RESUMEN
Sinomenii Caulis (SC), a commonly used traditional Chinese medicine for its therapeutic effects on rheumatoid arthritis, contains rich chemical components. At present, most studies mainly focus on sinomenine, with little research on other alkaloids. In this study, a comprehensive profile of compounds in SC extract, and biological samples of rats (including bile, urine, feces, and plasma) after oral administration of SC extract was conducted via ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS). The fragmentation patterns and potential biotransformation pathways of six main types of alkaloids in SC were summarized, and the corresponding characteristic product ions, relative ion intensity, and neutral losses were obtained to achieve rapid classification and identification of complex components of SC from in vitro to in vivo. As a result, a total of 114 alkaloid compounds were identified, including 12 benzyl alkaloids, 4 isoquinolone alkaloids, 32 aporphine alkaloids, 28 protoberberine alkaloids, 34 morphinan alkaloids and 4 organic amine alkaloids. After administration of SC extract to rats, a total of 324 prototypes and metabolites were identified from rat plasma, urine, feces and bile, including 81 aporphines, 95 protoberberines, 117 morphinans and 31 benzylisoquinolines. The main types of metabolites were demethylation, hydrogenation, dehydrogenation, aldehydation, oxidation, methylation, sulfate esterification, glucuronidation, glucose conjugation, glycine conjugation, acetylation, and dihydroxylation. In summary, this integrated strategy provides an additional approach for the incomplete identification caused by compound diversity and low abundance, laying the foundation for the discovery of new bioactive compounds of SC against rheumatoid arthritis.
Asunto(s)
Alcaloides , Medicamentos Herbarios Chinos , Ratas Sprague-Dawley , Animales , Ratas , Cromatografía Líquida de Alta Presión/métodos , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacocinética , Masculino , Alcaloides/análisis , Alcaloides/química , Alcaloides/farmacocinética , Sinomenium/química , Heces/química , Administración Oral , Bilis/química , Bilis/metabolismo , Espectrometría de Masas en Tándem/métodos , Extractos Vegetales/química , Extractos Vegetales/farmacocinética , Espectrometría de Masas/métodos , Medicina Tradicional China/métodos , Morfinanos/farmacocinética , Morfinanos/metabolismoRESUMEN
From the methanolic extract of the climbing stems and rhizomes of Sinomenium acutum, two new aporphine analogues, acutumalkaloids I and II, were isolated together with fifteen known compounds including lysicamine. The chemical structures of the isolated new compounds were elucidated based on chemical/physicochemical evidence such as NMR and MS spectra. For acutumalkaloids I and II, the absolute configurations were established by comparison of experimental and predicted electronic circular dichroism (ECD) data. We compared anti-proliferative activities of isolated compounds with reported naturally occurring Wnt/ß-catenin pathway inhibitor, nuciferine. Among the isolated compounds, we found lysicamine have anti-proliferative activity against both of HT-29 human colon cancer cell line and its cancer stem cells (CSCs). The IC50 values of lysicamine against non-CSCs and its CSCs were lower than that of nuciferine. In addition, the results of western blotting analysis suggested that lysicamine inhibited the expression of Wnt/ß-catenin pathway target protein such as survivin. These results suggested that lysicamine show cytotoxic activity via inhibition of Wnt/ß-catenin pathway.
Asunto(s)
Alcaloides , Antineoplásicos , Neoplasias , Humanos , Sinomenium/química , beta Catenina , Rizoma/química , Alcaloides/química , Antineoplásicos/farmacología , Vía de Señalización Wnt , Células Madre Neoplásicas , Línea Celular TumoralRESUMEN
Six new alkaloids (1-6) and six known alkaloids (7-12) were obtained from the stems of Sinomenium acutum. Among them, compounds 1-3 and 6 were four N-oxide alkaloids. The structures and absolute configurations of these new alkaloids were elucidated through comprehensive data of 1D and 2D NMR, HRESIMS and ECD spectra. All isolated compounds were evaluated in vitro for their inhibitory activities against nitric oxide (NO) production and inhibitory effects on AChE. Among them, the sinomenine N-oxide (9) was the most potent NO production inhibitor, with an IC50 value of 23.04 µM.
