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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.
J Enzyme Inhib Med Chem ; 35(1): 187-198, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31752552

RESUMO

Twenty novel talmapimod analogues were designed, synthesised and evaluated for the in vivo anti-inflammatory activities. Among them, compound 6n, the most potent one, was selected for exploring the mechanisms underlying its anti-inflammatory efficacy. In RAW264.7 cells, it effectively suppressed lipopolysaccharides-induced (LPS-induced) expressions of iNOS and COX-2. As illustrated by the western blot analysis, 6n downregulated both the NF-κB signalling and p38 MAPK phosphorylation. Further enzymatic assay identified 6n as a potent inhibitor against both p38α MAPK (IC50=1.95 µM) and COX-2 (IC50=0.036 µM). By virtue of the concomitant inhibition of p38α MAPK, its upstream effector, and COX-2, along with its capability to downregulate NF-κB and MAPK-signalling pathways, 6n, a polypharmacological anti-inflammatory agent, deserves further development as a novel anti-inflammatory drug.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Ciclo-Oxigenase 2/metabolismo , Descoberta de Drogas , NF-kappa B/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
3.
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
4.
Analyst ; 144(24): 7242-7249, 2019 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-31687669

RESUMO

Rapid detection and identification of bacteria is important for human health, biodefense, and food safety. Small arrays of different antimicrobial peptides (AMPs) enable the identification of lipopolysaccharide (LPS) samples from a variety of bacterial species and strains. A model system for examining how peptide presentation affects LPS detection is the sheep myeloid antimicrobial peptide (SMAP-29), which contains a helix-turn-helix motif. Varying the cysteine attachment site on SMAP-29 controls the three-dimensional presentation of the peptide on the surface, altering the ability of the peptide to discriminate between LPS samples. A small array of only SMAP-29 variants-and no other peptides-is capable of discriminating among LPS samples from multiple bacterial species, as well as between different strains within the same species, with high accuracy.


Assuntos
Peptídeos Catiônicos Antimicrobianos/química , Proteínas Sanguíneas/química , Catelicidinas/química , Lipopolissacarídeos/química , Animais , Peptídeos Catiônicos Antimicrobianos/farmacologia , Bactérias/metabolismo , Sítios de Ligação , Cisteína/química , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Ovinos , Especificidade da Espécie , Ressonância de Plasmônio de Superfície
5.
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
6.
J Enzyme Inhib Med Chem ; 34(1): 1678-1689, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31530032

RESUMO

A series of novel 4-ferrocenylchroman-2-one derivatives were designed and synthesised to discover potent anti-inflammatory agents for treatment of arthritis. All the target compounds had been screened for their anti-inflammatory activity by evaluating the inhibition effect of LPS-induced NO production in RAW 264.7 macrophages. Among them, 4-ferrocenyl-3,4-dihydro-2H-benzo[g]chromen-2-one (3h) was found to be the most potent compound in inhibiting the productions of NO with low toxicity. This compound also exhibited significant inhibition of the productions of IL-6 and TNF-α in RAW 264.7 macrophages. Preliminary mechanism studies indicated that compound 3h could inhibit the activation of LPS-induced NF-κB and MAPKs signalling pathways. The in vivo anti-inflammatory effect of this compound was determined in the rat adjuvant-induced arthritis model.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Artrite/tratamento farmacológico , Cromonas/farmacologia , Interleucina-6/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Artrite/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Cromonas/síntese química , Cromonas/química , Relação Dose-Resposta a Droga , Adjuvante de Freund , Interleucina-6/biossíntese , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estrutura Molecular , NF-kappa B/metabolismo , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossíntese
7.
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
8.
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
9.
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
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.
Mol Med Rep ; 20(2): 1007-1016, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173202

RESUMO

Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), has a complex etiology that may be associated with dysbiosis of the microbiota. Previously, our study revealed significant loss of Roseburia intestinalis from the gut of untreated patients with CD, and that R. intestinalis exerted anti­inflammatory functions in TNBS­induced colitis; however, the function of R. intestinalis supernatant is unknown. Therefore, LPS­induced macrophages, including RAW264.7 macrophages and bone marrow­derived macrophages were treated with R. intestinalis supernatant. The results indicated that R. intestinalis supernatant suppressed expression of interleukin (IL)­6 and signal transducer and activator of transcription 3 (STAT3) by macrophages. Additionally, these findings were further verified in vivo in DSS­ and TNBS­induced mouse models of colitis. It was observed that R. intestinalis supernatant ameliorated IBD colitis by reducing the number of inflammatory macrophages and Th17 cells in the colon, and by downregulating the expression of IL­6 and STAT3. Finally, the non­protein components of R. intestinalis supernatant were examined using gas chromatography­mass spectrometry analysis and identified the presence of short­chain fatty acids. In conclusion, the results of the present study indicated that R. intestinalis supernatant may regulate immune responses and ameliorate colitis.


