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1.
Nat Prod Res ; 38(11): 1864-1873, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38739563

RESUMO

Phytochemical studies of the stems and leaves of Stephania dielsiana Y.C.Wu yielded two new aporphine alkaloids (1 and 5), along with six known alkaloids (2-4 and 6-8). Their structures were characterised based on analyses of spectroscopic data, including one- and two-dimensional nuclear magnetic resonance (NMR) spectroscopy and high-resolution electrospray ionisation mass spectrometry (HR-ESI-MS). The cytotoxic activities of the isolated compounds against a small panel of tumour cell lines were assessed by MTS assay. Interestingly, compound 2 exhibited particularly strong cytotoxic activities against HepG2, MCF7 and OVCAR8 cancer cell lines, with IC50 values of 3.20 ± 0.18, 3.10 ± 0.06 and 3.40 ± 0.007 µM, respectively. Furthermore, molecular docking simulations were carried out to explore the interactions and binding mechanisms of the most active compound (compound 2) with proteins. Our results contribute to understanding the secondary metabolites produced by S. dielsiana and provide a scientific rationale for further investigations of cytotoxicity of this valuable medicinal plant.


Assuntos
Alcaloides , Antineoplásicos Fitogênicos , Aporfinas , Simulação de Acoplamento Molecular , Folhas de Planta , Caules de Planta , Stephania , Aporfinas/química , Aporfinas/farmacologia , Humanos , Folhas de Planta/química , Caules de Planta/química , Alcaloides/química , Alcaloides/farmacologia , Stephania/química , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Estrutura Molecular , Linhagem Celular Tumoral , Células Hep G2 , Células MCF-7 , Ensaios de Seleção de Medicamentos Antitumorais , Espectroscopia de Ressonância Magnética , Plantas Medicinais/química
2.
BMC Plant Biol ; 24(1): 276, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38605285

RESUMO

BACKGROUND: Stephania kwangsiensis Lo (Menispermaceae) is a well-known Chinese herbal medicine, and its bulbous stems are used medicinally. The storage stem of S. kwangsiensis originated from the hypocotyls. To date, there are no reports on the growth and development of S. kwangsiensis storage stems. RESULTS: The bulbous stem of S. kwangsiensis, the starch diameter was larger at the stable expanding stage (S3T) than at the unexpanded stage (S1T) or the rapidly expanding stage (S2T) at the three different time points. We used ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and Illumina sequencing to identify key genes involved in bulbous stem development. A large number of differentially accumulated metabolites (DAMs) and differentially expressed genes (DEGs) were identified. Based on the differential expression profiles of the metabolites, alkaloids, lipids, and phenolic acids were the top three differentially expressed classes. Compared with S2T, significant changes in plant signal transduction and isoquinoline alkaloid biosynthesis pathways occurred at both the transcriptional and metabolic levels in S1T. In S2T compared with S3T, several metabolites involved in tyrosine metabolism were decreased. Temporal analysis of S1T to S3T indicated the downregulation of phenylpropanoid biosynthesis, including lignin biosynthesis. The annotation of key pathways showed an up-down trend for genes and metabolites involved in isoquinoline alkaloid biosynthesis, whereas phenylpropanoid biosynthesis was not completely consistent. CONCLUSIONS: Downregulation of the phenylpropanoid biosynthesis pathway may be the result of carbon flow into alkaloid synthesis and storage of lipids and starch during the development of S. kwangsiensis bulbous stems. A decrease in the number of metabolites involved in tyrosine metabolism may also lead to a decrease in the upstream substrates of phenylpropane biosynthesis. Downregulation of lignin synthesis during phenylpropanoid biosynthesis may loosen restrictions on bulbous stem expansion. This study provides the first comprehensive analysis of the metabolome and transcriptome profiles of S. kwangsiensis bulbous stems. These data provide guidance for the cultivation, breeding, and harvesting of S. kwangsiensis.


Assuntos
Alcaloides , Plantas Medicinais , Stephania , Stephania/química , Stephania/metabolismo , Plantas Medicinais/metabolismo , Cromatografia Líquida/métodos , Lignina/metabolismo , Espectrometria de Massas em Tandem , Melhoramento Vegetal , Perfilação da Expressão Gênica , Transcriptoma , Alcaloides/metabolismo , Amido/metabolismo , Isoquinolinas/metabolismo , Tirosina/metabolismo , Lipídeos , Regulação da Expressão Gênica de Plantas
3.
Cell Rep ; 43(3): 113832, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38381605