Asunto(s)
Alcaloides , Medicamentos Herbarios Chinos , Sinomenium/química , Óxidos , Estructura Molecular , Alcaloides/farmacología , Alcaloides/química , Medicamentos Herbarios Chinos/farmacologíaRESUMEN
Sinomenium acutum is the dry stem of Sinomenium acutum (Thunb.) Rehd et Wils. (S. acutum) and Sinomenium acutum (Thunb.) Rehd. et Wils. var. cinereum Rehd. et Wils and is mainly distributed in China and Japan. As a traditional Chinese medicine (TCM) for dispelling wind and dampness in China, it is widely distributed and has a long history of drug use. In recent years, with the increase of the incidence of rheumatoid disease, S. acutum has become the focus of research. This paper reviews the literature on the chemical constituents, pharmacological effects, clinical applications and pharmacokinetics and safety of S. acutum from the past 60 years. At present, more than 210 natural compounds have been isolated from S. acutum, including alkaloids, lignans, triterpenoid saponins, steroids, and other structures. Pharmacological activities of S. acutum were mainly reported on anti-inflammatory, analgesic, anti-allergic, immunosuppressive, anti-tumor, liver-protective, anti-oxidative, and other effects, and clinical applications were mainly recorded on rheumatoid arthritis, ankylosing spondylitis, and other diseases. The clinical use of SIN has fewer side effects and more safety; only a small number of gastrointestinal reactions occurred, and the symptoms disappeared after the drug stopped. The purpose of this paper is to lay a foundation and provide reference for the follow-up research and wide application of S. acutum.
Asunto(s)
Alcaloides , Artritis Reumatoide , Botánica , Medicamentos Herbarios Chinos , Alcaloides/uso terapéutico , Antiinflamatorios no Esteroideos , Artritis Reumatoide/tratamiento farmacológico , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Humanos , Sinomenium/químicaRESUMEN
Three new alkaloids (1-3), one new diphenyl ether (4) and fifteen known alkaloids (5-19) were isolated from the rattan stems of Sinomenium acutum. Comprehensive analyses of HR-ESI-MS, 1D (1 H and 13 C), 2D-NMR (1 H-1 H COSY, HSQC, HMBC, NOESY), circular dichroism (CD), UV and IR revealed the structures and absolute configurations of these new compounds. The structures of other compounds were determined by comparison of their 1 H and 13 C-NMR data with previous literature reports. By measuring the amount of NO produced, the anti-inflammatory properties of the isolated compounds were studied. The results showed that compounds 4 and 5 had strong NO inhibitory activity.
Asunto(s)
Alcaloides , Artritis Reumatoide , Medicamentos Herbarios Chinos , Alcaloides/química , Alcaloides/farmacología , Artritis Reumatoide/tratamiento farmacológico , China , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Medicina Tradicional , Estructura Molecular , Sinomenium/químicaRESUMEN
Eleven previously undescribed alkaloids, named sinometumines A-K, along with three known alkaloids, were isolated from the rhizomes of Sinomenium acutum. The chemical structures of these unreported compounds were established using extensive spectroscopic methods (IR, UV, HRESIMS, and NMR), and their absolute configurations were determined by single crystal X-ray diffraction analyses and calculated electronic circular dichroism spectroscopy (ECD). Sinometumine D was the first aporphine-type derived alkaloid inner salt with a rearranged dibenzofuran ring backbone. Sinometumine E was a rare protoberberine-type alkaloid with a complex 6/6/6/6/6/6 hexacyclic skeleton. This was the first report of alkaloids with these two skeletons isolated from S. acutum. All isolates were evaluated for their inhibitory activities against indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO). Lysicamine possessed noteworthy inhibitory activities as an IDO1/TDO dual inhibitor with IC50 values of 6.22 ± 0.26 µM and 23.76 ± 2.93 µM, respectively, and liriodenine revealed moderate dual inhibition with IC50 values of 31.65 ± 4.44 µM and 15.64 ± 0.26 µM. The intermolecular interactions and binding modes between lysicamine and IDO1/TDO were elaborated by molecular docking studies.
