BACKGROUND The mortality rate for severe cases of acute pancreatitis(AP),a common gastrointestinal emergency,is as high as 30%.Our previous study has shown that rutaecarpine(Rut)has a therapeutic effect on AP.AIM To i...BACKGROUND The mortality rate for severe cases of acute pancreatitis(AP),a common gastrointestinal emergency,is as high as 30%.Our previous study has shown that rutaecarpine(Rut)has a therapeutic effect on AP.AIM To investigate the role of F-box and WD repeat domain containing 11(FBXW11)in AP models and to assess whether Rut mitigates AP by regulating FBXW11.METHODS AP rat model was established and treated with Rut,followed by biochemical analysis of serum amylase and lipase,hematoxylin and eosin staining of pancreatic tissue,and immunohistochemistry detection of pancreatic Ly6G,CD11b,and myeloperoxidase.Assay kits were used to detect oxidative stress-related indicators in pancreatic tissue and inflammatory factors in serum.AR42J cells were treated with cerulein to model AP and subjected to Cell Counting Kit-8 viability assay,flow cytometry apoptosis assay,and immunofluorescence detection of reactive oxygen species to elucidate the mechanistic involvement of the enhancer of zeste homolog 2(EZH2)-FBXW11 axis in Rut-mediated protection against AP.The EZH2-histone H3 binding and H3 methylation were evaluated using co-immunoprecipitation.RESULTS Rut treatment ameliorated AP severity,as evidenced by reduced serum levels of pancreatic enzymes(amylase and lipase)and attenuated histological damage.Rut also decreased inflammatory markers(interleukin-1 beta,interleukin-6,and tumor necrosis factor alpha),tissue oxidative stress(malondialdehyde),and neutrophil infiltration(Ly6G,CD11b,and myeloperoxidase)levels in rats with AP.Moreover,Rut restored pancreatic antioxidant capacity(glutathione and superoxide dismutase).In vitro,Rut pre-incubation enhanced cell viability and suppressed cerulein-induced apoptosis and oxidative stress.Rut increased EZH2 expression while decreasing FBXW11 expression.FBXW11 overexpression eliminated the protective effect of Rut against AP.Further analysis revealed that EZH2 binds to H3 and upregulates H3 methylation levels,thereby inhibiting FBXW11 expression.CONCLUSION Collectively,our findings demonstrate that Rut ameliorates AP by upregulating EZH2,thereby enhancing H3 methylation and suppressing FBXW11 expression.展开更多
The aims of the present study are to investigate the effect of vasoconstriction and to explore the mechanism of rutae- carpine. The research findings showed that rutaecarpine could induce contractions of the rat thora...The aims of the present study are to investigate the effect of vasoconstriction and to explore the mechanism of rutae- carpine. The research findings showed that rutaecarpine could induce contractions of the rat thoracic aorta in vitro. The inhibitors of Rho-kinase and inositol 1,4,5-triphosphate receptor （IP 3 R） could suppress the effect of rutaecarpine-induced vasoconstriction. In the study of A7r5 cells （a line of smooth muscle cells）, 300 μg/L rutaecarpine promoted the concentration of intracellular Ca 2＋ and enhanced the IP 3 R expression, which connects with 1,4,5-triphosphate to evoke the release of Ca 2＋ from the intracellular stores. Rutaecarpine increased the RhoA mRNA expression when the cells were pretreated with inhibitor H-1152, and improved the levels of phosphorylation of myosin light chain phosphatase （MLCP） and myosin light chain （MLC）. These results suggest that rutaecarpine plays a role in vasoconstriction relative to the RhoA/MLCP-MLC signaling pathway, which denotes a new field of rutaecarpine in pharmacology.展开更多
Rutaecarpine, an active component of the traditional Chinese medicine Tetradium ruticarpum, has been shown to improve myocardial ischemia repeffusion injury. Because both cardiovascular and cerebrovascular diseases ar...Rutaecarpine, an active component of the traditional Chinese medicine Tetradium ruticarpum, has been shown to improve myocardial ischemia repeffusion injury. Because both cardiovascular and cerebrovascular diseases are forms of ischemic vascular disease, they are closely related. We hypothesized that rutaecarpine also has neuroprotective effects on cerebral ischemia reperfusion injury. A cerebral ischemia reperfusion model was established after 84, 252 and 504 pg/kg rutae- carpine were given to mice via intrapedtoneal injection, daily for 7 days. Results of the step through test, 2,3,5-triphenyl tetrazolium chloride dyeing and oxidative stress indicators showed that rutae- carpine could improve learning and memory ability, neurological symptoms and reduce infarction volume and cerebral water content in mice with cerebral ischemia reperfusion injury. Rutaecarpine could significantly decrease the malondialdehyde content and increase the activities of superoxide dismutase and glutathione peroxidase in mouse brain. Therefore, rutaecarpine could improve neu- rological function following injury induced by cerebral ischemia reperfusion, and the mechanism of this improvement may be associated with oxidative stress. These results verify that rutaecarpine has neuroprotective effects on cerebral ischemia reperfusion in mice.展开更多
