RESUMO
Eight undescribed (1-8) and 46 known compounds (9-54) were isolated from the deep-sea-derived Aspergillus sp. MCCC 3A00392. Compounds 1-3 were three novel oxoindolo diterpenoids, 4-6 were three bisabolane sesquiterpenoids, while 7 and 8 were two monocyclic cyclopropanes. Their structures were established by exhaustive analyses of the HRESIMS, NMR, and theoretical calculations of the NMR data and ECD spectra. Compounds 10, 33, 38, and 39 were able to inhibit tumor necrosis factor (TNF)-induced necroptosis in murine L929 cell lines. Functional experiments verified that compounds 10 and 39 inhibited necroptosis by downregulating the phosphorylation of RIPK3 and MLKL. Moreover, compound 39 also reduced the phosphorylation of RIPK1. Compounds 10, 33, and 34 displayed potent inhibitory activities against RSL-3 induced ferroptosis with the EC50 value of 3.0 µM, 0.4 µM, and 0.1 µM, respectively. Compound 10 inhibited ferroptosis by the downregulation of HMOX1, while compounds 33 and 34 inhibited ferroptosis through regulation of NRF2/SLC7A11/GCLM axis. However, these compounds only showed weak effect in either the necroptosis or ferroptosis relative mouse disease models. Further studies of pharmacokinetics and pharmacodynamics might improve their in vivo bioactivities.
Assuntos
Ferroptose , Sesquiterpenos , Camundongos , Animais , Necroptose , Aspergillus/química , Sesquiterpenos/química , Sesquiterpenos MonocíclicosRESUMO
Four new lycoctonine-type C19-diterpenoid alkaloids kamaonensines H-K (1-4) have been isolated from the whole plants of Delphinium kamaonense, together with 12 known compounds (5-16). Interestingly, kamaonensines 1-3 contained a rare nitrone (immine N-oxide) moiety, respectively. Their structures were established by spectroscopic analyses. The active evaluation of compounds (1-16) by LPS induced RAW 264.7 macrophages showed that compounds 4 and 8 displayed strong anti-inflammatory activities. While compounds 11 and 12 also showed strong cytotoxicities by the RAW 264.7 cell viability assay.
RESUMO
Four monoterpenoid indole alkaloid dimers (MIADs), axidimins A-D (1-4), which possesses unprecedented apidosperma-aspidosperma-type skeletons, along with twelve known MIAs were isolated from Melodinus axillaris. Their structures were established by comprehensive analysis of the HRESIMS, NMR, ECD calculation and DP4 + analysis. A possible biosynthetic pathway for axidimins A-D was proposed. In vitro, axidimins C and D exhibited significant cytotoxicities against HCT116 cells with IC50 values of 5.3 µM and 3.9 µM, respectively. The results obtained from flow cytometry and Western blot analysis clearly demonstrated that axidimins C and D significantly induced a reverse G2/M phase arrest and apoptosis of HCT116 cells. The potential mechanism of axidimins C and D on HCT116 cells were thoroughly discussed through the utilization of network pharmacology and molecular docking research. Subsequently, the selected targets were validated using Western blot and CETSA analysis, confirming that axidimins C and D exert its cytotoxic effects through the activation of the p38 MAPK pathway, ultimately leading to HCT116 cells death. This study provides evidence indicating that axidimins C and D have the potential to induce cell cycle arrest and apoptosis in HCT116 cells by modulating the p38 MAPK signaling pathway. These findings offer a novel perspective for the development of anti-colorectal cancer drugs.
