RESUMO
In this phytochemical investigation, two pairs of new phenylethanoid derivative enantiomers (1a/1b and 2a/2b), a new phenylethanoid derivative 3b, and seven known compounds (3a, 4-9) were isolated from the leaves of Picrasma quassioides. Spectroscopic techniques were used for the elucidation of their chemical structures, and the absolute configurations were determined by a comparison between the experimental and calculated ECD data, as well as the application of Snatzke's method. Compounds (1a/1b-3a/3b) were measured for their production of NO levels in LPS-induced BV-2 microglial cells. The results showed that all compounds exhibited potential inhibitory effects, and compound 1a showed stronger activity than the positive control.
Assuntos
Anti-Inflamatórios , Microglia , Álcool Feniletílico , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Estrutura Molecular , Análise Espectral , Estereoisomerismo , Álcool Feniletílico/análogos & derivadosRESUMO
Two new compounds, including a norsesquiterpenoid, annuionone H (1), and a quassinoid, picraqualide G (2), along with eleven known compounds (3-13), were isolated from the twigs and leaves of Picrasma quassioides. Comprehensive spectroscopic analyses and NMR calculation with DP4+ analysis were used to identify their structures. Moreover, of all these compounds, compound 4 showed a week inhibition rate in the anti-inflammatory screening results against mouse macrophage J774A.1 cell.
Assuntos
Picrasma , Quassinas , Animais , Camundongos , Picrasma/química , Extratos Vegetais/química , Espectroscopia de Ressonância Magnética , Quassinas/química , Folhas de Planta , Estrutura MolecularRESUMO
Highly active and novel antifungal compounds are continuously researched from natural products for pesticide development. Picrasma quassioides (D. Don) Benn, a species of Simaroubaceae, is used in traditional Chinese medicine to treat colds and upper respiratory infections. In this study, the active ingredients of P. quassioides and their antifungal activities against plant pathogenic fungi are investigated to explore the practical application of the plant in the agricultural field. The results showed that the extracts of P. quassioides exhibited highly significant preventive and curative effects on apple valsa canker (AVC) with a reduction of lesion diameter were 80.28% and 83.63%, respectively, and can improve the resistance of apple trees to a pathogen. Five antifungal compounds, namely, canthin-6-one (T1), nigakinone (T2), 4,5-dimethoxycanthin-6-one (T3), 1-methoxycarbonyl-ß-carboline (T4), and 1-methoxycarbonyl-3-methoxyl-ß-carboline (T5), are isolated from P. quassioides using the bioassay-guided method. This is the first report of 1-methoxycarbonyl-3-methoxyl-ß-carboline as a natural product. Canthin-6-one shows strong in vitro inhibitory activity against 11 species of plant pathogenic fungi, and their EC50 values range from 1.49 to 8.80 mg/L. The control efficacy of canthin-6-one at 2000 mg/L are 87.88% and 94.37% against AVC and 80.10% and 84.73% against apple anthracnose (C. gloeosporioides), respectively. Additionally, V. mali is observed after treatment with cannin-6-one, although microscopic. This is the first study on the control of the secondary metabolites of P. quassioides against plant fungal diseases. The results show that P. quassioides is a potential resource for the development of botanical fungicides.
Assuntos
Alcaloides , Antineoplásicos , Produtos Biológicos , Malus , Picrasma , Antifúngicos/farmacologia , Fungos , CarbolinasRESUMO
Four new alkaloids (1-4) and one known alkaloid were isolated from the stems of Picrasma quassioides. The structures of these isolated compounds were elucidated by spectroscopic analyses, a combination of computer-assisted structure elucidation software (ACD/Structure Elucidator) and gauge-including atomic orbital (GIAO) calculation of 1 D NMR data. All compounds were evaluated for their cytotoxic activities against hepatocellular carcinoma HepG2 and Hep3B cells. However, they did not show obvious inhibitory activities.[Figure: see text].