Evodiamine,rutaecarpine,and dehydroevodiamine have been demonstrated as the major alkaloids in the fruits of Euodia rutaecarpa,a well-known traditional Chinese medicine with central nervous system activities.To study ...Evodiamine,rutaecarpine,and dehydroevodiamine have been demonstrated as the major alkaloids in the fruits of Euodia rutaecarpa,a well-known traditional Chinese medicine with central nervous system activities.To study their cerebrospinal fluid pharmacokinetics and cerebral nuclei distribution,the alkaloids were mixed at the weight ratio of 1:1:1 and orally administered via gavage to the rats at each dose of 15 mg/kg.A quick and reliable ultra-performance liquid chromatographic-tandem mass spectrometry method was developed and applied for the simultaneous analysis of the alkaloids in rat cerebrospinal fluid and cerebral nuclei collected at different time points.Non-compartmental pharmacokinetic profiles were calculated,and the distribution in cerebral nuclei was compared.All the tested compounds were absorbed into rat cerebrospinal fluid and distributed to the brain nuclei quickly.Their distribution in different nuclei varied,as evodiamine mainly in cerebellum and brainstem,rutaecarpine with its maximum in the brainstem,and dehydroevodiamine mostly in the cerebellum and hippocampus.They were eliminated from the brain rapidly without long-time accumulation.In summary,this study revealed the targeting discrepancy of evodiamine,rutaecarpine,and dehydroevodiamine in the brain,and highlighted the possibility for drug candidates in the encephalopathy treatment of the fruits of E.rutaecarpa.展开更多
Background:Pulmonary arterial hypertension presents with obliterative remodeling of the pulmonary arteries and progressive elevation of pulmonary vascular resistance,which increase the risk of right ventricular failur...Background:Pulmonary arterial hypertension presents with obliterative remodeling of the pulmonary arteries and progressive elevation of pulmonary vascular resistance,which increase the risk of right ventricular failure and death.It has been reported in previous studies that rutaecarpine plays a crucial role in anti-inflammatory and antioxidant activities,which may help regulate cell apoptosis and cell proliferation.The purpose of this study was to determine the effects of rutaecarpine in the rat model of monocrotaline-induced pulmonary hypertension.Methods:We induced pulmonary arterial hypertension in adult Sprague-Dawley rats by injecting monocrotaline(60 mg/kg)and then treated with rutaecarpine(40 mg/kg·d)or sildenafil(30 mg/kg·d)(positive control).Subsequently,pulmonary function,inflammation,cytokines and pulmonary vascular remodeling or proliferation were assessed.Results:Rutaecarpine was found to improve monocrotaline-induced mean pulmonary artery pressure,cardiac index,right heart index,right ventricular hypertrophy index,pulmonary artery remodeling and pulmonary function.reverse transcription-quantitative polymerase chain reaction demonstrated a decrease in tumor necrosis factor-α,interleukin-6 and interleukin-1β,whereas western blots a significantly decrease in the expression of nuclear factor kappa-B,endothelin-1,extracellular signal-regulated kinases 1/2,B cell lymphoma-2,Beclin1 and microtubule-associated protein1 light chain 3-II protein,and increase in the expression of Bax,caspase-3 and p62 protein.Conclusion:Rutaecarpine attenuated pulmonary arterial hypertension by inhibiting inflammation,oxidative stress,cell proliferation and autophagy,while promoting apoptosis.展开更多
The antitumor activities of two alkaloids, evodiamine（EVO） and rutaecarpine（RUT）, against MCF-7, SMMC-7721 and SW-1353 cells growth in vitro were investigated by MTT assay. The results showed that the anti-tumor e...The antitumor activities of two alkaloids, evodiamine（EVO） and rutaecarpine（RUT）, against MCF-7, SMMC-7721 and SW-1353 cells growth in vitro were investigated by MTT assay. The results showed that the anti-tumor effects of two alkaloids were remarkably different. In order to discover the relationship of antitumor activity and structures of the compounds, the dihedral angle, Natural Electron Configuration, frontier molecular orbital profiles（HOMO, LUMO）and bandgaps of these two compounds have been studied based on density functional theory（DFT）by means of DFT-B3LYP/6-31G（d） in Gaussian 03. The calculation results of dihedral angle showed that EVO, due to the existence of methyl group attached to the N（14） atom, have non-planar and twisted structures, which decrease the stability of EVO and increase the activity of EVO. Furthermore, the bandgaps of RUT are lower than that of EVO, indicating RUT has higher stability than EVO, so the activity of EVO is higher than that of RUT. In addition, the negative charge of N14 atom in EVO is lower than that of in RUT, so the positive charge of N（14） atom in EVO is higher than that of in RUT, which suggests that the nucleophile is easier to aggress the N（14） atom in EVO than that in RUT, so the reason of the different antitumor activities of EVO and RUT may be attacked by nucleophile.展开更多
Objective To investigate the anti-inflammatory effect of rutaecarpine(RUT)on monosodium urate crystal(MSU)-induced murine peritonitis in mice and further explored the underlying mechanism of RUT in lipopolysaccharide(...Objective To investigate the anti-inflammatory effect of rutaecarpine(RUT)on monosodium urate crystal(MSU)-induced murine peritonitis in mice and further explored the underlying mechanism of RUT in lipopolysaccharide(LPS)/MSU-induced gout model in vitro.Methods In MSU-induced mice,36 male C57BL/6 mice were randomly divided into 6 groups of 8 mice each group,including the control group,model group,RUT low-,medium-,and high-doses groups,and prednisone acetate group.The mice in each group were orally administered the corresponding drugs or vehicle once a day for 7 consecutive days.The gout inflammation model was established by intraperitoneal injection of MSU to evaluate the anti-gout inflammatory effects of RUT.Then the proinflammatory cytokines were measured by enzyme-linked immunosorbent assay(ELISA)and the proportions of infiltrating neutrophils cytokines were detected by flow cytometry.In LPS/MSU-treated or untreated