Evodia Rutaecarpa Research Articles

Research progress in pharmacology and toxicology of evodiamine

Evodiamine, a bioactive indole alkaloid from Evodia rutaecarpa, E. rutaecarpa var. officinalis, or E. rutaecarpa var. bodinieri, has been extensively investigated due to its pharmacological activities in recent years. At present, evodiamine is proved to significantly suppress the proliferation of a variety of cancer cells and mediate cell processes such as cell cycle arrest and cell migration. In addition, evodiamine displays significant pharmacological activities against cardiovascular diseases(hyperlipidemia, etc.), and tinea manus and pedis. Recently, evodiamine has been found to have potential toxic effects, such as hepatotoxicity, nephrotoxicity, and cardiotoxicity. However, the pharmacological and toxicological mechanism of evodiamine is not clear, and its toxicity in vitro and in vivo has been rarely reported. Therefore, this study reviewed the pharmacological and toxicological articles of evodiamine in recent years, aiming at providing new ideas and references for future research.

Dehydroevodiamine ameliorates indomethacin-induced gastric injury via inhibition of ERK and p38 signaling pathway

BackgroundDehydroevodiamine (DHE), a pivotal quinazoline alkaloid isolated from Fructus Evodiae (Tetradium ruticarpum (A. Juss.) Hartley), has various pharmacological effects. However, the effect of DHE on gastric injury is still uncharted. PurposeTo clarify the pharmacological effect and mechanism of DHE on gastric injury (GI) induced by indomethacin (IDO). Study designThe gastric injury was induced in rat by oral administration of 5 mg/kg IDO for 7 days. Then the rats were treated with DHE (10, 20, 40 mg/kg, ig) for 7 days. MethodsThe changes of food intake, body weight, gastric pH and general state observation were determined. And HE staining and AB-PAS staining was analyzed. Then, the inflammatory infiltration of gastric tissue was observed through MPO immunohistochemical approach, and the expression of TNF-α, IL-6 and IL-10 were measured. Furthermore, the levels of proteins ERK, p-ERK, P38, p-P38, JNK and p-JNK were determined to elucidate the molecular mechanism of DHE. ResultsDHE alleviated food intake reduction, weight loss and gastric injury induced by IDO and made gastric pH and mucosal thickness return to normal. In addition, DHE could down regulate the expression of MPO, TNF-α and IL-6 and up regulate the expression of IL-10 to reduce the damage induced by inflammatory, and create a healing environment. Furthermore, DHE could significantly inhibit the phosphorylation of ERK and p38 not JNK. ConclusionDHE ameliorated dyspepsia, inflammatory infiltration and tissue damage induced by IDO through ERK and p38 signaling pathways rather than JNK pathway.

Research progress on evodiamine, a bioactive alkaloid of Evodiae fructus: Focus on its anti-cancer activity and bioavailability (Review).

Evodiae fructus (Wu-Zhu-Yu in Chinese) can be isolated from the dried, unripe fruits of Tetradium ruticarpum and is a well-known traditional Chinese medicine that is applied extensively in China, Japan and Korea. Evodiae fructus has been traditionally used to treat headaches, abdominal pain and menorrhalgia. In addition, it is widely used as a dietary supplement to provide carboxylic acids, essential oils and flavonoids. Evodiamine (EVO) is one of the major bioactive components contained within Evodiae fructus and is considered to be a potential candidate anti-cancer agent. EVO has been reported to exert anti-cancer effects by inhibiting cell proliferation, invasion and metastasis, whilst inducing apoptosis in numerous types of cancer cells. However, EVO is susceptible to metabolism and may inhibit the activities of metabolizing enzymes, such as cytochrome P450. Clinical application of EVO in the treatment of cancers may prove difficult due to poor bioavailability and potential toxicity due to metabolism. Currently, novel drug carriers involving the use of solid dispersion techniques, phospholipids and nanocomplexes to deliver EVO to improve its bioavailability and mitigate side effects have been tested. The present review aims to summarize the reported anti-cancer effects of EVO whilst discussing the pharmacokinetic behaviors, characteristics and effective delivery systems of EVO.

Rutaecarpine Increases Anticancer Drug Sensitivity in Drug-Resistant Cells through MARCH8-Dependent ABCB1 Degradation.

The overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) subfamily B member 1 (ABCB1; P-glycoprotein; MDR1) in some types of cancer cells is one of the mechanisms responsible for the development of multidrug resistance (MDR), which leads to the failure of chemotherapy. Therefore, it is important to inhibit the activity or reduce the expression level of ABCB1 to maintain an effective intracellular level of chemotherapeutic drugs. In this study, we found that rutaecarpine, a bioactive alkaloid isolated from Evodia Rutaecarpa, has the capacity to reverse ABCB1-mediated MDR. Our data indicated that the reversal effect of rutaecarpine was related to the attenuation of the protein level of ABCB1. Mechanistically, we demonstrated that ABCB1 is a newly discovered substrate of E3 ubiquitin ligase membrane-associated RING-CH 8 (MARCH8). MARCH8 can interact with ABCB1 and promote its ubiquitination and degradation. In short, rutaecarpine increased the degradation of ABCB1 protein by upregulating the protein level of MARCH8, thereby antagonizing ABCB1-mediated MDR. Notably, the treatment of rutaecarpine combined with other anticancer drugs exhibits a therapeutic effect on transplanted tumors. Therefore, our study provides a potential chemotherapeutic strategy of co-administrating rutaecarpine with other conventional chemotherapeutic agents to overcome MDR and improve therapeutic effect.

A New Cytotoxic Evodiamine Derivative From Tetradium ruticarpum (A. Jussieu) T. G. Hartley

1-Hydroxymethyl goshuyuamide II (1), a new derivative of evodiamine with a quinazolinocarboline skeleton, along with nine known evodiamine derivatives were isolated from the dried and nearly ripe fruits of Tetradium ruticarpum (A. Jussieu) T. G. Hartley using several different chromatographic separations. Their structures were elucidated on the basis of extensive spectroscopic techniques, including 1D and 2D NMR spectra. Putative biosynthetic pathways toward 1 are proposed. Compounds 1 and 2 and 4 to 10 exhibited cytotoxic activity against six human tumor lines, and compounds 4 and 7 to 10 exhibited moderate inhibitory activity against nitric oxide production in LPS-activated RAW264.7 cells.

Rutaecarpine Increases Nitric Oxide Synthesis via eNOS Phosphorylation by TRPV1-Dependent CaMKII and CaMKKβ/AMPK Signaling Pathway in Human Endothelial Cells.

Rutaecarpine (RUT) is a bioactive alkaloid isolated from the fruit of Evodia rutaecarpa that exerts a cellular protective effect. However, its protective effects on endothelial cells and its mechanism of action are still unclear. In this study, we demonstrated the effects of RUT on nitric oxide (NO) synthesis via endothelial nitric oxide synthase (eNOS) phosphorylation in endothelial cells and the underlying molecular mechanisms. RUT treatment promoted NO generation by increasing eNOS phosphorylation. Additionally, RUT induced an increase in intracellular Ca2+ concentration and phosphorylation of Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ), AMP-activated protein kinase (AMPK), and Ca2+/calmodulin-dependent kinase II (CaMKII). Inhibition of transient receptor potential vanilloid type 1 (TRPV1) attenuated RUT-induced intracellular Ca2+ concentration and phosphorylation of CaMKII, CaMKKβ, AMPK, and eNOS. Treatment with KN-62 (a CaMKII inhibitor), Compound C (an AMPK inhibitor), and STO-609 (a CaMKKβ inhibitor) suppressed RUT-induced eNOS phosphorylation and NO generation. Interestingly, RUT attenuated the expression of ICAM-1 and VCAM-1 induced by TNF-α and inhibited the inflammation-related NF-κB signaling pathway. Taken together, these results suggest that RUT promotes NO synthesis and eNOS phosphorylation via the Ca2+/CaMKII and CaM/CaMKKβ/AMPK signaling pathways through TRPV1. These findings provide evidence that RUT prevents endothelial dysfunction and benefit cardiovascular health.

A two-step strategy for quality control of Xin-Yu-Tie-Pian, an ointment patch.

