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The rhizome of Corydalis decumbens is a traditional Chinese medicine commonly utilized in the clinical treatment of acute ischemic stroke. Numerous phytochemical and biological investigations have demonstrated that protoberberine alkaloids from C. decumbens exhibit diverse pharmaceutical activities against various diseases. Sinometumine E (SE), a protoberberine alkaloid isolated from C. decumbens for the first time, is characterized by a complex 6/6/6/6/6/6 hexacyclic skeleton. In the current study, we investigated the protective effects of SE on endothelial cell injury and its angiogenesis effects in zebrafish. The results suggested that SE showed significant anti-ischemic effects on OGD/R-induced HBEC-5i and HUVECs cell ischemia/reperfusion injury model. Furthermore, it promoted angiogenesis in PTK787-induced, MPTP-induced, and atorvastatin-induced vessel injury models of zebrafish, while also suppressing hypoxia-induced locomotor impairment in zebrafish. Transcriptome sequencing analysis provided a sign that SE likely to promotes angiogenesis through the HIF-1/VEGF signaling pathway to exert anti-ischemic effects. Consistently, SE modulated several genes related to HIF-1/VEGF signal pathway, such as hif-1, vegf, vegfr-2, pi3k, erk, akt and plcγ. Molecular docking analysis revealed that VEGFR-2 exhibited high binding affinity with SE, and western blot analysis confirmed that SE treatment enhanced the expression of VEGFR-2. In conclusion, our study profiled the angiogenic activities of SE in vitro and in vivo. The key targets and related pathways involved in anti-ischemic effects of SE, shedding light on the pharmacodynamic components and mechanisms of Corydalis decumbens, and provides valuable insights for identifying effective substances for the treatment of ischemic stroke.

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ETHNOPHARMACOLOGICAL RELEVANCE: Corydalis decumbens (Thunb.) Pers. was used as stasis-eliminating medicine traditionally to treat cardiovascular disease potentially attributed to its antithrombotic effect, but lack of pharmacological research on it. AIM OF THE STUDY: To investigate the antithrombotic effect of C. decumbens and its preliminary mechanism. MATERIALS AND METHODS: A carrageenan-induced mouse thrombus model and adenosine diphosphate stimulated platelet aggregation of rabbits were used to confirm the inhibitory effect of C. decumbens extract and compounds on thrombosis in vivo. Then, H2O2-induced human umbilical vein endothelial cells (HUVECs) injury model was further adopted to verify the effects of bioactive compounds in vitro. Moreover, in silico network pharmacology analyses and molecular docking were performed to predict the underlying mechanisms, targets, and pathways, and which were further confirmed through western blotting assay. RESULTS: The administration of total extract (TE), total alkaloids (TA) and tetrahydropalmatine (TET) resulted in a significant reduction in black tail thrombus and congestion, along with a decreasing in platelet aggregation of rabbits. A superior antithrombotic effect indicated the bioactive fraction, and then the isolated bioactive compounds, TET and protopine (PRO) increased cell survival, and decreased reactive oxygen species (ROS) and lactate dehydrogenase (LDH) release in H2O2-induced HUVECs injury model. Moreover, the two alkaloids targeted 33 major proteins and influenced 153 pathways in network pharmacology prediction. Among these, HSP90AA1, COX-2, NF-κB/p65, MMP1 and HIF-1α were the key proteins and PI3K-Akt emerged as the major signaling pathway. Further western blotting results supported that five key proteins were downregulated by the two bioactive compounds in H2O2-stimulated HUVECs model. CONCLUSION: C. decumbens exerted protective effect on thrombosis through inhibiting PI3K-Akt pathway and related key proteins, which supported the traditional use and presented potential antithrombotic alkaloids for further investigation.