THP-1 macrophages,cell viability was observed by cell counting kit 8 and proinflammatory cytokines were measured by ELISA.The percentage of pyroptotic cells were detected by flow cytometry.Respectively,the mRNA and protein levels were measured by real-time quantitative polymerase chain reaction(qRT-PCR)and Western blot,the nuclear translocation of nuclear factorκB(NF-κB)p65 was observed by laser confocal imaging.Additionally,surface plasmon resonance(SPR)and molecular docking were applied to validate the binding ability of RUT components to tumor necrosis factorα(TNF-α)targets.Results RUT reduced the levels of infiltrating neutrophils and monocytes and decreased the levels of the proinflammatory cytokines interleukin 1β(IL-1β)and interleukin 6(IL-6,all P<0.01).In vitro,RUT reduced the production of IL-1β,IL-6 and TNF-α.In addition,RT-PCR revealed the inhibitory effects of RUT on the mRNA levels of IL-1β,IL-6,cyclooxygenase-2 and TNF-α(P<0.05 or P<0.01).Mechanistically,RUT markedly reduced protein expressions of tumor necrosis factor receptor(TNFR),phospho-mitogen-activated protein kinase(p-MAPK),phospho-extracellular signal-regulated kinase,phospho-c-Jun N-terminal kinase,phospho-NF-κB,phospho-kinaseα/β,NOD-like receptor thermal protein domain associated protein 3(NLRPS),cleaved-cysteinyl aspartate specific proteinase-1 and cleaved-gasdermin D in macrophages(P<0.05 or P<0.01).Molecularly,SPR revealed that RUT bound to TNF-αwith a calculated equilibrium dissociation constant of 31.7µmol/L.Molecular docking further confirmed that RUT could interact directly with the TNF-αprotein via hydrogen bonding,van der Waals interactions,and carbon-hydrogen bonding.Conclusion RUT alleviated MSU-induced peritonitis and inhibited the TNFR1-MAPK/NF-κB and NLRP3 inflammasome signaling pathway to attenuate gouty inflammation induced by LPS/MSU in THP-1 macrophages,suggesting that RUT could be a potential therapeutic candidate for gout.展开更多
Objective： To evaluate the effects and possible mechanisms of rutaecarpine on angiotensin Ⅱ （Ang Ⅱ ）-induced proliferation in cultured rat vascular smooth muscle cells （VSMCs）. Methods： VSMCs were isolated fro...Objective： To evaluate the effects and possible mechanisms of rutaecarpine on angiotensin Ⅱ （Ang Ⅱ ）-induced proliferation in cultured rat vascular smooth muscle cells （VSMCs）. Methods： VSMCs were isolated from Male Sprague-Dawley rat aorta, and cultured by enzymic dispersion method. Experiments were performed with cells from passages 3-8. The cultured VSMCs were randomly divided into control, model （Ang Ⅱ 0.1 μ moVL）, and rutaecarpine （0.3-3.0μmol/L） groups. VMSC proliferation was induced by Ang Ⅱ, and was evaluated by the 3-（4, 5-dimethylthiazol-2-yl）-2, 5-diphenyltetrazolium bromide assay and cell counting. To examine the mechanisms involved in anti-proliferative effects of rutaecarpine, nitric oxide （NO） levels and NO synthetase （NOS） activity were determined. Expressions of VSMC proliferation-related genes including endothelial nitric oxide synthase （eNOS）, and c-myc hypertension related gene-1 （HRG-1） were determined by real-time reverse chain reaction （RT-PCR）. Results： Rutaecarpine （0.3-3.0μmol/l_） inhibited Ang R-induced VSMC proliferation and the best effects were achieved at 3.0 μmol/L. The Ang Ⅱ-induced decreases in cellular NO contents and NOS activities were antagonized by rutaecarpine （P〈0.05）. Ang Ⅱ administration suppressed the expressions of eNOS and HRG-1, while increased c-myc expression （P〈0.05）. All these effects were attenuated by 3.0μmol/L rutaecarpine （P〈0.05）. Conclusion： Rutaecarpine is effective against Ang Ⅱ-induced rat VSMC proliferation, and this effect is due, at least in part, to NO production and the modulation of VMSC proliferation-related gene expressions.展开更多
Objective： To investigate the effect and potential mechanisms of rutaecarpine （Rut） in a rat artery balloon-injury model. Methods： The intimal hyperplasia model was established by rubbing the endothelia with a bal...Objective： To investigate the effect and potential mechanisms of rutaecarpine （Rut） in a rat artery balloon-injury model. Methods： The intimal hyperplasia model was established by rubbing the endothelia with a balloon catheter in the common carotid artery （CCA） of rats. Fifty rats were randomly divided into five groups, ie. sham, model, Rut （25, 50 and 75 mg/kg） with 10 rats of each group. The rats were treated with or without Rut （25, 50, 75 mg/kg） by intragastric administration for 14 consecutive days following injury. The morphological changes of the intima were evaluated by hematoxylin-eosin staining. The expressions of proliferating cell nuclear antigen （PCNA） and smooth muscle （SM） oL-actin in the ateries were assayed by immunohistochemical staining. The mRNA expressions of c-myc, extracellular signal-regulated kinase 2 （ERK2）, MAPK phosphatase-1 （MKP-1） and endothelial nitric oxide synthase （eNOS） were determined by real-time reverse chain reaction. The protein expressions of MKP-1 and phosphorylated ERK2 （p-ERK2） were examined by Western blotting. The plasma contents of nitric oxide （NO） and cyclic guanosine 3＇,5＇-monophosphate （cGMP） were also determined. Results： Compared with the model group, Rut treatment significantly decreased intimal thickening and ameliorated endothelial injury （P〈0.05 or P〈0.01）. The positive expression rate of PCNA was decreased, while the expression rate of SM α -actin obviously increased in the vascular wall after Rut （50 and 75 mg/kg） administration （P〈0.05 or P〈0.01）. Furthermore, the mRNA expressions of c-myc, ERK2 and PCNA were downregulated while the expressions of eNOS and MKP-1 were upregulated （P〈0.05 or P〈0.01）. The protein expressions of MKP-1 and the phosphorylation of ERK2 were upregulated and downragulated after Rut （50 and 75 mg/kg） administration （P〈0.05 or P〈0.01）, respectively. In addition, Rut dramatically reversed balloon injury-induced decrease of NO and cGMP in the plasma （P〈0.05 or P〈0.01）. Conclusion： Rut could inhibit the balloon injury-induced carotid intimal hyperplasia in rats, possibly mediated by promotion of NO production and inhibiting ERK2 signal transduction pathways.展开更多
