RESUMO
Two new prenylated flavonoids named sinoflavonoids NJ and NK (1-2), along with ten known compounds were isolated from the fruits of Podophyllum hexandrum Royle. The chemical structures were determined through NMR spectroscopic data and MS analysis. Sinoflavonoid NJ (1) with an unusual 5,11-dioxabenzo[b]fluoren-10-one skeleton was firstly reported from Berberidaceae. The isolated flavonoids were tested with LPS-induced RAW 264.7 mouse macrophages model for their anti-inflammatory activity. Sinoflavonoid NJ (1) showed the most potent inhibition on nitric oxide production with IC50 value as 0.06 µM.
Assuntos
Berberidaceae , Flavonoides , Animais , Camundongos , Flavonoides/química , Frutas/química , Berberidaceae/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/análiseRESUMO
Five new biflavonoids, diphybiflavonoids A - E (1-5), were isolated from the roots and rhizomes of Diphylleia sinensis. Their structures were elucidated by extensive spectroscopic data, including UV, IR, HR-ESI-MS and 2D NMR. Their absolute configurations were determined by ECD spectra. All isolated compounds were evaluated for acetylcholinesterase (AChE) inhibitory activity. Compounds 1-4 exhibited the potent AChE inhibitory activities with IC50 values of 1.62, 2.10, 2.08, and 5.15 µM, respectively. The preliminary structure-activity relationship study indicated that the connection mode (C2-O-C4'''/C3-O-C3''' or C2-O-C3'''/C3-O-C4''') of biflavonoid subunits, and 3-hydroxy group of flavonol subunit were important structural factors for AChE inhibitory activity. Biflavonoids, containing a C2-O-C4'''/C3-O-C3''' or C2-O-C3'''/C3-O-C4''' linkage, can be a potentially useful platform for development of cholinesterase inhibitors.
Assuntos
Berberidaceae , Biflavonoides , Biflavonoides/farmacologia , Estrutura Molecular , Acetilcolinesterase/análise , Acetilcolinesterase/metabolismo , Relação Estrutura-Atividade , Raízes de Plantas/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/químicaRESUMO
One new dibenzyltyrolactone lignan dysoslignan A (1), three new arylnaphthalide lignans dysoslignan B-C (2-4), along with fourteen known metabolites (5-18), were isolated from the roots and rhizomes of Dysosma versipellis. Their structures and stereochemistry were determined from analysis of NMR spectroscopic and circular dichroism (CD) data. Compound 2 represents the first report of naturally occurring arylnaphthalide lignan triglycoside. The cytotoxic activities of all isolated compounds were evaluated against A-549 and SMMC-7721 cell lines. Compounds 7-10 and 14-16 were more toxic than cisplatin in two tumor cell lines. This investigation clarifies the potential effective substance basis of D. versipellis in tumor treatment.
Assuntos
Berberidaceae , Lignanas , Raízes de Plantas , Rizoma , Células A549 , Antineoplásicos/efeitos adversos , Antineoplásicos/toxicidade , Berberidaceae/química , Berberidaceae/metabolismo , Dicroísmo Circular , Cisplatino/efeitos adversos , Cisplatino/toxicidade , Lignanas/química , Lignanas/isolamento & purificação , Lignanas/metabolismo , Lignanas/toxicidade , Espectroscopia de Ressonância Magnética , Neoplasias/tratamento farmacológico , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Rizoma/química , Rizoma/metabolismo , Linhagem Celular TumoralRESUMO
Sinopodophyllum hexandrum (Royle) T. S. Ying, an important source of podophyllotoxin (PTOX), has become a rare and endangered plant because of over-harvesting. Somatic embryogenesis (SE) is the main way of seedling rapid propagation and germplasm enhancement, but the regeneration of S. hexandrum has not been well established, and the PTOX biosynthesis abilities at different SE stages remain unclear. Therefore, it is extremely important to elucidate the SE mechanism of S. hexandrum and clarify the biosynthesis variation of PTOX. In this study, the transcriptomes of S. hexandrum at different SE stages were sequenced, the contents of PTOX and 4'-demethylepipodophyllotoxin were assayed, and the transcript expression patterns were validated by qRT-PCR. The results revealed that plant hormone (such as auxins, abscisic acid, zeatin, and gibberellins) related pathways were significantly enriched among different SE stages, indicating these plant hormones play important roles in SE of S. hexandrum; the expression levels of a series of PTOX biosynthesis related genes as well as PTOX and 4'-demethylepipodophyllotoxin contents were much higher in embryogenic callus stage than in the other stages, suggesting embryogenic callus stage has the best PTOX biosynthesis ability among different SE stages. This study will contribute to germplasm conservation and fast propagation of S. hexandrum, and facilitate the production of PTOX.
