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BACKGROUND: The new tetrandrine derivative is an anti-human liver cancer cell inhibitor which can be used to design and develop anti-human-liver-cancer drugs. OBJECTIVE: A quantitative structure-activity relationship (QSAR) model was established to predict the physical properties of new tetrandrine derivatives using their chemical structures. METHODS: The best descriptors were selected through CODESSA software to build a multiple linear regression model. Then, gene expression programming (GEP) was used to establish a nonlinear quantitative QSAR model with descriptors to predict the activity of a series of novel tetrandrine chemotherapy drugs. The best active compound 31 was subjected to molecular docking experiments through SYBYL software with a small fragment of the protein receptor (PDB ID:2J6M). RESULTS: Four descriptors were selected to build a multiple linear regression model with correlation coefficients R2, R2CV and S2 with the values of 0.8352, 0.7806 and 0.0119, respectively. The training and test sets with a correlation coefficient of 0.85 and 0.83 were obtained via an automatic problem-solving program (APS) using the four selected operators as parameters, with a mean error of 1.49 and 1.08. Compound 31 had a good docking ability with an overall score of 5.8892, a collision rate of -2.8004 and an extreme value of 0.9836. CONCLUSION: The computer-constructed drug molecular model reveals the factors affecting the activity of human hepatocellular carcinoma cells, which provides directions and guidance for the development of highly effective anti-humanhepatocellular- carcinoma drugs in the future.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Relação Quantitativa Estrutura-Atividade , Carcinoma Hepatocelular/tratamento farmacológico , Simulação de Acoplamento Molecular , Neoplasias Hepáticas/tratamento farmacológicoRESUMO
Objective: The present study aimed to evaluate the therapeutic effect and explore the underlying mechanisms of Longxue Tongluo Capsule (LTC) on ischemic stroke rats. Methods: Twenty-six rats were randomly divided into four groups, including sham group, sham + LTC group, MCAO group, and MCAO + LTC group. Ischemic stroke rats were simulated by middle cerebral artery occlusion (MCAO), and LTC treatment group were orally administrated with 300 mg/kg of LTC once daily for seven consecutive days. LTC therapy was validated in terms of neurobehavioral abnormality evaluation, cerebral infarct area, and histological assessments. The plasma metabolome comparisons amongst different groups were conducted by UHPLC-Q Exactive MS in combination with subsequent multivariate statistical analysis, aiming to finding the molecules in respond to the surgery or LTC treatment. Results: Intragastric administration of LTC significantly decreased not only the neurobehavioral abnormality scores but also the cerebral infarct area of MCAO rats. The interstitial edema, atrophy, and pyknosis of glial and neuronal cells occurred in the infarcted area, core area, and marginal area of cerebral cortex were improved after LTC treatment. A total of 13 potential biomarkers were observed, and Youden index of 11 biomarkers such as LysoPC, SM, and PE were more than 0.7, which were involved in neuroprotective process. The correlation and pathway analysis showed that LTC was beneficial to ischemic stroke rats via regulating glycerophospholipid and sphingolipid metabolism, together with nicotinate and nicotinamide metabolism. Heatmap and ternary analysis indicated the synergistic effect of carbohydrates and lipids may be induced by flavonoid intake from LTC. Conclusion: The present study could provide evidence that metabolomics, as systematic approach, revealed its capacity to evaluate the holistic efficacy of TCM, and investigate the molecular mechanism underlying the clinical treatment of LTC on ischemic stroke.
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Eight previously undescribed phenolic compounds, dracoropins A - H (1-8), along with two known analogues (9 and 10) were isolated from the fruits of Daemonorops draco. Four pairs of isomers (1a/1b, 2a/2b, 3a/3b, and 4a/4b) were resolved by using chiral-phase HPLC separation. Their structures, including the absolute configurations of the resolved isomers, were elucidated by analysis of spectroscopic data (1D and 2D NMR, IR, and HRESIMS), single-crystal X-ray diffraction, and electronic circular dichroism (ECD) calculations. Compounds 1, 2, and 3 bear a rare 2-phenylbenzo[d]-1,3-dioxepine skeleton. All the isolates were evaluated for their inhibitory activity against ATP release in thrombin-activated platelets. Compounds 2b, 3a, and 6 could significantly inhibit ATP release in thrombin-activated platelets.