Objective: Chronic atrophic gastritis(CAG) is a complex and burdensome disease. However, side effects and compliance issues cannot be ignored due to the long treatment cycle. Numerous studies have confirmed the effect...Objective: Chronic atrophic gastritis(CAG) is a complex and burdensome disease. However, side effects and compliance issues cannot be ignored due to the long treatment cycle. Numerous studies have confirmed the effectiveness of rutaecarpine(RUT) for treating digestive dysfunction. However, the potential mechanism of action of RUT in the context of CAG treatment remains unclear. This study aimed to explore the therapeutic effects and mechanisms of RUT in 1-methyl-3-nitro-1-nitrosoguanidine-induced CAG using network pharmacology,metabolomics, and traditional pharmacological approaches. Materials and Methods: Pathological tests and ELISA assays were used to observe the therapeutic effects of RUT treatment on CAG. Differential metabolites were identified using ultra-high-performance liquid chromatography-tandem mass spectrometry, and metabolism-related target genes were enriched. The same target genes were identified between RUT and CAG diseases. The intersectional target genes were uploaded to Cytoscape for enrichment, and the nucleotide-binding oligomerization domain(NOD)-like receptor signaling pathway was selected to validate the mechanisms of the study. Finally, cell pyroptosis status was evaluated using the terminal deoxynucleotidyl transferase-mediated d UTP nick end labeling assay, and the expressions of associated proteins of the NOD-like receptor signaling pathway were assessed by Western blotting and immunohistochemistry. Results: RUT alleviated gastric mucosal damage and significantly downregulated indicators associated with infiammation and gastric atrophy. A total of 29 intersection target genes was identified, and core pathways were obtained. The NOD-like receptor signaling pathway and pyroptosis status were selected to validate the mechanisms of RUT treatment in CAG rats. The expression of NOD-related proteins and downstream factors was downregulated in the RUT group. Conclusions: RUT exerts a pharmacological effect on relieving gastric damage in CAG rats by inhibiting NOD-like receptors and infiammasomes.展开更多
In the present study, we studied the inhibitory effects of chelidonine and rutaecarpin on porcine pancreatic a-amylase （PPA） catalyzed hydrolysis using 2-chloro-4-nitrophenyl-4-O-β-D-galactopyranosylmaltoside （Gal...In the present study, we studied the inhibitory effects of chelidonine and rutaecarpin on porcine pancreatic a-amylase （PPA） catalyzed hydrolysis using 2-chloro-4-nitrophenyl-4-O-β-D-galactopyranosylmaltoside （Gal-G2-α-CNP）. We, for the first time, provided kinetic report and detailed inhibitory effects of both compounds on PPA. Lineweaver-Burk plot revealed that the inhibition was a mixed-noncompetitive type, and only one molecule of inhibitor bound to the enzyme or to the enzyme-substrate complex. Kinetic constants calculated from secondary plots were in millimole range. Dissociation constants of enzyme-inhibitor complex （KEI） were 0.9 mM and 3.5 mM, respectively. Moreover, dissociation constants of enzyme-inhibitor-substrate complex （KESI） were 0.04 mM and 0.31 mM, respectively. These data indicated that the inhibition was more inclined to competitive to Gal-G2-α-CNP hydrolysis. Further molecular docking study manifested that hydrogen bonding formed between acarbose and aspartic acid （Asp300）, histidine （His305） and glycine （Gly3-6）, while hydrogen bonding was observed between chelidonine and glutamic acid （Glu233）, lysine （Lys200） and His305. In addition, rutaecarpine had only one hydrogen bond with Lys200. Our data indicated that chelidonine and rutaecarpine were two promising drug candidates, and chelidonine possessed stronger inhibitory effect compared with rutaecarpine.展开更多
Objective To control the quality of Evodia rutaecarpa better.Methods An HPLC-DAD-MS/MS method was established for the rapid and efficient identification of bioactive constituents and for simultaneous quantitative anal...Objective To control the quality of Evodia rutaecarpa better.Methods An HPLC-DAD-MS/MS method was established for the rapid and efficient identification of bioactive constituents and for simultaneous quantitative analysis of four bioactive ingredients including evodiamine,rutaecarpine,dehydroevodiamine,and evodin in E.rutaecarpa,which was applied to evaluating eight samples of E.rutaecarpa and its varieties from different areas.Results Thirteen potentially bioactive constituents including one flavonoid glycoside,one limonin,four indoloquinazoline alkaloids,and seven quinolone alkaloids were identified in all samples and the contents of dehydroevodiamine,evodine,evodiamine,and rutaecarpine varied widely from 0.10%to 0.51%,0.49%to 3.12%,0.07%to 1.56%,and 0.10%to 0.69%,respectively.Conclusion This method is found to be convenient,fast,accurate,and it is facilitated to improve the quality control standard of E.rutaecarpa and related products.展开更多
基金Supported by Hunan Provincial Natural Science Foundation of China,No.2022JJ40836the Key Project of Research and Development Plan of Hunan Province,No.2023DK2002the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation,No.GZC20242045.