RESUMO

Stephania japonica is an early-diverging eudicotyledon plant with high levels of cepharanthine, proven to be effective in curing coronavirus infections. Here, we report a high-quality S. japonica genome. The genome size is 688.52 Mb, and 97.37% sequences anchor to 11 chromosomes. The genome comprises 67.46% repetitive sequences and 21,036 genes. It is closely related to two Ranunculaceae species, which diverged from their common ancestor 55.90-71.02 million years ago (Mya) with a whole-genome duplication 85.59-96.75 Mya. We further reconstruct ancestral karyotype of Ranunculales. Several cepharanthine biosynthesis genes are identified and verified by western blot. Two genes (Sja03G0243 and Sja03G0241) exhibit catalytic activity as shown by liquid chromatography-mass spectrometry. Then, cepharanthine biosynthesis genes, transcription factors, and CYP450 family genes are used to construct a comprehensive network. Finally, we construct an early-diverging eudicotyledonous genome resources (EEGR) database. As the first genome of the Menispermaceae family to be released, this study provides rich resources for genomic studies.


Assuntos
Benzodioxóis , Benzilisoquinolinas , Stephania , Tamanho do Genoma , Cariótipo , Filogenia
4.
Nat Commun ; 15(1): 1537, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38378731

RESUMO

Cepharanthine is a secondary metabolite isolated from Stephania. It has been reported that it has anti-conronaviruses activities including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Here, we assemble three Stephania genomes (S. japonica, S. yunnanensis, and S. cepharantha), propose the cepharanthine biosynthetic pathway, and assess the antiviral potential of compounds involved in the pathway. Among the three genomes, S. japonica has a near telomere-to-telomere assembly with one remaining gap, and S. cepharantha and S. yunnanensis have chromosome-level assemblies. Following by biosynthetic gene mining and metabolomics analysis, we identify seven cepharanthine analogs that have broad-spectrum anti-coronavirus activities, including SARS-CoV-2, Guangxi pangolin-CoV (GX_P2V), swine acute diarrhoea syndrome coronavirus (SADS-CoV), and porcine epidemic diarrhea virus (PEDV). We also show that two other genera, Nelumbo and Thalictrum, can produce cepharanthine analogs, and thus have the potential for antiviral compound discovery. Results generated from this study could accelerate broad-spectrum anti-coronavirus drug discovery.


Assuntos
Alphacoronavirus , Benzodioxóis , Benzilisoquinolinas , Stephania , Animais , Suínos , China/epidemiologia , SARS-CoV-2 , Antivirais/farmacologia
5.
J Ethnopharmacol ; 323: 117667, 2024 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-38159821

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The Stephania cephalantha Hayata is an important traditional medicinal plant widely used in traditional medicine to treat cancer. Cepharanthine (CEP) was extracted from the roots of Stephania cephalantha Hayata. It has been found to exhibit anticancer activity in different types of cancer cells. Nevertheless, the activity of CEP against nasopharyngeal carcinoma (NPC) and its underlying mechanism warrant further investigation. AIMS OF THE STUDY: NPC is an invasive and highly metastatic malignancy that affects the head and neck region. This research aimed to investigate the pharmacological properties and underlying mechanism of CEP against NPC, aiming to offer novel perspectives on treating NPC using CEP. MATERIALS AND METHODS: In vitro, the pharmacological activity of CEP against NPC was evaluated using the CCK-8 assay. To predict and elucidate the anticancer mechanism of CEP against NPC, we employed network pharmacology, conducted molecular docking analysis, and performed Western blot experiments. In vivo validation was performed through a nude mice xenograft model of human NPC, Western blot and immunohistochemical (IHC) assays to confirm pharmacological activity and the mechanism. RESULTS: In a dose-dependent manner, the proliferation and clonogenic capacity of NPC cells were significantly inhibited by CEP. Additionally, NPC cell migration was suppressed by CEP. The results obtained from network pharmacology experiments revealed that anti-NPC effect of CEP was associated with 8 core targets, including EGFR, AKT1, PIK3CA, and mTOR. By performing molecular docking, the binding capacity of CEP to the candidate core proteins (EGFR, AKT1, PIK3CA, and mTOR) was predicted, resulting in docking energies of -10.0 kcal/mol for EGFR, -12.4 kcal/mol for PIK3CA, -10.8 kcal/mol for AKT1, and -8.6 kcal/mol for mTOR. The Western blot analysis showed that CEP effectively suppressed the expression of EGFR and the phosphorylation levels of downstream signaling proteins, including PI3K, AKT, mTOR, and ERK. After CEP intervention, a noteworthy decrease in tumor size, without inducing any toxicity, was observed in NPC xenograft nude mice undergoing in vivo treatment. Additionally, IHC analysis demonstrated a significant reduction in the expression levels of EGFR and Ki-67 following CEP treatment. CONCLUSION: CEP exhibits significant pharmacological effects on NPC, and its mechanistic action involves restraining the activation of the EGFR/PI3K/AKT pathway. CEP represents a promising pharmaceutical agent for addressing and mitigating NPC.


