RESUMO
BACKGROUND: Ischemic stroke (IS) is a serious cerebrovascular disease characterized by significantly elevated mortality and disability rates, and the treatments available for this disease are limited. Neuroinflammation and oxidative stress are deemed the major causes of cerebral ischemic injury. N-Cinnamoylpyrrole alkaloids form a small group of natural products from the genus Piper and have not been extensively analyzed pharmacologically. Thus, identifying the effect and mechanism of N-cinnamoylpyrrole-derived alkaloids on IS is worthwhile. PURPOSE: The present research aimed to explore the antineuroinflammatory and antioxidative stress effects of N-cinnamoylpyrrole-derived alkaloids isolated from the genus Piper and to explain the effects and mechanism on IS. METHODS: N-cinnamoylpyrrole-derived alkaloids were isolated from Piper boehmeriaefolium var. tonkinense and Piper sarmentosum and identified by various chromatographic methods. Lipopolysaccharide (LPS)-induced BV-2 microglia and a mouse model intracerebroventricularly injected with LPS were used to evaluate the antineuroinflammatory and antioxidative stress effects. Oxygenâglucose deprivation/reperfusion (OGD/R) and transient middle cerebral artery occlusion (tMCAO) models were used to evaluate the effect of PB-1 on IS. To elucidate the fundamental mechanism, the functional target of PB-1 was identified by affinity-based protein profiling (ABPP) strategy and verified by cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS), and circular dichroism (CD) analyses. The effect of PB-1 on the NF-κB and NRF2 signaling pathways was subsequently evaluated via western blotting and immunofluorescence staining. RESULTS: The results showed that N-cinnamoylpyrrole-derived alkaloids significantly affected neuroinflammation and oxidative stress. The representative compound, PB-1 not only inhibited neuroinflammation and oxidative stress induced by LPS or OGD/R insult, but also alleviated cerebral ischemic injury induced by tMCAO. Further molecular mechanism research found that PB-1 promoted antineuroinflammatory and antioxidative stress activities via the NF-κB and NRF2 signaling pathways by targeting eEF1A1. CONCLUSION: Our research initially unveiled that the therapeutic impact of PB-1 on cerebral ischemic injury might rely on its ability to target eEF1A1, leading to antineuroinflammatory and antioxidative stress effects. The novel discovery highlights eEF1A1 as a potential target for IS treatment and shows that PB-1, as a lead compound that targets eEF1A1, may be a promising therapeutic agent for IS.
Assuntos
Alcaloides , AVC Isquêmico , Piper , Pirróis , Animais , Masculino , Camundongos , Alcaloides/farmacologia , Alcaloides/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Antioxidantes/farmacologia , Antioxidantes/química , Modelos Animais de Doenças , AVC Isquêmico/tratamento farmacológico , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Piper/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Pirróis/farmacologia , Pirróis/química , Cinamatos/química , Cinamatos/farmacologia , Fator 1 de Elongação de Peptídeos/antagonistas & inibidores , Fator 1 de Elongação de Peptídeos/metabolismoRESUMO
Seven undescribed polyoxygenated ursane-type triterpenoids (vitnegundins A-G), three undescribed triterpenoid saponins (vitnegundins H-J), and 17 known ones were isolated from an EtOH extract of the aerial parts of Vitex negundo L. The structures of the undescribed compounds were established by extensive spectroscopic analysis. The absolute configurations of vitnegundins A, B, and E were determined by single-crystal X-ray diffraction data. Vitnegundins B-D are pentacyclic triterpenoids possessing rare cis-fused C/D rings and vitnegundins C-H represent undescribed ursane-type triterpenoids with 12,19-epoxy moiety. In the biological activity assay, vitnegundin A, vitnegundin E, and swinhoeic acid displayed inhibitory effects against LPS-induced NO release in BV-2 microglial cells, with IC50 values of 11.8, 44.2, and 19.6 µM, respectively.