Assuntos
Apocynaceae , Alcaloides de Triptamina e Secologanina , Humanos , Células HCT116 , Simulação de Acoplamento Molecular , Apoptose , Pontos de Checagem do Ciclo Celular , Alcaloides Indólicos , Mitose , Monoterpenos/farmacologia , PolímerosRESUMO
Through a phytochemical investigation of Abrus mollis Hance, a folk medicinal plant in China, we isolated and identified three undescribed compounds, including two flavonoids and one amides alkaloid, along with nine known from this plant. Their structures were elucidated by analyses of 1D, 2D NMR, HR-ESI-MS, ECD, and DP4+ analysis. Furthermore, we evaluated the hepatoprotective effects of all twelve compounds on D-GalN-induced Brl-3â A cells. According to the results, at a concentration of 25â µM, the cell survival rates were observed to be 71.92±0.34 %, 70.03±1.29 %, and 69.11±1.90 % for compound 2, 4, and 11, respectively. Further experimental studies showed that compound 2 (EC50 5.76±0.37â µM) showed more significant protective activity than the bicyclol.
Assuntos
Abrus , Alcaloides , Flavonoides/química , Extratos Vegetais/química , Abrus/química , Amidas/farmacologia , Alcaloides/farmacologiaRESUMO
From the dried leaves of Ohwia caudata, two new compounds, namely (4E)-(4-hydroxyphenyl)-3-butenoic acid butyl ester (1), and 4-benzyl-1,3-phenylenedicarbamic acid methyl ester (2), together with five known compounds, were isolated and identified. The structures of compounds 1 and 2 were established using 1D-NMR, 2D-NMR and HR-ESI-MS spectral analysis. Previous studies on O. caudata had been reported to protect against Alzheimer's disease, two new compounds were evaluated for their neuroprotective effect against lipopolysaccharide-induced BV2 microglia cells. The result indicated two compounds showed well anti-neuroinflammatory activity at 12.5â µM.
Assuntos
Doença de Alzheimer , Fármacos Neuroprotetores , Humanos , Lipopolissacarídeos/farmacologia , Fármacos Neuroprotetores/farmacologia , Anti-Inflamatórios/farmacologia , Linhagem Celular , Microglia , Óxido NítricoRESUMO
In the investigation of Meehania fargesii, eighteen triterpenoids were isolated and identified, including a previously unknown compound with an 13,27-cycloursane skeleton, using techniques like 1D and 2D NMR, and HR-MS. Furthermore, the cytotoxicity of these compounds were evaluated against HCT116, MCF-7, and AGS cell lines using the CCK-8 method to examine their structure-activity relationship. Remarkably, compounds 13 and 16 exhibited higher cytotoxicity across all three cell lines compared to the positive drug. Western blot analysis revealed that these compounds activated apoptosis in HCT116 cells by promoting the Bax protein and inhibiting the Bcl-2 protein. This suggests that compounds 13 and 16 have potential as apoptosis-inducing agents in HCT116 cells.
RESUMO
Two previously undescribed compounds (1 and 2) were isolated from Clinopodium polycephalum, a medicinal plant distributed in southwestern and eastern China. Their structures were elucidated using MS analyses and extensive 2D-homo and heteronuclear NMR data interpretations. Both compounds 1 and 2 could significantly shorten APTT and PT, and their procoagulant effect was comparable to that of positive drugs. At the same time, compound 2 had certain antioxidant activity (IC50 value of 2.25±0.05â µM in ABTS assay).
Assuntos
Lamiaceae , Plantas Medicinais , Anticoagulantes/farmacologia , Lamiaceae/química , Antioxidantes/farmacologia , Antioxidantes/química , China , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Estrutura MolecularRESUMO
One new alkaloid, (S)-2-acetamido-4-(2-(methylamino)phenyl)-4-oxobutanoic acid (1), was isolated from the deep-sea-derived Penicillium citrinum XIA-16, together with 25 known compounds including ten polyketones (2-11), eight alkaloids (12-19), six steroids (20-25), and a fatty acid (26). Their planar and relative structures were determined by an analysis of 1D and 2D nuclear magnetic resonance (NMR) as well as high resolution electrospray ionization mass spectroscopy (HR-ESI-MS) data. The absolute configuration of 1 was determined by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. Penicitrinol B (6) significantly inhibited RSL3-induced ferroptosis (EC50 =2.0â µM) by reducing lipid peroxidation and heme oxygenase 1 (HMOX1) expression. Under the concentration of 10â µM, penicitrinol A (7) was able to inhibit cuproptosis with the cell viabilities of 68.2 % compared to the negative control (copper and elesclomol) with the cell viabilities of 14.8 %.