Assuntos
Alcaloides , Neoplasias Hepáticas , Picrasma , Alcaloides/farmacologia , Computadores , Humanos , Estrutura MolecularRESUMO
Nine new N-methoxy-ß-carboline alkaloids (NMCAs) (1a/1b-3a/3b and 4-6) and two known NMCAs (7 and 8) were isolated from the stems of Picrasma quassioides. Their structures were elucidated by spectroscopic data analyses, quantum chemical calculations, and single-crystal X-ray crystallographic data. An analysis of the 13C NMR chemical shifts of the N-methoxy groups in these NMCAs and 41 gathered known compounds reveals the phenomenon that the chemical shifts of all these N-methoxy groups are greater than δC 62, which can be used to recognize the N-methoxy group rapidly. In addition, the acetylcholinesterase (AChE) and Aß42 aggregation inhibitory activities of 1-8 were evaluated. Compounds 1, 2, 7, and 8 displayed AChE inhibitory activity with IC50 values of 14.9, 13.2, 17.6, and 43.9 µM, respectively. Compound 2 showed inhibition activity against Aß42 aggregation with an IC50 value of 10.1 µM.
Assuntos
Alcaloides/química , Peptídeos beta-Amiloides/efeitos dos fármacos , Fragmentos de Peptídeos/efeitos dos fármacos , Picrasma/química , Acetilcolinesterase , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Alzheimer disease (AD), a prevalent neurodegenerative disorder, is one of the leading causes of dementia. However, there is no effective drug for this disease to date. Picrasma quassioides (D.Don) Benn, a Chinese traditional medicine, was used mainly for the treatment of inflammation, fever, microbial infection and dysentery. In this paper, we reported that the EtOAc extract of Picrasma quassioides stems showed potential neuroprotective activities in l-glutamate-stimulated PC12 and Aß25-35-stimulated SH-SY5Y cell models, as well as improved memory and cognitive abilities in AD mice induced by amyloid-ß peptide. Moreover, it was revealed that the anti-AD mechanism was related to suppressing neuroinflammatory and reducing Aß1-42 deposition using ELISA assay kits. To clarify the active components of the EtOAc extract of Picrasma quassioides stems, a systematic phytochemistry study led to isolate and identify six ß-carboline alkaloids (1-6), seven canthin-6-one alkaloids (7-13), and five quassinoids (14-18). Among them, four ß-carbolines (1-3, and 6) and six canthin-6-ones (7-11, and 13) exhibited potential neuroprotective activities in vitro. Based on these date, the structure-activity relationships of alkaloids were discussed. Furthermore, molecular docking experiments showed that compounds 2 and 3 have high affinity for both of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYPKIA) and butyrylcholinesterase (BuChE).
Assuntos
Doença de Alzheimer/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Picrasma/química , Extratos Vegetais/farmacologia , Doença de Alzheimer/patologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Células PC12 , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Ratos , Relação Estrutura-AtividadeRESUMO
Seven new tirucallane-type triterpenoids (1-7), kumuquassin A-G, along with 20 known analogues (8-27) were isolated from the stems of Picrasma quassioides. The structures and the absolute configurations of new compounds were elucidated by spectroscopic data, electronic circular dichroism (ECD) spectroscopic analyses and quantum ECD calculations. Notably, kumuquassin A (1) contains a rare Δ17, 20 double bond, kumuquassin B (2) is the first example of tirucallane triterpenoid possessing a 5/3 biheterocyclic ring system at the side chain. All the compounds were screened for the cytotoxicity against two human hepatoma cell lines, HepG2 and Hep3B, and several compounds exhibited promising activity. The most potential compound 3 was selected for cell cycle analysis, which showed that 3 could cause an accumulation of HepG2 cells at subG1 peak. Annexin V-FITC/PI staining further confirmed that compound 3 caused death of hepatoma cells through apoptosis induction.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Picrasma/química , Triterpenos/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Conformação Molecular , Picrasma/metabolismo , Caules de Planta/química , Caules de Planta/metabolismo , Triterpenos/isolamento & purificação , Triterpenos/farmacologiaRESUMO