Assuntos
Berberidaceae , Podofilotoxina , Perfilação da Expressão Gênica , Berberidaceae/genética , Transcriptoma/genética , Reguladores de Crescimento de Plantas , Técnicas de Embriogênese Somática de PlantasRESUMO
Six new flavonols, including four glucosylated flavonols (dysosmaflavonoid A-D), one phenylpropanoid-substituted flavonol (dysosmaflavonoid E), and one phenyl-substituted flavonol (dysosmaflavonoid F), together with five known analogues, were isolated from the roots and rhizomes of Dysosma versipellis. Their structures were elucidated by comprehensive analysis of their NMR, IR, UV, HRESIMS, and HPLC data. The antioxidant activities of all isolated compounds were examined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. Compounds 2, 3, 5-8, and 12 exhibited significant DPPH scavenging capacity with IC50 values of 33.95, 39.02, 31.17, 32.79, 31.85, 30.48, and 23.75 µM, respectively, in comparison with Trolox (IC50, 15.80 µM). Compound 12 displayed more potent DPPH radical scavenging activity than prenylated and (or) glucosided derivatives (2-4, or 10). The preliminary structure-activity relationship showed that the catechol structure in flavonol is essential for DPPH radical scavenging effect.
Assuntos
Berberidaceae , Flavonóis , Flavonóis/farmacologia , Flavonóis/química , Estrutura Molecular , Antioxidantes/farmacologia , Antioxidantes/química , Berberidaceae/química , Relação Estrutura-Atividade , Sequestradores de Radicais Livres/química , Compostos de Bifenilo , Picratos/químicaRESUMO
BACKGROUND: Elucidating the phylogenetic relationships within species-rich genera is essential but challenging, especially when lineages are assumed to have been going through radiation events. Mahonia Nutt. (Berberidaceae) is a genus with cosmopolitan distribution, comprising approximately 100 species, two of which are known as Caulis Mahoniae (M. bealei and M. fortunei) with crucial pharmacological significance in Chinese herbal medicine. Mahonia is a taxonomically challenging genus, and intrageneric phylogenetic relationships still need to be explored using genome data. Universal DNA barcodes and floral morphological attributes have limited discriminatory power in Mahonia. RESULTS: We sequenced 17 representative plastomes and integrated three published plastome data together to conduct comparative and phylogenetic analyses. We found that Mahonia and Berberis share a large IR expansion (~ 12 kb), which is recognized as a typical character of Berberideae. Repeated sequences are revealed in the species of Mahonia, which are valuable for further population genetic studies. Using a comparative plastome analysis, we determined eight hypervariable regions whose discriminative power is comparable to that of the whole plastid genomes. The incongruence of the ITS and the plastome tree topologies may be ascribed to ancestral hybridization events and/or to incomplete lineage sorting. In addition, we suggest that leaf epidermal characters could help to distinguish closely related species in Mahonia. CONCLUSIONS: We propose an integrative approach combining special barcodes and micromorphological traits to circumscribe Mahonia species. The results cast a new light on the development of an integrative method for accurate species circumscription and provide abundant genetic resources for further research on Mahonia.
