feminino , Deleção de Genes , Expressão Gênica , Interações Hospedeiro-Patógeno , Proteínas com Ferro-Enxofre/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Viabilidade Microbiana , NADH NADPH Oxirredutases/metabolismo , Óxido Nítrico/antagonistas & inibidores , Baço/microbiologia , Yersinia pseudotuberculosis/enzimologia
7.
Chem Pharm Bull (Tokyo) ; 67(9): 966-976, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31257308

RESUMO

Honokiol, a biphenolic neolignan isolated from Magnolia officinalis, was reported to have a promising anti-inflammatory activity for the treatment of various diseases. There are many efforts on the synthesis and structure-activity relationship of honokiol derivatives. However, regioselective O-alkylation of honokiol remains a challenge and serves as a tool to provide not only some derivatives but also chemical probes for target identification and mode of action. In this study, we examined the reaction condition for regioselective O-alkylation, in which C2 and C4'-alkylated analogs of honokiol were synthesized and evaluated for inhibitory activity on nitric oxide production and cyclooxygenase-2 expression. Furthermore, we successfully synthesized a potential photoaffinity probe consisting of biotin and benzophenone based on a C4'-alkylated derivative.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Compostos de Bifenilo/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inflamação/tratamento farmacológico , Lignanas/farmacologia , Alquilação , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Humanos , Inflamação/metabolismo , Lignanas/síntese química , Lignanas/química , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Estereoisomerismo
8.
Eur J Med Chem ; 179: 233-245, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31255924

RESUMO

A series of S-allyl-l-cysteine (SAC) with garlic acid conjugates as anti-inflammatory agents were designed and synthesized. Among the 40 tested compounds, SMU-8c exhibited the most potent inhibitory activity to Pam3CSK4-induced nitric oxide (NO) in RAW264.7 macrophages with IC50 of 22.54 ±â€¯2.60 µM. The structure-activity relationship (SAR) study suggested that the esterified carboxyl group, carbon chain extension and methoxylation phenol hydroxy could improve the anti-inflammatory efficacy. Preliminary anti-inflammatory mechanism studies showed that SMU-8c significantly down-regulated the levels of Pam3CSK4 triggered TNF-α cytokine in human THP-1 cells, mouse RAW 264.7 macrophages, as well as in ex-vivo human peripheral blood mononuclear cells (PBMC) with no influence on cell viability. SMU-8c specifically blocked the Pam3CSK4 ignited secreted embryonic alkaline phosphatase (SEAP) signaling with no influence to Poly I:C or LPS triggered TLR3 or TLR4 signaling. Moreover, SMU-8c suppressed TLR2 in HEK-Blue hTLR2 cells and inhibited the formation of TLR1-TLR2, and TLR2-TLR6 complex in human PBMC. In summary, SMU-8c inhibited the TLR2 signaling pathway to down-regulate the inflammation cytokines, such as NO, SEAP and TNF-α, to realize its anti-inflammatory activity.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Cisteína/análogos & derivados , Alho/química , Hidroxibenzoatos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Cisteína/química , Cisteína/farmacologia , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Humanos , Hidroxibenzoatos/química , Lipopeptídeos/antagonistas & inibidores , Lipopeptídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Relação Estrutura-Atividade , Células THP-1
9.
Molecules ; 24(14)2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31336599

RESUMO

Lignans are known to be an important class of phenylpropanoid secondary metabolites. In the course of our studies on the chemodiversity of lignans, the necessity arose to develop a method for the fast detection and identification of bioactive lignan subclasses. In this study, we detected 10 lignan derivatives of different extracts of F. viridissima by UHPLC-ESI-QTOF-MS. Lignan glycosides (1 and 2), lignans (3 and 4), and lignan dimers (5-10) were identified by analysis of their exact masses and MSe spectra along with the characteristic mass fragmentation patterns and molecular formulas. We further investigated NO inhibitory effects of F. viridissima fractions and their major lignan derivatives to evaluate those anti-inflammatory effects. The methylene chloride fraction of F. viridissima as well as compounds 8 and 10 showed potent dose-dependent NO inhibitory effects on RAW 264.7 cells. Corresponding to the NO inhibition by compounds 8 and 10, lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) expression was notably reduced by both compounds. Our combined data with the bioactive results and the component analysis by UHPLC-ESI-QTOF-MS suggest that the methylene chloride fraction of F. viridissima roots could be potential anti-inflammatory agents and these are related to major lignans including dimeric dibenzylbutyrolactone lignans.