Asunto(s)
Alcaloides , Antineoplásicos , Alcaloides/química , Antineoplásicos/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Rizoma/química , Sinomenium/químicaRESUMEN
Atherosclerosis (AS) is a cardiovascular disease that arise due to dysfunction of lipid deposition and metabolism. AS is causes the mortality and morbidity worldwide. Sinomenine isolated from the Sinomenium acutum is used extensively against the various cardiac diseases in China. However, the anti-atherosclerosis effect of sinomenine still not explore. In this study, we explore the cardioprotective and anti-atherosclerosis effect of sinomenine against Vitamin D3 and High fat induced atherosclerosis in rats. Sprague Dawley (SD) rats were used in this study. The rats were received the vitamin D (60000) and High fat diet to induce the atherosclerosis and divided into groups and received the oral administration of sinomenine (2.5, 5 and 10 mg/kg) and simvastatin (5 mg/kg). Body weight, organ weight and biochemical parameters were estimated. The mRNA expression of MyD88, TLR4, NF-κB and IκB were estimated. Sinomenine treated rats significantly (p<0.001) suppressed the body weight and modulated the organ weight (hepatic, renal and heart). Sinomenine significantly (p<0.001) decreased the level of triacylglycerols (TG), low density lipoprotein cholesterol (LDL-c), total cholesterol (TC), very low-density lipoprotein cholesterol (VLDL-c) and augmented the level of high-density lipoprotein cholesterol (HDL-c). Sinomenine treatment also reduced the level of atherogenic index (TC/HDL-c and LDL-c/HDL-c). Sinomenine treatment decrease the ratio of HMG CoA/Mevalonate and level of collagen and total protein. Sinomenine significantly (p<0.001) altered the level of heart parameters, antioxidant parameters and inflammatory cytokines. Sinomenine significantly (p<0.001) reduced the expression of MyD88, TLR4, NF-κB and IκB. Taken together, sinomenine exhibited the protective effect against the atherosclerosis via alteration of TLR4/NF-κB signaling pathway.
Asunto(s)
Aterosclerosis/tratamiento farmacológico , Aterosclerosis/etiología , Colecalciferol/efectos adversos , Dieta Alta en Grasa/efectos adversos , Morfinanos/administración & dosificación , Morfinanos/farmacología , Estrés Oxidativo/efectos de los fármacos , Fitoterapia , Administración Oral , Animales , Antioxidantes , Aterosclerosis/genética , Aterosclerosis/prevención & control , Citocinas/metabolismo , Inflamación , Mediadores de Inflamación/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/genética , Masculino , Morfinanos/aislamiento & purificación , FN-kappa B/metabolismo , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Sinomenium/química , Receptor Toll-Like 4/metabolismoRESUMEN
A large number of macrophages in inflamed sites not only amplify the severity of inflammatory responses but also contribute to the deleterious progression of many chronic inflammatory diseases, autoimmune diseases and cancers. Macrophage migration is a prerequisite for their entry into inflammatory sites and their participation of macrophages in the pathologic processes. Inhibition of macrophage migration is therefore a potential anti-inflammatory mechanism. Moreover, alleviation of inflammation also prevents the macrophages infiltration. Sinomenine (SIN) is an alkaloid derived from the Chinese medicinal plant Sinomenium acutum. It has multiple pharmacological effects, including anti-inflammation, immunosuppression, and anti-arthritis. However, its anti-inflammatory molecular mechanisms and effect on macrophage migration are not fully understood. The purpose of this research was to investigate the pharmacological effects and the molecular mechanism of SIN on macrophage migration in vivo and in vitro as well as to elucidate its anti-inflammatory mechanisms associated with macrophage migration. Our results showed that SIN reduced the number of RAW264.7 cells migrating into inflammatory paws and blocked lipopolysaccharide (LPS)-induced RAW264.7 cells and bone marrow-derived macrophages (BMDMs) migration in vitro. Furthermore, SIN attenuated the 3D mesenchymal migration of BMDMs. The absence of macrophage migration after circulatory and periphery macrophages depletion led to a reduction in the severity of inflammatory response. In macrophages depleted (macrophages-/-) mice, as inflammatory severity decreased, RAW264.7 cells migration was suppressed. A non-obvious effect of SIN on the inflammatory response was found in macrophages-/- mice, while the inhibitory effect of SIN on RAW264.7 cells migration was still observed. Furthermore, the migration of RAW264.7 cells pre-treated with SIN was suppressed in normal mice. Finally, Src/focal adhesion kinase (FAK)/P130Cas axis activation, which supports macrophages mesenchymal migration, and iNOS expression, NO production, integrin αV and in integrin ß3 expressions, which promote Src/FAK/P130Cas activation, were down-regulated by SIN. However, SIN had no obvious effect on the expression of the monocyte chemoattractant protein-1 (MCP-1), which is an important chemokine for macrophage migration. These results indicated that SIN significantly inhibited macrophage mesenchymal migration by down-regulating on Src/FAK/P130Cas axis activation. There was a mutual regulatory correlation between the inflammatory response and macrophage migration, and the effects of SIN on macrophage migration were involved in its anti-inflammatory activity.