Assuntos
Alcaloides , Antineoplásicos , Penicillium , Animais , Penicillium/química , Antineoplásicos/farmacologia , Espectroscopia de Ressonância Magnética/métodos , Alcaloides/química , Crustáceos , Estrutura MolecularRESUMO
We used UV-guided method to isolate and identify 12 secondary metabolites from Meehania fargesii var. Radicans for the first time, including eight triterpenoids (1-8), two phenylpropanoid derivatives (9-10) and two flavone glycosides (11-12). Their structures were identified by NMR spectroscopic methods, as well as literature comparison. The identified compounds and positive drugs (amoxicillin, omeprazole and clarithromycin) were further analyzed for their in silico docking interactions with HtrA using igemdock. Docking studies revealed the high binding affinity of phytochemicals at significant sites with HtrA, compounds 11 and 12 exhibiting stronger binding ability than standard drug, 1 and 3-10 demonstrating comparable docking capacity to standard drugs. The chemotaxonomic relationships were carried out to exploring the possibilities of other medicinal plants against Hp-induced gastric carcinoma. The results demonstrated there are closely chemotaxonomic similarity among several genera of the Lamiaceae family as well as among Lamiaceae, Actinidiaceae and Rosaceae families, indicating a similar chemical compositions and anti-Hp-induces gastric carcinoma activity among them.
Assuntos
Carcinoma , Infecções por Helicobacter , Helicobacter pylori , Lamiaceae , Antibacterianos/farmacologia , Carcinoma/tratamento farmacológico , Infecções por Helicobacter/tratamento farmacológico , Humanos , Simulação de Acoplamento Molecular , Compostos Fitoquímicos/farmacologiaRESUMO
Liver is an important metabolic organ with numerous functions in human body. Hepatitis is defined as the inflammation of the liver tissue, which could lead to acute liver failure, liver fibrosis, liver cirrhosis and hepatocellular carcinoma. Corydalis tomentella Franch., a precious herb in China, is often used in the treatment of hepatitis, liver cirrhosis and liver cancer. In this study, 41 isoquinoline alkaloids and derivatives isolated by our lab from C.â tomentella and 61 related targets were analyzed by network pharmacology. Their activities were further verified by cell assay evaluated for antitumor activity against HepG2 cells and molecular docking. The results confirmed that the alkaloids from C.tomentella had extensive hepatoprotective effects, and TNF-α was the key target of hendersinate B methyl ester against acute liver damage by viral hepatitis and HCC, which provided a foundation for further inâ vivo studies.
Assuntos
Alcaloides , Carcinoma Hepatocelular , Corydalis , Neoplasias Hepáticas , Alcaloides/farmacologia , Humanos , Simulação de Acoplamento Molecular , Farmacologia em RedeRESUMO
A new amide (1), two new phenylpropanoid derivatives (2, 3), along with three new natural products, including three nitrogen chirality compounds, N-(3-methoxy-1,3-dioxopropyl)-D-phenylalanine methyl ester (4), N-(3-methoxy-1,3-dioxopropyl)-L-phenylalanine methyl ester (5), and N-acetyl-L-phenylalanine methyl ester (6), as well as dimethyl (2R,3R)-2-hydroxy-3-(((E)-3-(4-hydroxyphenyl)acryloyl)oxy)succinate (7) and dimethyl (S,E)-2-((3-(4-hydroxy-3-methoxyphenyl)acryloyl)oxy)succinate (8) were isolated from Delphinium kamaonense Hunth. Their structures were elucidated by extensive analysis of 1D and 2D NMR, and HR-ESI-MS experiments, and the absolute configurations were determined by comparative analysis of specific optical rotation. Compound 1 exhibited a moderate cytotoxicity effect against Hep-3B cancer cell lines (IC50 41.39±0.13â µM) and an excellent antioxidant activity (IC50 0.527±0.06â µM in ABTS assay, and 1.235±0.09â µM in DPPH assay, respectively), which was superior to vitaminâ C in ABTS (IC50 1.670±0.07â µM) and DPPH (IC50 19.10±0.40â µM) methods.
