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The pharmacodynamic results of uniform design experiments. (a, b, c) The contents of monoamine neurotransmitters determined by electrochemical detector. (d, e) The contents of NO-b and NO-p determined by NO assay kit. Data are shown as mean ± SEM (Fold change of normal group). ∗ P < 0.05 and ∗ ∗ P < 0.01 versus Normal group; # P < 0.05 and # # P < 0.01 versus Model group. Data were analysed by One-way ANOVA followed by least significant difference or Tambane’s T2 analysis (n = 6 animals per group).
Source publication
Wuzhuyu decoction (WZYD) has been clinically used to treat migraine effectively since Eastern Han Dynasty of ancient China. However, its antimigrainic ingredients remain unclear. In present study, the antimigrainic ingredients of WZYD were explored and optimized in nitroglycerin-induced migraine rats through correlation analysis of decoction spectr...
Citations
... to promote the revitalization and development of tcM, the china administration of traditional chinese Medicine issued the first batch of the ancient classic Prescriptions catalogue in 2018, which included 100 ancient classic prescriptions as key R&D targets, of which WZYD was the 11th. therefore, the research on it has been more in-depth in recent years, but mainly concentrated on the clinical therapeutic effect (li, chi, et al., 2022; liu et al., 2018), identification and metabolism of active ingredients (liu et al., 2017;Wu et al., 2018;Xu et al., 2019Xu et al., , 2020, chemical composition analysis Xu et al., 2016), and animal efficacy (li, chen, et al., 2022;Nan et al., 2022;Wu et al., 2016), and there is no toxicological study of WZYD have been published. in addition, according to the chinese Pharmacopoeia (version 2015), Evodia rutaecarpa (Juss.) ...
Wuzhuyu decoction (WZYD) is a well-known classic traditional Chinese medicine prescription and has been widely used to treat headache, nausea, vomiting, insomnia, etc. However, little published information is available about its safety. Our aim was to investigate the acute and subacute oral toxicity of WZYD extract in rats following the technical guidelines from China's National Medical Products Administration (NMPA) for single and repeated doses toxicity studies of drugs. Acute oral toxicity was assessed in rats via oral administration of WZYD extract at 4 g/kg three times within a day followed by a 14-day observation period. To evaluate the subacute toxicity, rats were orally administered with WZYD extract at doses of 0, 0.44, 1.33, and 4 g/kg for 28 days. The items examined included clinical signs, body weight, food consumption, hematological and biochemical parameters, bone marrow smear, organ index, and histopathology. After the rats were administered with 12 g/kg (3 × 4 g/kg) WZYD extract, no mortality and toxic effects were observed during the observation period. In the subacute toxicity study, WZYD extract did not cause any significant treatment-related abnormality in each examined item of rats, so the no observed adverse effect level (NOAEL) of WZYD extract for 28 days orally administered to rats is considered to be 4 g/kg, which is approximately 80-fold of its clinical proposed dosage.
... Wuzhuyu decoction is a classical Chinese formula that has been used for over 2,000 years to treat gastrointestinal diseases, hyperalgesia, and headaches. 6,7 It was derived from the Shang Han Lun, a renowned treatise written in 219 AD by Zhongjing Zhang. The formula consists of four primary herbs: Euodia rutaecarpa (Juss.) ...
Objective
Chronic non-atrophic gastritis (CNAG) is a common clinical gastrointestinal disease with a long and recurrent course. In China, Wuzhuyu decoction (WZYD) has been used for centuries to treat gastrointestinal disorders. To unravel the efficacy and mechanism of WZYD for CNAG, a clinical study was conducted. And metabolomics was used to explore the mechanism of WZYD for CNAG patients.
Methods
Twenty patients in total were recruited in this study (Nos. ChiCTR2200062296) and the protocol was approved by the Ethics Committee (Approval number: KY-2022-2-6-1) and complied with the Declaration of Helsinki. The formula granule of WZYD were assessed by UHPLC-QQQ-TOF to discern the main potential active compounds. The endoscopy evaluation and histopathological changes were detected as effective indicators. Serum samples from patients were used for metabolomics. Inflammatory factors in patients’ serum were determined by ELISA. Metabolomics revealed a series of differential metabolites and signaling pathways.
Results
WZYD was capable to prevent CNAG by ameliorating score of endoscopy evaluation including erosion, hemorrhage, as well as chronic inflammation and active chronic inflammation score after treatment were decreased. The results indicated that 10 core metabolic components were associated with the treatment of WZYD. Moreover, these metabolic components proved that pyrimidine metabolism and thiamine metabolism were critically responsible for CNAG. In addition, WZYD treatment effectively reduced serum levels of TNF-α, IL-10, and COX-2.
Conclusion
Altogether, WZYD can effectively alleviate CNAG by inhibiting inflammation and regulating related metabolic processes, which might be the molecular mechanism of WZYD treatment of CNAG. More studies are warranted to be conducted in this area.