文摘BACKGROUND The mortality rate for severe cases of acute pancreatitis(AP),a common gastrointestinal emergency,is as high as 30%.Our previous study has shown that rutaecarpine(Rut)has a therapeutic effect on AP.AIM To investigate the role of F-box and WD repeat domain containing 11(FBXW11)in AP models and to assess whether Rut mitigates AP by regulating FBXW11.METHODS AP rat model was established and treated with Rut,followed by biochemical analysis of serum amylase and lipase,hematoxylin and eosin staining of pancreatic tissue,and immunohistochemistry detection of pancreatic Ly6G,CD11b,and myeloperoxidase.Assay kits were used to detect oxidative stress-related indicators in pancreatic tissue and inflammatory factors in serum.AR42J cells were treated with cerulein to model AP and subjected to Cell Counting Kit-8 viability assay,flow cytometry apoptosis assay,and immunofluorescence detection of reactive oxygen species to elucidate the mechanistic involvement of the enhancer of zeste homolog 2(EZH2)-FBXW11 axis in Rut-mediated protection against AP.The EZH2-histone H3 binding and H3 methylation were evaluated using co-immunoprecipitation.RESULTS Rut treatment ameliorated AP severity,as evidenced by reduced serum levels of pancreatic enzymes(amylase and lipase)and attenuated histological damage.Rut also decreased inflammatory markers(interleukin-1 beta,interleukin-6,and tumor necrosis factor alpha),tissue oxidative stress(malondialdehyde),and neutrophil infiltration(Ly6G,CD11b,and myeloperoxidase)levels in rats with AP.Moreover,Rut restored pancreatic antioxidant capacity(glutathione and superoxide dismutase).In vitro,Rut pre-incubation enhanced cell viability and suppressed cerulein-induced apoptosis and oxidative stress.Rut increased EZH2 expression while decreasing FBXW11 expression.FBXW11 overexpression eliminated the protective effect of Rut against AP.Further analysis revealed that EZH2 binds to H3 and upregulates H3 methylation levels,thereby inhibiting FBXW11 expression.CONCLUSION Collectively,our findings demonstrate that Rut ameliorates AP by upregulating EZH2,thereby enhancing H3 methylation and suppressing FBXW11 expression.
基金National Natural Science Foundation of China (Grant No.30801523,30973896,and 81073092)the Projects of Science Research for the 11th Five-Year Plan of the Ministry of Science and Technology of China (Grant No.2006BAI08B03-09)+1 种基金the China's Post-Doctoral Science Fund (Grant No.20080440418)the National S&T Major Special Project for New Drug R&D of China (Grant No.2012ZX09102-201-008,2012ZX09103-201-041and2011ZX09101-002-11)
文摘The aims of the present study are to investigate the effect of vasoconstriction and to explore the mechanism of rutae- carpine. The research findings showed that rutaecarpine could induce contractions of the rat thoracic aorta in vitro. The inhibitors of Rho-kinase and inositol 1,4,5-triphosphate receptor （IP 3 R） could suppress the effect of rutaecarpine-induced vasoconstriction. In the study of A7r5 cells （a line of smooth muscle cells）, 300 μg/L rutaecarpine promoted the concentration of intracellular Ca 2＋ and enhanced the IP 3 R expression, which connects with 1,4,5-triphosphate to evoke the release of Ca 2＋ from the intracellular stores. Rutaecarpine increased the RhoA mRNA expression when the cells were pretreated with inhibitor H-1152, and improved the levels of phosphorylation of myosin light chain phosphatase （MLCP） and myosin light chain （MLC）. These results suggest that rutaecarpine plays a role in vasoconstriction relative to the RhoA/MLCP-MLC signaling pathway, which denotes a new field of rutaecarpine in pharmacology.
基金financially supported by Zhangjiakou Science and Technology Commission Foundation,No.1021095Dthe Hebei North University Foundation,No.Q2010018
文摘Rutaecarpine, an active component of the traditional Chinese medicine Tetradium ruticarpum, has been shown to improve myocardial ischemia repeffusion injury. Because both cardiovascular and cerebrovascular diseases are forms of ischemic vascular disease, they are closely related. We hypothesized that rutaecarpine also has neuroprotective effects on cerebral ischemia reperfusion injury. A cerebral ischemia reperfusion model was established after 84, 252 and 504 pg/kg rutae- carpine were given to mice via intrapedtoneal injection, daily for 7 days. Results of the step through test, 2,3,5-triphenyl tetrazolium chloride dyeing and oxidative stress indicators showed that rutae- carpine could improve learning and memory ability, neurological symptoms and reduce infarction volume and cerebral water content in mice with cerebral ischemia reperfusion injury. Rutaecarpine could significantly decrease the malondialdehyde content and increase the activities of superoxide dismutase and glutathione peroxidase in mouse brain. Therefore, rutaecarpine could improve neu- rological function following injury induced by cerebral ischemia reperfusion, and the mechanism of this improvement may be associated with oxidative stress. These results verify that rutaecarpine has neuroprotective effects on cerebral ischemia reperfusion in mice.