Assuntos
Benzodioxóis , Benzilisoquinolinas , Neoplasias Nasofaríngeas , Proteínas Proto-Oncogênicas c-akt , Stephania , Animais , Camundongos , Humanos , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/metabolismo , Simulação de Acoplamento Molecular , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Farmacologia em Rede , Linhagem Celular Tumoral , Serina-Treonina Quinases TOR/metabolismo , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/uso terapêutico , Receptores ErbB
6.
Bioorg Chem ; 139: 106717, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37454495

RESUMO

1H NMR-guided fractionation led to the isolation of 16 alkaloids from the alkaloidal extract of Stephania longa, including 11 new hasubanan alkaloids (1-11) and five known alkaloids (12-16). Interestingly, compounds 2 and 11 are typically considered protonated tertiary amine compounds, whereas compounds 1 and 10 are regarded as oxidized versions of the corresponding compounds. Their gross structures were determined through an extensive analysis of spectroscopic data (NMR (nuclear magnetic resonance) and HRESIMS (high resolution electrospray ionization mass spectroscopy)), and their absolute configurations were established by comparing their experimental and calculated electronic circular dichroism (ECD) spectra. The new (3) and a known (12) compounds in all isolates displayed stronger antineuroinflammatory effects (IC50 values of 1.8 and 11.1 µM, respectively) than minocycline (IC50 value of 15.5 µM) against NO production on LPS-activated BV2 cells.


Assuntos
Alcaloides , Antineoplásicos , Stephania , Stephania/química , Espectroscopia de Prótons por Ressonância Magnética , Alcaloides/farmacologia , Alcaloides/química , Espectroscopia de Ressonância Magnética , Extratos Vegetais , Estrutura Molecular
7.
Inflammopharmacology ; 31(4): 2023-2035, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37129718

RESUMO

Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) have high mortality rates. Though corticosteroids are commonly used for the treatment of these conditions, their efficacy has not been conclusively demonstrated and their use can induce various adverse reactions. Hence, the application of corticosteroids as therapeutic modalities for ALI/ARDS is limited. Meanwhile, the aporphine alkaloid oxocrebanine isolated from Stephania pierrei tubers has demonstrated anti-inflammatory efficacy in murine/human macrophage cell lines stimulated by lipopolysaccharide (LPS). Accordingly, the primary objectives of the present study are to investigate the anti-inflammatory effects of oxocrebanine on LPS-induced murine alveolar epithelial (MLE-12) cells and its efficacy against LPS-induced murine ALI. Results show that oxocrebanine downregulates the abundance of interleukin (IL)-1beta, IL-6, and inducible nitric oxide synthase, as well as the phosphorylation of nuclear factor-kappaB (NF-κB), stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), p38, protein kinase B (Akt), and glycogen synthase kinase-3beta signalling proteins in LPS-induced MLE-12 cells. Moreover, in a murine ALI model, oxocrebanine lowers lung injury scores and lung wet/dry weight ratios while reducing inflammatory cell infiltration. It also suppresses LPS-induced tumour necrosis factor-alpha and IL-6 in the bronchoalveolar lavage fluid and plasma. Moreover, oxocrebanine downregulates NF-κB, SAPK/JNK, p38, and Akt phosphorylation in the lung tissues of LPS-treated mice. Taken together, the foregoing results show that oxocrebanine provides significant protection against LPS-induced ALI in mice primarily by suppressing various inflammatory signalling pathways in alveolar epithelial cells and lung tissues. Hence, oxocrebanine might prove effective as an anti-inflammatory agent for the treatment of lung inflammation.