Trial Registration
ChiCTR, ChiCTR2200062296. Registered 1 August 2022, https://www.chictr.org.cn/com/25/showprojen.aspx?proj=174027.
... It is used to solve many problems that cannot be solved by conventional multiple regression and is appropriate to investigate the quality control of Chinese herbs or TCM overcoming the complexity of chemical compositions and efficacy. It was used successfully to recognize and optimize antimigraine ingredients from Wuzhuyu Decoction [38] and identify quality markers in Chuanxiong Rhizoma and Cyperi Rhizoma herbal pair [39] in our previous work. Here we employed the PLSR method to analyze the correlation between the pharmacological activity and concentration of 8 constituents in GUF. ...
Licorice (Glycyrrhiza uralensis Fisch. (GUF), Leguminosae) has been extensively applied in traditional Chinese medicine (TCM) to treat diseases, exactly, in almost half of Chinese herbal prescription. However, the relationship between chemical contents and efficacy has not been established, which could evaluate GUF quality. To create a simple and effective quality-evaluation method, 33 batches of GUF from different habitats in China were collected. The correlation between eight constituents (liquiritin, isoliquiritin, liquiritigenin, isoliquiritigenin, glycyrrhizic acid, licochalcone A, glabridin and glycyrrhetinic acid) and pharmacological activities (anti-inflammatory, antioxidant and immunoregulatory) was analyzed per the partial least squares regression method. Results showed that eight constituents correlated significantly with the pharmacological activity. The correlation equation modes between pharmacological activity and contents of eight constituents were constructed and verified to be reliable. In GUF extract, the main constituents liquiritin, isoliquiritin and glycyrrhizic acid exhibited positive influence on anti-inflammatory and antioxidant effect with different potent, while the metabolites liquiritigenin and isoliquiritigenin exhibited positive effect on the immunoregulatory activity and glycyrrhetinic acid exhibited positive effect on all the tested activities. Thus, our chemical-efficacy correlation method is reliable and feasible to predict the pharmacological activity based on its eight constituents. It could be powerful in quality control of GUF and provides a useful way for quality evaluation of other medicinal herbs.
... The raw materials of WZYD were extracted, decompressed, concentrated, and dried into dry powder as previously reported [11]. There are four raw materials in WZYD, Euodiae Fructus, Ginseng Radix et Rhizoma, Jujubae Fructus, and Zingiberis Rhizoma Recens. ...
... The traditional Chinese medicine has clinical experience and efficacy for thousands of years, and a number of studies have clarified their potential for CM. In previous studies, WZYD was found to ameliorate CM by increasing 5-HT and norepinephrine [11], and the gut microbiota also changed during the disease and treatment [7]. Based on the above findings, in order to clarify the roles of gut microbiota in WZYD treatment migraine, the efficacy of WZYD on IS-induced CM model rats associated with gut microbiota depletion was observed in this study. ...
... The treatment of WZYD not only decreased the expression of CGRP and c-Fos but also regulated the content of 5-HIAA/5-HT, MAOA, and SERT in the center and increased the contents of 5-HT, TPH, Piezo1, and SERT in the periphery. Part of the results was similar to previous study [11,14]. Moreover it was found that WZYD elevated central 5-HT through the inhibition of 5-HT metabolism in this study. ...
We previously found that Wuzhuyu Decoction (WZYD) could affect central and peripheral 5-HT to relieve hyperalgesia in chronic migraine (CM) model rats, possibly related to gut microbiota. However, the exact role of gut microbiota has not been elucidated. Accumulating evidence points to the possibility of treating central nervous system disease via the gut-brain axis. In our study, the inflammatory soup-induced CM model rats presented depression- and anxiety-like behaviors which both related to insufficient 5-HT. It was found that antibiotic administration caused community dysbiosis, and proteobacteria became the main dominant bacteria. The bacteria related to short-chain fatty acids and 5-HT generation were reduced, resulting in reduced levels of 5-HT, tryptophan hydroxylase, and secondary bile acids. Functional prediction-revealed sphingolipid signaling pathway in CM rats was significantly decreased and elevated after WZYD treatment. The effect of WZYD could be weakened by antibiotics. The CM rats exhibited anxiety- and depression-like behavior with 5-HT and number of neurons decreased in the CA1 and CA2 regions of hippocampal. The treatment of WZYD could recover to varying degrees. Antibiotics combined with WZYD attenuate the effect of WZYD on increasing the 5-HT content and related protein expression in the brain stem, plasma and colon, reducing CGRP, c-Fos, and inflammatory factors. And antibiotics also led to colon length increasing and stool retention, so that the antimigraine effect was weakened compared with WZYD. This experiment revealed that gut microbiota mediated WZYD treatment of CM rats with anxiety-depression like behavior.
