Comprehensive Analysis of 11 Species of Euodia (Rutaceae) by Untargeted LC-IT-TOF/MS Metabolomics and In Vitro Functional Methods.

The Euodia genus comprises numerous untapped medicinal plants that warrant thorough evaluation for their potential as valuable natural sources of herbal medicine or food flavorings. In this study, untargeted metabolomics and in vitro functional methods were employed to analyze fruit extracts from 11 significant species of the Euodia genus. An investigation of the distribution of metabolites (quinolone and indole quinazoline alkaloids) in these species indicated that E. rutaecarpa (Euodia rutaecarpa) was the most widely distributed species, followed by E. compacta (Euodia compacta), E. glabrifolia (Euodia glabrifolia), E. austrosinensis (Euodia austrosinensis), and E. fargesii (Euodia fargesii). There have been reports on the close correlation between indole quinazoline alkaloids and their anti-tumor activity, especially in E. rutaecarpa fruits which exhibit effectiveness against various types of cancer, such as SGC-7901, Hela, A549, and other cancer cell lines. Additionally, the E. rutaecarpa plant contains indole quinazoline alkaloids, which possess remarkable antibacterial properties. Our results offer novel insights into the utilization of Euodia resources in the pharmaceutical industry.

New indolequinazoline alkaloids from the fruits of Tetradium ruticarpum.

In this research, five new indolequinazoline alkaloids (1-5), along with six known indolequinazoline alkaloids (6-11) were obtained from the fruits of Tetradium ruticarpum. Their structures were elucidated through comprehensive spectroscopic data of 1D and 2D NMR, HRESIMS and ECD spectra. Additionally, all isolates were assayed for their SIRT1 inhibitory activities in vitro and compounds 2, 7, 10 and 11 exhibited activities with IC50 values ranged from 43.16 to 118.35 µM.

KIT-SNAP-tag/cell membrane chromatography model coupled with liquid chromatography-mass spectrometry for anti-GIST compound screening from Evodia rutaecarpa.

Gastrointestinal mesenchymal tumors, as the most common mesenchymal tumors in the gastrointestinal tract, are adjuvantly treated with multi-targeted tyrosine kinase inhibitors, such as imatinib and sunitinib, but there are problems of drug resistance and complex methods of monitoring therapeutic agents. The pathogenesis of this disease is related to mutations in tyrosine kinase (KIT) or platelet-derived growth factor receptor α, an important target for drug therapy. In recent years, the screening of relevant tyrosine kinase inhibitors from traditional Chinese medicine has become a hotspot in antitumor drug research. In the current study, the KIT-SNAP-tag cell membrane chromatography (KIT-SNAP-tag/CMC) column was prepared with satisfying specificity, selectivity, and reproducibility by chemically bonding high KIT expression cell membranes to the silica gel surface using the SNAP-tag technology. The KIT-SNAP-tag/CMC-HPLC-MS two-dimensional coupling system was investigated using the positive drug imatinib, and the results showed that the system was a reliable model for screening potential antitumor compounds from complex systems. This system screened and identified three potential active compounds of evodiamine (EVO), rutaecarpin (RUT), and dehydroevodiamine (DEVO), which possibly target the KIT receptor, from the alcoholic extract of the traditional Chinese medicine Evodia rutaecarpa. Then, the KD values of the interaction of EVO, RUT, and DEVO with KIT receptors measured using nonlinear chromatography were 7.75 (±4.93) × 10-6, 1.42 (±0.71) × 10-6, and 2.34 (±1.86) × 10-6 mol/L, respectively. In addition, the methyl thiazolyl tetrazolium assay validated the active effects of EVO and RUT in inhibiting the proliferation of high KIT-expressing cells in the ranges of 0.1-10 µmol/L and 0.1-50 µmol/L, respectively. In conclusion, the KIT-SNAP-tag/CMC could be a reliable model for screening antitumor components from complex systems.