Xin-Yu-Tie-Pian, an ointment patch which is composed of Tetradium ruticarpum and Asarum sieboldii Miquel, can be used for curing recurrent oral ulcers owing to its good bioactivities. Currently, the lack of a method for its quality evaluation hinders the development and clinical application of Xin-Yu-Tie-Pian. Thus, it is necessary to perform research on quality control. The chromatographic fingerprint, as an identification method, and the simultaneous determination method for two bioactive constituents, evodiamine and rutecarpine, can be used to evaluate the quality of traditional medicine. In this study, a two-step strategy including fingerprint analysis for identification and a simultaneous determination method for two bioactive constituents was performed for Xin-Yu-Tie-Pian quality control. The fingerprint analysis was validated by stability, precision and repeatability tests and a similarity evaluation was performed with 10 selected characteristic fingerprint peaks of 10 batches of Xin-Yu-Tie-Pian patch. Meanwhile, the simultaneous determination method was evaluated by methodological experiments, including linearity, accuracy, repeatability, stability and feasibility. Finally, the results indicate that this two-step strategy, including HPLC fingerprint analysis and simultaneous determination method, can be successfully applied for the assessment of the quality and quantity of Xin-Yu-Tie-Pian.

Simultaneous LC-MS/MS bioanalysis of alkaloids, terpenoids, and flavonoids in rat plasma through salting-out-assisted liquid-liquid extraction after oral administration of extract from Tetradium ruticarpum and Glycyrrhiza uralensis: a sample preparation strategy to broaden analyte coverage of herbal medicines.

Herbal medicines have historically been practiced in combinatorial way, which achieves therapeutic efficacy by integrative effects of multi-components. Thus, the accurate and precise measurement of multi bioactive components in matrices is inalienable to understanding the metabolism and disposition of herbal medicines. In this study, aiming to provide a strategy that improves analyte coverage, evaluation of six protocols employing sample pretreatment methods- protein precipitation (PPT), liquid-liquid extraction (LLE), sugaring-out-assisted liquid-liquid extraction (SULLE), and salting-out-assisted liquid-liquid extraction (SALLE)- was performed by LC-MS/MS using rat plasma and a mixture of alkaloid (evodiamine, rutaecarpine, dehydroevodiamine), terpenoid (limonin, rutaevin, obacunone), and flavonoid (liquiritin, isoliquiritin, liquiritigenin) standards isolated from Tetradium ruticarpum and Glycyrrhiza uralensis. These protocols were as follows: (1) PPT with methanol, (2) PPT with acetonitrile, (3) LLE with methyl tertiary-butyl ether-dichloromethane, (4) LLE with ethyl acetate-n-butanol, (5) SALLE with ammonium acetate, (6) SULLE with glucose. The results suggested that SALLE produced broader analyte coverage with satisfactory reproducibility, acceptable recovery, and low matrix interference. Then, sample preparation procedure of SALLE, chromatographic conditions, and mass spectrometric parameters were optimized, followed by method validation, showing that good sensitivity (LLOQ ≤1 ng mL-1), linearity (r ≥0.9933),precision (RSD≤ 14.45%), accuracy (89.54~110.87%), and stability could be achieved. Next, the developed method was applied successfully to determine the pharmacokinetic behavior of the nine compounds in rat plasma after intragastric administration with an extract from Tetradium ruticarpum and Glycyrrhiza uralensis (Wuzhuyu-Gancao pair). Based on an extensive review and experiments, a sample preparation procedure that matches with LC-MS/MS technique and can get wider analyte coverage was outlined. The developed SALLE method is rapid, reliable, and suitable for bioanalysis of analytes with diverse polarity, which was expected to be a promising strategy for the pharmacokinetic studies of herbal medicines. Graphical abstract.

Identification of evodiamine and rutecarpine as novel TMEM16A inhibitors and their inhibitory effects on peristalsis in isolated Guinea-pig ileum