Three pairs of enantiomeric neolignans 1a/1b-3a/3b were isolated from the stems of Picrasma quassioides, and separated successfully by chiral-phase HPLC. Their structures were established by comprehensive spectroscopic analyses as well as ECD spectroscopy. The in vitro cytotoxicity of the isolates was evaluated against human hepatocellular carcinoma HepG2 and Hep3B cells. Among them, 1 and its enantiomers 1a/1b, 3 and 3a/3b displayed similar cytotoxicity in pair-wise comparison against HepG2 and Hep3B cells, and the similar effects of 2 and 2a/2b were found in Hep3B cells. Interestingly, 2a and 2b had different cytotoxic activities on HepG2 cells with IC50 values of 35.6⯵M and 104.4⯵M, respectively. In addition, 2 exerted middle cytotoxicity against HepG2 cells with an IC50 value of 78.6⯵M. The different cytotoxicity between enantiomers 2a and 2b attracted our interest. To investigate the underlying mechanisms responsible for the distinct cytotoxicity, we further assessed the effects of 2a and 2b on cell cycle distribution, cell apoptosis and reactive oxygen species (ROS) generation. The results indicated that 2a had more significant effect than 2b on apoptosis induction and ROS generation, but both had no obvious effect on cell cycle of HepG2 cells. It is concluded that the different configurations of 2a/2b determined the enantioselective cytotoxicity on HepG2 cells through apoptosis induction and ROS generation.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Lignanas/farmacologia , Fenóis/farmacologia , Picrasma/química , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Humanos , Lignanas/química , Lignanas/isolamento & purificação , Fenóis/química , Fenóis/isolamento & purificação , Caules de Planta/química , EstereoisomerismoRESUMO
BACKGROUND/AIMS: Osteoporosis is a metabolic bone disorder that tortures about millions of people worldwide. Recent study demonstrated agents derived from picrasma quassioides is a promising drug for targets multiple signaling pathways. However its potential in treatment of bone loss has not been fully understood. METHODS: The bone marrow macrophages (BMMs) were cultured and induced with M-CSF and RANKL followed by picrasidine I (PI) treatment. Then the effects of PI on osteoclast formation were evaluated by counting tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells. Moreover, effects of PI on bone resorption activity of mature osteoclast were studied through bone resorption pit counting and actin ring structure analysis. Further, the involved potential signaling pathways cross-talking were investigated by performed Western blotting and quantitative real-time PCR examination. RESULTS: Results demonstrated PI strongly inhibited RANKL induced osteoclast formation from its precursors. Mechanistically, the inhibitory effect of PI on osteoclast differentiation was due to the suppression of osteoclastogenic transcription factors, c-Fos and NFATc1. Moreover, PI markedly blocked the RANKL-induced osteoclastogenesis by attenuating MAPKs and NF-κB signaling pathways. In addition, PI decreased the ROS generation in osteoclast and osteoblast. CONCLUSION: Taken together our data demonstrate that PI has antiosteoclastogenic effect by inhibiting inflammation induced activation of MAPKs, NF-κB and ROS generation followed by suppressing the gene expression of c-Fos and NFATc1 in osteoclast precursors.
Assuntos
Carbolinas/farmacologia , Osteoclastos/efeitos dos fármacos , Ligante RANK/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Carbolinas/química , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Fatores de Transcrição NFATC/genética , Osteoclastos/citologia , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Picrasma/química , Proteínas Proto-Oncogênicas c-fos/genéticaRESUMO
A method of total ion chromatogram combined with chemometrics and mass defect filter was established for the prediction of active ingredients in Picrasma quassioides samples. The total ion chromatogram data of 28 batches were pretreated with wavelet transformation and correlation optimized warping to correct baseline drifts and retention time shifts. Then partial least squares regression was applied to construct a regression model to bridge the total ion chromatogram fingerprints and the antitumor activity of P. quassioides. Finally, the regression coefficients were used to predict the active peaks in total ion chromatogram fingerprints. In this strategy, mass defect filter was employed to classify and characterize the active peaks from a chemical point of view. A total of 17 constituents were predicted as the potential active compounds, 16 of which were identified as alkaloids by this developed approach. The results showed that the established method was not only simple and easy to operate, but also suitable to predict ultraviolet undetectable compounds and provide chemical information for the prediction of active compounds in herbs.