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Plaquetas , Frutas , Estrutura Molecular , Trombina , Trifosfato de AdenosinaRESUMO
Background: Currently, predictive models were not developed based on the signaling pathway signatures of immune-related lncRNAs in breast cancer (BRCA) patients. Methods: We selected unsupervised hierarchical clustering algorithm to classify patients with BRCA based on the significant immune-derived lncRNAs from the TCGA dataset. And different methods including ESTIMATE, ImmuneCellAI, and CIBERSORT were performed to evaluate the immune infiltration of tumor microenvironment. Using Lasso regression algorithm, we filtered the significant signaling pathways enriched by GSEA, GSVA, or PPI analysis to develop a prognostic model. And a nomogram integrated with clinical factors and significant pathways was constructed to predict the precise probability of overall survival (OS) of BRCA patients in the TCGA dataset (n = 1,098) and another two testing sets (n = 415). Results: BRCA patients were stratified into the PC (n = 571) and GC (n = 527) subgroup with significantly different prognosis with 550 immune-related lncRNAs in the TCGA dataset. Integrated analysis revealed different immune response, oncogenic signaling, and metabolic reprograming pathways between these two subgroups. And a 5-pathway signature could predict the prognosis of BRCA patients between these two subgroups independently in the TCGA dataset, which was confirmed in another two cohorts from the GEO dataset. In the TCGA dataset, 5-year OS rate was 78% (95% CI: 73-84) vs. 82% (95% CI: 77-87) for the PC and GC group (HR = 1.63 (95% CI: 1.17-2.28), p = 0.004). The predictive power was similar in another two testing sets (HR > 1.20, p < 0.01). Finally, a nomogram is developed for clinical application, which integrated this signature and age to accurately predict the survival probability in BRCA patients. Conclusion: This 5-pathway signature correlated with immune-derived lncRNAs was able to precisely predict the prognosis for patients with BRCA and provided a rich source characterizing immune-related lncRNAs and further informed strategies to target BRCA vulnerabilities.
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In light of related methods in Chinese Pharmacopoeia(2020 edition), this study established the quality standard for Lobeliae Chinensis Herba. The TLC identification method was established with silica gel GF_(254) thin layer plate, diosmin standard, linarin standard, and the reference material of Lobeliae Chinensis Herba. The loss on drying, total ash, acid-insoluble ash, and ethanol-soluble extracts of 18 batches of Lobeliae Chinensis Herba samples were determined according to the general principles in Chinese Pharmacopoeia. Then, HPLC was adopted in the establishment of characteristic chromatogram and content determination. The results showed that the established method can achieve good separation for diosmin, linarin, and lobetyolin. Based on the results of detection for 18 batches of Lobeliae Chinensis Herba samples, the draft quality standard was established, which was expected to provide reference for the revision of this medicinal herb in Chinese Pharmacopoeia.
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Medicamentos de Ervas Chinesas , Lobelia/química , Plantas Medicinais , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/normas , Plantas Medicinais/químicaRESUMO
A new unsaturated fatty acid trewioidesine A (1), together with seven known compounds (2 - 8) were isolated from the rhizomes of Alchornea trewioides (Benth.) Muell. Arg. Their structures were established on the basis of extensive spectroscopic data interpretation (1 D and 2 D NMR, and HRESIMS). The absolute configuration of 1 was determined by electronic circular dichroism (ECD) calculations, confirming as trewioidesine A. The functionality of isolated compounds was tested in cultured PC12 cells, a cell line from rat pheochromocytoma. Trewioidesine A was the one showing robust activity in inducing neuronal differentiation: the induction was synergized when co-applied with nerve growth factor (NGF). In addition, a neurofilament 200 (NF200) promoter-luciferase (pNF200-Luc) reporter was used to evaluate the differentiating ability in the transfected PC12 cells for the isolated compounds. Trewioidesine A exhibited a strong NF200 promoter activation, and application of trewioidesine A with low dose of NGF significantly induced the promoter activity over 50%.