Assuntos
Berberidaceae , Genomas de Plastídeos , Mahonia , Filogenia , Hibridização GenéticaRESUMO
INTRODUCTION: Epimedium L., the largest herbaceous genus of Berberidaceae, is one of the most taxonomically difficult representatives. The classification and phylogenetic relationships within Epimedium are controversial and unresolved. OBJECTIVES: For the first time, we systematically studied the phylogeny and evolution of Epimedium based on plastid genome (plastome) data for better understanding this enigmatic genus. METHODS: We explored the molecular phylogeny, assessed the infrageneric classification, estimated the divergence times, and inferred the ancestral states for flower traits of Epimedium based on 45 plastomes from 32 species. RESULTS: The Epimedium plastome length ranged from 156,635 bp to 159,956 bp. Four types of plastome organization with different inverted repeat boundary changes were identified. Phylogenetic analysis revealed a strong support for the sister relationship of sect. Macroceras and sect. Diphyllon but did not provide a distinct route for petal evolution in sect. Diphyllon. Disharmony between phylogenetic relationships and traditional classification of sect. Diphyllon was observed. Results from divergence time analysis showed that Epimedium diverged in the early Pleistocene (~2.11 Ma, 95% HPD = 1.88-2.35 Ma). Ancestral character state reconstructions indicated transitions from long spur (large-flowered group) to other petal types (small-flowered group) in Epimedium. CONCLUSION: These findings provide new insights into the relationships among Epimedium species and pave the way for better elucidation of the classification and evolution of this genus.
Assuntos
Berberidaceae , Epimedium , Genomas de Plastídeos , Berberidaceae/genética , Epimedium/genética , Flores/genética , Genomas de Plastídeos/genética , FilogeniaRESUMO
Evolutionary and biogeographic processes determine species richness patterns of vascular plants between Eastern Asia (EA) and Eastern North America (ENA). However, the strikingly higher species richness of EA relative to ENA remains poorly understood from this perspective. Here, we studied the relative importance of biogeographical, evolutionary and ecological factors underlying differences in species richness between EA and ENA in Podophylloideae (Berberidaceae, Ranunculales; in total 10 spp. in EA vs. 2 spp. in ENA). Based on large-scale transcriptome data, our phylogenomic analyses strongly supported Podophylloideae and its two multi-species genera, i.e. Dysosma (EA) and Diphylleia (EA/ENA), as monophyletic groups. Sinopodophyllum hexandrum (EA) was identified as sister to the remainder of Podophylloideae. Dysosma (7 spp.) was recovered as sister to Podophyllum peltatum (ENA), forming an EA-ENA disjunct pair with a strong bias of species diversity in the EA counterpart. Our biogeographic analyses support the 'out-of-Tibet' hypothesis, suggesting that Podophylloideae started to diversify in the Himalaya-Hengduan Mountains (Mid-Miocene) and migrated eastward (since the Late Miocene) into Central-eastern China, Japan, and ENA (only P. peltatum and Diphylleia cymosa). Overall, we conclude that the striking species diversity anomaly between EA and ENA in Podophylloideae may be explained by a combination of (1) a longer period of time available to accumulate species in EA; and (2) a greater diversification rate in EA, which might have been promoted by greater physiographic and environmental heterogeneity in this region.
Assuntos
Berberidaceae , Evolução Molecular , Filogenia , Ranunculales , Berberidaceae/genética , Ásia Oriental , América do Norte , Ranunculales/genéticaRESUMO
Human exposure to radiation has expanded considerably in recent years, due to a wide range of medical, agricultural, and industrial applications. Despite its beneficial utilities, radiation is also known to have a deleterious effect on cells and tissues, largely through the creation of free radicals, which cause severe damage to biological systems through processes such as DNA double/single-strand fragmentation, protein modification, and upregulation of lipid peroxidation pathways. In addition, radiation damages genetic material while inducing hereditary genotoxicity. Developing measures to counter radiation-induced damage is thus considered to be of significant importance. Considering the inherent capability of plants to survive radiative conditions, certain plants and natural compounds have been the subject of investigations to explore and harness their natural radioprotective abilities. Podophyllum hexandrum, an Indian medicinal plant with several known traditional phytotherapeutic uses, is considered in particular to be of immense therapeutic importance. Recent studies have been conducted to validate its radioprotective potential alongside discovering its protective mechanisms following γ-radiation-induced mortality and disorder in both mice and human cells. These findings show that Podophyllum and its constituents/natural compounds protect the lungs, gastrointestinal tissues, hemopoietic system, and testis by inducing DNA repair pathways, apoptosis inhibition, free radical scavenging, metal chelation, anti-oxidation and anti-inflammatory mechanisms. In this review, we have provided an updated, comprehensive summary of ionizing radiations and their impacts on biological systems, highlighting the mechanistic and radioprotective role of natural compounds from Podophyllum hexandrum.