The transmembrane member 16A (TMEM16A)-encoded Ca2+-activated Cl− channel (CaCC) is expressed in interstitial cells of Cajal (ICCs) and involved in the generation of the slow-wave currents of gastrointestinal (GI) smooth muscles. TMEM16A modulators have been shown to positively or negatively regulate the contraction of gastrointestinal smooth muscle. Therefore, targeting the pharmacological modulation of TMEM16A may represent a novel treatment approach for gastrointestinal dysfunctions such as constipation and diarrhoea. In this study, evodiamine and rutecarpine were extracted from the traditional Chinese medicine Evodia rutaecarpa and identified as novel TMEM16A inhibitors with comparable inhibitory effects. Their effects on intestinal peristalsis were examined. Whole-cell patch clamp results show that evodiamine and rutecarpine inhibited TMEM16A Cl− currents in CHO cells. The half-maximal inhibition values (IC50) of evodiamine and rutecarpine on TMEM16A Cl− currents were 11.8 ± 1.3 μΜ and 9.2 ± 0.4 μM, and the maximal effect values (Emax) were 95.8 ± 5.1% and 99.1 ± 1.6%, respectively. The Lys384, Thr385, and Met524 in TMEM16A are critical for evodiamine and rutecarpine's inhibitory effects. Further functional studies show that both evodiamine and rutecarpine can significantly suppress the peristalsis in isolated guinea-pig ileum. These findings demonstrate that evodiamine and rutecarpine are new TMEM16A inhibitors and support the regulation effect of TMEM16A modulators on gastrointestinal motility.

Comparison of the effects of rutaecarpine on molecular subtypes of breast cancer

Natural compounds have gained considerable attention in recent years due to disadvantages and properties of current chemotherapy drugs in cancer therapy. In addition, the impact of these compounds is specific for each type and/or subtypes of cancer due to different treatment response. Rutaecarpine, an alkaloid obtained from Evodia Rutaecarpa Chinese herb, has anticancer activity by inhibiting topoisomerase and/or cyclo-oxygenase-2 levels. However, the effectiveness of rutaecarpine has not been well known in breast cancer in terms of subtype. Therefore, we investigated the potential therapeutic effects of rutaecarpine on two different subtypes of breast cancer cells. The cytotoxic and apoptotic effects of rutaecarpine on MCF-7 and MDA-MB-231 cells were analyzed by WST-1, Annexin V, cell cycle, and acridine orange staining. WST-1 results indicated that rutaecarpine significantly inhibited the growth of both cancer cells for 48 h (P < 0.05). In addition, rutaecarpine treatment caused apoptotic cell death through chromatin condensation and nuclear blebbing and G0/G1 arrest in both breast cancer cells. However, the efficacy of rutaecarpine was more profound in MCF-7 cells than MDA-MB-231 cells. Consequently, rutaecarpine has a potential therapeutic effect on breast cancer. However, the effectiveness of rutaecarpine is dependent on the subtype of breast cancer.

On the Inhibitability of Natural Products Isolated from Tetradium ruticarpum towards Tyrosine Phosphatase 1B (PTP1B) and α-Glucosidase (3W37): An In Vitro and In Silico Study.

Folk experiences suggest natural products in Tetradium ruticarpum can be effective inhibitors towards diabetes-related enzymes. The compounds were experimentally isolated, structurally elucidated, and tested in vitro for their inhibition effects on tyrosine phosphatase 1B (PTP1B) and α-glucosidase (3W37). Density functional theory and molecular docking techniques were utilized as computational methods to predict the stability of the ligands and simulate interaction between the studied inhibitory agents and the targeted proteins. Structural elucidation identifies two natural products: 2-heptyl-1-methylquinolin-4-one (1) and 3-[4-(4-methylhydroxy-2-butenyloxy)-phenyl]-2-propenol (2). In vitro study shows that the compounds (1 and 2) possess high potentiality for the inhibition of PTP1B (IC50 values of 24.3 ± 0.8, and 47.7 ± 1.1 μM) and α-glucosidase (IC50 values of 92.1 ± 0.8, and 167.4 ± 0.4 μM). DS values and the number of interactions obtained from docking simulation highly correlate with the experimental results yielded. Furthermore, in-depth analyses of the structure–activity relationship suggest significant contributions of amino acids Arg254 and Arg676 to the conformational distortion of PTP1B and 3W37 structures overall, thus leading to the deterioration of their enzymatic activity observed in assay-based experiments. This study encourages further investigations either to develop appropriate alternatives for diabetes treatment or to verify the role of amino acids Arg254 and Arg676.

Neuroprotective Studies of Evodiamine in an Okadaic Acid-Induced Neurotoxicity.