Therapeutic Effects of the major alkaloid constituents of Evodia rutaecarpa in Alzheimer's disease.

Since the report of Alzheimer's disease (AD) in 1907, it has garnered widespread attention due to its intricate pathogenic mechanisms, significant impact on patients' lives, and the substantial burden it places on society. Presently, effective treatments for AD remain elusive. Recent pharmacological studies on the traditional East Asian herb, Evodia rutaecarpa, have revealed that the bioactive alkaloid components within it can ameliorate AD-related cognitive impairments and neurological damage through various pathways, including anti-inflammatory, antioxidant, and anti-acetylcholinesterase activities. Consequently, this article provides an overview of the pharmacological effects and research status of the four main alkaloid components found in Evodia concerning AD. We hope this article will serve as a valuable reference for experimental and clinical research on the use of Evodia in AD prevention and treatment.

Evodiae Fructus extract suppresses inflammatory response in HaCaT cells and improves house dust mite-induced atopic dermatitis in NC/Nga mice.

This study was conducted to assess the effect of Evodiae Fructus 70% ethanol extract (EFE) on the pathology of atopic dermatitis using in vitro and in vivo models. The major compounds in EFE were identified by ultra-performance liquid chromatography with tandem mass spectrometry as rutaecarpine, evodiamine, evodol, dehydroevodiamine, limonin, synephrine, evocarpine, dihydroevocarpine, and hydroxyevodiamine. EFE significantly decreased chemokine levels in tumor necrosis factor-α/interferon-γ-stimulated HaCaT cells. In house dust mite-treated NC/Nga mice, topical application of EFE significantly decreased the dermatitis score, epidermal hyperplasia and thickening, mast cell infiltration, and plasma levels of histamine and corticosterone. Thymic stromal lymphopoietin, CD4+ T cells, interleukin-4, and intercellular adhesion molecule-1 expression in the lesioned skin was reduced in the treated mice. The mechanism of EFE was elucidated using transcriptome analysis, followed by experimental validation using Western blotting in HaCaT cells. EFE down-regulated the activation of Janus kinase (JAK)-signal transducers and activators of transcription (STAT) and mitogen-activated protein kinases (MAPK) signaling pathways in HaCaT cells. EFE improves atopic dermatitis-like symptoms by suppressing inflammatory mediators, cytokines, and chemokines by regulating the JAK-STAT and MAPK signaling pathways, suggesting its use as a potential agent for the treatment of atopic dermatitis.

Ethanol extract of Evodia lepta Merr. ameliorates cognitive impairment through inhibiting NLRP3 inflammasome in scopolamine-treated mice.

Evodia lepta Merr. (Evodia lepta) is a well-known traditional Chinese medicine, which has been widely used in herbal tea. We previously reported that the coumarin compounds from the root of Evodia lepta exhibited neuroprotective effects. However, whether Evodia lepta could inhibit NLRP3 inflammasome in dementia was still unknown. In this study, the components of the Evodia lepta extract were identified by HPLC-Q-TOF HRMS. We employed a scopolamine-treated mouse model. Evodia lepta extract (10 or 20 mg/kg) and donepezil were treated by gavage once a day for 14 consecutive days. Following the behavioral tests, oxidative stress levels were measured. Then, Western blot and immunofluorescence analysis were used to evaluate the expressions of NLRP3 inflammasome. 14 major components of the Evodia lepta extract were identified by HPLC-Q-TOF HRMS. The results of Morris water maze, object recognition task and open field test indicated that Evodia lepta extract could ameliorate cognitive impairment in scopolamine-treated mice. Evodia lepta extract improved cholinergic system. Moreover, Evodia lepta extract improved the expressions of PSD95 and BDNF. Evodia lepta extract suppressed neuronal oxidative stress and apoptosis. In addition, Evodia lepta extract inhibited NLRP3 inflammasome in the hippocampus of scopolamine-treated mice. Evodia lepta extract could protect against cognitive impairment by inhibiting NLRP3 inflammasome in scopolamine-treated mice.