Asunto(s)
Antiinflamatorios/farmacología , Movimiento Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Macrófagos/efectos de los fármacos , Morfinanos/farmacología , Animales , Antiinflamatorios/química , Proteína Sustrato Asociada a CrK/metabolismo , Quinasa 1 de Adhesión Focal/metabolismo , Macrófagos/citología , Macrófagos/metabolismo , Ratones , Morfinanos/química , Células RAW 264.7 , Transducción de Señal/efectos de los fármacos , Sinomenium/química , Familia-src Quinasas/metabolismoRESUMEN
Sinomenium acutum stem is a popular traditional Chinese medicine used to treat bone and joint diseases. Sinomenine is considered the only chemical marker for the quality control of S. acutum stem in mainstream pharmacopeias. However, higenamine in S. acutum stem is a novel stimulant that was banned by the World Anti-Doping Agency in 2017. Therefore, enhancing the quality and safety control of S. acutum stem to avoid potential safety risks is of utmost importance. In this study, a fast, sensitive, precise, and accurate method for the simultaneous determination of 11 alkaloids in S. acutum stem by ultrahigh-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry (UHPLC-QQQ-MS/MS) was established. This method successfully analyzed thirty-five batches of S. acutum stem samples. The average contents of sinomenine, magnoflorine, coclaurine, acutumine, higenamine, sinoacutine, palmatine, magnocurarine, columbamine, 8-oxypalmatine, and jatrorrhizine were 24.9 mg/g, 6.35 mg/g, 435 µg/g, 435 µg/g, 288 µg/g, 44.4 µg/g, 22.5 µg/g, 21.1 µg/g, 15.8 µg/g, 9.30 µg/g, and 8.75 µg/g, respectively. Multivariate analysis, including principal component analysis (PCA), orthogonal partial least square method-discriminant analysis (OPLS-DA), and hierarchical cluster analysis (HCA), were performed to characterize the importance and differences among these alkaloids in S. acutum stem samples. As a result, sinomenine, magnoflorine, coclaurine, acutumine, and higenamine are proposed as chemical markers for quality control. Higenamine and coclaurine are also recommended as chemical markers for safety control. This report provides five alkaloids that can be used as chemical markers for improving the quality and safety control of S. acutum stem. It also alerts athletes to avoid the risks associated with consuming S. acutum stem.
Asunto(s)
Alcaloides/análisis , Cromatografía Líquida de Alta Presión/métodos , Medicamentos Herbarios Chinos/química , Tallos de la Planta/química , Sinomenium/química , Espectrometría de Masas en Tándem/métodos , Alcaloides/toxicidad , Aporfinas/análisis , Aporfinas/toxicidad , Análisis por Conglomerados , Isoquinolinas/análisis , Isoquinolinas/toxicidad , Análisis de los Mínimos Cuadrados , Morfinanos/análisis , Morfinanos/toxicidad , Extractos Vegetales/química , Análisis de Componente Principal , Solventes , Compuestos de Espiro/análisis , Compuestos de Espiro/toxicidad , Tetrahidroisoquinolinas/análisis , Tetrahidroisoquinolinas/toxicidadRESUMEN
OBJECTIVE: Premature and ill neonates undergo painful but medically necessary procedures while hospitalized. Although opiate drugs are administered as analgesics, problems associated with their side effects, tolerance, and potential dependence necessitate research into alternative pain-relieving medications. Here we test two plant-derived compounds in infant rats: sinomenine, which targets the Mas-related G-protein-coupled receptor member X2 opioid receptor; and salvinorin A, which is a κ opioid receptor agonist. In adult animals both sinomenine and salvinorin A are analgesic, but neither has been tested in infants. METHODS: We used the formalin and thermal plantar tests in rats 7 and 21 days of age (PN7 and PN21) for behavioral signs of pain. In addition, brain sections were stained using Fos immunohistochemistry to examine patterns of brain activation in the midbrain periaqueductal gray and the paraventricular nucleus of the hypothalamus. RESULTS: Sinomenine was analgesic in both the formalin and thermal tests on animals 21 days of age. At PN7 only the highest dose elevated response latencies in the thermal test and there were no effects of sinomenine in the formalin test. Analysis of Fos expression in the sinomenine-treated animals showed no drug effect, in contrast to the behavioral results. Salvinorin A was analgesic in the formalin test only at the highest dose at 21 days of age but not in the thermal test at either age. CONCLUSION: The increased modest effectiveness of sinomenine in older animals and the minimum salvinorin A drug effect suggest that the compounds act on sites that develop during the preweaning period (sinomenine) or after weaning (salvinorin A).