Assuntos
Lesão Pulmonar Aguda , Aporfinas , Síndrome do Desconforto Respiratório , Stephania , Humanos , Camundongos , Animais , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Lipopolissacarídeos , Interleucina-6 , Stephania/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Pulmão/metabolismo , Aporfinas/efeitos adversos , Anti-Inflamatórios/uso terapêutico , Síndrome do Desconforto Respiratório/tratamento farmacológico
8.
J Nat Prod ; 86(4): 1061-1073, 2023 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-37043739

RESUMO

Botanical natural products have been widely consumed for their purported usefulness against COVID-19. Here, six botanical species from multiple sources and 173 isolated natural product compounds were screened for blockade of wild-type (WT) SARS-CoV-2 infection in human 293T epithelial cells overexpressing ACE-2 and TMPRSS2 protease (293TAT). Antiviral activity was demonstrated by an extract from Stephania tetrandra. Extract fractionation, liquid chromatography-mass spectrometry (LC-MS), antiviral assays, and computational analyses revealed that the alkaloid fraction and purified alkaloids tetrandrine, fangchinoline, and cepharanthine inhibited WT SARS-CoV-2 infection. The alkaloids and alkaloid fraction also inhibited the delta variant of concern but not WT SARS-CoV-2 in VeroAT cells. Membrane permeability assays demonstrate that the alkaloids are biologically available, although fangchinoline showed lower permeability than tetrandrine. At high concentrations, the extract, alkaloid fractions, and pure alkaloids induced phospholipidosis in 293TAT cells and less so in VeroAT cells. Gene expression profiling during virus infection suggested that alkaloid fraction and tetrandrine displayed similar effects on cellular gene expression and pathways, while fangchinoline showed distinct effects on cells. Our study demonstrates a multifaceted approach to systematically investigate the diverse activities conferred by complex botanical mixtures, their cell-context specificity, and their pleiotropic effects on biological systems.


Assuntos
Alcaloides , Antineoplásicos , Benzilisoquinolinas , COVID-19 , Stephania tetrandra , Stephania , Humanos , Stephania tetrandra/química , SARS-CoV-2 , Benzilisoquinolinas/farmacologia , Benzilisoquinolinas/química , Alcaloides/farmacologia , Alcaloides/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Antivirais/farmacologia , Stephania/química
9.
Nat Prod Res ; 37(2): 204-215, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34348525

RESUMO

Four undescribed bisbenzylisoquinoline alkaloids, designated as Stephtetrandrine A-D, were isolated from the roots of Stephania tetrandra. Their structures were elucidated by IR, HRESIMS, ECD spectra, 1 D and 2 D NMR spectra and comparison with the literature data. Additional five known compounds (limacine, tetrandrine, N-trans-Feruloyltyramine, 2'-N-chloromethyltetrandrine, 2,2'-N-N-dichloromethyltetrandrine) were also isolated. N-trans-Feruloyltyramine was isolated from Stephania tetrandra for the first time. The isolated compounds were tested for monoamine oxidase, acetylcholinesterase, phosphoinositide 3-kinase α and human hepatoma cell HepG2 inhibitory activities. Stephtetrandrine C showed obvious inhibitory effect on human hepatoma HepG2, with IC50 value of 16.2 µM. Limacine and 2'-N-chloromethyltetrandrine showed moderate monoamine oxidase inhibitory effect with the IC50 values of 37.7 and 29.2 µM, respectively.


Assuntos
Alcaloides , Benzilisoquinolinas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Stephania tetrandra , Stephania , Humanos , Stephania tetrandra/química , Acetilcolinesterase , Fosfatidilinositol 3-Quinases , Alcaloides/farmacologia , Alcaloides/química , Benzilisoquinolinas/farmacologia , Stephania/química , Estrutura Molecular
10.
Inflammopharmacology ; 30(4): 1369-1382, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35831735

RESUMO

Plant-derived medicinal compounds are increasingly being used to treat acute and chronic inflammatory diseases, which are generally caused by aberrant inflammatory responses. Stephania pierrei Diels, also known as Sabu-lueat in Thai, is a traditional medicinal plant that is used as a remedy for several inflammatory disorders. Since aporphine alkaloids isolated from S. pierrei tubers exhibit diverse pharmacological characteristics, we aimed to determine the anti-inflammatory effects of crude extracts and alkaloids isolated from S. pierrei tubers against lipopolysaccharide (LPS)-activated RAW264.7 macrophages. Notably, the n-hexane extract strongly suppressed nitric oxide (NO) while exhibiting reduced cytotoxicity. Among the five alkaloids isolated from the n-hexane extract, the aporphine alkaloid oxocrebanine exerted considerable anti-inflammatory effects by inhibiting NO secretion. Oxocrebanine also significantly suppressed prostaglandin E2, tumour necrosis factor-α, interleukin (IL)-1ß, IL-6, inducible nitric oxide synthase, and cyclooxygenase (COX)-2 protein expression by inactivating the nuclear factor κB, c-Jun NH2-terminal kinase, extracellular signal-regulated kinase 1/2, and phosphatidylinositol 3-kinase/Akt inflammatory signalling pathways. Molecular docking analysis further revealed that oxocrebanine has a higher affinity for toll-like receptor 4/myeloid differentiation primary response 88 signalling targets and the COX-2 protein than native ligands. Thus, our findings highlight the potential anti-inflammatory effects of oxocrebanine and suggest that certain alkaloids of S. pierrei could be used to treat inflammatory diseases.