Characterization of Evodia rutaecarpa (Juss) Benth honey: volatile profile, odor-active compounds and odor properties.

BACKGROUND: Aroma is one of the most important quality criterion of different honeys and even defines their merchant value. The composition of volatile compounds, especially the characteristic odor-active compounds, contributes significantly to the aroma of honey. Evodia rutaecarpa (Juss) Benth honey (ERBH) is a special honey in China with unique flavor characteristics. However, no work in the literature has investigated the volatile compounds and characteristic odor-active compounds of ERBHs. Therefore, it is imperative to conduct systematic investigation into the volatile profile, odor-active compounds and odor properties of ERBHs. RESULTS: The characteristic fingerprint of ERBHs was successfully constructed with 12 characteristic peaks and a similarity range of 0.785-0.975. In total, 297 volatile compounds were identified and relatively quantified by headspace solid-phase microextraction coupled with gas chromatography quadrupole time-of-flight mass spectrometry, of which 61 and 31 were identified as odor-active compounds by relative odor activity values and GC-olfactometry analysis, respectively, especially the common 22 odor-active compounds (E)-ß-damascenone, phenethyl acetate, linalool, cis-linalool oxide (furanoid), octanal, hotrienol, trans-linalool oxide (furanoid), 4-oxoisophorone and eugenol, etc., contributed significantly to the aroma of ERBHs. The primary odor properties of ERBHs were floral, followed by fruity, herbaceous and woody aromas. The partial least-squares regression results showed that the odor-active compounds had good correlations with the odor properties. CONCLUSION: Identifying the aroma differences of different honeys is of great importance. The present study provides a reliable theoretical basis for the quality and authenticity of ERBHs. © 2023 Society of Chemical Industry.

Integrated network pharmacology and metabolomics to investigate the effects and possible mechanisms of Dehydroevodiamine against ethanol-induced gastric ulcers.

ETHNOPHARMACOLOGICAL RELEVANCE: Tetradium ruticarpum (A.Juss.) T.G.Hartley, a traditional Chinese medicine with thousands of years of medicinal history, has been employed to address issues such as indigestion, abdominal pain, and vomiting. Dehydroevodiamine (DHE) is a quinazoline alkaloid extracted from traditional Chinese medicine Tetradium ruticarpum (A.Juss.) T.G.Hartley. Previous studies have shown that DHE has anti-inflammatory, analgesic, and antioxidant activities. However, it is still unclear whether DHE has an effect on ethanol-induced gastric ulcers. AIM OF THE STUDY: The objective of this study is to investigate the therapeutic efficacy and underlying mechanisms of action of DHE on ethanol-induced gastric ulcers using network pharmacology and metabolomics strategies. METHODS: In this study, we used ethanol-induced rats as a model to assess the efficacy of DHE by biochemical indicator assays and pathological tissue detection. The integration of network pharmacology and metabolomics was used to explore possible mechanisms and was validated by western blot experiments. Finally, molecular docking was used to analyze the binding energy between DHE and the targets of PIK3CG and PLA2G2A. RESULTS: DHE was able to reverse ethanol-induced abnormalities in biochemical indicators and improve pathological tissue. Network pharmacology results indicated that DHE may be involved in the regulation of gastric ulcers by modulating 79 targets, and metabolomics results showed that a total of 13 metabolites were changed before and after DHE administration. Integrating network pharmacology and metabolomics, PIK3CG and PLA2G2A were identified as possible targets to exert therapeutic effects. In addition, the MAPKs pathway may also be involved in the regulation of ethanol-induced gastric ulcers. Finally, molecular docking results showed that DHE had low binding energies with both PIK3CG and PLA2G2A. CONCLUSIONS: These findings suggest that DHE was able to exert a protective effect against ethanol-induced gastric ulcers by modulating multiple metabolites with multiple targets. This study provides a valuable reference for the development of antiulcer drugs.