Assuntos
Antineoplásicos Fitogênicos/análise , Medicamentos de Ervas Chinesas/análise , Picrasma/química , Extratos Vegetais/análise , Estruturas Vegetais/química , Algoritmos , Antineoplásicos Fitogênicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Espectrometria de Massas , Estrutura Molecular , Extratos Vegetais/farmacologia , Análise de Componente Principal , Células Tumorais CultivadasRESUMO
In the present study, we examined the effects of methanol extracts of Picrasma quassioides (MEPQ) on apoptosis in human cervical cancer cells. The results showed that MEPQ decreased the viability and induced caspase-dependent apoptosis in HEp-2 cells. MEPQ decreased specificity protein 1 (Sp1) in HEp-2 cells, whereas Sp1 mRNA was not changed. We found that MEPQ reduced Sp1 protein through proteasome-dependent protein degradation, but not the inhibition of protein synthesis. Also, MEPQ increased the expressions of Bad and truncated Bid (t-Bid) but did not alter other Bcl-2 family members. The knock-down of Sp1 by both Sp1 interfering RNA and Mithramycin A, Sp1 specific inhibitor clearly increased Bad and t-Bid expression to decrease cell viability and induce apoptosis. In addition, MEPQ inhibited cell viability and induced apoptotic cell death through the modulation of Sp1 in KB cells. These results suggest that MEPQ may be a potential anticancer agent for human cervical cancer.
Assuntos
Apoptose/efeitos dos fármacos , Picrasma , Extratos Vegetais/farmacologia , Fator de Transcrição Sp1/metabolismo , Neoplasias do Colo do Útero/metabolismo , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Metanol , Plicamicina/análogos & derivados , Plicamicina/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , RNA Interferente Pequeno/genética , Solventes , Fator de Transcrição Sp1/genética , Neoplasias do Colo do Útero/patologia , Proteína de Morte Celular Associada a bcl/metabolismoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Picrasma quassioides (D. Don) Benn is a vascular plant belonging to the genus Picrasma of Simaroubaceae family and grows in Korea, China, India, Taiwan, and Japan. Picrasma quassioides extract has been reported to have anti-inflammatory, anti-bacterial, and anti-cancer properties. Moreover, this plant has been also traditionally used to alleviate symptoms of eczema, atopic dermatitis, psoriasis, scabies, and boils in skin. AIM OF THE STUDY: The Pq-EE has been reported in Chinese pharmacopoeia for its pharmacological effects on skin. However, the detailed mechanism on alleviating skin conditions is not understood. Hence, we investigated the skin improvement potential of Pq-EE against skin damage. MATERIALS AND METHODS: We used the human keratinocyte cell line (HaCaT) and mouse melanoma cell line (B16F10) to study the effects of Pq-EE on the epidermis. Additionally, in vitro antioxidant assays were performed using a solution that included either metal ions or free radicals. RESULTS: In colorimetric antioxidant assays, Pq-EE inhibited free radicals in a dose-dependent manner. The Pq-EE did not affect cell viability and promoted cell survival under UVB exposure conditions in the MTT assay. The Pq-EE downregulated the mRNA levels of apoptotic factors. Moreover, MMP1 and inflammatory cytokine iNOS mRNA levels decreased with Pq-EE treatment. With regard to protein levels, caspases and cleaved caspases were more powerfully inhibited by Pq-EE than UVB-irritated conditions. p53 and Bax also decreased with Pq-EE treatment. The melanin contents and secretion were decreased at nontoxic concentrations of Pq-EE. The pigmentation pathway genes also were inhibited by treatment with Pq-EE. CONCLUSIONS: In summary, we suggest the cell protective potential of Pq-EE against UVB and ROS, indicating its use in UV-protective cosmeceutical materials.