Assuntos
Aporfinas , Stephania , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Aporfinas/metabolismo , Aporfinas/farmacologia , Ciclo-Oxigenase 2/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Stephania/metabolismo
11.
J Ethnopharmacol ; 293: 115248, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35430287

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Approximately 60 species of the genus Stephania (Menispermaceae) are distributed worldwide. Among these, 39 species are located in South and Southwest China; in particular, these plants are rich in alkaloids and were used in traditional Chinese medicine (TCM) against numerous ailments. AIM OF THIS REVIEW: The purpose of this study was to provide organized information on the ethnopharmacological uses as well as the phytochemical, pharmacological, and toxicological evaluation of the alkaloids derived from plant species included in the genus Stephania. In addition, we aimed to provide comprehensive basic knowledge on the medicinal properties of these plants and establish meaningful guidelines for further research. MATERIALS AND METHODS: Information related to the Stephania genus was collected from scientific databases, such as Web of Science, PubMed, Baidu Scholar, and China Academic Journals (CNKI), within the last 20 years on phytochemistry, pharmacology, and toxicology of the plants in genus Stephania. Furthermore, information was obtained from the Pharmacopoeia of the People's Republic of China. Chinese Pharmacopoeia and Flora of China. RESULTS: Plant species belonging to the genus Stephania have been mentioned as traditional remedies and various alkaloidal compounds have been identified and isolated, including aporphine, proaporphine, morphinane, hasubanane, protoberberine, benzylisoquinoline, and bisbenzylisoquinoline and among others. The isolated alkaloidal compounds reportedly exhibited promising pharmacological properties, such as antimicrobial, antiviral, antitumor, antioxidant, antihyperglycemic, anti-inflammatory, antinociceptive, anti-multidrug resistance, neuroprotective, and cardioprotective activities. CONCLUSIONS: The genus Stephania is widely used in TCM. The ethnopharmacological uses, phytochemistry, and pharmacology of the Stephania sp. Described in this review demonstrated that these plants contain numerous alkaloids and active constituents and display myriad pharmacological activities. Typically, research on the plants' pharmacological activity focuses on parts of the plants and the associated compounds. However, many Stephania species have rarely been studied, and the ethnomedicinal potential of those discovered has not been scientifically evaluated and needs to be further elucidated. Furthermore, quality control and toxicology studies are warranted in the future.


Assuntos
Alcaloides , Menispermaceae , Stephania , Alcaloides/toxicidade , Etnofarmacologia , Humanos , Medicina Tradicional , Compostos Fitoquímicos/uso terapêutico , Compostos Fitoquímicos/toxicidade , Fitoterapia , Extratos Vegetais/farmacologia
12.
Phytochem Anal ; 33(2): 239-248, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34390060

RESUMO

INTRODUCTION: The roots of Stephania succifera are used in traditional medicine for the treatment of several diseases. Research on this plant has mainly focused on bioactive alkaloids from the roots, and no previous work on compounds from the abundant leaves has yet been reported. OBJECTIVE: To identify and compare alkaloidal compounds in S. succifera roots and leaves and to predict the potential bioactivity of some alkaloids. METHODS: High-performance liquid chromatography with quadrupole time-of-flight tandem mass spectrometry (HPLC-QTOF-MS/MS) was employed to identify alkaloidal compounds from S. succifera. The potential targets and bioactivities of most alkaloids were predicted using the PharmMapper server. RESULTS: Fifty-six alkaloidal compounds, including protoberberine-, aporphine-, proaporphine-, benzylisoquinoline-, and lactam-type alkaloids, were identified or tentatively identified in S. succifera roots and leaves based on the HPLC-MS data. Forty-one compounds have not been previously reported in S. succifera and eight of them have not been previously reported in the literature. Twenty-four alkaloidal compounds were found in both roots and leaves. Twelve potential targets with different indications were predicted for some alkaloids. CONCLUSION: Comparison of chemical constituents and their potential bioactivities for S. succifera roots and leaves indicated that diverse bioactive alkaloids were present in the leaves as well as the roots. PharmMapper provided new directions for bioactivity screening. This study will be helpful for further understanding the medicinal components of S. succifera and the rational utilisation of plant resources.