Assuntos
Anti-Inflamatórios , Extratos Vegetais , Saponinas , Triterpenos , Vitex , Vitex/química , Triterpenos/química , Triterpenos/isolamento & purificação , Triterpenos/farmacologia , Saponinas/química , Saponinas/isolamento & purificação , Saponinas/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Etanol/química , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Difração de Raios X , Concentração Inibidora 50 , Microglia/efeitos dos fármacos , Linhagem CelularRESUMO
Three new phenolic glycosides (1-3) and a new lignan glycoside (4), together with five known compounds (5-9) were isolated from the ethanol extract of the aerial part of Gaultheria leucocarpa var. yunnanensis (Franch.) T.Z.Hsu & R.C.Fang. Their structures were determined on the basis of spectroscopic techniques, experimental and calculated ECD spectra, acid hydrolysis, and enzymatic hydrolysis experiments. All the isolates were evaluated for their anti-inflammatory and antioxidant activities. Compounds 7 and 8 exhibited inhibitory effects against the LPS-induced production of NO with IC50 of 63.71 and 10.66 µM, respectively, compared to L-NMMA having an IC50 of 6.95 µM. Besides, compound 7 also represented significant DPPH radical scavenging activity with EC50 of 18.75 µM, comparable with vitamin C (EC50 = 15.77 µM).
Assuntos
Glicosídeos Cardíacos , Gaultheria , Lignanas , Glicosídeos/química , Lignanas/farmacologia , Gaultheria/química , Estrutura Molecular , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/químicaRESUMO
Seven new glycosides (1 - 7) with galloyl groups and two known kaempferol glycosides (8 and 9) were obtained from the overground parts of Balakata baccata. The structures of the new compounds were determined by comprehensive spectroscopic analyses. The rarely seen allene moiety in compounds 6 and 7 were described by detailed analysis of 1D and 2D NMR data. The antineuroinflammatory effect of all the isolates was assessed through inhibiting nitric oxide (NO) production in lipopolysaccharide (LPS)-induced BV-2 microglial cells. Compounds 1, 2, 6, and 7 showed potent inhibitory activities with IC50 values of 25.7, 17.2, 15.5 and 24.4 µM, respectively, compared with the positive control minocycline (IC50 = 16.1 µM).
Assuntos
Glicosídeos , Microglia , Sapium , Glicosídeos/farmacologia , Glicosídeos/química , Espectroscopia de Ressonância Magnética , Óxido Nítrico , Estrutura MolecularRESUMO
Phytochemical investigation on the aerial parts of Gnetum parvifolium led to the isolation of 15 new and eight known structurally diverse stilbenes. The isolated compounds comprised (E)- or (Z)-stilbene (1-6, 15-20), dihydrostilbene (21), phenylbenzofuran (7, 8, 22), benzylated stilbene (9-11), benzylated stilbene dimer (12), and nitrogen-containing stilbene (13a, 13b, 14) types. The structures of the new compounds (1-12, 13a, 13b, 14) were established through spectroscopic analyses and experimental and calculated ECD data. Compound 12 is the first stilbene dimer connected through a benzyl group. In the anti-neuroinflammatory activity assay, compounds 4, 5, 9-11, 13b, and 16-21 displayed significant inhibitory effects against LPS-induced NO release in BV-2 microglial cells, with IC50 values of 0.35-16.1 µM. Compound 10 had the most potent activity (IC50 = 0.35 µM), and the further research indicated that it could decrease the mRNA levels of iNOS, IL-1ß, IL-6, and TNF-α in a dose-dependent manner.
Assuntos
Gnetum , Estilbenos , Estrutura Molecular , Gnetum/química , Estilbenos/farmacologia , Estilbenos/químicaRESUMO
Twenty-four new phenylpropanoid esters of sucrose, phanerosides A-X (1-24), were isolated from an EtOH extract of the rattans of Phanera championii Benth. (Fabaceae). Their structures were elucidated on the basis of comprehensive spectroscopic data analysis. A wide range of structural analogues were presented due to the different numbers and positions of acetyl substituents and the structures of phenylpropanoid moieties. Phenylpropanoid esters of sucrose were isolated from the Fabaceae family for the first time. Biologically, the inhibitory effects of compounds 6 and 21 on NO production in LPS-induced BV-2 microglial cells were better than that of the positive control, with IC50 values of 6.7 and 5.2 µM, respectively. The antioxidant activity assay showed that compounds 5, 15, 17, and 24 displayed moderate DPPH radical scavenging activity, with IC50 values ranging from 34.9 to 43.9 µM.