Asunto(s)
Analgésicos/uso terapéutico , Diterpenos de Tipo Clerodano/uso terapéutico , Morfinanos/uso terapéutico , Dolor/tratamiento farmacológico , Receptores Opioides/agonistas , Salvia/química , Sinomenium/química , Analgésicos/farmacología , Analgésicos Opioides/farmacología , Analgésicos Opioides/uso terapéutico , Animales , Conducta Animal , Diterpenos de Tipo Clerodano/farmacología , Calor , Humanos , Lactante , Recién Nacido , Morfinanos/farmacología , Dimensión del Dolor , Fitoterapia , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Ratas Long-Evans , Receptores Opioides kappa/agonistasRESUMEN
Alkaloids, the principal constituents in the caulis of Sinomenium acutum, have gained an increasing interest over the past decades since they are widely employed as a clinical treatment for rheumatoid arthritis. In the present study, an integrated characterization strategy by combining mass defect filtering-based structure classification (MDFSC) and diagnostic fragment-ion-based extension (DFIBE) was firstly proposed for rapid profiling of alkaloids in Sinomenii Caulis (SC) via ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS). The rectangular MDFSC window could more accurately screen the target alkaloids of different types, and the DFIBE could facilitate the acquisition of characteristic fragment ions for structural elucidation of alkaloids. High-performance liquid chromatography (HPLC) fingerprints with principal component analysis (PCA) and hierarchical clustering analysis (HCA) was established for identifying the chemical markers and simultaneous determination of sinomenine, magnoflorine, menisperine, stepharanine and ehydrodiscretine. A total of 91 alkaloids, including 82 targeted ones (26 morphinans, 22 aporphines, 20 protoberberines and 14 benzylisoquinolines) were unambiguously identified or tentatively characterized in SC, and 14 of them were reported for the first time. Sinomenine and magnoflorine could be selected as chemical markers to evaluate the quality of SC from different localities. In conclusion, the proposed method provided a potential approach for chemical profiling and holistic quality control of herbal medicines.
Asunto(s)
Alcaloides/análisis , Sinomenium/química , Aporfinas/análisis , Artritis Reumatoide/tratamiento farmacológico , Cromatografía Líquida de Alta Presión , Análisis por Conglomerados , Medicamentos Herbarios Chinos/química , Humanos , Inflamación , Límite de Detección , Espectrometría de Masas , Modelos Teóricos , Plantas Medicinales/química , Análisis de Componente Principal , Control de CalidadRESUMEN
The present study aimed to identify the anti-inflammatory components in Sinomenii Caulis (SC) based on spectrum-effect relationship and chemometric methods. A phytochemical investigation of SC extract was performed firstly and afforded eleven potential bioactive compounds. The HPLC fingerprints of 19 batches of SC samples were evaluated by the chemometric methods such as similarity analysis (SA) and hierarchical clustering analysis (HCA). The anti-inflammatory effects of these samples were determined by inhibition of Nitric Oxide (NO) production. Partial least squares regression (PLSR) and artificial neural network (ANN) were used to explore the spectrum-effect relationship of SC. The results indicated that there was a close correlation between chemical fingerprint and anti-inflammatory activity of SC, and peaks 8, 9, 12, 13, 14, 16, 19 and 22 might be potential anti-inflammatory compounds in SC. The verification experiments by testing individual compounds and a combination of them indicated that sinomenine (P8), magnoflorine (P13), menisperine (P16) and stepharanine (P19) were the major anti-inflammatory compounds in SC. Collectively, the present study established the spectrum-effect relationship mode of SC and discovered the anti-inflammatory compounds in SC, which could be used for exploration of bioactive components and quality control of herbal medicines.