Network pharmacology-based strategy to investigate the bioactive ingredients and molecular mechanism of Evodia rutaecarpa in colorectal cancer.

BACKGROUND: Evodia rutaecarpa, a traditional herbal drug, is widely used as an analgesic and antiemetic. Many studies have confirmed that Evodia rutaecarpa has an anticancer effect. Here, our study explored the bioactive ingredients in Evodia rutaecarpa acting on colorectal cancer (CRC) by utilizing network pharmacology. METHODS: We clarified the effective ingredients and corresponding targets of Evodia rutaecarpa. CRC-related genes were obtained from several public databases to extract candidate targets. Candidate targets were used to construct a protein-protein interaction (PPI) network for screening out core targets with topological analysis, and then we selected the core targets and corresponding ingredients for molecular docking. Cell proliferation experiments and enzyme-linked immunosorbent assays (ELISAs) verified the anticancer effect of the bioactive ingredients and the results of molecular docking. RESULTS: Our study obtained a total of 24 bioactive ingredients and 100 candidate targets after intersecting ingredient-related targets and CRC-related genes, and finally, 10 genes-TNF, MAPK1, TP53, AKT1, RELA, RB1, ESR1, JUN, CCND1 and MYC-were screened out as core targets. In vitro experiments suggested that rutaecarpine excelled isorhamnetin, evodiamine and quercetin in the inhibition of CRC cells and the release of TNF-α was altered with the concentrations of rutaecarpine. Molecular docking showed that rutaecarpine could effectively bind with TNF-α. CONCLUSION: The pairs of ingredients-targets in Evodia rutaecarpa acted on CRC were excavated. Rutaecarpine as a bioactive ingredient of Evodia rutaecarpamight effectively inhibit the proliferation of CRC cells by suppressing TNF-α.

Different ratios of Schisandra chinensis and Evodia rutaecarpa combination for treating Alzheimer's disease.

Schisandra chinensis and Evodia rutaecarpa are traditional Chinese herbs that have been used for many years to treat neurodegenerative diseases. In Chinese medicine, multiple herbs are often used in combination to enhance their efficacy, and different combination ratios can produce different therapeutic effects, thus flexibly responding to the needs of various patients. This study aimed to investigate the effects of different ratios of Schisandra and Evodia herbs on learning and memory impairment in rats with Alzheimer's disease (AD) and their specific mechanisms of action. Morris water maze and hematoxylin and eosin (HE) staining experiments were performed to evaluate the effects of different ratios of Schisandra-Evodia on learning memory in AD model rats. Immunohistochemical experiments were performed to investigate the effects of Schisandra-Evodia on the Aß1-42 and P-Tau proteins, and protein immunoblotting (WB) was performed to determine the expression of key proteins in two pathways, BDNF/TrkB/CREB and GSK-3ß/Tau. Our experimental results show that all Schisandra-Evodia groups showed significant neuroprotective effects, improved learning memory impairment, and reduced levels of Aß1-42 and P-Tau proteins in AD model rats. Schisandra-Evodia upregulated BDNF, P-TrkB/TrkB, and P-CREB/CREB protein expression and downregulated GSK-3ß and P-Tau/Tau protein expression. Among the different Schisandra-Evodia ratio groups, the 2:1 group showed the strongest therapeutic effect on AD. Our research results indicate that Schisandra-Evodia can reduce Aß1-42 and P-Tau protein content by modulating the activity of two pathways, BDNF/TrkB/CREB and GSK-3ß/Tau, thus improving neuronal cell damage and cognitive deficits caused by AD. In addition, we found that a Schisandra-Evodia ratio of 2:1 had the most profound therapeutic effect on AD.

Coptidis Rhizoma processed with Evodia Rutaecarpa improves the effect on ulcerative colitis by increasing intestinal energy metabolites alpha-ketoglutarate and Lactobacillus reuteri.