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Twelve phthalideisoquinoline hemiacetal alkaloids including eight new ones (1-8) and one natural alkaloid characterized by an aziridine moiety with unassigned NMR data (9), were isolated and identified from the bulbs of Corydalis decumbens. Their structures were established by comprehensive analyses of HRESIMS, NMR, X-ray crystallography, and ECD analyses. The unambiguously established structures of the phthalideisoquinoline hemiacetal alkaloids indicated that the absolute configurations of C-1, C-9, and C-7' were confusable only relied on coupling constants. A summary of their ECD spectra was concluded and provided an insight for C-1, C-9, and C-7' absolute configuration assignment. These new compounds were evaluated to induce autophagy flux through flow cytometry analysis. Moreover, compounds 2 and 6 could significantly induce autophagy and inhibit Tau pathology by AMPK-ULK1 pathway activation, which provided an avenue for anti-AD lead compounds discovery.

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Centrifugal partition chromatography in the pH-zone-refining mode was successfully applied to the separation of alkaloids from the crude extract of Corydalis decumbens. The experiment was performed with a two-phase solvent system composed of petroleum ether-ethyl acetate-ethanol-water (5:5:3:7, v/v/v/v) where triethylamine (10 mM) was added to the stationary phase and hydrochloric acid (10 mM) to the mobile phase. From 1.6 g of the crude extract, 43 mg protopine, 189 mg (+)-egenine, and 158 mg tetrahydropalmatine were obtained with a purity of 98.2%, 94.6%, and 96.7%, respectively. Tetrahydropalmatine showed an interesting anticomplement effect with CH50 0.11 and AP50 0.25 mg/mL, respectively. In a mechanistic study, tetrahydropalmatine interacted with C1, C3, C4, and C5 components in the complement activation cascade.

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(±)-Decumicorine A (1) and (±)-epi-decumicorine A (2), two pairs of enantiomeric isoquinoline alkaloids featuring a novel phenylpropanoid-conjugated protoberberine skeleton, were isolated and purified from the rhizomes of Corydalis decumbens. The separation of (±)-1 and (±)-2 was achieved by chiral HPLC to produce four optically pure enantiomers. The structures and absolute configurations of compounds (-)-1, (+)-1, (-)-2, and (+)-2 were elucidated by spectroscopic analysis, ECD calculations, and X-ray crystallographic analyses. The two racemates were generated from a Diels-Alder [4 + 2] cycloaddition between jatrorrhizine and ferulic acid in the proposed biosynthetic pathways, which were fully verified by a biomimetic synthesis. Moreover, compound (+)-1 exhibited an antiviral entry effect on SARS-CoV-2 pseudovirus by blocking spike binding to the ACE2 receptor on HEK-293T-ACE2h host cells.

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Two new alkaloids (1 and 2), named 1,7-dimethoxy-2'-prenyl-1',9-dihydropyrrolo-carbazole (1) and 1,7-dimethoxy-4',5'-dimethylcyclopenta-carbazole-1',3'-dione (2), along with thirteen known alkaloids (3-15) were isolated by means of silica gel, sephadex LH-20, and semi-preparative HPLC from the CHCl3 extraction of Corydalis decumbens for the first time. Their structures were determined by NMR, MS, IR, UV, and related references. Compounds (1-15) were evaluated for their antidepressant activities by measuring inhibition of monoamine neurotransmitter reuptake in vitro. Among them, compounds 1, 2, 4, and 6 showed certain antidepressant activities.

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Two novel Diels-Alder [4 + 2] cycloadducts of quaternary protoberberine alkaloids and fumaric acid monoanion, corydecumbenines A and B (1 and 2), and six known isoquinoline analogues (3-8) were isolated from the rhizomes of Corydalis decumbens. The planar structures of 1 and 2 were elucidated by extensive spectroscopic analysis including UV, IR, HRESIMS, 1D and 2D NMR. Chiral chromatography of 1 and 2 afforded two pairs of enantiomers (+)-corydecumbenine A (1a), (-)-corydecumbenine A (1b), (+)-corydecumbenine B (2a), and (-)-corydecumbenine B (2b), respectively, and their absolute configurations were determined by single-crystal X-ray crystallography and comparison of experimental and calculated electronic circular dichroism (ECD) spectra. Compounds 1b and 2b exhibited significant nitric oxide (NO) inhibitory activities in lipopolysaccharide (LPS)-stimulated BV-2 cells with IC50 values of 11.6 and 16.2 µM, respectively, comparable to the positive control indomethacin (IC50 = 10.3 µM), and they could also decrease the level of interleukin (IL)-1ß in BV-2 cells in a dose-dependent manner. Most of the isolates showed neuroprotective effects against the injury of OGD/R-induced PC12 cells at 20 µM.