Background: Alzheimer’s disease (AD) is the most common neurodegenerative disease, and it manifests as progressive memory loss and cognitive decline. However, there are no effective therapies for AD, which is an urgent problem to solve. Evodiamine, one of the main bioactive ingredients of Evodia rutaecarpa, has been reported to ameliorate blood–brain barrier (BBB) permeability and improve cognitive impairment in ischemia and AD mouse models. However, whether evodiamine alleviates tauopathy remains unclear. This study aimed to examine whether evodiamine ameliorates tau phosphorylation and cognitive deficits in AD models. Methods: A protein phosphatase 2A inhibitor, okadaic acid (OA), was used to induce tau phosphorylation to mimic AD-like models in neuronal cells. Protein expression and cell apoptosis were detected using Western blotting and flow cytometry, respectively. Spatial memory/cognition was assessed using water maze, passive avoidance tests, and magnetic resonance imaging assay in OA-induced mice models, and brain slices were evaluated further by immunohistochemistry. Results: The results showed that evodiamine significantly reduced the expression of phosphor-tau, and further decreased tau aggregation and neuronal cell death in response to OA treatment. This inhibition was found to be via the inhibition of glycogen synthase kinase 3β, cyclin-dependent kinase 5, and mitogen-activated protein kinase pathways. In vivo results indicated that evodiamine treatment ameliorated learning and memory impairments in mice, whereas Western blotting and immunohistochemical analysis of the mouse brain also confirmed the neuroprotective effects of evodiamine. Conclusions: Evodiamine can decrease the neurotoxicity of tau aggregation and exhibit a neuroprotective effect. Our results demonstrate that evodiamine has a therapeutic potential for AD treatment.

New limonoids and quinolone alkaloids with cytotoxic and anti-platelet aggregation activities from Evodia rutaecarpa (Juss.) Benth

One new limonoid, named 19-hydroxy methyl isoobacunoate diosphenol (1); one new degraded limonoid, named 9α-methoxyl dictamdiol (9); two new quinolone alkaloids, 1-methyl-3-[(7E,9E,12Z)-7,9,12-pentadecadienyl]-4(1H)-quinolone (11) and 1-methyl-3-[(7E,9E,11E)-7,9,11-pentadecadienyl]-4(1H)-quinolone (12), along with eight known compounds, evodol (2), 7β-acetoxy-5-epilimonin (3), rutaevine (4), 6β-acetoxy-5-epilimonin (5), limonin (6), obacunone (7), clauemargine L (8), hiiranlactone E (10) were isolated from the fruits of Evodia rutaecarpa (Juss.) Benth.. Structures of the four new compounds were elucidated on the basis of extensive spectroscopic techniques, including 1D and 2D NMR techniques. Compounds 3, 5, 9, 11 and 12 showed obviously cytotoxic activity against six human tumor lines, while compounds 11, 12 displayed anti-platelet aggregation induced by ADP at 50 μM and 100 μM.

Evodiamine alleviates lipopolysaccharide-induced pulmonary inflammation and fibrosis by activating apelin pathway.

Inflammation can cause a series of inflammatory lung disease, which seriously endangers human health. Pulmonary fibrosis is a kind of inflammatory disease with end-stage lung pathological changes. It has complicated and unknown pathogenesis and is still lack of effective therapeutic drugs. LPS-induced inflammation is a common feature of many infectious inflammations such as pneumonia, bacteremia, glomerulonephritis, etc. Evodiamine, one of the main components of Evodia rutaecarpa, is an alkaloid with excellent antiinflammatory effects. In this study, we evaluated the protective capacities of evodiamine on LPS-induced inflammatory damages in vitro and in vivo. MTT method, flow cytometry, immunofluorescence, and other methods were used for in vitro study to determine the protective capacities of evodiamine. The results suggest that evodiamine can protect murine macrophages from the LPS-nigericin-induced damages by (a) inhibiting cellular apoptosis, (b) inhibiting inflammatory cytokines releasing, and (c) activating the apelin pathway. We also used the exogenous apelin-13 peptide co-cultured with LPS-nigericin in RAW264.7 cells and found that apelin-13 contributes to protecting the effects of evodiamine. In vivo, the ELISA method and immunohistochemistry were used to examine inflammatory cytokines, apelin, and histological changes. BALB/c mice were exposed to LPS and subsequent administration of evodiamine （p.o.）for some time, the results of the alveolar lavage fluid and the tissue slices showed that evodiamine treatment alleviated the pulmonary inflammation and fibrosis, stimulated apelin expression and inhibited the inflammatory cytokines. These results provide a basis for the protective effect and mechanism of evodiamine in LPS-induced inflammation and suggest that it might be potential therapeutics in human pulmonary infections.