Assuntos
Berberidaceae , Extratos Vegetais/farmacologia , Protetores contra Radiação/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quelantes/farmacologia , Reparo do DNA/efeitos dos fármacos , Sequestradores de Radicais Livres/metabolismo , Dose Máxima Tolerável , Medicina Tradicional , Mitocôndrias/efeitos dos fármacos , Protetores contra Radiação/químicaRESUMO
Deoxypodophyllotoxin contains a core of four fused rings (A to D) with three consecutive chiral centers, the last being created by the attachment of a peripheral trimethoxyphenyl ring (E) to ring C. Previous studies have suggested that the iron(II)- and 2-oxoglutarate-dependent (Fe/2OG) oxygenase, deoxypodophyllotoxin synthase (DPS), catalyzes the oxidative coupling of ring B and ring E to form ring C and complete the tetracyclic core. Despite recent efforts to deploy DPS in the preparation of deoxypodophyllotoxin analogs, the mechanism underlying the regio- and stereoselectivity of this cyclization event has not been elucidated. Herein, we report 1) two structures of DPS in complex with 2OG and (±)-yatein, 2) in vitro analysis of enzymatic reactivity with substrate analogs, and 3) model reactions addressing DPS's catalytic mechanism. The results disfavor a prior proposal of on-pathway benzylic hydroxylation. Rather, the DPS-catalyzed cyclization likely proceeds by hydrogen atom abstraction from C7', oxidation of the benzylic radical to a carbocation, Friedel-Crafts-like ring closure, and rearomatization of ring B by C6 deprotonation. This mechanism adds to the known pathways for transformation of the carbon-centered radical in Fe/2OG enzymes and suggests what types of substrate modification are likely tolerable in DPS-catalyzed production of deoxypodophyllotoxin analogs.
Assuntos
Berberidaceae/enzimologia , Medicamentos de Ervas Chinesas/química , Ligases/química , Proteínas de Plantas/química , Podofilotoxina/análogos & derivados , Oxirredução , Podofilotoxina/químicaRESUMO
BACKGROUND: Comprehensive bioinformatics analysis of the effective molecular screening of Podophyllum octagonal in breast cancer treatment by using network pharmacology. METHODS: We collected the active ingredients and target genes of Chinese medicine octagonal lotus through the Traditional Chinese Medicine System Pharmacology Analysis Platform (TCMSP); downloaded human protein annotation information on the protein database Uniport; and collected data from five databases: GeneCards, OMIM, PharmGkb, TDD, and DrugBank. Construct the practical ingredient-target gene data intersection to obtain the target gene-disease gene and draw the Venn diagram. We use Cytoscape 3.8.0 software to construct the effective component-target gene-disease gene network. The STRING database protein interaction (PPI) networks were erected, and we used Cytoscape 3.8.0 software to screen out its core sub-networks and hub gene networks. Through survival analysis, core genes and hub genes were screened to identify several key genes. We performed key target gene ontology (GO) analysis and gene interaction (KEGG) analysis, which were followed by molecular docking of the key active ingredients in the star anise corresponding to several key genes. RESULTS: 19 active ingredients, 444 drug targets, and 10,941 disease-related genes were obtained. The key active ingredient was quercetin. GO analysis revealed 2471 affected biological processes, and 167 pathways were obtained in KEGG enrichment analysis. CONCLUSION: This study initially screened the key active ingredients of star aniseed lotus and analyzed key genes and several essential pathways. Traditional Chinese medicine is expected to provide new evidence and research ideas to prevent and treat breast cancer.