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Eight new alkaloids, including five isoquinoline alkaloids, a benzoazepine alkaloid, two isoindole alkaloids, and three synthetic alkaloids firstly obtained from the natural sources, together with three known ones were isolated from the bulbs of Corydalis decumbens. The structures were determined by analysis of their spectroscopic data and single-crystal X-ray diffraction. This is the first report of isoindole alkaloid and benzoazepine alkaloid from the genus Corydalis. Full NMR data for 9-11 are reported here for the first time. Moreover, the ability to modulate neuronal Ca2+ mobilization of the isolated alkaloids was tested in primary cultured neocortical neurons. Compound 7 inhibited spontaneous Ca2+ oscillations in primary neocortical neuron cultures at low micromolar concentrations.

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Two new phthalideisoquinoline hemiacetal alkaloid derivatives, named corybensines A and B (1 and 2), and four known alkaloids (3-6) were isolated from the bulbs of Corydalis decumbens. Their structures were characterized by analysis of 1D/2D NMR and ECD data, quantum chemical ECD calculations, and X-ray diffraction analysis. Among them, compound 2 represents the first naturally occurring phthalideisoquinoline hemiacetal alkaloid derivative with a 2-pyrrolidinone moiety. The activity of the isolated compounds towards neuronal excitability was examined.

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To establish a DNA molecular markers method for identification of Corydalis yanhusuo,C. turtschaninovii and C. decumbens,the mat K,trn G and psb A-trn H sequences of 56 samples from 14 species of C. yanhusuo,C. turtschaninovii,C. decumbens and their related species were obtained by sequencing. The SNP loci were obtained by Bio Edit 7. 2. 2 software. The primers for AS-PCR identification were designed based on the mutation sites,and the conditions of PCR were optimized to identify C. yanhusuo,C. turtschaninovii,and C. decumbens according to the specific bands. The results showed that the amount of template( 0. 6-1 200 ng)and annealing temperature( 42-60 ℃) had little influence on the amplification results,and the number of cycles had much influence on the amplification results. When the number of cycles was 20,the specific bands of 297 bp( mat K),353 bp( trn G) and 544 bp( mat K) were amplified from C. yanhusuo,C. turtschaninovii and C. decumbens,respectively. The method established in this study had a minimum detection limit of 6 ng for C. yanhusuo,60 ng for C. decumbens and less than 0. 6 ng for C. turtschaninovii. Thus,the allelespecific PCR method established in the research can specifically identify C. yanhusuo,C. turtschaninovii,and C. decumbens.

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To establish a DNA molecular markers method for identification of Corydalis yanhusuo,C. turtschaninovii and C. decumbens,the mat K,trn G and psb A-trn H sequences of 56 samples from 14 species of C. yanhusuo,C. turtschaninovii,C. decumbens and their related species were obtained by sequencing. The SNP loci were obtained by Bio Edit 7. 2. 2 software. The primers for AS-PCR identification were designed based on the mutation sites,and the conditions of PCR were optimized to identify C. yanhusuo,C. turtschaninovii,and C. decumbens according to the specific bands. The results showed that the amount of template( 0. 6-1 200 ng)and annealing temperature( 42-60 ℃) had little influence on the amplification results,and the number of cycles had much influence on the amplification results. When the number of cycles was 20,the specific bands of 297 bp( mat K),353 bp( trn G) and 544 bp( mat K) were amplified from C. yanhusuo,C. turtschaninovii and C. decumbens,respectively. The method established in this study had a minimum detection limit of 6 ng for C. yanhusuo,60 ng for C. decumbens and less than 0. 6 ng for C. turtschaninovii. Thus,the allelespecific PCR method established in the research can specifically identify C. yanhusuo,C. turtschaninovii,and C. decumbens.