Asunto(s)
Antiinflamatorios/farmacología , Medicamentos Herbarios Chinos/química , Sinomenium/química , Animales , Antiinflamatorios/aislamiento & purificación , Supervivencia Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Análisis de los Mínimos Cuadrados , Lipopolisacáridos , Ratones , Estructura Molecular , Redes Neurales de la Computación , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Tallos de la Planta/química , Células RAW 264.7RESUMEN
Menisdaurin (1), a cyano glucoside, was first isolated in 1978 from Menispermum dauricum (Menispermaceae) and named after the plant. It has been also isolated from several plant sources. The stereochemistry of the aglycone part was first reported as (Z,4R,6S)-enantiomer of (4,6-dihydroxy-2-cyclohexen-1-ylidene)acetonitrile based on the CD spectrum of menisdaurilide (2), the α,ß-unsaturated γ-lactone obtained by an acid hydrolysis of menisdaurin. Later, the absolute stereochemistry was revised as (Z,4S,6R) by X-ray crystal analysis of 1 isolated from Saniculiphyllum guangxiens. The aglycone part of menisdaurin (1) has not been obtained from 1, because an acid hydrolysis of 1 gave menisdaurilide (2), and enzymatic hydrolysis with emulsin did not give the aglycone. On the other hand, a compound named coculauril (3) was isolated from Cocculus lauriforius. This compound has the same planner structure corresponding to the aglycone of 1, but the stereochemistry was reported to be (E,4R,6S). Here, we confirmed the absolute stereochemistry of 1 by Mosher's method to be (Z,4S,6R), and prepared the aglycone of 1, i.e., menisdaurigenin (4) by an enzymatic hydrolysis of 1. We also revealed that 4 is a different compound from 3 and unstable in water and MeOH.
Asunto(s)
Glucósidos/química , Glucósidos/síntesis química , Glucósidos/aislamiento & purificación , Hidrólisis , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Sinomenium/química , EstereoisomerismoRESUMEN
OBJECTIVE: To decipher the possible mechanisms of Sinomenium Acutum (SA) in treating diseases by a bioinformatics method. METHODS: SA ingredients were searched according to Chinese Pharmacopoeia, Chinese Medicine Dictionary and Traditional Chinese Medicines Database (TCMD). Active compounds and target proteins of SA were acquired through the Pubchem platform. Pathway, network and function analyses of SA were performed with ingenuity pathway analysis (IPA), a bioinformatics analysis platform. Disease, biofunction-target networks were established with Cytoscape. RESULTS: Eighteen ingredients from SA were obtained. Seven active ingredients with 31 active target proteins were acquired according to PubChem Bioassay test. By IPA analysis, 277 canonical pathways belonging to 17 function categories were collected, 23 kinds of diseases, 21 categories bio-functions were obtained. Based on P value, calculated by IPA, the top 5 significant pathway of SA targets include phosphatidylinositol 3 kinase/Akt (PI3K/Akt) signaling, prostate cancer signaling, macrophage migration inhibitory factor (MIF) regulation of innate immunity, Guanosine-binding protein coupled receptor (GPCR) signaling, and ataxia telangiectasia mutated protein (ATM) signaling. Disease and bio-function network analysis indicated that mitogen activated protein kinase 1 (MAPK1), MAPK3, p65 nuclear factor κB (RELA), nuclear factor of κB inhibitor alpha (NFκBIA), interleukin 1ß(IL-1ß), prostaglandin G/H synthase 2 (PTGS2) and tumor protein 53 (TP53) were the critical targets in various diseases treated by SA. CONCLUSION: In the different view of target, pathway, disease and bio-function, inflammation was found to be a central theme in many chronic conditions. SA could be used not only as an anti-inflammatory agent, but also for the treatment of cancers, neurological diseases, psychological disorders and metabolic diseases.
Asunto(s)
Biología Computacional/métodos , Sinomenium/química , Enfermedad , Humanos , Terapia Molecular Dirigida , Proteínas/metabolismo , Transducción de SeñalRESUMEN
Thirteen undescribed alkaloids (sinotumines A-M), including five oxoisoaporphine, a benzo[h]quinoline, an aporphine, two protoberberine, two hasubanane, and two proaporphine alkaloids, and 50 known analogues were isolated from the 95% aqueous EtOH extract of the stems and rhizomes of Sinomenium acutum. The structures and absolute configurations of the isolates were elucidated on the basis of comprehensive analysis of 1D and 2D NMR, HRMS, single-crystal X-ray diffraction, and comparison of the experimental and calculated electronic circular dichroism (ECD) data. Sinotumine F, a rare benzo[h]quinoline alkaloid, was speculated as an oxidation product of the oxoisoaporphine alkaloid, and its putative biosynthetic pathway is proposed. Sinotumines L and M are the first samples of proaporphine-based heterodimers coupled with 1-heptanone and coniferol alcohol moiety, respectively. The T-cell suppression and NO inhibition effects of the isolates were evaluated.