Assuntos
Anti-Inflamatórios , Antioxidantes , Apoptose , Melaninas , Picrasma , Extratos Vegetais , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/isolamento & purificação , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Apoptose/efeitos dos fármacos , Humanos , Camundongos , Picrasma/química , Antioxidantes/farmacologia , Melaninas/metabolismo , Etanol/química , Células HaCaT , Queratinócitos/efeitos dos fármacos , Queratinócitos/efeitos da radiação , Linhagem Celular Tumoral , Melanoma Experimental/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo II/genéticaRESUMO
In this study, eight new natural products were isolated from the leaves of Picrasma quassioides. Spectroscopic techniques were used for the elucidation of their planar structures. Their absolute configurations were elucidated on the basis of electron circular dichroism (ECD) techniques combined with the P/M helicity rule for the 2,3-dihydrobenzofuran chromophore, and saccharide hydrolysis. Cholinesterase inhibitors are often used as Alzheimer's disease inhibitors.Thus, acetylcholinesterase and butyrylcholinesterase inhibitory activity of these eight compounds were tested, and results showed that only compound 6 showed weakly acetylcholinesterase inhibitory activity. In particular, molecular docking was used to illustrate the bindings between compound 6 and the active sites of AChE.
Assuntos
Lignanas , Picrasma , Lignanas/farmacologia , Estrutura Molecular , Acetilcolinesterase , Picrasma/química , Butirilcolinesterase , Glicosídeos/farmacologia , Simulação de Acoplamento Molecular , Inibidores da Colinesterase/farmacologia , Dicroísmo CircularRESUMO
BACKGROUND: In Chinese Pharmacopeia, Picrasma quassioides (PQ) stems and leaves are recorded as Kumu with antimicrobial, anti-cancer, anti-parasitic effects, etc. However, thick stems are predominantly utilized as medicine in many Asian countries, with leaves rarely used. By now, the phytochemistry and bioactivity of PQ leaves are not well investigated. METHODS: An Orbitrap Elite mass spectrometer was employed to comprehensively investigate PQ stems and leaves sourced from 7 different locations. Additionally, their bioactivities were evaluated against 5 fungi, 6 Gram-positive bacteria and 9 Gram-negative bacteria, a tumor cell line (A549), a non-tumor cell line (WI-26 VA4) and N2 wild-type Caenorhabditis elegans. RESULTS: Bioassay results demonstrated the efficacy of both leaves and stems against tumor cells, several bacteria and fungi, while only leaves exhibited anthelmintic activity against C. elegans. A total of 181 compounds were identified from PQ stems and leaves, including 43 ß-carbolines, 20 bis ß-carbolines, 8 canthinone alkaloids, 56 quassinoids, 12 triterpenoids, 13 terpenoid derivatives, 11 flavonoids, 7 coumarins, and 11 phenolic derivatives, from which 10 compounds were identified as indicator components for quality evaluation. Most alkaloids and triterpenoids were concentrated in PQ stems, while leaves exhibited higher levels of quassinoids and other carbohydrate (CHO) components. CONCLUSION: PQ leaves exhibit distinct chemical profiles and bioactivity with the stems, suggesting their suitability for medicinal purposes. So far, the antibacterial, antifungal, and anthelmintic activities of PQ leaves were first reported here, and considering PQ sustainability, the abundant leaves are recommended for increased utilization, particularly for their rich content of PQ quassinoids.