Assuntos
Bauhinia , Sacarose , Sacarose/química , Ésteres/química , Antioxidantes/farmacologia , Antioxidantes/química , Estrutura MolecularRESUMO
Twelve pairs of sesquineolignan enantiomers (1a/1b-6a/6b and 1c/1d-6c/6d), including twenty one undescribed and three known (2b, 3b, and 4b) sesquineolignans were isolated from an ethanol extract of the stems and leaves of Neoshirakia japonica (Euphorbiaceae). The successful separation of twelve pairs of enantiomers with mirror image-like electronic circular dichroism (ECD) curves and opposite specific rotation values, as one of the most important steps in compound isolation, was carried out by chiral HPLC columns. The absolute configurations of all undescribed sesquineolignans were elucidated by comprehensive analysis of their experimental ECD spectra. The effects of all the isolates on antineuroinflammatory and radical scavenging activity were evaluated. Compared with the positive control minocycline (IC50 = 1.2 µM), compounds 1a/1b/1c/1d-6a/6b/6c/6d with IC50 values being greater than 50 µM displayed almost no effect on the inhibition of NO production in LPS-induced BV-2 microglial cells. The results of DPPH-radical scavenging activity for them showed that compound 3c had moderate radical scavenging ability (EC50 = 48.47 µM), while the EC50 value of positive control vitamin C was 18.21 µM.
Assuntos
Euphorbiaceae , Folhas de Planta , Microglia , Estrutura MolecularRESUMO
Seven undescribed abietane-type diterpenoids, gauleucins A-G, and 11 known ones were isolated from an EtOH extract of the aerial parts of Gaultheria leucocarpa var. yunnanensis. These isolates could be classified into four subtypes: abietanes, 16-nor-abietanes, 16,18-di-nor-abietanes, and 3,4-seco-16-nor-abietane. Their structures were established by extensive spectroscopic analysis, and the absolute configurations of an undescribed and two known diterpenoids were determined by single-crystal X-ray diffraction data. Four compounds showed moderate inhibitory effects against the LPS-induced production of nitric oxide in BV-2 microglial cells. In an α-glucosidase inhibitory assay, gauleucin E and margoclin displayed inhibitory activities with IC50 values of 319.3 and 327.9 µM, respectively, while the IC50 value of the positive control (acarbose) was 387.8 µM.
Assuntos
Diterpenos , Gaultheria , Abietanos/química , Abietanos/farmacologia , Diterpenos/análise , Gaultheria/química , Estrutura Molecular , Óxido Nítrico , Componentes Aéreos da Planta/químicaRESUMO
Six new lignans with various type of linkage between two C6-C3 fragments (1a, 1b, 2a, 2b, 3, 4), two new meroterpenoids (5, 6) and 24 known compounds (7-30) were isolated from an EtOH extract of the stems and leaves of Piper puberulum. The absolute configurations of enantiomers 1a and 1b were determined by single-crystal X-ray diffraction analysis, 2a and 2b were determined by comparing their calculated and experimental ECD spectra. Biogenetically, all the new lignans may come from the polymerization of two molecules of hydroxychavicol (30). In the anti-neuroinflammation activity assay, the IC50 values of fifteen compounds were lower than those of the positive control minocycline, and compound 1a showed good activity, but its enantiomer 1b showed no activity. Compound 1a have notable anti-neuroinflammatory activity, and can significantly decrease mRNA levels of proinflammatory cytokines (IL-1ß, IL-6, TNF-α) in a dose-dependent manner.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Lignanas/farmacologia , Óxido Nítrico/antagonistas & inibidores , Piper/química , Extratos Vegetais/farmacologia , Terpenos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Linhagem Celular , Cristalografia por Raios X , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Lignanas/química , Lignanas/isolamento & purificação , Camundongos , Modelos Moleculares , Estrutura Molecular , Óxido Nítrico/metabolismo , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Terpenos/química , Terpenos/isolamento & purificaçãoRESUMO