基金National Natural Science Foundation of China(Grant No.81773865)the National Key R&D Program of China(Grant No.2018YFC1704500,2018YFC1704506)。
文摘Evodiamine,rutaecarpine,and dehydroevodiamine have been demonstrated as the major alkaloids in the fruits of Euodia rutaecarpa,a well-known traditional Chinese medicine with central nervous system activities.To study their cerebrospinal fluid pharmacokinetics and cerebral nuclei distribution,the alkaloids were mixed at the weight ratio of 1:1:1 and orally administered via gavage to the rats at each dose of 15 mg/kg.A quick and reliable ultra-performance liquid chromatographic-tandem mass spectrometry method was developed and applied for the simultaneous analysis of the alkaloids in rat cerebrospinal fluid and cerebral nuclei collected at different time points.Non-compartmental pharmacokinetic profiles were calculated,and the distribution in cerebral nuclei was compared.All the tested compounds were absorbed into rat cerebrospinal fluid and distributed to the brain nuclei quickly.Their distribution in different nuclei varied,as evodiamine mainly in cerebellum and brainstem,rutaecarpine with its maximum in the brainstem,and dehydroevodiamine mostly in the cerebellum and hippocampus.They were eliminated from the brain rapidly without long-time accumulation.In summary,this study revealed the targeting discrepancy of evodiamine,rutaecarpine,and dehydroevodiamine in the brain,and highlighted the possibility for drug candidates in the encephalopathy treatment of the fruits of E.rutaecarpa.
文摘Background:Pulmonary arterial hypertension presents with obliterative remodeling of the pulmonary arteries and progressive elevation of pulmonary vascular resistance,which increase the risk of right ventricular failure and death.It has been reported in previous studies that rutaecarpine plays a crucial role in anti-inflammatory and antioxidant activities,which may help regulate cell apoptosis and cell proliferation.The purpose of this study was to determine the effects of rutaecarpine in the rat model of monocrotaline-induced pulmonary hypertension.Methods:We induced pulmonary arterial hypertension in adult Sprague-Dawley rats by injecting monocrotaline(60 mg/kg)and then treated with rutaecarpine(40 mg/kg·d)or sildenafil(30 mg/kg·d)(positive control).Subsequently,pulmonary function,inflammation,cytokines and pulmonary vascular remodeling or proliferation were assessed.Results:Rutaecarpine was found to improve monocrotaline-induced mean pulmonary artery pressure,cardiac index,right heart index,right ventricular hypertrophy index,pulmonary artery remodeling and pulmonary function.reverse transcription-quantitative polymerase chain reaction demonstrated a decrease in tumor necrosis factor-α,interleukin-6 and interleukin-1β,whereas western blots a significantly decrease in the expression of nuclear factor kappa-B,endothelin-1,extracellular signal-regulated kinases 1/2,B cell lymphoma-2,Beclin1 and microtubule-associated protein1 light chain 3-II protein,and increase in the expression of Bax,caspase-3 and p62 protein.Conclusion:Rutaecarpine attenuated pulmonary arterial hypertension by inhibiting inflammation,oxidative stress,cell proliferation and autophagy,while promoting apoptosis.
基金Supported by the National Natural Science Foundation of China(81001669,81373944)the Natural Science Basic Research Plan in Shaanxi Province(2016JM8028)
文摘The antitumor activities of two alkaloids, evodiamine（EVO） and rutaecarpine（RUT）, against MCF-7, SMMC-7721 and SW-1353 cells growth in vitro were investigated by MTT assay. The results showed that the anti-tumor effects of two alkaloids were remarkably different. In order to discover the relationship of antitumor activity and structures of the compounds, the dihedral angle, Natural Electron Configuration, frontier molecular orbital profiles（HOMO, LUMO）and bandgaps of these two compounds have been studied based on density functional theory（DFT）by means of DFT-B3LYP/6-31G（d） in Gaussian 03. The calculation results of dihedral angle showed that EVO, due to the existence of methyl group attached to the N（14） atom, have non-planar and twisted structures, which decrease the stability of EVO and increase the activity of EVO. Furthermore, the bandgaps of RUT are lower than that of EVO, indicating RUT has higher stability than EVO, so the activity of EVO is higher than that of RUT. In addition, the negative charge of N14 atom in EVO is lower than that of in RUT, so the positive charge of N（14） atom in EVO is higher than that of in RUT, which suggests that the nucleophile is easier to aggress the N（14） atom in EVO than that in RUT, so the reason of the different antitumor activities of EVO and RUT may be attacked by nucleophile.