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Neoplasias das Glândulas Suprarrenais , Euphorbiaceae , Feocromocitoma , Animais , Diferenciação Celular , Ácidos Graxos Insaturados/farmacologia , Fator de Crescimento Neural/farmacologia , Células PC12 , Ratos , RizomaRESUMO
Introduction: Longxuetongluo Capsule (LTC) is wildly applied to treat ischemic stroke in clinical practice in China. However, the pharmacological mechanism of LTC on ischemic stroke is still unstated. Objective: Our research was designed to study the protective effect of LTC against cerebral ischemia-reperfusion (I/R) injury and reveal the underlying mechanism both in vivo and in vitro. Methods: PC12 cells treated with glucose deprivation/reperfusion (OGD/R) were used to simulate in vitro ischemia/reperfusion (I/R) injury. The cell viability, apoptosis rate, and protein expressions of PC12 cells were evaluated. In vivo validation of the protective effect of LTC was carried out by middle cerebral artery occlusion (MCAO)/reperfusion treatment, and the underlying mechanism of its anti-apoptosis ability was further revealed by immunohistochemistry staining and Western blotting. Results: In the current study, we observed that LTC effectively inhibited oxygen-glucose deprivation/reperfusion (OGD/R) induced apoptosis of PC12 cells through suppressing the cleavage of poly ADP-ribose polymerase (PARP), caspase-3, and caspase-9. Further investigation revealed that OGD/R insult remarkably triggered the endoplasmic reticulum stress responses (ER stress) to induce PC12 cell apoptosis. LTC treatment alleviated OGD/R induced ER stress by inhibiting the activation of protein kinase RNA (PKR)-like ER kinase (PERK)/eukaryotic translation initiation factor 2 (eIF2α) and inositol requiring enzyme 1 (IRE1)/tumor necrosis factor receptor-associated factor 2 (TRAF2) pathways. Additionally, LTC also restrained the OGD/R-induced PC12 cell apoptosis by reversing the activated mitogen-activated protein kinase (MAPK) through IRE1/TRAF2 pathway. Animal studies demonstrated LTC significantly restricted the infarct region induced by middle cerebral artery occlusion (MCAO)/reperfusion, the activation of ER stress and apoptosis of neuronal cells had also been suppressed by LTC in the penumbra region. Conclusion: LTC protects the cerebral neuronal cell against ischemia/reperfusion injury through ER stress and MAPK-mediated mechanisms.
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Isquemia Encefálica , Traumatismo por Reperfusão , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/prevenção & controle , Medicamentos de Ervas Chinesas , Estresse do Retículo Endoplasmático , Proteínas Quinases Ativadas por Mitógeno , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controleRESUMO
This study aims to study the chemical components from the gum resin of Boswellia carterii. Five cembranoid diterpenes were isolated from the gum resin of B. carterii by various of column chromatographies including silica gel, Sephadex LH-20, and semi-preparative HPLC. Their structures were identified on the basis of physicochemical properties, mass spectrometry(MS), nuclear magnetic resonance(NMR), Ultraviolet(UV) and infrared(IR) spectroscopic data. These compounds were identified as(1S,2E,4R,5S,7E,11E)-4-methoxy-5-hydroxycembrane(1),(1R~*,4R~*,5E,8E,12E,15E)-4-hydroxycembra-5,8,12,15-tetraene(2), cembrene A(3),(3S,4S,7R)-4-hydroxycembrane(4), and pavidolide D(5). Compound 1 was a new compound. Compounds 2, 4, and 5 were obtained from the gum resin of B. carterii for the first time. Compound 2 showed weak inhibition on the human liver cancer cell line HepG2.