Asunto(s)
Alcaloides/aislamiento & purificación , Medicamentos Herbarios Chinos/química , Tallos de la Planta/química , Rizoma/química , Sinomenium/química , Alcaloides/química , China , Estructura MolecularRESUMEN
The use of plantbased compounds derived from traditional medicine to improve human diseases has been gaining momentum, due to their high bioavailability and moderate adverse effects. Sinomenine is one such biomonomer alkali compound derived from Sinomenium acutum and is known for its antiinflammatory and antitumor effects. However, the molecular mechanism(s) of its antitumor properties are not fully characterized. In the present study, we evaluated the radiosensitizing effects of the watersoluble sinomenine, sinomenine hydrochloride (SH) in human cervical cancer cell line (HeLa). SH sensitized HeLa cells to ionizing radiation (IR) by promoting accumulation of IRinduced DNA doublestrand breaks (DSBs) and also by interfering with DNA damage checkpoint activation. We then investigated the molecular mechanisms underlying the SHmediated cellular sensitization to IR and found that SH inhibited the expression of DNA damage response (DDR) factors Ku80 and Rad51 at the transcription level. Finally, the radiosensitizing activity of SH was confirmed in a cervical cancer mouse xenograft model. The combinatorial treatment of SH and IR significantly slowed the tumor growth rate compared with IR alone. Collectively, our study not only provides molecular insights into the novel role of SH in cellular response to IR, but also suggests a therapeutic potential of SH as a radiosensitizer in cervical cancer therapy.
Asunto(s)
Morfinanos/farmacología , Fármacos Sensibilizantes a Radiaciones/farmacología , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/radioterapia , Animales , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de la radiación , Roturas del ADN de Doble Cadena/efectos de los fármacos , Roturas del ADN de Doble Cadena/efectos de la radiación , Daño del ADN/efectos de los fármacos , Daño del ADN/efectos de la radiación , Femenino , Células HeLa , Humanos , Ratones , Morfinanos/química , Tolerancia a Radiación/genética , Radiación Ionizante , Fármacos Sensibilizantes a Radiaciones/química , Sinomenium/química , Neoplasias del Cuello Uterino/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Sinomenine (SIN), a pure alkaloid isolated from Sinomenium acutum, has been widely used in arthritis for its antiinflammatory effect, but little is known about the effect of SIN on human ulcerative colitis (UC). In the present study, the effect and mechanism of SIN was examined in a dextran sulfate sodium (DSS)induced murine colitis model, which mimics human UC. Oral administration of SIN significantly suppressed the elevated disease activity index and ameliorated colonic histological damage in a DSSinduced colitis model. Tumor necrosis factorα, interleukin6 and inducible nitric oxide synthase levels were also reduced as detected by reverse transcriptionquantitative polymerase chain reaction. In addition, SIN reversed the decreased colon length and colonic superoxide dismutase activity. Furthermore, western blot analysis revealed that nuclear factorerythroid 2related factor 2 (Nrf2) and its downstream genes, heme oxygenase1 and NADP(H) quinone oxidoreductase 1 (NQO1), were markedly activated by SIN. The current results indicated that SIN alleviated DSSinduced colitis in mice, which may be due to its antioxidant properties and was at least in part dependent on the Nrf2/NQO1 signaling pathway. Therefore, SIN may have potential applications as a protective drug for patients with UC.
Asunto(s)
Antioxidantes/uso terapéutico , Colitis/tratamiento farmacológico , Morfinanos/uso terapéutico , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/química , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/patología , Sulfato de Dextran , Femenino , Ratones Endogámicos C57BL , Morfinanos/química , Transducción de Señal/efectos de los fármacos , Sinomenium/químicaRESUMEN
Studies have shown that the inflammatory activation of miroglia (MG) and nuclear factor kappa B ( NF-κB ) play a dominant role in inflammatory response. Previous studies have shown that sinomenine, an anti-inflammatory agent extracted from Sinomenium acutum, can directly protect neurons against cerebral ischemia injury. However, there are no reports on its effect on ischemia/reperfusion-induced inflammatory activation of MG. In the present study, an in vitro ischemia/reperfusion model was developed with mouse BV-2 microglia cells, a model of oxygen-glucose deprivation/reperfusion (OGD/R), and the inhibitory effect of sinomenine pretreatment on inflammatory activation was confirmed through measurement of inflammatory indicators. Mechanistically, sinomenine suppressed OGD/R-induced inflammatory activation through the SP1/miRNA-183-5p/IκB-α pathway. In conclusion, this study shows that sinomenine effectively inhibits OGD/R-induced inflammatory activation in MG by suppressing the activation of transcription specificity protein 1 (SP 1). This finding is of significance for the clinical use of sinomenine in treating cerebral ischemia/reperfusion injury.