基金Supported by the Science and Technology Department of Sichuan Province(No.2023NSFSC0669)the Sichuan Provincial Administration of Traditional Chinese Medicine(Nos.2023MS469 and 2022C009)。
文摘Objective To investigate the anti-inflammatory effect of rutaecarpine(RUT)on monosodium urate crystal(MSU)-induced murine peritonitis in mice and further explored the underlying mechanism of RUT in lipopolysaccharide(LPS)/MSU-induced gout model in vitro.Methods In MSU-induced mice,36 male C57BL/6 mice were randomly divided into 6 groups of 8 mice each group,including the control group,model group,RUT low-,medium-,and high-doses groups,and prednisone acetate group.The mice in each group were orally administered the corresponding drugs or vehicle once a day for 7 consecutive days.The gout inflammation model was established by intraperitoneal injection of MSU to evaluate the anti-gout inflammatory effects of RUT.Then the proinflammatory cytokines were measured by enzyme-linked immunosorbent assay(ELISA)and the proportions of infiltrating neutrophils cytokines were detected by flow cytometry.In LPS/MSU-treated or untreated THP-1 macrophages,cell viability was observed by cell counting kit 8 and proinflammatory cytokines were measured by ELISA.The percentage of pyroptotic cells were detected by flow cytometry.Respectively,the mRNA and protein levels were measured by real-time quantitative polymerase chain reaction(qRT-PCR)and Western blot,the nuclear translocation of nuclear factorκB(NF-κB)p65 was observed by laser confocal imaging.Additionally,surface plasmon resonance(SPR)and molecular docking were applied to validate the binding ability of RUT components to tumor necrosis factorα(TNF-α)targets.Results RUT reduced the levels of infiltrating neutrophils and monocytes and decreased the levels of the proinflammatory cytokines interleukin 1β(IL-1β)and interleukin 6(IL-6,all P<0.01).In vitro,RUT reduced the production of IL-1β,IL-6 and TNF-α.In addition,RT-PCR revealed the inhibitory effects of RUT on the mRNA levels of IL-1β,IL-6,cyclooxygenase-2 and TNF-α(P<0.05 or P<0.01).Mechanistically,RUT markedly reduced protein expressions of tumor necrosis factor receptor(TNFR),phospho-mitogen-activated protein kinase(p-MAPK),phospho-extracellular signal-regulated kinase,phospho-c-Jun N-terminal kinase,phospho-NF-κB,phospho-kinaseα/β,NOD-like receptor thermal protein domain associated protein 3(NLRPS),cleaved-cysteinyl aspartate specific proteinase-1 and cleaved-gasdermin D in macrophages(P<0.05 or P<0.01).Molecularly,SPR revealed that RUT bound to TNF-αwith a calculated equilibrium dissociation constant of 31.7µmol/L.Molecular docking further confirmed that RUT could interact directly with the TNF-αprotein via hydrogen bonding,van der Waals interactions,and carbon-hydrogen bonding.Conclusion RUT alleviated MSU-induced peritonitis and inhibited the TNFR1-MAPK/NF-κB and NLRP3 inflammasome signaling pathway to attenuate gouty inflammation induced by LPS/MSU in THP-1 macrophages,suggesting that RUT could be a potential therapeutic candidate for gout.
基金Supported by the National Natural Science Foundation of China(No.81160528)the Governor Foundation of Guizhou Province(No.2006-07)Administration of Traditional Chinese Medicine of Guizhou Province Foundation(No.2009-79)
文摘Objective： To evaluate the effects and possible mechanisms of rutaecarpine on angiotensin Ⅱ （Ang Ⅱ ）-induced proliferation in cultured rat vascular smooth muscle cells （VSMCs）. Methods： VSMCs were isolated from Male Sprague-Dawley rat aorta, and cultured by enzymic dispersion method. Experiments were performed with cells from passages 3-8. The cultured VSMCs were randomly divided into control, model （Ang Ⅱ 0.1 μ moVL）, and rutaecarpine （0.3-3.0μmol/L） groups. VMSC proliferation was induced by Ang Ⅱ, and was evaluated by the 3-（4, 5-dimethylthiazol-2-yl）-2, 5-diphenyltetrazolium bromide assay and cell counting. To examine the mechanisms involved in anti-proliferative effects of rutaecarpine, nitric oxide （NO） levels and NO synthetase （NOS） activity were determined. Expressions of VSMC proliferation-related genes including endothelial nitric oxide synthase （eNOS）, and c-myc hypertension related gene-1 （HRG-1） were determined by real-time reverse chain reaction （RT-PCR）. Results： Rutaecarpine （0.3-3.0μmol/l_） inhibited Ang R-induced VSMC proliferation and the best effects were achieved at 3.0 μmol/L. The Ang Ⅱ-induced decreases in cellular NO contents and NOS activities were antagonized by rutaecarpine （P〈0.05）. Ang Ⅱ administration suppressed the expressions of eNOS and HRG-1, while increased c-myc expression （P〈0.05）. All these effects were attenuated by 3.0μmol/L rutaecarpine （P〈0.05）. Conclusion： Rutaecarpine is effective against Ang Ⅱ-induced rat VSMC proliferation, and this effect is due, at least in part, to NO production and the modulation of VMSC proliferation-related gene expressions.
基金Supported by National Natural Science Foundation of China(No.81160528)Administration of Traditional Chinese Medicine of Guizhou Province foundation,China(No.2009-79)
文摘Objective： To investigate the effect and potential mechanisms of rutaecarpine （Rut） in a rat artery balloon-injury model. Methods： The intimal hyperplasia model was established by rubbing the endothelia with a balloon catheter in the common carotid artery （CCA） of rats. Fifty rats were randomly divided into five groups, ie. sham, model, Rut （25, 50 and 75 mg/kg） with 10 rats of each group. The rats were treated with or without Rut （25, 50, 75 mg/kg） by intragastric administration for 14 consecutive days following injury. The morphological changes of the intima were evaluated by hematoxylin-eosin staining. The expressions of proliferating cell nuclear antigen （PCNA） and smooth muscle （SM） oL-actin in the ateries were assayed by immunohistochemical staining. The mRNA expressions of c-myc, extracellular signal-regulated kinase 2 （ERK2）, MAPK phosphatase-1 （MKP-1） and endothelial nitric oxide synthase （eNOS） were determined by real-time reverse chain reaction. The protein expressions of MKP-1 and phosphorylated ERK2 （p-ERK2） were examined by Western blotting. The plasma contents of nitric oxide （NO） and cyclic guanosine 3＇,5＇-monophosphate （cGMP） were also determined. Results： Compared with the model group, Rut treatment significantly decreased intimal thickening and ameliorated endothelial injury （P〈0.05 or P〈0.01）. The positive expression rate of PCNA was decreased, while the expression rate of SM α -actin obviously increased in the vascular wall after Rut （50 and 75 mg/kg） administration （P〈0.05 or P〈0.01）. Furthermore, the mRNA expressions of c-myc, ERK2 and PCNA were downregulated while the expressions of eNOS and MKP-1 were upregulated （P〈0.05 or P〈0.01）. The protein expressions of MKP-1 and the phosphorylation of ERK2 were upregulated and downragulated after Rut （50 and 75 mg/kg） administration （P〈0.05 or P〈0.01）, respectively. In addition, Rut dramatically reversed balloon injury-induced decrease of NO and cGMP in the plasma （P〈0.05 or P〈0.01）. Conclusion： Rut could inhibit the balloon injury-induced carotid intimal hyperplasia in rats, possibly mediated by promotion of NO production and inhibiting ERK2 signal transduction pathways.