Assuntos
Caenorhabditis elegans , Compostos Fitoquímicos , Picrasma , Folhas de Planta , Caules de Planta , Folhas de Planta/química , Picrasma/química , Animais , Caules de Planta/química , Caenorhabditis elegans/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Humanos , Linhagem Celular Tumoral , Estrutura Molecular , Antineoplásicos Fitogênicos/farmacologia , Alcaloides/farmacologia , Quassinas/farmacologia , Quassinas/química , Quassinas/isolamento & purificação , Anti-Helmínticos/farmacologia , Anti-Helmínticos/química , Fungos/efeitos dos fármacos , Flavonoides/farmacologia , Flavonoides/análiseRESUMO
Chromobacterium violaceum an opportunistic human pathogenic bacterium, exhibits resistance to conventional antibiotics by exploiting its quorum sensing mechanism to regulate virulence factor expression. In light of this, disrupting the quorum sensing mechanism presents a promising avenue for treating infections caused by this pathogen. The study focused on using the cytoplasmic quorum sensing receptor CviR from C. violaceum as a model target to identify novel quorum sensing inhibitors from P. quassioides through in silico computational approaches. Molecular docking analyses unveiled that several phytochemicals derived from Picrasma quassioides exhibit the potential to inhibit quorum sensing by binding to CviR protein. Notably, the compounds such as Quassidine I (- 8.8 kcal/mol), Quassidine J (- 8.8 kcal/mol), Kumudine B (- 9.1 kcal/mol) and Picrasamide A (- 8.9 kcal/mol) exhibited high docking scores, indicating strong binding affinity to the CviR protein. The native ligand C6-HSL (N-hexanoyl-L-homoserine lactone) as a positive control/co-crystal inhibitor also demonstrated a significant binding energy of-7.7 kcal/mol. The molecular dynamics simulation for 200 ns showed the thermodynamic stability and binding affinity refinement of the top-ranked CviR inhibitor (Kumudine B) with its stable binding and minor fluctuations compared to positive control (C6-HSL). Pharmacokinetic predictions indicated that Kumudine B possesses favourable drug-like properties, which suggest its potential as a drug candidate. The study highlight Kumudine B as a potential agent for inhibiting the CviR protein in C. violaceum. The comprehensive evaluation of Kumudine B provides valuable insights into its pharmacological profiles, facilitating its assessment for diverse therapeutic applications and guiding future research activities, particularly as antibacterial agents for clinical drug development.
RESUMO
Two new ß-carboline alkaloids (1-2), 1-pyrrolidone propionyl-ß-carboline (1) and 1-(3-hydroxy-2-oxopiperidine-1-ethyl)-4,8-dimethoxyl-ß-carboline (2), named kumujantine W and J respectively, together with ten known compounds (3-12) were isolated from the stems of Picrasma quassioides (D. Don) Benn. Their structures were elucidated from spectral data including 1D and 2D NMR, UV, IR, HR-ESI-MS spectroscopic analysis and ECD calculations as well as by comparison to the reference databases or literature. The anti-inflammatory effects of these alkaloids (1-12) and six other ß-carboline alkaloids (13-18) in LPS-induced RAW 264.7 cells were evaluated by measuring nitric oxide (NO) concentrations. Among them, compounds 1, 3, 6, 15, and 17 could inhibit the secretion of NO, displaying significant anti-inflammatory activity without affecting cell viability in vitro, and 3D-QSAR analysis further revealed the influence of groups on the activity in ß-carboline alkaloids.
Assuntos
Alcaloides , Picrasma , Animais , Camundongos , Picrasma/química , Lipopolissacarídeos , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Células RAW 264.7 , Alcaloides/farmacologia , Alcaloides/química , Carbolinas/farmacologia , Carbolinas/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/químicaRESUMO
New drug delivery systems have rarely been used in the formulation of traditional Chinese medicine, especially those that are crude active Chinese medicinal ingredients. In the present study, hyaluronic acid decorated lipid-polymer hybrid nanoparticles were used to prepare a targeted drug delivery system (TDDS) for total alkaloid extract from Picrasma quassioides (TAPQ) to improve its targeting property and anti-inflammatory activity. Picrasma quassioides, a common-used traditional Chinese medicine (TCM), containing a series of hydrophobic total alkaloids including ß-carboline and canthin-6-one alkaloids show great anti-inflammatory activity. However, its high toxicity (IC50= 8.088±0.903 µg/ml), poor water solubility (need to dissolve with 0.8% Tween-80) and poor targeting property severely limits its clinical application. Herein, hyaluronic acid (HA) decorated lipid-polymer hybrid nanoparticles loaded with TAPQ (TAPQ-NPs) were designed to overcome above mentioned deficiencies. TAPQ-NPs have good water solubility, strong anti-inflammatory activity and great joint targeting property. The in vitro anti-inflammatory activity assay showed that the efficacy of TAPQ-NPs was significantly higher than TAPQ(P<0.001). Animal experiments showed that the nanoparticles had good joint targeting property and had strong inhibitory activity against collagen-induced arthritis (CIA). These results indicate that the application of this novel targeted drug delivery system in the formulation of traditional Chinese medicine is feasible.