Asunto(s)
Antiinflamatorios/farmacología , Inflamación/tratamiento farmacológico , Microglía/efectos de los fármacos , Morfinanos/farmacología , Daño por Reperfusión/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Animales , Antiinflamatorios/química , Línea Celular , Glucosa/inmunología , Inflamación/complicaciones , Inflamación/inmunología , Ratones , MicroARNs/inmunología , Microglía/inmunología , Morfinanos/química , Inhibidor NF-kappaB alfa/inmunología , Oxígeno/inmunología , Daño por Reperfusión/complicaciones , Daño por Reperfusión/inmunología , Sinomenium/química , Factor de Transcripción Sp1/inmunologíaRESUMEN
The characterization of alkaloids is challenging because of the diversity of structures and the complicated fragmentation of collision induced structural dissociation in mass spectrometry. In this study, we analyzed the alkaloids in Sinomenium acutum (Thunb.) Rehderet Wil by high resolution mass spectrometry. Chromatographic separation was achieved on a Phenomenex Kinetex C18 (2.1 mm × 100 mm, 2.6 µm) column with a mobile phase consisting of acetonitrile and water (0.1% formic acid) under gradient elution. A total of 52 alkaloids were well separated and 45 of them were structurally characterized, including morphinans, aporphines, benzylisoquinolines, and protoberberines. Specially, mass spectrometric study of the morphinan alkaloids were explicitly investigated. Electrostatic potential plot from simulation was calculated for determination of protonation sites. Further fragmentation analysis suggested that the C3H7N, CH4O, and H2O elimination was displayed in MS² spectrum. These fragmentation pathways are universal for morphinan alkaloids having methoxy substituted cyclohexenone or cyclohexadienone moieties. Additionally, for nitrogen oxides, an ion-neutral complex intermediate is involved in the fragmentation process, generating additional oxygenated ions. All these results provided the universal rules of fragmentation used for detection of alkaloids, and will be expected to be highly useful for comprehensive study of multi-components in the herbal medicine analysis.
Asunto(s)
Alcaloides/química , Alcaloides/aislamiento & purificación , Sinomenium/química , Cromatografía Liquida , Espectrometría de Masas , Modelos Moleculares , Estructura Molecular , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificaciónRESUMEN
Rheumatoid arthritis (RA) is a type of chronic systemic inflammatory disease; it has a very complicated pathogenesis, and multiple pathological changes are implicated. Traditional Chinese medicine (TCM) like Tripterygium wilfordii Hook. F. or Sinomenium acutum (Thunb.) Rehd et Wils. has been extensively used for centuries in the treatment of arthritic diseases and been reported effective for relieving the severity of RA. Hei-Gu-Teng Zhuifenghuoluo granule (HGT) which contains Periploca forrestii Schltr., Sinomenium acutum (Thunb.) Rehd et Wils., and Lysimachia paridiformis Franch. var. stenophylla Franch. was a representative natural rattan herb formula for the treatment of RA in China, but the mechanism has not been elucidated. This study aimed at exploring the mechanism of HGT on RA using the bioinformatics analysis with in vivo and in vitro experiment validation. The potential action mechanism was first investigated by bioinformatics analysis via Ingenuity Pathway Analysis (IPA) software. After that, we use experimental validation such as collagen-induced arthritis (CIA) mice model in vivo and U937 cell model in vitro. The bioinformatics results suggested that HGT may have anti-inflammatory characteristic on RA and IL-12 signaling pathway could be the potential key trigger. In vivo experiments demonstrated that HGT ameliorated the symptoms in CIA mice and decreased the production of inflammatory cytokines in both mice ankle joints and serum. Furthermore, HGT effectively inhibited the activation of IL-12R and STAT4 on IL-12 signaling pathway. In vitro experiments showed that HGT inhibited the production of IL-12R and STAT4 induced by IL-12 in lipopolysaccharide- (LPS-) stimulated U937 cells. Moreover, IL-12R knockdown was able to interfere with the inhibition effects of HGT on the production of these cytokines. Our results confirmed the anti-inflammatory property of HGT, which was attributed to its inhibition on IL-12 signaling pathway.