Assuntos
Forsythia/química , Lignanas/química , Lignanas/farmacologia , Óxido Nítrico/antagonistas & inibidores , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Sobrevivência Celular , Cromatografia Líquida de Alta Pressão , Camundongos , Estrutura Molecular , Óxido Nítrico/metabolismo , Raízes de Plantas/química , Células RAW 264.7 , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
10.
Molecules ; 24(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340484

RESUMO

In order to enrich and separate three coumarins (columbianetin acetate, osthole and columbianadin) from Angelicae Pubescentis Radix (APR), an efficient method was established by combining macroporous resins (MARs) with preparative high-performance liquid chromatography (PHPLC). Five different macroporous resins (D101, AB-8, DA-201, HP-20 and GDX-201) were used to assess the adsorption and desorption characteristics of three coumarins. The result demonstrated that HP-20 resin possessed the best adsorption and desorption capacities for these three coumarins. Moreover, the adsorption dynamics profiles of three coumarins were well fitted to the pseudo second order equation (R2 > 0.99) for the HP-20 resin. The adsorption process was described by the three isotherms models including Langmuir (R2 > 0.98, 0.046 ≤ RL ≤ 0.103), Freundlich (R2 > 0.99, 0.2748 ≤ 1/n ≤ 0.3103) and Dubinin Radushkevich (R2 > 0.97). The contents of columbianetin acetate, osthole and columbianadin in the product were increased 10.69-fold, 19.98-fold and 19.68-fold after enrichment, respectively. Three coumarins were further purified by PHPLC and the purities of them reached above 98%. Additionally, the anti-inflammatory effects of these three coumarins were assessed by Lipopolysaccharide (LPS)-induced RAW 264.7 cells. It was found that the production of NO and MCP-1 was obviously inhibited by three coumarins. Columbianetin acetate, osthole and columbianadin could be used as potentially natural anti-inflammatory ingredients in pharmaceutical products. It was concluded that the new method combining MARs with PHPLC was efficient and economical for enlarging scale separation and enrichment of columbianetin acetate, osthole and columbianadin with anti-inflammatory effect from the APR extract.


Assuntos
Angelica/química , Anti-Inflamatórios/farmacologia , Cumarínicos/farmacologia , Medicamentos de Ervas Chinesas/química , Furocumarinas/farmacologia , Adsorção , Animais , Anti-Inflamatórios/isolamento & purificação , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Cumarínicos/isolamento & purificação , Furocumarinas/isolamento & purificação , Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Óxido Nítrico/imunologia , Porosidade , Células RAW 264.7 , Resinas Sintéticas/química
11.
J Dairy Sci ; 102(8): 6718-6725, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31155246

RESUMO

This study aimed to screen lactic acid bacteria (LAB) for their anti-inflammatory activity by using RAW264.7 cells and dextran sulfate sodium (DSS)-induced colitis. In all, 192 LAB strains were isolated from healthy human feces, of which 8 strains showed excellent nitric oxide (NO) inhibitory activity. Peptidoglycan extracts of these 8 LAB strains were subjected to NO assay, Western blot, and ELISA. Among the 8 tested strains, extracts of 4 strains significantly inhibited the production of NO, related enzyme activities such as inducible nitric oxide synthase and cyclooxygenase 2, and key cytokines such as tumor necrosis factor-α and IL-6 in RAW264.7 cells. The 4 strains belonged to Lactobacillus (CAU1054, CAU1055, CAU1064, and CAU1301). Oral administration of the 4 strains inhibited DSS-induced body weight loss, colon shortening, and colon damage in ICR mice. The colon tissue of the mice treated with Lactobacillus plantarum strain CAU1055 had significantly reduced levels of inducible nitric oxide synthase, cyclooxygenase 2, tumor necrosis factor-α, and IL-6. We found that strain CAU1055 could be used as a candidate probiotic strain for the prevention and treatment of inflammatory bowel disease. Further studies are warranted to confirm the mechanisms of interaction between peptidoglycan of L. plantarum strain CAU1055 and upstream cellular signaling mediators.