Assuntos
Antineoplásicos , Delphinium , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Delphinium/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , SuccinatosRESUMO
Fifteen metabolites, including two flavonols (1-2), three lignans (3-5), and ten diterpenoids (6-15), were isolated from the leaves of Pinus yunnanensis. Among them, flavanonol (1) were identified as undescribed flavonol derivative with natural rarely B-ring fission lactone. Massive spectroscopic methods, the DP4+ probabilities and CD/ECD calculations were applied to establish the structure of component 1. Among these compounds, taxifolin (2) showed potent cytotoxicity, having IC50 values from 21.33 to 45.48â µg/mL, it also showed broad antibacterial activity against human pathogens with MIC values from 32 to 64â µg/mL.
Assuntos
Antibacterianos/química , Pinus/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Diterpenos/química , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Flavonóis/química , Flavonóis/isolamento & purificação , Flavonóis/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Conformação Molecular , Pinus/metabolismo , Extratos Vegetais/química , Folhas de Planta/química , Folhas de Planta/metabolismoRESUMO
Six new guaiane-type sesquiterpenes (1-6), and one monoterpenoid (7) along with five known analogues (8-12), were isolated from the leaves of Artemisia argyi Lévl et Vant. The new compounds were characterized by the basic analysis of the spectroscopic data (HRMS, 1D and 2D NMR), and the absolute configurations were determined by both calculated electronic circular dichroism and DP4 calculations. The inhibitory effects of 1-12 against human gastric adenocarcinoma (AGS) cells were investigated in vitro, among which 1-3 and 8 showed remarkable cytotoxic activity with IC50 values in the range of 6.69-10.25 µM. The results suggested that the variation in the inhibitory activities of the compounds are the result of different substitutions on C-8. In order to rationalize the binding interactions of active compounds with the active site of NF-кB, in silico study was conducted and the results were in complete agreement with the experimental data for cytotoxicity evaluation.
Assuntos
Adenocarcinoma/patologia , NF-kappa B/antagonistas & inibidores , Sesquiterpenos de Guaiano/farmacologia , Neoplasias Gástricas/patologia , Humanos , Análise Espectral/métodos , Células Tumorais CultivadasRESUMO
Two new (1-2) as well as five known (3-7) compounds were isolated from Polytrichum commune, a folk herbal medicine in China, and three of them (2, 4, 5) belong to benzonaphthoxanthenones that are rarely found in nature. Their structures were elucidated by the approach to 1D and 2D NMR spectra. The absolute configuration of 2 was assigned by comparing its experimental and calculated ECD data. 1-5 were investigated for their anti-neuroinflammatory activity against LPS-induced BV-2 cells. 1 and 3 exhibited well protective effect at a concentration of 2.5 µmol/mL. Molecular docking studies were adopted to further investigate the possible mechanism, whose results suggested that 1 might exert anti-neuroinflammatory effect by inhibiting activity of p38α, JNK2 and TAK1 to reduce the liberation of pro-inflammatory cytokines.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Xantenos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/análise , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Medicina Tradicional Chinesa , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Xantenos/química , Xantenos/isolamento & purificaçãoRESUMO
Five new isoquinolines (1-5) were isolated from national herb Corydalis tomentella. Their structures were elucidated by extensive analysis of the 1D and 2D NMR spectra and from the HRESIMS. Absolute configurations of 1-3 were determined by comparing their experimental and computed ECD data. Since plants from Corydalis have been reported to protect against Alzheimer's disease, all compounds were evaluated for their neuroprotective effect against lipopolysaccharide-induced BV2 microglia cells. Compound 2 and 3 showed well anti-neuroinflammatory activity at low concentration (25 µM).