BACKGROUND: Evodia Rutaecarpa-processed Coptidis Rhizoma (ECR) is a traditional Chinese medicine for the treatment of ulcerative colitis (UC) in China. However, the mechanisms underlying the ECR processing are not elucidated. PURPOSE: Coptidis Rhizoma (CR) regulates the gut microbiota in the treatment of gastrointestinal diseases. This study explored the mechanism of action of ECR before and after processing in UC in view of the regulation of gut microecology. STUDY DESIGN: A preclinical experimental investigation was performed using a mouse model of UC to examine the regulatory effect of ECR and its mechanisms through gut microbiota analysis and metabolomic assays. METHODS: Mice received 4% dextran sulfate sodium to establish a UC model and treated with ECR and CR. Colonic histopathology and inflammatory changes were observed. Gut microbiota was analyzed using 16 s rRNA sequencing. Transplants of Lactobacillus reuteri were used to explore the correlation between ECR processing and the gut microbiota. The expression of mucin-2, Lgr5, and PCNA in colonic epithelial cells was measured using immunofluorescence. Wnt3a and ß-catenin levels were detected by western blotting. The metabolites in the colon tissue were analyzed using a targeted energy metabolomic assay. The effect of energy metabolite α-ketoglutarate (α-KG) on L. reuteri growth and UC were verified in mice. RESULTS: ECR improved the effects on UC in mice compared to CR, including alleviating colonic injury and inflammation, and modulating gut microbiota by increasing L. reuteri level. L. reuteri dose-dependently alleviated colonic injury, increased mucin-2 level, and promoted colonic epithelial regeneration by increasing Lgr5 and PCNA expression. This was consistent with the results before and after ECR processing. L. reuteri promoted epithelial regeneration by upregulating Wnt/ß-catenin pathway. Moreover, ECR increased metabolites levels (especially α-KG) to promote energy metabolism in the colon tissue compared to CR. α-KG treatment increased L. reuteri level and alleviated mucosal damage in UC mice. It promoted L. reuteri growth by increasing the energy metabolic status by enhancing α-KG dehydrogenase activity. CONCLUSION: ECR processing improves the therapeutic effects of UC via the α-KG-L. reuteri-epithelial regeneration axis.

Major Indole Alkaloids in Evodia Rutaecarpa: The Latest Insights and Review of Their Impact on Gastrointestinal Diseases.

Evodia rutaecarpa, the near-ripe fruit of Euodia rutaecarpa (Juss.) Benth, Euodia rutaecarpa (Juss.) Benth. var. officinalis (Dode) Huang, or Euodia rutaecarpa (Juss.) Benth. var. bodinieri (Dode) Huang, is a famous herbal medicine with several biological activities and therapeutic values, which has been applied for abdominalgia, abdominal distension, vomiting, and diarrhea as a complementary and alternative therapy in clinic. Indole alkaloids, particularly evodiamine (EVO), rutaecarpine (RUT), and dedhydroevodiamine (DHE), are received rising attention as the major bioactivity compounds in Evodia rutaecarpa. Therefore, this review summarizes the physicochemical properties, pharmacological activities, pharmacokinetics, and therapeutic effects on gastrointestinal diseases of these three indole alkaloids with original literature collected by PubMed, Web of Science Core Collection, and CNKI up to June 2023. Despite sharing the same parent nucleus, EVO, RUT, and DHE have different structural and chemical properties, which result in different advantages of biological effects. In their wide range of pharmacological activities, the anti-migratory activity of RUT is less effective than that of EVO, and the neuroprotection of DHE is significant. Additionally, although DHE has a higher bioavailability, EVO and RUT display better permeabilities within blood-brain barrier. These three indole alkaloids can alleviate gastrointestinal inflammatory in particular, and EVO also has outstanding anti-cancer effect, although clinical trials are still required to further support their therapeutic potential.