Assuntos
Colite/prevenção & controle , Sulfato de Dextrana/farmacologia , Inflamação/prevenção & controle , Lactobacillus plantarum/fisiologia , Lipopolissacarídeos/farmacologia , Animais , Colite/induzido quimicamente , Colite/terapia , Inibidores de Ciclo-Oxigenase 2 , Citocinas/antagonistas & inibidores , Modelos Animais de Doenças , Fezes/microbiologia , Humanos , Inflamação/terapia , Lactobacillus plantarum/isolamento & purificação , Camundongos , Camundongos Endogâmicos ICR , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Probióticos/administração & dosagem , Células RAW 264.7 , Fator de Necrose Tumoral alfa/metabolismo
12.
Phytochemistry ; 164: 206-214, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31177053

RESUMO

Eight undescribed cholestane glycosides named osaundersioside A-H, along with three previously known compounds named osaundersioside I-K were isolated from Ornithogalum saundersiae Baker bulbs (Asparagaceae). Their structures were elucidated by extensive spectroscopic analysis and chemical methods. All isolates were evaluated for their cytotoxic activity and inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production. Osaundersioside C was thus determined to exhibit specific cytotoxicity towards MCF-7 cell line with an IC50 value of 0.20 µM, Osaundersioside H exhibited inhibitory effect on NO production in macrophages at the concentration of 10-5 M, with inhibition rate of 56.81%.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Asparagaceae/química , Colestanos/farmacologia , Glicosídeos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Colestanos/química , Colestanos/isolamento & purificação , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glicosídeos/química , Glicosídeos/isolamento & purificação , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Células MCF-7 , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Casca de Planta/química , Raízes de Plantas/química , Relação Estrutura-Atividade
13.
Phytochemistry ; 164: 236-242, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31185420

RESUMO

Mangiterpenes A-C and 2',3'-seco-manginoid C, four undescribed sesquiterpene/monoterpene-shikimate-conjugated meroterpenoids with spiro ring systems, were isolated from Guignardia mangiferae. The structures and absolute configurations of these compounds were established by comprehensive spectroscopic analyses and electronic circular dichroism (ECD) calculations. Mangiterpenes A-C represent the first examples of sesquiterpene-shikimate-conjugated spirocyclic meroterpenoids, and 2',3'-seco-manginoid C features an unexpected 2',3'-seco-manginoids skeleton. Mangiterpene C strongly inhibited the production of NO inducted by LPS, with an IC50 value of 5.97 µM. It showed an anti-inflammatory effect by means of blocking in the NF-κB signaling pathway and decreasing the expression of inflammatory mediators.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Monoterpenos/farmacologia , Ácido Chiquímico/farmacologia , Compostos de Espiro/farmacologia , Terpenos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Relação Dose-Resposta a Droga , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Monoterpenos/química , Monoterpenos/isolamento & purificação , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Ácido Chiquímico/química , Ácido Chiquímico/isolamento & purificação , Transdução de Sinais/efeitos dos fármacos , Compostos de Espiro/química , Compostos de Espiro/isolamento & purificação , Relação Estrutura-Atividade , Terpenos/química , Terpenos/isolamento & purificação
14.
Phytochemistry ; 165: 112044, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31202041

RESUMO

Oligostilbenes are polyphenol oligomers derived from resveratrol and are commonly produced by members of the Gnetaceae family, and many researchers have focused on their anti-inflammatory activities. The EtOAc fraction of a Gnetum latifolium extract showed inhibitory activity against neuroinflammation induced by the transfection of Aß1-42 into microglial BV-2 cells. The bioassay-guided isolation of the 70% EtOH extract of this plant resulted in three previously undescribed resveratrol oligostilbenes and ten known stilbene derivatives. The structures of the isolated compounds were established based on extensive NMR spectroscopic analysis. The absolute configurations of the three undescribed compounds were confirmed by comparison with available compounds with known stereochemistry and by ECD calculations and molecular modelling. Latifoliols A and B are the first reported oligostilbenes with a bridged 3-oxabicyclo[3.3.0]octane moiety, and latifoliol C was formed by the condensation of gnemontanin G with oxyresveratrol. Moreover, the hypothetical biogenetic pathway of latifoliols A, B and C was proposed. The potential anti-inflammatory activities of the thirteen isolated compounds were tested by measuring their effect on the secreted NO concentrations induced by transfection with plasmids expressing the Aß1-42 gene in the BV-2 cell line. Interestingly, cis- and trans-shegansu B and latifolol, whose structures contained double bonds, strongly inhibited NO secretion in BV-2 cells, supporting the double binding effect of the stilbene derivative on inhibitory activity.