Assuntos
Alcaloides , Stephania , Alcaloides/análise , Cromatografia Líquida de Alta Pressão/métodos , Extratos Vegetais/química , Folhas de Planta/química , Stephania/química , Espectrometria de Massas em Tandem/métodos
13.
Nat Prod Res ; 36(11): 2800-2805, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34018446

RESUMO

Two new hasubanan alkaloids, stephalonester A (1) and stephalonester B (2), together with four known compounds, stephalonine E (3), longanone (4), cephatonine (5), and prostephabyssine (6) were isolated from the whole plant of Stephania longa. Their structures were determined by HR-ESI-MS, 1 D and 2 D NMR, ECD calculations, as well as by comparison with literature values. All compounds were evaluated for their anti-inflammatory activity in vitro. Compounds 4, 5, and 6 exhibited significantly inhibitory effects on TNF-α and IL-6 production with IC50 values range from 6.54 to 30.44 µM.


Assuntos
Alcaloides , Stephania , Alcaloides/química , Alcaloides/farmacologia , Anti-Inflamatórios/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis , Estrutura Molecular , Stephania/química
14.
FEBS Open Bio ; 12(1): 285-294, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34850606

RESUMO

Cepharanthine (CEP) is a natural biscoclaurine alkaloid of plant origin and was recently demonstrated to have anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) activity. In this study, we evaluated whether natural analogues of CEP may act as potential anti-coronavirus disease 2019 drugs. A total of 24 compounds resembling CEP were extracted from the KNApSAcK database, and their binding affinities to target proteins, including the spike protein and main protease of SARS-CoV-2, NPC1 and TPC2 in humans, were predicted via molecular docking simulations. Selected analogues were further evaluated by a cell-based SARS-CoV-2 infection assay. In addition, the efficacies of CEP and its analogue tetrandrine were assessed. A comparison of the docking conformations of these compounds suggested that the diphenyl ester moiety of the molecules was a putative pharmacophore of the CEP analogues.


Assuntos
Antivirais/farmacologia , Benzilisoquinolinas/farmacologia , COVID-19/prevenção & controle , Preparações de Plantas/farmacologia , SARS-CoV-2/efeitos dos fármacos , Animais , Antivirais/química , Antivirais/metabolismo , Benzilisoquinolinas/química , Benzilisoquinolinas/metabolismo , COVID-19/virologia , Chlorocebus aethiops , Proteínas M de Coronavírus/antagonistas & inibidores , Proteínas M de Coronavírus/química , Proteínas M de Coronavírus/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Preparações de Plantas/química , Preparações de Plantas/metabolismo , Ligação Proteica , Conformação Proteica , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Stephania/química , Células Vero
15.
Biomed Res Int ; 2021: 4730341, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34660790

RESUMO

Stephania abyssinica is a medicinal plant used in Cameroon alternative medicine to treat arterial hypertension (AHT). Previous in vitro studies demonstrated the endothelium nitric oxide-independent vasorelaxant property of the aqueous extract from Stephania abyssinica (AESA). But its effect on AHT is unknown. The present study was undertaken to explore other vasorelaxant mechanisms and to determine the antihypertensive effects of AESA in male Wistar rats. Phytochemical analysis of AESA was carried out using the liquid chromatography-mass spectrometry (LC-MS) method. The vasorelaxant effects of AESA (1-1000 µg/mL) were studied on rat isolated thoracic aorta rings, in the absence or presence of indomethacin (10 µM) or methylene blue (10 µM). The inhibitory effect of AESA on phenylephrine (PE, 10 µM) or KCl- (60 mM) induced contraction as well as the intracellular calcium release was also evaluated. The in vivo antihypertensive activity of AESA (43, 86, or 172 mg/kg/day) or captopril (20 mg/kg/day) administered orally was assessed in L-NAME- (40 mg/kg/day) treated rats. Blood pressure and heart rate (HR) were measured at the end of each week while serum or urinary nitric oxide (NO), creatinine, and glomerular filtration rate (GFR) were determined at the end of the 6 weeks of treatment, as well as histological analysis of the heart and the kidney. The LC-MS profiling of AESA identified 9 compounds including 7 alkaloids. AESA produced a concentration-dependent relaxation on contraction induced either by PE and KCl, which was significantly reduced in endothelium-denuded vessels, as well as in vessels pretreated with indomethacin and methylene blue. Moreover, AESA inhibited the intracellular Ca2+ release-induced contraction. In vivo, AESA reduced the AHT, heart rate (HR), and ventricular hypertrophy and increased serum NO, urine creatinine, and GFR. AESA also ameliorated heart and kidney lesions as compared to the L-NAME group. These findings supported the use of AESA as a potential antihypertensive drug.