Sixteen chebulic acid derivatives, including nine new (1-9) and seven known (10-16) ones, were isolated from an ethanol extract of the branches and leaves of Balakata baccata. The structures of the new compounds were elucidated by their UV, IR, HRESIMS, NMR, electronic circular dichroism (ECD) and single-crystal X-ray diffraction data. The effects of all the isolates on antineuroinflammatory and antioxidant activities were evaluated. Compared with the positive control minocycline (IC50 = 1.21 ± 0.71 µM), compounds 1-16 with IC50 values being greater than 50 µM, displayed almost no effects on the inhibition of NO production in LPS-induced BV-2 microglial cells, however, the results of antioxidant activity for compounds 1-16 showed significant DPPH-radical scavenging abilities with EC50 value ranging from 3.98 to 14.24 µM, while the EC50 value of positive control vitamin C was 14.31 µM. At last, the results of PCR (qRT-PCR) analysis showed that compound 1 could enhance the expression of antioxidases (HO-1, GCLC, and NQO1) at the mRNA levels.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Benzopiranos/farmacologia , Inflamação/tratamento farmacológico , Sapium/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/química , Antioxidantes/isolamento & purificação , Benzopiranos/química , Benzopiranos/isolamento & purificação , Compostos de Bifenilo/antagonistas & inibidores , Linhagem Celular , Relação Dose-Resposta a Droga , Inflamação/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Picratos/antagonistas & inibidores , Folhas de Planta/química , Relação Estrutura-AtividadeRESUMO
Three new tyramine-type alkamides (1-3), three new natural products (4-6), five new N-acylated/formylated aporphine alkamides with different ratios of rotational isomers (7-11), and 20 known alkamides (12-31) were isolated from an EtOH extract of the stems and leaves of Piper puberulum. The absolute configurations of compounds 7, 8, and 10 were determined by single-crystal X-ray diffraction analysis. In the biological activity assay, compounds 3, 5, and 10-23 displayed inhibitory effects against lipopolysaccharide-induced NO release in BV-2 microglial cells, exhibiting IC50 values of 0.93-45 µM.
Assuntos
Aporfinas/farmacologia , Microglia/efeitos dos fármacos , Piper/química , Tiramina/farmacologia , Animais , Aporfinas/isolamento & purificação , Linhagem Celular , China , Camundongos , Estrutura Molecular , Óxido Nítrico , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Folhas de Planta/química , Caules de Planta/química , Tiramina/isolamento & purificaçãoRESUMO
Two pairs of cycloneolignane enantiomers, piperhancins A and B (1 and 2, respectively), along with two enantiomeric pairs of biosynthetic related neolignanes, hancinone C (3) and piperhancin C (4), were isolated from the stems of Piper hancei. Compound 1 is an unprecedented 1',2:1,2'-dicyclo-8,3'-neolignane. Their structures and absolute configurations were elucidated by spectroscopic analyses, X-ray diffraction, and electronic circular dichroism calculations. Among all of the isolates, compounds (+)-1, (-)-1, (+)-2, (-)-2, and (+)-3 could significantly inhibit the production of nitric oxide secreted by lipopolysaccharide (LPS)-induced neuroinflammation in BV-2 microglial cells, with IC50 values of 1.1-26.3 µM. In addition, compound (-)-1 could decrease the mRNA levels of iNOS, IL-6, and TNF-α induced by LPS in BV-2 microglial cells.
Assuntos
Piper , Lipopolissacarídeos , Microglia , Estrutura Molecular , Óxido Nítrico , EstereoisomerismoRESUMO
Four new diterpenoids (1-4), three new triterpenoids (12-14), and seven known diterpenoids (5-11) were obtained from an aqueous EtOH extract of the aerial parts of Triadica rotundifolia. The structures of new compounds were determined by spectroscopic techniques. Their absolute configurations were verified via single-crystal X-ray diffraction data, Mo2(OAc)4 induced electronic circular dichroism (ECD), and ECD calculations. The antineuroinflammatory effects of the isolates were assessed by inhibiting NO production in LPS-induced BV-2 microglial cells. Compared with the positive control minocycline (IC50 = 16.1 µM), compounds 3, 8, 11 showed moderate inhibitory activities with IC50 values of 35.9, 17.0, 31.5 µM, respectively.