Assuntos
Gnetum/química , Inflamação/tratamento farmacológico , Folhas de Planta/química , Estilbenos/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Inflamação/patologia , Camundongos , Conformação Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Estilbenos/química , Estilbenos/isolamento & purificação , Relação Estrutura-Atividade
15.
Molecules ; 24(11)2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31212689

RESUMO

Verbascoside is found in many medicinal plant families such as Verbenaceae. Important biological activities have been ascribed to verbascoside. Investigated in this study is the potential of verbascoside as an adjuvant during tuberculosis treatment. The present study reports on the in vitro metabolism in human hepatic microsomes and cytosol incubations as well as the presence and quantity of verbascoside within Lippia scaberrima. Additionally, studied are the inhibitory properties on human hepatic CYP enzymes together with antioxidant and cytotoxic properties. The results yielded no metabolites in the hydrolysis or cytochrome P450 (CYP) oxidation incubations. However, five different methylated conjugates of verbascoside could be found in S-adenosylmethionine incubation, three different sulphate conjugates with 3'-phosphoadenosine 5'-phosphosulfate (PAPS) incubation with human liver samples, and very low levels of glucuronide metabolites after incubation with recombinant human uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A7, UGT1A8, and UGT1A10. Additionally, verbascoside showed weak inhibitory potency against CYP1A2 and CYP1B1 with IC50 values of 83 µM and 86 µM, respectively. Potent antioxidant and low cytotoxic potential were observed. Based on these data, verbascoside does not possess any clinically relevant CYP-mediated interaction potential, but it has effective biological activity. Therefore, verbascoside could be considered as a lead compound for further drug development and as an adjuvant during tuberculosis treatment.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Glucosídeos/farmacologia , Fenóis/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Compostos de Bifenilo/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Ativação Enzimática/efeitos dos fármacos , Glucosídeos/química , Células Hep G2 , Humanos , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Oxirredução/efeitos dos fármacos , Fenóis/química , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Picratos/antagonistas & inibidores , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
16.
Anal Cell Pathol (Amst) ; 2019: 8253850, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223559

RESUMO

Background: Neuropathic pain not only affects individual life quality but also increases economic burden for the society. Treatment to alleviate neuropathic pain is required. Methodology: Fifty rats were randomly assigned into sham, spinal nerve ligation, and three treatment groups with different doses of Tempol (100, 200, and 300 mg/kg, respectively), with 10 rats in each group. A neuropathic pain model was created with spinal nerve L5 and L6 ligation. Mechanical allodynia and thermal hyperalgesia were tested preoperatively (day 0) and postoperatively (days 1, 3, 5, and 7). Spinal cord levels of nitric oxide, as well as activities of nitric oxide synthase and acetylcholinesterase, were tested in postoperative day 7. Results: Compared with rats in the spinal nerve ligation group, rats in Tempol treatment groups had decreased responses to mechanical pain and cold plate stimulations. A high dose of Tempol produced more attenuating effects. The level of nitric oxide and activity of nitric oxide synthase were also decreased with Tempol treatments, whereas no significant changes were observed in the activity of acetylcholinesterase. Conclusions: Tempol attenuated an experimental rat model with neuropathic pain by inhibiting nitric oxide production.


Assuntos
Óxidos N-Cíclicos/farmacologia , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico/antagonistas & inibidores , Animais , Óxidos N-Cíclicos/uso terapêutico , Masculino , Fármacos Neuroprotetores/uso terapêutico , Óxido Nítrico/metabolismo , Ratos , Ratos Sprague-Dawley , Marcadores de Spin , Nervos Espinhais/fisiopatologia
17.
Free Radic Res ; 53(5): 562-573, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31039619

RESUMO

The main flavonoid components of Radix Tetrastigma (RTF) were extracted and identified by UPLC-TOF/MS. In vitro, RTF prevented inflammation in RAW 264.7 cells by suppressing morphological (both cell and nucleus) changes, and decreasing nitric oxide (NO), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) contents. Exposure to LPS also leads to oxidant damage, and RTF alleviated damage to mitochondria, decreased O2- accumulation, and restored the glutathione level. RTF intervention decreased the expression of c-Jun N-terminal kinase (JNK) and p38 phosphorylation, accompanied by downregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and forkhead box protein O1 (FoxO1). In vivo, aging of Caenorhabditis elegans (C. elegans) by paraquat (PQ) was observed through lifespan, lipofuscin, and enzyme analysis. RTF protected against damage in N2 worms but not in daf-16 mutants. Gene expression was further assessed, and p38/PMK-1 and Nrf2/SKN-1 expression in worms was suppressed by PQ, which was reversed by RTF treatment. Together, these results suggested that RTF could help ameliorate inflammation-induced damage through JNK, p38 and Nrf2 pathways.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Flavonoides/farmacologia , Longevidade/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/genética , Fatores de Transcrição/genética , Vitaceae/química , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Proteínas de Ligação a DNA/metabolismo , Flavonoides/química , Flavonoides/isolamento & purificação , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Regulação da Expressão Gênica , Glutationa/metabolismo , Inflamação , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Longevidade/genética , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Paraquat/antagonistas & inibidores , Paraquat/farmacologia , Extratos Vegetais/química , Células RAW 264.7 , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
18.
Eur J Med Chem ; 175: 114-128, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31077997