Assuntos
Clostridiales/fisiologia , Colite/terapia , Meios de Cultivo Condicionados/farmacologia , Imunidade Inata/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Animais , Clostridiales/química , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Meios de Cultivo Condicionados/química , Sulfato de Dextrana/administração & dosagem , Ácidos Graxos Voláteis/química , Ácidos Graxos Voláteis/isolamento & purificação , Regulação da Expressão Gênica , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Interleucina-6/imunologia , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Cultura Primária de Células , Células RAW 264.7 , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Transdução de Sinais , Células Th17 , Ácido Trinitrobenzenossulfônico/administração & dosagem
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.
Eur J Med Chem ; 179: 182-195, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31254920

RESUMO

A series of (1,2,4)triazole[4,3-a]pyridine (TZP) derivatives have been designed and synthesized. Compound 8d was identified as having the most potent inhibitory activity on NO release in response to lipopolysaccharide (LPS) stimulation and inhibition of the migration induced by MCP-1 protein on RAW264.7 macrophages. Based on the screening data, an immunofluorescence assay and a real-time qPCR assay were conducted, indicating that compound 8d suppressed NF-κB p65 translocation and expression of inflammatory genes by concanavalin A (Con A)-induced RAW264.7 macrophages. More importantly, 8d also exhibited potent efficacy, alleviating Con A-induced hepatitis by downregulating the levels of plasma alanine transaminase (ALT), aspartate transaminase (AST) and inflammatory infiltration in a mouse autoimmune hepatitis (AIH) model. In addition, the flow cytometry (FCM) data showed that compound 8d inhibited the accumulation of MDSCs in the liver of Con A-induced mice. These findings raise the possibility that compound 8d might serve as a potential agent for the treatment of AIH.


Assuntos
Concanavalina A/antagonistas & inibidores , Hepatite/tratamento farmacológico , Piridinas/farmacologia , Triazóis/farmacologia , Animais , Sobrevivência Celular , Células Cultivadas , Concanavalina A/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Desenho de Drogas , Feminino , Hepatite/metabolismo , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Óxido Nítrico/análise , Óxido Nítrico/biossíntese , Piridinas/síntese química , Piridinas/química , Células RAW 264.7 , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
15.
Drug Des Devel Ther ; 13: 1763-1772, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31213766

RESUMO

Background and aim: A potent and selective vascular endothelial growth factor receptor (VEGFR) inhibitor SU5416, has been developed for the treatment of solid human tumors. The binding of VEGF to VEGFR plays a crucial role in the pathophysiology of respiratory disorders. However, the impact of SU5416 on lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains unclear. Thus, this study aimed to illuminate the biofunction of SU5416 in the mouse model of ALI. Methods: Wild-type (WT) and toll-like receptor 4 (TLR4)-deficient (TLR4-/-) C57BL/6 mice were used to establish LPS-induced ALI model. The primary pulmonary microvascular endothelial cell (PMVEC) was extracted for detection of endothelial barrier function. Results: LPS significantly increased the number of inflammatory cells and inflammatory cytokines in bronchoalveolar lavage fluid (BALF). In addition, LPS increased alveolar epithelial cells injury, inflammation infiltration and vascular permeability of PMVEC in WT and TLR4-/- mice. Western blotting experiment indicated VEGF/VEGFR and TLR4/NF-κB pathways were involved in the progression of LPS-stimulated ALI. Consistent with previous research, dexamethasone treatment appeared to be an effective therapeutic for mice with ALI. Moreover, treatment with SU5416 dramatically attenuated LPS-induced immune responses in mice lung tissues via inhibiting VEGF/VEGFR and TLR4/NF-κB pathways. Finally, SU5416 also decreased vascular permeability of PMVEC in vitro. Conclusion: SU5416 ameliorated alveolar epithelial cells injury and histopathological changes in mice lung via inhibiting VEGF/VEGFR and TLR4/NF-κB signaling pathways. We also confirmed that SU5416 could restrain vascular permeability in PMVEC through improving the integrity of endothelial cell. These findings suggested that SU5416 may serve as a potential agent for the treatment of patients with ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Células Endoteliais/efeitos dos fármacos , Indóis/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Pirróis/farmacologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor 4 Toll-Like/deficiência , Receptor 4 Toll-Like/metabolismo
16.
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
17.
Cell Biochem Funct ; 37(5): 348-358, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31066476