Assuntos
Doença de Alzheimer/tratamento farmacológico , Corydalis/química , Isoquinolinas/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Isoquinolinas/química , Isoquinolinas/isolamento & purificação , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Relação Estrutura-AtividadeRESUMO
37 compounds mainly including triterpenoids with the quassinoid skeleton and ß-carboline alkaloids have been isolated from the roots of Eurycoma longifolia Jack (EL), which has been used as traditional medicine for a long history. It has been demonstrated that the total extracts from EL could significantly inhibit the joint swelling in MSU-induced acute gout arthritis rat model at middle and high doses (Pâ¯<â¯0.05, Pâ¯<â¯0.01), as meanwhile, better performance than that of positive control (Pâ¯<â¯0.05, Pâ¯<â¯0.01) has been observed at the dose of 10â¯g/kg. Aiming to search potential compounds and probable mechanisms, network pharmacology, molecular docking and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were adopted, leading to the hypothesis of 17 targets related to different pathogenesis of gout and 5 potential compounds (C36, C107, C124, C125 and C130) among 156 selected compounds, playing synergetic role with multiple targets. Instead of the guiding ideology of "a gene, a drug, a disease", varieties of compounds but not a single one from EL display holistic performance through multiple pathways with multi-targets. It was noteworthy that Xanthine dehydrogenase/oxidase (XDH), Prostaglandin G/H synthase 2 (PTGS2), Fatty acid-binding protein, liver (FABP1), Purine nucleoside phosphorylase (PNP), and Peroxisome proliferator activated receptor alpha (PPARA) were the key targets with intensely interaction. Furthermore, the functional enrichment analysis indicated that EL probably produced the gout protection effects by synergistic regulation in multiple biological pathways, including Toll-like receptor signaling pathway, MAPK signaling pathway, and NOD-like receptor signaling pathway, etc.
Assuntos
Alcaloides/uso terapêutico , Artrite Gotosa/tratamento farmacológico , Cumarínicos/uso terapêutico , Eurycoma/química , Extratos Vegetais/uso terapêutico , Triterpenos/uso terapêutico , Doença Aguda , Alcaloides/química , Alcaloides/isolamento & purificação , Animais , Artrite Gotosa/induzido quimicamente , Cumarínicos/química , Cumarínicos/isolamento & purificação , Relação Dose-Resposta a Droga , Simulação de Acoplamento Molecular , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Triterpenos/química , Triterpenos/isolamento & purificação , Ácido ÚricoRESUMO
Artemisia argyi (AA) is one of the renowned herbs in China often used in the treatment of gastric ulcer (GU). Aiming to predict the active compounds and systematically investigate the mechanisms of Artemisia argyi for GU treatment, the approach of network pharmacology, molecular docking, gene ontology (GO) analysis, and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were adopted, respectively, in present study. A total of 13 predicted targets of the 103 compounds in Artemisia argyi were obtained. Sorted by pathogenic mechanisms of targets and structure types of compounds, it was revealed that flavonoids and sesquiterpenes had better performance than monoterpenes. The network analysis showed that Phospholipase a2 (PA21B), Sulfotransferase family cytosolic 2b member 1 (ST2B1), Nitric-oxide synthase, endothelial (NOS3), Gastrin (GAST), neutrophil collagenase (MMP-8), Leukotriene A-4 hydrolase (LKHA4), Urease maturation factor HypB (HYPB), and Periplasmic serine endoprotease DegP (HtrA) were the key targets with intensely interaction. The functional enrichment analysis indicated that AA probably produced the gastric mucosa protection effects by synergistically regulating many biological pathways, such as NF-κB signaling pathway, HIF-1 signaling pathway, TNF signaling pathway, VEGF signaling pathway, and Toll-like receptor signaling pathway, etc. In addition, C73 and C15 might be promising leading compounds with good molecular docking score. As a consequence, this study holistically illuminates the active constituents and mechanisms based on data analysis, which contributes to searching for leading compounds and the development of new drugs for gastric ulcer.