Assuntos
Antineoplásicos Fitogênicos , Berberidaceae , Neoplasias da Mama , Quimiocina CXCL10/genética , Quimiocina CXCL11/genética , Fator de Transcrição E2F1/genética , Proteínas Proto-Oncogênicas c-myc/genética , Quercetina , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Biologia Computacional , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , Farmacologia em Rede , Mapas de Interação de ProteínasRESUMO
Two new pyrrole alkaloids methyl-E-mangolamide (1) and methyl-Z-mangolamide (2), four new megastigmane glycosides nandinamegastigmanes I-IV (3-6), and eight known compounds (7-14) were isolated from the methanol extract of the fruits of Nandina domestica. The structures of the new compounds were elucidated based on chemical and spectroscopic evidence. The absolute stereochemistry of nandinamegastigmane I (3) was established upon comparing the experimental and predicted electronic circular dichroism (ECD) data. Among the isolated compounds, 1 and 2 showed cell death-inducing activity on the Adriamycin-treated HeLa cells. In addition, one of the mechanisms for cell death-inducing activity of 1 and 2 was suggested as inhibition of P-glycoprotein.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Alcaloides/farmacologia , Berberidaceae/química , Morte Celular/efeitos dos fármacos , Alcaloides/isolamento & purificação , Frutas/química , Glicosídeos/isolamento & purificação , Células HeLa , Humanos , Japão , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologiaRESUMO
We report the complete genome sequence of a novel virus isolated from Nandina domestica 'Firepower' in Auckland, New Zealand. It was mechanically transmitted to Nicotiana species, although all of these infections were symptomless. The complete genome of the new virus is 8892 nucleotides (nt) long, excluding the 3' poly(A) tail, contains three open reading frames (ORF), and is most closely related to citrus leaf blotch virus (CLBV) Actinidia isolate (CLBV-Act; 72% nt sequence identity), a member of the genus Citrivirus. Replicase and coat proteins, encoded by genome ORFs 1 and 3 respectively, shared 81-83% and 76-79% amino acid (aa) sequence identity, respectively, with CLBV-Act. Computer-based analysis suggests that this novel virus is the result of recombination between CLBV-Act and an unknown virus, highlighting the importance of this phenomenon for betaflexivirus evolution.
Assuntos
Berberidaceae/virologia , Flexiviridae/genética , Sequência de Aminoácidos , Sequência de Bases , Flexiviridae/classificação , Flexiviridae/fisiologia , Genoma Viral/genética , Especificidade de Hospedeiro , Nova Zelândia , Fases de Leitura Aberta , Filogenia , Doenças das Plantas/virologia , RNA Viral/genética , Recombinação Genética , Proteínas Virais/genéticaRESUMO
Petals are important floral organs that exhibit considerable morphological diversity in terms of colour, shape, and size. The varied morphologies of mature petals can be linked to developmental differences. The petals of Berberidaceae (a core group of Ranunculales) range from flat sheets to complex structures with nectaries, but studies on petal development and structural diversity in this group are lacking. Here, the petal development, structure, and micromorphology of seven Berberidaceae genera are characterized by microscopy to clarify the diversity of petals within this group. The results indicate that no common petal-stamen primordium exists, that petal development proceeds through five stages, and that the differentiation responsible for the diversity of the mature petals occurs during stage 4. Processes contributing to the morphological diversity of mature petals include edge thickening, gland formation, and spur formation. Nandina and Diphylleia lack nectaries. Gymnospermium has saccate nectaries, Caulophyllum has nectaries on the petal margin, Epimedium has spur nectaries, and Berberis and Mahonia have glands at the base of petals. Petal nectaries usually consist of a secretory epidermis, two to twenty layers of secretory parenchyma cells, and vascular tissues. Eleven distinct cell types were observed in the petal epidermis, three of which are secretory; papillose cells appear to be absent in Diphylleia, which shows relatively little micromorphological variation. The ancestors of Berberidaceae may have nectaries in thickened areas of their petals. The micromorphology and nectary structures of the petals in Ranunculales are also compared.