RESUMO

Pneumonia is an inflammatory disease that occurs in the lungs associated with pathogens or other factors. It has been well established that long noncoding RNA X inactivate-specific transcript (XIST) is involved in several cancers. The present study focused on the effect and detailed mechanism of XIST in lipopolysaccharide (LPS)-induced injury in pneumonia. Here, XIST was silenced by transfection with XIST-targeted siRNA, and then, mRNA expression, cell viability, apoptosis, and protein expression were, respectively, assessed by qRT-PCR, CCK-8, flow cytometry, and Western blotting. Luciferase reporter, RIP, and RNA pull-down assays were used to detect the combination of miR-370-3p and XIST. Besides, the tested proinflammatory factors were analysed by qRT-PCR and Western blot, and their productions were quantified by ELISA. The results showed that XIST expression was robustly increased in serum of patients with acute-stage pneumonia and LPS-induced WI-38 human lung fibroblasts cells. Functional analyses demonstrated that knockdown of XIST remarkably alleviated LPS-induced cell injury through increasing cell viability and inhibiting apoptosis and inflammatory cytokine levels. Mechanistically, XIST functioned as a competitive endogenous RNA (ceRNA) by effectively binding to miR-370-3p and then restoring TLR4 expression. More importantly, miR-370-3p inhibitor abolished the function of XIST knockdown on cell injury and JAK/STAT and NF-κB pathways. Taken together, XIST may be involved in progression of cell inflammatory response, and XIST/miR-370-3p/TLR4 axis thus may shed light on the development of novel therapeutics to the treatment of acute stage of pneumonia. SIGNIFICANCE OF THE STUDY: Our study demonstrated that XIST was highly expressed in patients with acute stage of pneumonia. Knockdown of XIST remarkably alleviated LPS-induced cell injury through increasing cell viability and inhibiting apoptosis and inflammatory cytokine levels through regulating JAK/STAT and NF-κB pathways.


Assuntos
Apoptose/efeitos dos fármacos , Inflamação/tratamento farmacológico , Lipopolissacarídeos/farmacologia , MicroRNAs/antagonistas & inibidores , Pneumonia/tratamento farmacológico , RNA Longo não Codificante/genética , RNA Interferente Pequeno/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Doença Aguda , Adulto , Células Cultivadas , Feminino , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Masculino , MicroRNAs/análise , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Pneumonia/diagnóstico , Pneumonia/metabolismo , RNA Longo não Codificante/biossíntese , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/análise , Receptor 4 Toll-Like/metabolismo
18.
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
19.
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
20.
Eur J Med Chem ; 173: 282-293, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31009914

RESUMO

Two series of andrographolide derivatives with introduction of amide moiety into ring A by Beckmann rearrangement were synthesized. In series 1, the ring A was converted to caprolactam, and an amide moiety was linked to C-19 of ring A in series 2. Among them, compound 8h exhibited obvious inhibition on HK2 enzyme activity (IC50 = 9.36 ±â€¯0.08 µM) and LPS-induced NO production in RAW264.7 cells (IC50 = 22.38 ±â€¯3.57 µM), and potent binding affinity with HK2 (Kd = 5.12 ±â€¯0.82 µM). The preliminary structure-activity relationships (SARs) suggested that the formation of caprolactam of ring A and esterification of C-19-hydroxyl could improve the inhibitory effects on HK2 enzyme of andrographolide derivatives. Furthermore, compound 8h significantly reduced the levels of IL-1ß and IL-6, down-regulated the expressions of iNOS and COX-2. Its anti-inflammatory effect was related to the inhibition of both NF-κB pathway and glycolysis enzyme HK2. Since HK2 could be a novel and effective target for anti-inflammation, compound 8h might be a new anti-inflammatory agent targeting at HK2, or serve as a lead compound to design and synthesize more HK2 inhibitors with better inflammatory effects.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Diterpenos/farmacologia , Inibidores Enzimáticos/farmacologia , Hexoquinase/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Células Cultivadas , Diterpenos/síntese química , Diterpenos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Hexoquinase/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Relação Estrutura-Atividade
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