Assuntos
Alcaloides , Antineoplásicos , Artrite Experimental , Picrasma , Ratos , Animais , Picrasma/química , Estrutura Molecular , Artrite Experimental/tratamento farmacológico , Ácido Hialurônico , Alcaloides/química , Alcaloides/farmacologia , Sistemas de Liberação de Medicamentos , Anti-Inflamatórios/química , Lipídeos , ÁguaRESUMO
BACKGROUND: P38α, emerging as a hot spot for drug discovery, is a member of the mitogen- activated protein kinase (MAPK) family and plays a crucial role in regulating the production of inflammatory mediators. However, despite a massive number of highly potent molecules being reported and several under clinical trials, no p38α inhibitor has been approved yet. There is still demand to discover novel p38α to deal with the safety issue induced by off-target effects. OBJECTIVE: In this study, we performed a machine learning-based virtual screening to identify p38α inhibitors from a natural products library, expecting to find novel drug lead scaffolds. METHODS: Firstly, the training dataset was processed with similarity screening to fit the chemical space of the natural products library. Then, six classifiers were constructed by combing two sets of molecular features with three different machine learning algorithms. After model evaluation, the three best classifiers were used for virtual screening. RESULTS: Among the 15 compounds selected for experimental validation, picrasidine S was identified as a p38α inhibitor with the IC50 as 34.14 µM. Molecular docking was performed to predict the interaction mode of picrasidine S and p38α, indicating a specific hydrogen bond with Met109. CONCLUSION: This work provides a protocol and example for machine learning-assisted discovery of p38α inhibitor from natural products, as well as a novel lead scaffold represented by picrasidine S for further optimization and investigation.
Assuntos
Proteína Quinase 14 Ativada por Mitógeno , Simulação de Acoplamento Molecular , Proteína Quinase 14 Ativada por Mitógeno/química , Descoberta de Drogas , Aprendizado de Máquina , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/químicaRESUMO
Picrasma quassioides, a member of the Simaroubaceae family, is the subject of research in numerous pharmacological and chemical studies. This plant mainly contains alkaloids, quassinoids and terpenoids. These molecules exhibit various pharmacological benefits, such as anti-inflammatory, anticancer, and anti-viral effects, on the cardiovascular system. Alkaloids make up the majority of these molecules. This review describes 127 alkaloid substances from P. quassioides. These alkaloids can be divided into the following classes: ß-carbolines, canthinones and alkaloid dimers. A compilation of their nuclear magnetic resonance spectroscopy data and possible biosynthetic pathways of these compounds and the pharmacological effects of P. quassioides are also included.
Assuntos
Alcaloides , Picrasma , Alcaloides/farmacologia , Vias Biossintéticas , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
Picrasma quassioides is a member of the Simaroubaceae family and is widely used as a medicinal plant. In this study, we sequenced and assembled the complete chloroplast genome of P. quassioides. The chloroplast genome is 160,015 bp in length, with a large single-copy region of 87,136 bp, a small single-copy region of 18,069 bp, and a pair of inverted repeat regions of 27,405 bp. It contains a total of 110 unique genes, including 77 protein-coding genes, 29 tRNA genes, and 4 rRNA genes. Phylogenetic analysis showed that P. quassioides clustered well with Simaroubaceae plants, Eurycoma longifolia, Leitneria floridana, and Ailanthus latissimus.