RESUMO

In order to discover novel anti-inflammatory agents, total thirty-seven new resveratrol-based flavonol derivatives were designed and synthesized. All compounds have been screened for their anti-inflammatory activity by evaluating their inhibition effect of LPS-induced NO production in RAW 264.7 macrophages. Their toxicity was also assessed in vitro. Structure-activity relationships (SARs) have been concluded, and finally 2-(2,4-dimethoxy-6-(4-methoxystyryl)phenyl)-3-hydroxy-4H-chromen-4-one was found to be the most active scaffold with low toxicity. This compound could significantly decrease productions of NO, IL-6 and TNF-α with IC50 values of 1.35, 1.12 and 1.92 µM, respectively in RAW 264.7 macrophages. Preliminary mechanism studies indicated that it could inhibit the expression of TLR4 protein, resulting in activation of the NF-ĸB cell signaling pathway. The in vivo anti-inflammatory activity of this compound could reduce pulmonary inflammation by mouse model of LPS-induced acute lung injury (ALI). We believe these findings would further support studies of rational design of more efficient acute lung injury regulatory inhibitors.


Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Flavonoides/síntese química , Flavonoides/farmacologia , Interleucina-6/antagonistas & inibidores , Óxido Nítrico/antagonistas & inibidores , Resveratrol/química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Anti-Inflamatórios/toxicidade , Flavonoides/química , Flavonoides/toxicidade , Técnicas In Vitro , Concentração Inibidora 50 , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Células RAW 264.7 , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
J Enzyme Inhib Med Chem ; 34(1): 1121-1130, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31117832

RESUMO

Four series of total 35 new pyrazolo[4,3-d]pyrimidine compounds were designed, synthesized and evaluated for their inhibitory activity against LPS-induced NO production in RAW264.7 macrophages. Among them, compound 4e was found to be the most potent inhibitor, which decreased the production of cytokines in vitro, such as NO, IL-6 and TNF-α, with IC50 values of 2.64, 4.38 and 5.63 µM, respectively. Further studies showed that compound 4e inhibited cytokines secretion of macrophages through suppressing TLR4/p38 signaling pathway. Additionally, compound 4e showed in vivo anti-inflammatory activity in LPS-induced model of acute lung injury. These data suggested that compound 4e may be a promising lead structure for the treatment of ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Desenho de Drogas , Pirazóis/farmacologia , Pirimidinas/farmacologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Pirazóis/síntese química , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/química , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
20.
Chem Biodivers ; 16(7): e1900202, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115136

RESUMO

Asprellosides A-K, nine new ursane-type triterpenoid glycosides (1-9), and two new oleanane-type triterpenoid glycosides (10 and 11), including six rare sulfated triterpenoid glycosides, were isolated from the roots of Ilex asprella. Their structures were determined on the basis of comprehensive spectroscopic analysis and chemical methods. Among these compounds, asprelloside B (2) and asprelloside C (3) are the first examples of triterpenoid glycosides bearing a rare 3,4-O-disulfo-xylopyranosyl residue. All the saponins isolated showed no significant effects against respiratory syncytial virus (RSV) and lipopolysaccharide-induced nitric oxide production in Raw264.7 macrophages.


Assuntos
Antivirais/farmacologia , Glicosídeos/farmacologia , Ilex/química , Óxido Nítrico/antagonistas & inibidores , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Antivirais/química , Antivirais/isolamento & purificação , Glicosídeos/química , Glicosídeos/isolamento & purificação , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Testes de Sensibilidade Microbiana , Conformação Molecular , Óxido Nítrico/biossíntese , Raízes de Plantas/química , Células RAW 264.7 , Triterpenos/química , Triterpenos/isolamento & purificação
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