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Many species of Corydalis (Papaveraceae) have been used as medicinal plants in East Asia, and the most well-known species are Corydalis yanhusuo and C. decumbens in the Pharmacopoeia of China. However, authentication of these species remains problematic because of their high morphological variation. Here, we selected 14 closely related species and five genomic regions (chloroplast: matK, trnG, rbcL, psbA-trnH; nuclear: ITS) to explore the utility of DNA barcoding for authenticating these herbs. In addition, the Poisson tree process (PTP) and automatic barcode gap discovery (ABGD) were also used and compared with DNA barcoding. Our results showed that the ITS region was not suitable for molecular analysis because of its heterogeneous nature in Corydalis. In contrast, matK was an ideal region for species identification because all species could be resolved when matK was used along with the other three chloroplast regions. We found that at least five traditional identified species were lumped into one genetic species by ABGD and PTP methods; thus, highlighting the overestimation of species diversity using the morphological approach. In conclusion, our first attempt of molecular analysis of Corydalis herbs presented here successfully resolved the identification of medicinal species and encouraged their taxonomic re-assessment.

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Eight previously undescribed alkaloids, named corydemine, dihydrocorydemine, corydedine, 8,13-dioxo-14-hydroxytetrahydropalmatine, egenine-α-N-oxide, egenine-ß-N-oxide, 7'-O-ethylegenine-α-N-oxide, and 7'-O-ethylegenine-ß-N-oxide, together with three known ones, muramine, l-tetrahydropalmatine, and (+)-egenine, were isolated from the bulbs of Corydalis decumbens. Their structures were elucidated by comprehensive spectroscopic analysis and chemical correlation. The isolated compounds were tested for their ability to modulate neuronal excitability in primary cultured neocortical neurons. Four of the compounds, corydemine, dihydrocorydemine, muramine, and l-tetrahydropalmatine, inhibited neuronal excitability with IC50 values of 3.6, 16.7, 13.5 and 14.0 µM, respectively.

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The roots of Corydalis decumbens are used in Chinese folk herbal medicine for treatment of a variety of diseases. In this article, developments of chemical composition, pharmacology, clinical application and recent stud-ies on pharmacokinetics of C. decumbens were reviewed and summarized for its further development and utilization.

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Objective: To study the alkaloids chemical composition from stem of Corydalis decumbens. Methods: The compounds from the ethyl acetate part were separated and purified through various kinds of chromatographic methods and their structures were identified by physico-chemical properties of spectroscopic methods. Results: Eleven alkaloids compounds were isolated and identified. They were protopine (1), muramine (2), β-allocryptopine (3), cryptopine (4), (6S, 6aS, M)-isocorydine (5), bulbocapine (6), (+)-egenine (7), (-)-corypalmine (8), bicuculline (9), (-)-7'-O-methylegenine (10), and epi-coryximine (11). Conclusion: Compounds 5 and 10 are isolated from this genus for the first time. Compound 3, 8, and 10 are isolated from this plant for the first time.