Elucidation of Pharmacological Mechanism Underlying the Anti-Alzheimer's Disease Effects of Evodia rutaecarpa and Discovery of Novel Lead Molecules: An In Silico Study.

Alzheimer's disease (AD) is a brain disease with a peculiarity of multiformity and an insidious onset. Multiple-target drugs, especially Chinese traditional medicine, have achieved a measure of success in AD treatment. Evodia rutaecarpa (Juss.) Benth. (Wuzhuyu, WZY, i.e., E. rutaecarpa), a traditional Chinese herb, has been identified as an effective drug to cure migraines. To our surprise, our in silico study showed that rather than migraines, Alzheimer's disease was the primary disease to which the E. rutaecarpa active compounds were targeted. Correspondingly, a behavioral experiment showed that E. rutaecarpa extract could improve impairments in learning and memory in AD model mice. However, the mechanism underlying the way that E. rutaecarpa compounds target AD is still not clear. For this purpose, we employed methods of pharmacology networking and molecular docking to explore this mechanism. We found that E. rutaecarpa showed significant AD-targeting characteristics, and alkaloids of E. rutaecarpa played the main role in binding to the key nodes of AD. Our research detected that E. rutaecarpa affects the pathologic development of AD through the serotonergic synapse signaling pathway (SLC6A4), hormones (PTGS2, ESR1, AR), anti-neuroinflammation (SRC, TNF, NOS3), transcription regulation (NR3C1), and molecular chaperones (HSP90AA1), especially in the key nodes of PTGS2, AR, SLCA64, and SRC. Graveoline, 5-methoxy-N, N-dimethyltryptamine, dehydroevodiamine, and goshuyuamide II in E. rutaecarpa show stronger binding affinities to these key proteins than currently known preclinical and clinical drugs, showing a great potential to be developed as lead molecules for treating AD.

Phloroglucinol derivatives, coumarins and an alkaloid from the roots of Evodia lepta Merr.

Two previously undescribed phloroglucinol derivatives [(±) evolephloroglucinols A and B], five unusual coumarins [evolecoumarins A and B and (±) evolecoumarins C-E], and one novel enantiomeric quinoline-type alkaloid [(±) evolealkaloid A], along with 20 known compounds, were isolated from the EtOH extract of the roots of Evodia lepta Merr. Their structures were elucidated by extensive spectroscopic analyses. The absolute configurations of the undescribed compounds were determined by X-ray diffraction or computational calculations. Their anti-neuroinflammatory effects were assayed. Among the identified compounds, compound 5a effectively reduced nitric oxide (NO) production with an EC50 value of 22.08 ± 0.46 µM. Hence, it could indeed inhibit the lipopolysaccharide (LPS)-induced Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome.

Coptidis rhizoma and evodiae fructus against lipid droplet deposition in nonalcoholic fatty liver disease-related liver cancer by AKT.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. NAFLD has become one of the major factors contributing to hepatocellular carcinoma (HCC) development. However, there are no clear targets and therapeutic drugs for NAFLD-related liver cancer. This study explored the active compounds, target and mechanism of coptidis rhizoma and evodiae fructus in the treatment of NAFLD-related liver cancer based on the network pharmacology and experimental verification. There were 455 intersection targets of NAFLD-related liver cancer, and 65 drug-disease common targets. AKT1 has the highest degree, indicating that it may be a key target of coptidis rhizoma and evodiae fructus in the treatment of NAFLD-related liver cancer. The expression level of AKT1 was high in high-risk group, and the overall survival rate was lower than that in low-risk group. After oleic acid induction, p-AKT expression and lipid droplet deposition were promoted in HepG2 cells. Quercetin and resveratrol reduced lipid droplet deposition in vivo. Moreover, quercetin inhibited p-AKT expression, resveratrol both reduced the expression of p-AKT and AKT. The overall findings suggested that quercetin inhibited AKT in the treatment of NAFLD-related liver cancer.