HOẠT CHẤT ỨC CHẾ TẾ BÀO UNG THƯ VÚ TRONG QUẢ CÂY THÔI CHANH TRẮNG (Tetradium ruticarpum)

Three alkaloids (named rutaecarpine (1), evodiamine (2), schinifoline (3) and one phenylpropanoid, integrifoliodiol (4)) have been isolated from the EtOAc extract of the fruits of Tetradium ruticarpum (A. Juss.) T. G. Hartley collected in Lang Son province. Their structures have been identified by using 1D and 2D NMR spectroscopies. All four compounds were tested for their cytotoxicity against the human breast cancer cell line (MCF-7) and tamoxifen-resistant breast cancer cell line (MCF\TAMR). The results showed that rutaecarpine (1) inhibited the growth of MCF7 and MCF\TAMR with its IC50 values of 41.2 and 64.6 µM, respectively. In addition, compounds 1, 2, and 4 showed moderate activity toward MCF-7 cell line.

UHPLC-UV-Q-Orbitrap HRMS combined with machine learning algorithms reveals the chemical markers of Euodiae Fructus among closely related cultivars

Euodiae Fructus (EF, the fruit of Tetradium ruticarpum) belongs to the family Rutaceae which has a complex genetic background, making classification a challenge. In order to classify the three closely related cultivars (small flower EF, medium flower EF, and big flower EF) and simplify the identification procedure in the future, an approach integrating ultra-high performance liquid chromatography-ultraviolet spectrum-hybrid quadrupole-Orbitrap high resolution mass spectrometry (UHPLC-UV-Q-Orbitrap HRMS) with machine learning algorithms was developed. Orthogonal partial least squares-discriminant analysis (OPLS-DA) and random forest (RF) were used to assort the processed EF products and select the chemical markers to differentiate among the three EF cultivars, respectively. Then the thresholds of classification were determined using the eXtreme Gradient Boosting (XGboost) model based on the quantitative data of chemical markers by the UHPLC-Q-Orbitrap HRMS. The results demonstrated that the approach successfully discriminated among three closely related cultivars of EF, and five chemical markers (neochlorogenic acid, (+)-catechin, chlorogenic acid, dehydroevodiamine, and limonin) were selected. Thresholds were obtained to classify the three cultivars. If the content of neochlorogenic acid was greater than 7.52 mg/g, the sample belonged to small flower EF, otherwise, it belonged to medium flower EF or big flower EF. Furthermore, if the content of dehydroevodiamine was greater than 3.84 mg/g, the sample was medium flower EF, otherwise, it was big flower EF. In general, this research provides a novel strategy for the discrimination of Euodiae Fructus cultivars to avoid misapplication and possible side effects.

Zuojin Pill ameliorates chronic atrophic gastritis induced by MNNG through TGF-β1/PI3K/Akt axis

Ethnopharmacological relevanceZuojin Pill (ZJP) is a classic prescription composed of Coptis chinensis and Tetradium ruticarpum (A.Juss.) T.G.Hartley, which is often used in the treatment of digestive system diseases. Aim of this studyThe purpose of this study was to explore the therapeutic effect and potential mechanism of ZJP on chronic atrophic gastritis (CAG) induced by MNNG. Materials and methodsThe GES-1 and rat model of CAG was established by MNNG. Detection of cell viability, morphological changes and proliferation of GES-1 by CCK-8 and high content screening (HCS) assay. G-17, IL-8 and TNF-α in rat serum were detected by ELISA kit. The expression of related mRNA and protein on TGF-β1/PI3K/Akt signal axis were detected by RT-PCR and Western blot. ResultsThe results showed that ZJP could significantly improve the GES-1 damage induced by MNNG and improve the gastric histomorphology of CAG rats. The intervention of ZJP could significantly reduce the content of G-17 and inflammatory factors IL-8, TNF- α, IL-6 and IL-1β, inhibit the expression of TGF-β1, PI3K and their downstream signals p-Akt, p-mTOR, P70S6K, and promote the expression level of PTEN, LC3-II and Beclin-1. ConclusionZJP has a good therapeutic effect on CAG induced by MNNG, which may be closely related to the inhibition of TGF-β1/PI3K/Akt signal pathway.