Assuntos
Diterpenos/química , Euphorbiaceae/química , Microglia/efeitos dos fármacos , Óxido Nítrico/metabolismo , Componentes Aéreos da Planta/química , Extratos Vegetais/química , Triterpenos/química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Diterpenos/farmacologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Minociclina/farmacologia , Minociclina/uso terapêutico , Modelos Moleculares , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Triterpenos/farmacologiaRESUMO
Twenty new chebulic acid and brevifolincarboxylic acid derivatives, including eight optically pure or achiral compounds (1-7 and 14) and six pairs of enantiomers (8a/8b-13a/13b), along with nine known analogues (15-23), were isolated from an EtOH extract of the aerial parts of Euphorbia hirta. The absolute configurations of the new compounds were assigned based on single-crystal X-ray diffraction analysis and comparison of the experimental and calculated ECD data. Racemic or scalemic mixtures of 8-13 were isolated, and their enantiomers were analyzed by chiral-phase HPLC-ECD measurements. Compound 12 possesses an unprecedented 2H-cyclopenta[de]chromene-2,5(4H)-dione scaffold. Compounds 12, 20, and 23 displayed moderate inhibitory effects against lipopolysaccharide-induced nitric oxide production in BV-2 microglial cells, while all the isolates exhibited significant DPPH radical scavenging activities with EC50 values of 2.2-15.8 µM.
Assuntos
Benzopiranos/química , Benzopiranos/farmacologia , Euphorbia/química , Benzopiranos/isolamento & purificação , Ácidos Carboxílicos/química , Ácidos Carboxílicos/isolamento & purificação , Ácidos Carboxílicos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Dicroísmo Circular , Sequestradores de Radicais Livres/farmacologia , Humanos , Lipopolissacarídeos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Componentes Aéreos da Planta/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Estereoisomerismo , Difração de Raios XRESUMO
Metal (II) complexes derived from S-benzyl-N-(1-ferrocenyl-3-(4-methylbenzene)acrylketone) dithiocarbazate; HL(1), S-benzyl-N-(1-ferrocenyl-3-(4-chlorobenzene)acrylketone)dithiocarbazate; HL(2), all the compounds were characterized using various spectroscopic techniques. The molar conductance data revealed that the chelates were non-electrolytes. IR spectra showed that the Schiff bases were coordinated to the metal ions in a bidentate manner with N, S donor sites. The ligands and their metal complexes have been screened for in vitro antibacterial, antifungal properties. The result of these studies have revealed that zinc (II) complexes 6 and 13 of both the ligands and copper (II) complexes 9 of the HL(2) were observed to be the most active against all bacterial strains, antifungal activity was overall enhanced after complexation of the ligands.
Assuntos
Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Compostos Ferrosos/síntese química , Compostos Ferrosos/farmacologia , Bases de Schiff/síntese química , Bases de Schiff/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Complexos de Coordenação/química , Condutividade Elétrica , Compostos Ferrosos/química , Fungos/efeitos dos fármacos , Ligantes , Espectroscopia de Ressonância Magnética , Metalocenos , Testes de Sensibilidade Microbiana , Bases de Schiff/química , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , EstereoisomerismoRESUMO
OBJECTIVE: To find out the relationship of traffic accidents with life events, driving stress, aggressive driving, etc. METHODS: A total of 905 automobile drivers were investigated with life events scale (LES), general driver stress questionnaire, driver behavior inventory and accidents experience, etc. RESULTS: The scores of life events, driving stress, and aggressive driving in accident drivers (21.79 +/- 14.10, 23.81 +/- 11.86, 9.42 +/- 8.25 respectively) were higher than those in nonaccident drivers (16.82 +/- 8.45, 20.09 +/- 10.63, 5.66 +/- 7.54) (P < 0.01). The number of vehicle accidents was significantly correlated with the scores of LES, driving stress, driver's aggressive behavior, drowsy driving, weekly time of driving, drinking index (P < 0.05). A logistic analysis (Forward:LR) showed that the driving hour, drowsy driving, aggressive driving, and drinking index were closely related with traffic accidents (P < 0.01). CONCLUSION: Life events, driving stress and aggressive driving of the drivers are important factors related to traffic accidents.