Mechanism and Pharmacodynamic Substance Basis of Raw and Wine-Processed Evodia rutaecarpa on Smooth Muscle Cells of Dysmenorrhea Mice.

Objectives: Evodia rutaecarpa (ER) is a well-known herbal Chinese medicine traditionally used for analgesia in dysmenorrhea, headaches, abdominal pain, etc. Notably, the analgesic effect of wine-processed Evodia rutaecarpa (PER) was more potent than that of raw ER. This research aimed to investigate the mechanism and pharmacodynamic substance basis of raw ER and PER on smooth muscle cells of dysmenorrhea mice. Methods: Metabolomics methods based on UPLC-Q-TOF-MS were utilized to analyse the differential components of ER before and after wine processing. Afterwards, the uterine smooth muscle cells were isolated from the uterine tissue of dysmenorrhea and normal mice. The isolated dysmenorrhea uterine smooth muscle cells were randomly divided into four groups: model group, 7-hydroxycoumarin group (1 mmol/L), chlorogenic acid (1 mmol/L), and limonin (50 µmol/L). The normal group consisted of the isolated normal mouse uterine smooth muscle cells, which were repeated 3 times in each group. The cell contraction and the expression of P2X3 and Ca2+ in vitro were determined using immunofluorescence staining and laser confocal; ELISA was used for detection of PGE2, ET-1, and NO content after 7-hydroxycoumarin, chlorogenic acid, and limonin administered for 24 h. Results: The metabolomics results suggested that seven differential compounds were identified in the extracts of raw ER and PER, including chlorogenic acid, 7-hydroxycoumarin, hydroxy evodiamine, laudanosine, evollionines A, limonin, and 1-methyl-2-[(z)-4-nonenyl]-4 (1H)-quinolone. The in vitro results showed that 7-hydroxycoumarin, chlorogenic acid, and limonin were able to inhibit cell contraction and PGE2, ET-1, P2X3, and Ca2+ in dysmenorrhea mouse uterine smooth muscle cells and increase the content of NO. Conclusion: Our finding suggested that the compounds of the PER were different from those of the raw ER, and 7-hydroxycoumarin, chlorogenic acid, and limonin could improve dysmenorrhea in mice whose uterine smooth muscle cell contraction was closed with endocrine factors and P2X3-Ca2+ pathway.

Dietary Evodiamine Inhibits Atherosclerosis-Associated Changes in Vascular Smooth Muscle Cells.

Evodia rutaecarpa (Juss.) Benth is a traditional Chinese medicine. The active ingredient, evodiamine, is a quinolone alkaloid and is found in Evodiae fructus. We investigated the effect of evodiamine on atherosclerosis using LDLR-/- mice fed on a high-fat diet and ox-LDL-induced MOVAS cell lines to construct mouse models and cell-line models. We report a significant reduction in atherosclerotic plaque formation in mice exposed to evodiamine. Our mechanistic studies have revealled that evodiamine can regulate the proliferation, migration, and inflammatory response of and oxidative stress in vascular smooth muscle cells by inhibiting the activation of the PI3K/Akt axis, thus inhibiting the occurrence and development of atherosclerosis. In conclusion, our findings reveal a role for evodiamine in the regulation of vascular smooth muscle cells in atherosclerosis, highlighting a potential future role for the compound as an anti-atherosclerotic agent.

Untargeted serum and liver metabolomics analyses reveal the gastroprotective effect of polysaccharide from Evodiae fructus on ethanol-induced gastric ulcer in mice.