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Boswellia , Diterpenos , Linhagem Celular , Humanos , Estrutura Molecular , Resinas VegetaisRESUMO
Either widely targeted metabolomics or quantitative proteomics usually requires unique analytical platform. However, cross-platform omics studies entail higher levels of complexity and uncertainty, and result in a significant obstacle for high throughput assay as well. It is thereby urgent to pursue an integrative approach being capable of merging these two omics terms, namely widely targeted bi-omics. As an eligible analytical tool for large-scale targeted metabolomics, reversed phase liquid chromatography-hydrophilic interaction liquid chromatography-tailored selected reaction monitoring (RPLC-HILIC-tailored SRM) was deployed here to further receive the tryptic peptides as the analytes. Comparative evaluation of metabolites and tryptic peptides, 101 ones in total, between HepG2 and SK-Hep1 cells was conducted as a proof-of-concept. All analytes, regardless of metabolites or peptides, exhibited satisfactory chromatographic behaviors on RPLC-HILIC. Quantitative MS parameters, such as SRM transitions and collision energies (CEs), of either tryptic peptides or metabolites were online optimized in a standard compound-independent manner. It was worthwhile to mention that the signal responses of the peptides-of-choice generated by the optimized CEs were significantly superior to those values suggested by Skyline software. Calibration curves of both metabolites and peptides were constructed by serially diluting a so-called universal metabolome standard (UMS) sample. The quasi-content of each peptide or metabolite was gained according to applying those regressive calibration curves. After subjecting the quasi-content dataset into SIMCA-P software, significant differences took place between the two hepatic cell lines, and not only metabolites but tryptic peptides contributed to the discrimination. Above all, RPLC-HILIC-tailored SRM offered a promising choice towards widely targeted bi-omics attributing to the advantage of simultaneous monitoring metabolites and tryptic peptides.
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Metabolômica/métodos , Proteômica/métodos , Linhagem Celular Tumoral , Cromatografia Líquida , Humanos , Espectrometria de Massas , Estrutura MolecularRESUMO
Induction of excessive, prolonged, or dysregulated immune responses causes immunological disorders, such as inflammatory diseases, autoimmune diseases, allergic diseases, and organ-graft rejections. In the present study, we investigated the inhibitory effects of HHX-5, a derivative of sesquiterpene from Chinese agarwood, on innate and adaptive immunity for revealing its potential to treat above immunological disorders. The results showed that HHX-5 significantly inhibited the activation of macrophages and neutrophils which play important roles in innate immunity. Furthermore, HHX-5 strongly suppressed adaptive immunity via inhibiting differentiation of naive CD4+ T cells into Th1, Th2, and Th17 cells and suppressing activation, proliferation and differentiation of CD8+ T cells and B cells. The mechanism study showed that HHX-5 significantly inhibited STAT1 signaling pathway in macrophages and suppressed STAT1, STAT4, STAT5, and STAT6 signaling pathways in naive CD4+ T cells. In conclusion, we demonstrated that HHX-5 can strongly inhibit innate and adaptive immunity via suppressing STAT signaling pathways and has potential to be developed into therapeutic drug for treat immunological disorders.
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Imunidade Adaptativa/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Madeira/química , Animais , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Proliferação de Células/efeitos dos fármacos , Citocinas/biossíntese , Imunossupressores/química , Imunossupressores/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , NF-kappa B/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Células RAW 264.7 , Transdução de Sinais/imunologia , Baço/imunologiaRESUMO
Chemical constituents from the fruits of Vitex negundo var. cannabifolia and their nitric oxide (NO) inhibitory and cytotoxic activities were investigated. The compounds were isolated and purified by various column chromatography, and their structures were identified by physiochemical properties and spectroscopic data. Thirteen lignans and six phenolic compounds were isolated from the CH2Cl2 extract of the fruits of V. negundo var. cannabifolia, respectively. Their structures were elucidated as 6-hydroxy-4-(4-hydroxy-3-methoxyphenyl)-3-hydroxymethyl-7-methoxy-3,4-dihydro-2-naphthaldehyde (1), vitedoin A (2), vitexdoin F (3), detetrahydroconidendrin (4), vitexdoin E (5), 4-oxosesamin (6), L-sesamin (7), (+)-beechenol (8), ligballinol (9), 2-(4-hydroxyphenyl)-6-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane (10), (-)-pinoresinol (11), balanophonin (12), thero-guaiacylglycerol-ß-coniferyl aldehyde ether (13), trans-p-coumaryl aldehyde (14), coniferyl aldehyde (15), 5,7-dihydroxychromone (16), trans-3,5-dimethoxy-4-hydroxy-cinnamic aldehyde (17), frambinone (18), and alternariol 4-methyl ether (19). Compounds 8-10,14,18,19 were firstly isolated from Verbenaceae family, compound 13 was obtained from Vitex species, and 6,7,12,15-17 from V. negundo var. cannabifolia for the first time, respectively. The isolated compounds were evaluated for their anti-inflammatory and cytotoxic effects in vitro. Eight compounds (3,5,7,10,11,14,15,17) showed inhibition against NO production in LPS-stimulated RAW 267.4 cells (IC50 in the range of 7.8-81.1 µmolâ¢L⻹) and four compounds (1-4) showed cytotoxicity on HepG-2 cells (IC50 in the range of 5.2-24.2 µmolâ¢L⻹).