Assuntos
Berberidaceae , FloresRESUMO
Two new flavonoid glucosides, sinoflavonoidgs A (1) and B (2), along with three known analogues 3-5, were isolated from the fruits of Sinopodophyllum hexandrum. Their structures were established on the basis of extensive spectroscopic (UV, IR, HR-ESI-MS, 1H-NMR, 13C-NMR, HSQC, HMBC) and chromatographic (HPLC) analysis. The isolation of compounds 1-2 represents the first report of ring B-glucosided flavonoids from the genus Sinopodophyllum. The cytotoxic activities of all isolated compounds were evaluated in comparison with etoposide against four cell lines (MCF-7, HepG2, HeLa, KB). The antioxidant activities of all isolated compounds were examined by DPPH free radical-scavenging assay. The preliminary structure-activity relationships showed that the glycosilation of 3-methoxyquercetin at C-3' resulted in a greater decrease of cytotoxic and antioxidant activity.
Assuntos
Berberidaceae/química , Flavonoides/isolamento & purificação , Frutas/química , Glucosídeos/isolamento & purificação , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Flavonoides/química , Glucosídeos/química , Humanos , Concentração Inibidora 50 , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
Two new isoquinoline alkaloids, 6 R,6aS-N-nantenine Nß-oxide (1), 6S,6aS-N-nantenine Nα-oxide (2), along with nine known alkaloids, nantenine (3), oxonantenine (4), protopine (5), nornantenine (6), N-methyl-laurotetanine (7), isocorydine (8), O-methyflavinantine (9), N-methyl-2,3,6-trimethoxymorphinan-dien-7-one Nß-oxide (10) and (+)-10-O-methylhernovine Nß-oxide (11) were isolated from the seeds of Nandina domestica. Their structures were elucidated by extensive analyses of spectroscopic data (IR, UV, HRESIMS, 1 D and 2 D NMR), ECD calculation and comparison with the related literatures. In addition, the cytotoxicity against A549 cells of these alkaloids was determined by the MTT assay.
Assuntos
Alcaloides , Berberidaceae , Isoquinolinas/farmacologia , Células A549 , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Berberidaceae/química , Humanos , Isoquinolinas/isolamento & purificação , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Extratos Vegetais , Sementes/químicaRESUMO
Lignans are plant secondary metabolites with a wide range of reported health-promoting bioactivities. Traditional routes toward these natural products involve, among others, the extraction from plant sources and chemical synthesis. However, the availability of the sources and the complex chemical structures of lignans often limit the feasibility of these approaches. In this work, we introduce a newly assembled biosynthetic route in E. coli for the efficient conversion of the common higher-lignan precursor (+)-pinoresinol to the noncommercially available (-)-pluviatolide via three intermediates. (-)-Pluviatolide is considered a crossroad compound in lignan biosynthesis, because the methylenedioxy bridge in its structure, resulting from the oxidation of (-)-matairesinol, channels the biosynthetic pathway toward the microtubule depolymerizer (-)-podophyllotoxin. This oxidation reaction is catalyzed with high regio- and enantioselectivity by a cytochrome P450 monooxygenase from Sinopodophyllum hexandrum (CYP719A23), which was expressed and optimized regarding redox partners in E. coli. Pinoresinol-lariciresinol reductase from Forsythia intermedia (FiPLR), secoisolariciresinol dehydrogenase from Podophyllum pleianthum (PpSDH), and CYP719A23 were coexpressed together with a suitable NADPH-dependent reductase to ensure P450 activity, allowing for four sequential biotransformations without intermediate isolation. By using an E. coli strain coexpressing the enzymes originating from four plants, (+)-pinoresinol was efficiently converted, allowing the isolation of enantiopure (-)-pluviatolide at a concentration of 137 mg/L (ee ≥99% with 76% isolated yield).