基金supported by the Major Program of the National Natural Science Foundation of China (No. 82192915)the National Key Research and Development Program (No. 2018YFC1704500)
文摘Objective: Chronic atrophic gastritis(CAG) is a complex and burdensome disease. However, side effects and compliance issues cannot be ignored due to the long treatment cycle. Numerous studies have confirmed the effectiveness of rutaecarpine(RUT) for treating digestive dysfunction. However, the potential mechanism of action of RUT in the context of CAG treatment remains unclear. This study aimed to explore the therapeutic effects and mechanisms of RUT in 1-methyl-3-nitro-1-nitrosoguanidine-induced CAG using network pharmacology,metabolomics, and traditional pharmacological approaches. Materials and Methods: Pathological tests and ELISA assays were used to observe the therapeutic effects of RUT treatment on CAG. Differential metabolites were identified using ultra-high-performance liquid chromatography-tandem mass spectrometry, and metabolism-related target genes were enriched. The same target genes were identified between RUT and CAG diseases. The intersectional target genes were uploaded to Cytoscape for enrichment, and the nucleotide-binding oligomerization domain(NOD)-like receptor signaling pathway was selected to validate the mechanisms of the study. Finally, cell pyroptosis status was evaluated using the terminal deoxynucleotidyl transferase-mediated d UTP nick end labeling assay, and the expressions of associated proteins of the NOD-like receptor signaling pathway were assessed by Western blotting and immunohistochemistry. Results: RUT alleviated gastric mucosal damage and significantly downregulated indicators associated with infiammation and gastric atrophy. A total of 29 intersection target genes was identified, and core pathways were obtained. The NOD-like receptor signaling pathway and pyroptosis status were selected to validate the mechanisms of RUT treatment in CAG rats. The expression of NOD-related proteins and downstream factors was downregulated in the RUT group. Conclusions: RUT exerts a pharmacological effect on relieving gastric damage in CAG rats by inhibiting NOD-like receptors and infiammasomes.
基金State Key Laboratory of Natural and Biomimetic Drugs 2013 Funded Project "Establishment and Application an Online Natural Medicines System with Efficient Separation,Structural Identification and Activity Detection"
文摘In the present study, we studied the inhibitory effects of chelidonine and rutaecarpin on porcine pancreatic a-amylase （PPA） catalyzed hydrolysis using 2-chloro-4-nitrophenyl-4-O-β-D-galactopyranosylmaltoside （Gal-G2-α-CNP）. We, for the first time, provided kinetic report and detailed inhibitory effects of both compounds on PPA. Lineweaver-Burk plot revealed that the inhibition was a mixed-noncompetitive type, and only one molecule of inhibitor bound to the enzyme or to the enzyme-substrate complex. Kinetic constants calculated from secondary plots were in millimole range. Dissociation constants of enzyme-inhibitor complex （KEI） were 0.9 mM and 3.5 mM, respectively. Moreover, dissociation constants of enzyme-inhibitor-substrate complex （KESI） were 0.04 mM and 0.31 mM, respectively. These data indicated that the inhibition was more inclined to competitive to Gal-G2-α-CNP hydrolysis. Further molecular docking study manifested that hydrogen bonding formed between acarbose and aspartic acid （Asp300）, histidine （His305） and glycine （Gly3-6）, while hydrogen bonding was observed between chelidonine and glutamic acid （Glu233）, lysine （Lys200） and His305. In addition, rutaecarpine had only one hydrogen bond with Lys200. Our data indicated that chelidonine and rutaecarpine were two promising drug candidates, and chelidonine possessed stronger inhibitory effect compared with rutaecarpine.
文摘Objective To control the quality of Evodia rutaecarpa better.Methods An HPLC-DAD-MS/MS method was established for the rapid and efficient identification of bioactive constituents and for simultaneous quantitative analysis of four bioactive ingredients including evodiamine,rutaecarpine,dehydroevodiamine,and evodin in E.rutaecarpa,which was applied to evaluating eight samples of E.rutaecarpa and its varieties from different areas.Results Thirteen potentially bioactive constituents including one flavonoid glycoside,one limonin,four indoloquinazoline alkaloids,and seven quinolone alkaloids were identified in all samples and the contents of dehydroevodiamine,evodine,evodiamine,and rutaecarpine varied widely from 0.10%to 0.51%,0.49%to 3.12%,0.07%to 1.56%,and 0.10%to 0.69%,respectively.Conclusion This method is found to be convenient,fast,accurate,and it is facilitated to improve the quality control standard of E.rutaecarpa and related products.