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Frutas/química , Compostos Fitoquímicos/isolamento & purificação , Vitex/química , Animais , Células Hep G2 , Humanos , Camundongos , Óxido Nítrico/metabolismo , Compostos Fitoquímicos/farmacologia , Células RAW 264.7RESUMO
A new γ-alkylated-γ-butyrolactone, named melongenolide A (1), along with nine known compounds were obtained from the roots of Solanum melongena, and their structures were identified as melongenolide A (1), (+)-syringaresinol (2), (+)-lyoniresinol (3), 5,5'-dimethoxy lariciresinol (4), (+)-(7R,8R)-4-hydroxy-3,3',5'-trimethoxy-8',9'-dinor-8,4'-oxyneoligna-7, 9-diol-7'-aldehyde (5), kaempferol-3-O-(2â³,6â³-di-O-p-trans-coumaroyl)-ß-glucoside (6), arjunolic acid (7), vanillic acid (8), scoparone (9), and ß-sitosterol (10). Compounds 2, 6, and 7 showed potent inhibitory effects on nitric oxide production in lipopolysaccharide-induced RAW 264.7 macrophages, with IC50 values being 5.62 ± 0.86, 11.47 ± 0.98, and 27.75 ± 1.26 µmol·L(-1), respectively.
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4-Butirolactona/análogos & derivados , Extratos Vegetais/química , Raízes de Plantas/química , Solanum melongena/química , 4-Butirolactona/isolamento & purificação , Animais , Furanos/isolamento & purificação , Furanos/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Concentração Inibidora 50 , Quempferóis/isolamento & purificação , Quempferóis/farmacologia , Lignanas/isolamento & purificação , Lignanas/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Células RAW 264.7 , Triterpenos/isolamento & purificação , Triterpenos/farmacologiaRESUMO
Two new dihydrochalcones, 4-hydroxy-2,4'-dimethoxydihydrochalcone (1) and 3,4'-dihydroxy-2,4,6-trimethoxydihydrochalcone (2), and a new homoisoflavane, 7,3'-dihydroxy-8,4'-dimethoxyhomoisoflavane (3), along with 12 known compounds (4-15), were isolated from the red resin of Dracaena cochinchinensis (Chinese dragon's blood). Their structures were assigned by a variety of spectroscopic techniques. Diversity of cleavage pathways were proposed for dihydrochalcones and homoisoflavanes based on the mass spectroscopic behaviors of those identified compounds using hybrid ion trap-time of flight mass spectrometry. All the compounds were evaluated for their inhibitory effects on nitric oxide production in lipopolysaccharide-induced RAW 264.7 macrophages, and compound 9 exhibited mild inhibition of NO production in this assay with IC50 value of 50.3 µM.
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Anti-Inflamatórios/química , Chalconas/química , Dracaena/química , Isoflavonas/química , Resinas Vegetais/química , Animais , Anti-Inflamatórios/isolamento & purificação , Linhagem Celular , Chalconas/isolamento & purificação , Isoflavonas/isolamento & purificação , Macrófagos/efeitos dos fármacos , Camundongos , Estrutura Molecular , Óxido Nítrico/metabolismoRESUMO
Four new lignanamides, melongenamides A-D (1-4), together with six known ones (5-10), were isolated from the roots of Solanum melongena L. Their structures were elucidated on the basis of 1D and 2D NMR experiments and by comparison of their spectroscopic and physical data with the literature values. Compounds 2-8 exhibited inhibitions of nitric oxide production in lipopolysaccharide-induced RAW 264.7 macrophages with IC50 values ranging from 16.2 to 58.5 µM.