Assuntos
4-Butirolactona/análogos & derivados , Escherichia coli/metabolismo , Podofilotoxina/metabolismo , 4-Butirolactona/metabolismo , Berberidaceae/metabolismo , Biotransformação/fisiologia , Sistema Enzimático do Citocromo P-450/metabolismo , Forsythia/metabolismo , Furanos/metabolismo , Lignanas/metabolismo , NADP/metabolismo , Oxirredução , Podophyllum peltatum/metabolismoRESUMO
The first racemic total synthesis of the isoquinoline-benzylisoquinoline alkaloid muraricine is reported herein. Pharmacological characterization identified muraricine as a moderate inhibitor of P-glycoprotein, a crucial factor of multidrug resistance in cancer. When combined with vincristine, muraricine partly reversed the chemoresistance of vincristine-resistant leukemia cells at a nontoxic concentration. Furthermore, no cytotoxic effects on noncancerous human cells in therapeutically relevant concentrations were observed.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Isoquinolinas/farmacologia , Alcaloides/síntese química , Alcaloides/química , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Berberidaceae/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Dysosma Versipellis (DV), a traditional Chinese medicine, has the functions of eliminating phlegm, detoxification, dispersing knots . However, its serious toxicity limits its further use. Therefore, it is necessary to conduct a comprehensive toxicity study of DV, screen the basis of potential toxic substances and understand its toxic mechanism. Based on the concept of toxicological evidence chain (TEC), this study utilizes the technologies and means of chemomics, metabolomics, molecular docking and network toxicology flexibly, step by step to find the evidence of potential toxic components in the development of hepatotoxicity induced by DV, evidence of critical toxicity events, evidence of adverse outcomes, thus, a chain of toxicity evidence with reference and directivity can be organized. It further confirmed the toxic damage and potential molecular mechanism of DV. 5 potential toxic components were identified, namely, Podophyllotoxin-4-O-D-glucoside, Podorhizol, Podophyllotoxin, Podophyllotoxone and 3',4'-O,O-Didemethylpophyllotoxin. These chemical constituents affect phenylalanine metabolism, glycerophospholipid metabolism, energy metabolism and other related pathways by regulating PAH, SOD1, SOD2 and other related targets, then it induces oxidative stress, cell apoptosis, inflammatory reaction and energy consumption, which ultimately induces the occurrence of liver injury. The results of this study provide some reference for the follow-up analysis of toxicity mechanism of DV.
Assuntos
Berberidaceae , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Compostos Fitoquímicos/toxicidade , Animais , Apoptose/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Masculino , Medicina Tradicional Chinesa , Metabolômica , Simulação de Acoplamento Molecular , Estresse Oxidativo/efeitos dos fármacos , Compostos Fitoquímicos/análise , Ratos WistarRESUMO
Dysosma pleiantha (Hance) Woodson is one of the endangered traditional Chinese medicinal herbs, highly valued for its medicinal properties by Taiwan's mountain tribes. The present study aims to develop an efficient protocol for callus biomass by optimizing suitable culture medium, carbon source culture condition, and enhanced production of pharmaceutically important podophyllotoxin, kaempferol, and quercetin from callus culture of D. pleiantha under the influence of different additives. Best callus induction was achieved in Gamborg's medium (B5) with 1 mg/L 2,4-dichlorophenoxyacetic acid (2,4-D) along with 0.2 mg/L kinetin under dark condition. Tender leaves of D. pleiantha showed the maximum of 86% callus induction among the different explants tested. Highest leaf callus proliferation was noted in B5 medium with 1 mg/L 2,4-D incubated under complete darkness. In addition, it was found that B5 medium with 1 mg/L 2,4-D along with 2 g/L peptone produced more leaf callus biomass and enhanced production of podophyllotoxin (16.3-fold), kaempferol (12.39-fold), and quercetin (5.03-fold) compared to control. Therefore, D. pleiantha callogenesis can provide an alternative source for enhanced production of secondary compounds regardless of the exploitation of its natural plant population.