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ETHNOPHARMACOLOGICAL RELEVANCE: Corydalis decumbens, a Traditional Chinese Medicine listed in Chinese Pharmacopoeia, is clinically used for the treatment of paralytic stroke, headache, rheumatic arthritis and sciatica in China. AIM OF THE STUDY: This study was aimed to compare the pharmacokinetics and bioavailability of protopine, tetrahydropalmatine, bicuculline, and egenine in three formulations prepared from the rhizomes of Corydalis decumbens. MATERIALS AND METHODS: Alkaloid extract (CDAs-SFE) was prepared from the rhizomes of Corydalis decumbens by supercritical CO2 fluid extraction; CDAs-SFE/HPßCD (hydroxypropyl-ß-cyclodextrin inclusion complex), and CDAs-SFE/HCl (hydrochloride freeze-dried powder) were resulted from CDAs-SFE through complexation with HPßCD and hydrochloride, respectively. An UFLC-MS/MS method was developed for quantitative analysis of protopine, tetrahydropalmatine, bicuculline and egenine simultaneously in rat plasma after oral administration. The differences of pharmacokinetics and bioavailability of the four alkaloids in three formulations were determined by pharmacokinetics analyses. RESULTS AND CONCLUSIONS: The Cmax, AUC and bioavailability of protopine and tetrahydropalamatine (bioactive components) in CDAs-SFE/HCl were significantly higher than in CDAs-SFE and in CDAs-SFE/HPßCD. In contrast, in CDAs-SFE/HPßCD, AUC and bioavailability of tetrahydropalamatine were significantly lower, while those of bicuculline (toxic compound) appeared to be higher than both in CDAs-SFE and in CDAs-SFE/HCl. The results indicated that CDAs-SFE/HCl was the best beneficial formulation among the three formulations for the alkaloid extract prepared from the rhizomes of Corydalis decumbens, in which protopine and tetrahydropalamatine displayed higher bioavailability, but lower for bicuculline.

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Objective To extract alkaloids from Corydalis decumbens (AsCD) by supercritical CO2 fluid extraction (SFE) and to evaluate protective effects of AsCD against hydrogen peroxide (H2O2)-induced apoptosis in rat PC12 cells.Methods AsCD were extracted by SFE and oxidative damage PC12 cells model was induced by H2O2.The survival rate of the cells was determined by MTT assay; Lactate dehydrogenase release was determined by ultraviolet spectrophotometry; Flow cytometry was used to detect apoptosis; Caspase-3 mRNA and protein were determined by real-time PCR and Western blotting assay,respectively.Results AsCD remarkably reduced the cytotoxicity,prevented membrane damage,and inhibited cell apoptosis.AsCD inhibited Caspase-3 mRNA and protein expression induced by H2O2 in PC12 cells.Conclusion AsCD possess protective effects against H2O2-induced apoptosis in PC12 cells,and the mechanism of AsCD responsible to the inhibition of apoptosis is possibly attributed to thedown-regulating Caspase-3 expression.AsCD might be useful in the treatment of oxidative stress-related neurodegenerative diseases.

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AIM: To observe the effects of Corydalis decumbens Pers Injection(CDPI) on the learning,memory and Ang-1 expression of hippocampus in vascular dementia rats,and to explore the protective mechanisms. METHOD: The VD model rat model was established by the ligation of both carotids of the rat.Morris water-maze was used to examine the ability of spatial learning and memory of VD model rats.Hippocampal histopathological change was observed through optical microscope after being stained with Hematoxylin-eosin(HE).The semi quantitative analysis of Ang-1 expression in hippocampus was analysed by BI2000 image analysis system after immunohistochemistry staining. RESULTS: In the place naviga test,the mean escape latency significantly shorted and the explporing distance obviously decreased in CDPI 2 mg/kg、5 mg/kg groups after one month and two months compared with model group.After two months with CDPI treatment,Ang-1 exprssion of hippocampus increased in VD rats. CONCLUSIONS: CDPI can improve the ability of spatial learning and memory.The mechanism may be related to increasing expression of Ang-1 in hippocampus.

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Objective:To establish the content determination method of the main alkaloids protopine and tetrahydropalmatine in Corydalis decumbens (Thunb.) Pers. Methods: HPLC was used to determinate the main alkaloids protopine and tetrahydropalmatine in Corydalis decumbene (Thunb.) Pers. Supelcosil LC 18 DB Column was used, mobile phase consisted of Methol NaAc/HAc(75∶25 pH5.0) and detection wavelength at UV 285 nm. Results: Linearity of this method was good with the average recoveries, 98.04% and 99.63%. Conclusion: This method is accurate, reliable with good separability and reproducibility, it can be applied as standard for the control of Corydalis decumbens (Thunb.) Pers.