Assuntos
Antiulcerosos/metabolismo , Artemisia/química , Farmacologia/métodos , Proteínas/metabolismo , Antiulcerosos/química , Simulação de Acoplamento Molecular , Ligação Proteica , Proteínas/química , Transdução de SinaisRESUMO
Stauntonia brachyanthera Hand.-Mazz. (SB), reported as a traditional Chinese medicine, displays a wide spectrum of interesting bioactivities, such as anti-inflammatory and analgesia. It is noteworthy that anti-gout effects of the components in SB have been reported. Hence, this study contributes to the prediction of promising active compounds and mechanisms for the treatment of gout. The active compounds with better oral bioavailability, and drug-likeness of SB were selected for further investigation by the approach of network pharmacology, molecular docking, gene ontology (GO) analysis, and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis, respectively. A total of 34 predicted targets and 98 compounds in SB were obtained. Sorted by structure types of compounds, phenylethanoid glycosides exhibited the best anti-gout activity, followed by phenolics and flavonoids. What's more, it was shown in the network analysis that Serine/threonine-protein kinase mTOR (mTOR), Mitogen-activated protein kinase 12 (MAPK12), tumor necrosis factor (TNF-α), Integrin alpha-4 (ITGA4) and Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG) were the key targets with intensely interaction, which should be attached more attention for further study. The functional enrichment analysis indicated that SB probably produced the anti-gout effects by synergistically regulating many biological pathways, such as MAPK signaling pathway, PI3K-Akt signaling pathway, Toll-like receptor signaling pathway and NOD-like receptor signaling pathway, etc. In addition, C61, C67, C68 and C81 might be promising leading compounds with good molecular docking score. As a consequence, the active constituents and mechanisms based on data analysis were holistically illuminated, which was of vital importance to the development of new drugs for gout.
Assuntos
Anti-Inflamatórios/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Gota/tratamento farmacológico , Magnoliopsida/química , Extratos Vegetais/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Gota/metabolismo , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , Estrutura Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Ohwia caudata (OC)-a traditional Chinese medicine (TCM)-has been reported to have large numbers of flavonoids, alkaloids, and triterpenoids. The previous studies on OC for treating Alzheimer's disease (AD) only focused on single targets and its mechanisms, while no report had shown about the synergistic mechanism of the constituents from OC related to their potential treatment on dementia in any database. This study aimed to predict the bioactive targets constituents and find potential compounds from OC with better oral bioavailability and blood-brain barrier permeability against AD, by using a system network level-based in silico approach. The results revealed that two new flavonoids, and another 26 compounds isolated from OC in our lab, were highly connected to AD-related signaling pathways and biological processes, which were confirmed by compound-target network, Gene Ontology (GO) analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, respectively. Predicted by the virtual screening and various network pharmacology methods, we found the multiple mechanisms of OC, which are effective for alleviating AD symptoms through multiple targets in a synergetic way.
Assuntos
Doença de Alzheimer , Medicamentos de Ervas Chinesas/farmacologia , Fabaceae/química , Regulação da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Redes Reguladoras de Genes/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Disponibilidade Biológica , Medicamentos de Ervas Chinesas/química , HumanosRESUMO
Extracellular alkalinization and H2O2 production are important early events during induced resistance establishment in plants. In a screen for metabolites as plant resistance activators from 98 fungal isolates associated with marine sponge Hymeniacidon perleve, the cyclopiazonic acids (CPAs) produced by Aspergillus oryzae HMP-F28 induced significant extracellular alkalinization coupled with augmented H2O2 production in tobacco cell suspensions. Bioassay-guided fractionation led to the isolation and structural elucidation of a new CPA congener (4, 3-hydroxysperadine A) and three known ones (1-3). To construct a mutasynthetic strain to generate unnatural CPA analogues, a hybrid pks-nrps gene (cpaS) was disrupted to abolish the production of the critical precursor of cyclo-acetoacetyl-L-tryptophan (cAATrp) and all the downstream CPA products. Elimination of cAATrp will allow cAATrp mimics being processed by the CPA biosynthetic machinery to produce CPA derivatives with designed structural features.