Assuntos
Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Extratos Vegetais/farmacologia , Folhas de Planta/química , Stephania/química , Vasodilatadores/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Modelos Animais de Doenças , Inibidores Enzimáticos/toxicidade , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão/patologia , Masculino , NG-Nitroarginina Metil Éster/toxicidade , Ratos , Ratos Wistar
16.
BMC Complement Med Ther ; 21(1): 202, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34284768

RESUMO

BACKGROUND: Gout is initiated by the precipitation of monosodium urate (MSU) crystals within the joints and soft tissues, and it can eventually cause acute or chronic arthritis. MSU crystals trigger, amplify, and maintain a strong inflammatory response through promoting proinflammatory activity. In this study, the therapeutic effects of Stephania hainanensis (S. hainanensis) total alkaloid (SHA) were tested and evaluated on MSU-induced acute gouty arthritis in a mouse model. METHODS: After oral administration of SHA (10 or 20 mg/kg) or the antigout medicine colchicine (0.5 mg/kg) once daily for 3 consecutive days, MSU crystals suspended in saline (2.5 mg/50 µl) were intradermally injected into the right paw of the mice. Then, SHA and colchicine were administered for another 2 days. During this period, swelling of the ankle and clinical scores were measured at 12, 24, and 48 h postinjection. After the mice were euthanized, inflammatory cytokine expression and paw tissue inflammation-related gene and protein expression, and a histopathological analysis was performed. RESULTS: SHA had obvious therapeutic effects on MSU-induced acute gouty arthritis in mice. SHA alleviated ankle swelling and inhibited the production of cytokines, such as IL-1ß and TNF-α. In addition, NLRP3, Caspase-1 and IL-1ß, which are activated by MSU were also suppressed by SHA. The histological evaluation showed that SHA relieved the infiltration of inflammation around the ankle. CONCLUSIONS: These results suggest that SHA is capable of anti-inflammatory activities and may be useful for treating gouty arthritis.


Assuntos
Alcaloides/farmacologia , Anti-Inflamatórios/farmacologia , Antioxidantes/toxicidade , Artrite Gotosa/induzido quimicamente , Stephania/metabolismo , Ácido Úrico/toxicidade , Animais , Antioxidantes/farmacologia , Camundongos
17.
Arch Virol ; 166(8): 2187-2198, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34041610

RESUMO

Stephania hernandifolia (Nimukho), an ethnomedicinal herb from rural Bengal, has been used traditionally for the management of nerve, skin, urinary, and digestive ailments. Here, we attempted to confirm the antiviral potential of aqueous, methanol, and chloroform extracts of S. hernandifolia against herpes simplex virus type 1 (HSV-1), the causative agent of orolabial herpes in humans, and decipher its underlying mechanism of action. The bioactive extract was standardized and characterized by gas chromatography-mass spectroscopy, while cytotoxicity and antiviral activity were evaluated by MTT and plaque reduction assay, respectively. Two HSV strains, HSV-1F and the clinical isolate VU-09, were inhibited by the chloroform extract (CE) with a median effective concentration (EC50) of 4.32 and 4.50 µg/ml respectively, with a selectivity index (SI) of 11. Time-of-addition assays showed that pre-treatment of virus-infected cells with the CE and its removal before infection reduced the number of plaques without lasting toxicity to the cell, indicating that the CE affected the early stage in the viral life cycle. The number of plaques was also reduced by direct inactivation of virions and by the addition of CE for a short time following attachment of virions. These results together suggest that modification of either the virion surface or the cell surface by the CE inhibits virus entry into the host cell.


Assuntos
Herpes Simples/virologia , Herpesvirus Humano 1/fisiologia , Extratos Vegetais/farmacologia , Stephania/química , Animais , Chlorocebus aethiops , Clorofórmio/química , Cromatografia Gasosa-Espectrometria de Massas , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 1/efeitos dos fármacos , Medicina Tradicional , Metanol/química , Modelos Biológicos , Extratos Vegetais/química , Células Vero , Ativação Viral/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos
18.
Bioorg Chem ; 107: 104597, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33450546