Rutaecarpine Ameliorates Pressure Overload Cardiac Hypertrophy by Suppression of Calcineurin and Angiotensin II

Cardiac hypertrophy is a major pathological process to result in heart failure and sudden death. Rutaecarpine, a pentacyclic indolopyridoquinazolinone alkaloid extracted from Evodia rutaecarpa with multiple pharmacological activities, yet the underlying protective effects and the mechanisms on cardiac hypertrophy remain unclear. This study aimed to evaluate the potential effects of rutaecarpine on pressure overload cardiac hypertrophy. Cardiac hypertrophy in rat was developed by abdominal aortic constriction (AAC) for 4 weeks, which was improved by rutaecarpine supplementation (20 or 40 mg/kg/day, i.g.) for another 4 weeks. The level of angiotensin II was increased; the mRNA expression and the activity of calcineurin in the left ventricular tissue were augmented following cardiac hypertrophy. Rutaecarpine administration decreased angiotensin II content and reduced calcineurin expression and activity. Noteworthily, in angiotensin II-induced cardiomyocytes, rutaecarpine ameliorated the hypertrophic effects in a dose-dependent manner and downregulated the increased mRNA expression and activity of calcineurin. In conclusion, rutaecarpine can improve cardiac hypertrophy in pressure overload rats, which may be related to the inhibition of angiotensin II-calcineurin signal pathway.

Evodiamine protects against airway remodelling and inflammation in asthmatic rats by modulating the HMGB1/NF-κB/TLR-4 signalling pathway

Context Evodiamine, which is isolated from Evodia rutaecarpa (Rutaceae), possess strong anti-inflammatory, immunomodulatory, and antibacterial properties. Objective The protective effects of evodiamine in asthma were evaluated. Materials and methods Thirty-two Sprague-Dawley (SD) rats were used, asthma was induced by injecting intraperitoneally with a mixture of Al(OH)3 (100 mg) and ovalbumin (OA; 1 mg/kg), further exposing them to a 2% OA aerosol for 1 week. All animals were divided into four groups: control, asthma, and evodiamine 40 and 80 mg/kg p.o. treated group. Serum levels of inflammatory cytokines, interferon gamma (IFN-γ), and immunoglobulin E (IgE) and infiltrations of inflammatory cells in the bronchoalveolar lavage fluid (BALF) of the animals were determined. The thickness of the smooth muscle layer and airway wall in the intact small bronchioles of asthmatic rats was examined as well. Results Cytokine levels in the serum and BALF were lower in the evodiamine-treated group than in the asthma group. Evodiamine treatment reduced IgE and IFN-γ levels as well as the inflammatory cell infiltrate in the lung tissue of asthmatic rats. The thickness of the smooth muscle layer and airway wall of intact small bronchioles was less in the evodiamine-treated group than in the asthma group. Lower levels of TLR-4, MyD88, NF-κB, and HMGB1 mRNA in lung tissue were measured in the evodiamine-treated group than in the asthma group. Discussion and conclusion The effect of evodiamine treatment protects the asthma, as evodiamine reduces airway inflammation and remodelling in the lung tissue by downregulating the HMGB1/NF-κB/TLR-4 pathway in asthma.

Screening of the active compound from Tetradium ruticarpum fruits and analysis of its binding characteristics to the α1A adrenoceptor by high expression α1A adrenoceptor cell membrane chromatography

The dried fruit of the Tetradium ruticarpum (Wu Zhu Yu) tree is commonly used in traditional Chinese medicine, and its decoction can be used for treating conditions such as headaches and hypotension. In the present study, an offline two-dimensional combination method of α1A/HEK293 cell membrane chromatography (α1A/CMC) and UHPLC-MS/MS was established to screen and identify the active compound from the Tetradium ruticarpum fruits. The binding characteristics between this active compound and the α1A receptor were also analyzed by an α1A/CMC method. By this process, dehydroevodiamine was identified as the potential active compound. Equilibrium dissociation constant (Kd) values between α1A receptor and dehydroevodiamine, obtained by both stepwise frontal analysis and zonal elution analysis, were (5.18 ± 0.50) × 10−6 mol/L and (2.70 ± 0.74) × 10−6 mol/L, respectively. Our results indicate that the α1A/CMC method can not only screen active compounds from complex sample, but can also be used to calculate the binding parameters of the identified compound.