This study aimed at investigating the gastroprotective effect of Evodiae fructus polysaccharide (EFP) against ethanol-induced gastric ulcer in mice. Biochemical indexes along with untargeted serum and liver metabolomics were determined. Results showed that pre-treatment of EFP alleviated ethanol-induced gastric ulcer in mice. EFP lessened oxidative stress and inflammation levels of stomachs, showing as increments of SOD and GSH-Px activities, GSH content and IL-10 level, and reductions of MDA and IL-6 levels. Meanwhile, EFP activated the Keap1/Nrf2/HO-1 signaling pathway through increasing Nrf2 and HO-1 protein expressions, and decreasing Keap1 protein expression. Serum and liver metabolomics analyses indicated that 10 metabolic potential biomarkers were identified among normal control, ulcer control and 200 mg/kg·bw of EFP groups, which were related to 5 enriched metabolic pathways including vitamin B6 metabolism, nicotinate and nicotinamide metabolism, pentose phosphate pathway, bile secretion and ascorbate and aldarate metabolism. Further pearson's correlation analysis indicated that there were some positive and negative correlations between the biomarkers and the biochemical indexes. It could be concluded that the gastroprotection of EFP might be related to anti-oxidative stress, anti-inflammation, activation of Keap1/Nrf2/HO-1 signaling pathway and alteration of metabolic pathways. This study supports the potential application of EFP in preventing ethanol-induced gastric ulcer.

Molecular mechanisms of hepatotoxicity induced by compounds occurring in Evodiae Fructus.

Evodiae Fructus (EF) is a common herbal medicine with thousands of years of medicinal history in China, which has been demonstrated with many promising pharmacological effects on cancer, cardiovascular diseases and Alzheimer's disease. However, there have been increasing reports of hepatotoxicity associated with EF consumption. Unfortunately, in a long term, many implicit constituents of EF as well as their toxic mechanisms remain poorly understood. Recently, metabolic activation of hepatotoxic compounds of EF to generate reactive metabolites (RMs) has been implicated. Herein, we capture metabolic reactions relevant to hepatotoxicity of these compounds. Initially, catalyzed by the hepatic cytochrome P450 enzymes (CYP450s), the hepatotoxic compounds of EF are oxidized to generate RMs. Subsequently, the highly electrophilic RMs could react with nucleophilic groups contained in biomolecules, such as hepatic proteins, enzymes, and nucleic acids to form conjugates and/or adducts, leading to a sequence of toxicological consequences. In addition, currently proposed biological pathogenesis, including oxidative stress, mitochondrial damage and dysfunction, endoplasmic reticulum (ER) stress, hepatic metabolism disorder, and cell apoptosis are represented. In short, this review updates the knowledge on the pathways of metabolic activation of seven hepatotoxic compounds of EF and provides considerable insights into the relevance of proposed molecular hepatotoxicity mechanisms from a biochemical standpoint, for the purpose of providing a theoretical guideline for the rational application of EF in clinics.

The Ethanol Extract of Evodiae Fructus and Its Ingredient, Rutaecarpine, Inhibit Infection of SARS-CoV-2 and Inflammatory Responses.

COVID-19, derived from SARS-CoV-2, has resulted in millions of deaths and caused unprecedented socioeconomic damage since its outbreak in 2019. Although the vaccines developed against SARS-CoV-2 provide some protection, they have unexpected side effects in some people. Furthermore, new viral mutations reduce the effectiveness of the current vaccines. Thus, there is still an urgent need to develop potent non-vaccine therapeutics against this infectious disease. We recently established a series of detecting platforms to screen a large library of Chinese medicinal herbs and phytochemicals. Here, we reveal that the ethanolic extract of Evodiae Fructus and one of its components, rutaecarpine, showed promising potency in inhibiting the activity of 3C-like (3CL) protease, blocking the entry of the pseudo-typed SARS-CoV-2 (including wild-type and omicron) into cultured cells. In addition, inflammatory responses induced by pseudo-typed SARS-CoV-2 were markedly reduced by Evodiae Fructus extract and rutaecarpine. Together our data indicate that the herbal extract of Evodiae Fructus and rutaecarpine are potent anti-SARS-CoV-2 agents, which might be considered as a treatment against COVID-19 in clinical applications.