RESUMO

Stephania epigaea H. S. Lo is a folk medicine widely distributed in the south of China, especially in Yunnan and Guangxi province. An in vitro anti-neuroinflammatory study showed that total alkaloids of it can potently inhibit LPS-induced NO releasing of BV2 cells with an IC50 value of 10.05 ± 2.03 µg/mL (minocycline as the positive drug, IC50 15.49 ± 2.14 µM). The phytochemical investigation of the total alkaloids afforded three new phenanthrene (1-3), two lactams (4a, 4b), and nine aporphine derivatives (5-13). The final structure of 1 was identified by computer-assisted structure elucidation (ACD/Structure Elucidator software and the 13C NMR calculation with GIAO method) due to many possibilities of the substituent pattern. All isolates were evaluated for their anti-neuroinflammatory effects, and as a result, 5, 8, 10, and 11 exhibited stronger inhibitory activities than the minocycline. The results suggested S. epigaea could provide potential therapeutic agents for neurodegenerative diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Produtos Biológicos/farmacologia , Inflamação/tratamento farmacológico , Compostos Fitoquímicos/farmacologia , Stephania/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Relação Estrutura-Atividade
19.
Molecules ; 25(16)2020 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-32824689

RESUMO

Natural products remain a viable source of novel therapeutics, and as detection and extraction techniques improve, we can identify more molecules from a broader set of plant tissues. The aim of this study was an investigation of the cytotoxic and anti-plasmodial activities of the methanol extract from Stephania dielsiana Y.C. Wu leaves and its isolated compounds. Our study led to the isolation of seven alkaloids, among which oxostephanine (1) is the most active against several cancer cell lines including HeLa, MDA-MB231, MDA-MB-468, MCF-7, and non-cancer cell lines, such as 184B5 and MCF10A, with IC50 values ranging from 1.66 to 4.35 µM. Morever, oxostephanine (1) is on average two-fold more active against cancer cells than stephanine (3), having a similar chemical structure. Cells treated with oxostephanine (1) are arrested at G2/M cell cycle, followed by the formation of aneuploidy and apoptotic cell death. The G2/M arrest appears to be due, at least in part, to the inactivation of Aurora kinases, which is implicated in the onset and progression of many forms of human cancer. An in-silico molecular modeling study suggests that oxostephanine (1) binds to the ATP binding pocket of Aurora kinases to inactivate their activities. Unlike oxostephanine (1), thailandine (2) is highly effective against only the triple-negative MDA-MB-468 breast cancer cells. However, it showed excellent selectivity against the cancer cell line when compared to its effects on non-cancer cells. Furthermore, thailandine (2) showed excellent anti-plasmodial activity against both chloroquine-susceptible 3D7 and chloroquine-resistant W2 Plasmodium falciparum strains. The structure-activity relationship of isolated compound was also discussed in this study. The results of this study support the traditional use of Stephania dielsiana Y.C. Wu and the lead molecules identified can be further optimized for the development of highly effective and safe anti-cancer and anti-plasmodial drugs.


Assuntos
Alcaloides/farmacologia , Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Extratos Vegetais/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Stephania/química , Apoptose , Humanos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Neoplasias/patologia , Testes de Sensibilidade Parasitária , Folhas de Planta/química , Células Tumorais Cultivadas
20.
Pharm Biol ; 58(1): 247-252, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32223485

RESUMO

Context: Cepharanthine (CEP) extracted from the roots of Stephania cepharantha Hayata (Menispermaceae), has a range of therapeutic potential in clinical conditions. Whether it affects the activity of human liver cytochrome P450 (CYP) enzymes remains unclear.Materials and methods: The effects of CEP (100 µM) on eight human liver CYP isoforms (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19 and 2C8) were investigated in vitro using human liver microsomes (HLMs) with specific probe actions and probe substrates. In addition, the enzyme kinetic parameters were calculated.Results: The results showed that the activity of CYP3A4, CYP2E1 and CYP2C9 was inhibited by CEP, with IC50 values of 16.29, 25.62 and 24.57 µM, respectively, but other CYP isoforms were not affected. Enzyme kinetic studies showed that CEP was not only a non-competitive inhibitor of CYP3A4 but also a competitive inhibitor of CYP2E1 and CYP2C9, with Ki values of 8.12, 11.78 and 13.06 µM, respectively. Additionally, CEP is a time-dependent inhibitor for CYP3A4 with KI/Kinact value of 10.84/0.058 min/µM.Discussion and conclusions: The in vitro studies of CEP with CYP isoforms indicate that CEP has the potential to cause pharmacokinetic drug interactions with other co-administered drugs metabolized by CYP3A4, CYP2E1 and CYP2C9. Further clinical studies are needed to evaluate the significance of this interaction.


Assuntos
Benzilisoquinolinas/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Fígado/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Stephania/química , Benzilisoquinolinas/isolamento & purificação , Inibidores das Enzimas do Citocromo P-450/isolamento & purificação , Humanos , Técnicas In Vitro , Concentração Inibidora 50 , Fígado/enzimologia , Microssomos Hepáticos/enzimologia , Estrutura Molecular , Raízes de Plantas/química
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