... Evodia rutaecarpa [12] has been used in traditional Chinese medicine for hundreds of years. In addition to treating migraines, Evodia rutaecarpa is widely used in the treatment and prevention of chronic diseases such as diabetes, cardiovascular disease, and cancer [13]. ...
Evodia rutaecarpa has multiple pharmacological effects and is widely used in the prevention and treatment of migraine, diabetes, cardiovascular disease, cancer, and other chronic diseases; however, the pharmacological effects of its active compound evodiamine (Evo) have not been thoroughly investigated. The purpose of this study was to investigate the effects of Evo on antiplatelet activation and thrombosis. We discovered that Evo effectively inhibited collagen-induced platelet activation but had no effect on platelet aggregation caused by activators such as thrombin, ADP, and U46619. Second, we found that Evo effectively inhibited the release of platelet granules induced by collagen. Finally, evodiamine inhibits the transduction of the SFKs/Syk/Akt/PLCγ2 activation pathway in platelets. According to in vivo studies, Evo significantly prolonged the mesenteric thromboembolism induced by ferric chloride and had no discernible effect on the coagulation function of mice. In conclusion, the antiplatelet and thrombotic effects of Evo discovered in this study provide an experimental basis for the investigation of the pharmacological mechanisms of Evo and the development of antiplatelet drugs.
... It could be inferred that CYP3A4 played a critical role in the hepatotoxicity of EF. Clinically, EF was generally used in many traditional Chinese medicine formulations, such as Zuojin pills (Coptidis Rhizoma and EF) (Wang et al., 2013), Wuzhuyu decoction, (EF, Zingiberis Rhizoma, Ginseng Radix et Rhizoma, and jujube Fructus) (Xu et al., 2019) and etc. for thousands of years. And, some drugs had effect on CYP3A activities, for instance, Coptidis Rhizoma was reported to enhance CYP3A activities (Yu et al., 2018). ...
Ethnopharmacological relevance
Evodiae Fructus (EF), the traditional Chinese medicine, has been typically used to treat headache, abdominal pain, hernias, and menorrhagia for thousands of years. It is a mild toxicity herb-medicine listed in Sheng Nong's Herbal Classic. Recently, EF was reported to have toxicity or no toxicity in some investigations. Toxicity and approaches to reducing toxicity of EF are of great interest. Limonin (LIM), a major triterpenoid component of EF, also had various pharmacological activities such as anti-inflammatory, anticancer, and antioxidant effects. However, little attention was paid to the role of LIM in EF-induced hepatotoxicity.
Aim of Study
The study aimed to address the problem of controversial hepatotoxicity of EF, evaluate the role of CYP3A4 inducer/inhibitor in EF-induced hepatotoxicity and disclose the effect of LIM in EF-induced hepatotoxicity.
Materials and methods
The chemical compositions and hepatotoxicity of small flower EF (SEF), medium flower EF (MEF), big flower EF (BEF) and the “organ knock-out” samples (the shell and seed part of BEF) were investigated. Simultaneously, C57BL-6 mice were randomly divided into four groups, which were given orally administered BEF, BEF in combination with dexamethasone (DEX), BEF in combination with ketoconazole (KTC), and BEF in combination with LIM, respectively.
Results
In this study, more alkaloids and less LIM were detected in BEF compared with the compounds in SEF and MEF. Furthermore, we found that BEF group induced hepatotoxicity whereas no hepatotoxicity was observed in SEF and MEF groups. In addition, no LIM was detected in the shell part of BEF and five alkaloids were not detected in the seed part of BEF. Correspondingly, the shell part of BEF group induced hepatotoxicity whereas no hepatotoxicity was observed in the seed part of BEF group. It was also found that the BEF-induced hepatotoxicity was remarkably exacerbated when the mice were pretreated with DEX whereas the BEF-induced hepatotoxicity could be reversed by pretreatment with KTC or LIM.
Conclusions
Based on the results in this study, the misuse of BEF but not SEF and MEF could produce hepatotoxicity. The hepatotoxicity difference of different categories of EF might be associated with the relative contents of alkaloids and LIM. In addition, the results demonstrated that CYP3A4 inducer aggravated BEF-induced hepatotoxicity and LIM attenuated its hepatotoxicity.
... Rats had open access to water throughout the study. For pharmacokinetic analysis, 18 SD rats were randomly divided into 3 groups and 0.4 mL of nitroglycerin (dosage: 10 mg/kg) was injected into the forehead to establish the migraine model [19]. After 1 h, rats were intragastrically administered PA alone (372.4 mg/kg), ISO alone (40 mg/kg), and PI coadministered (ISO: 40 mg/ kg, PA: 372.4 mg/kg). ...
Migraine is a chronic brain disease that leads to periodic neurological attacks. Parishin A and isorhynchophylline (PI) is the active monomer component extracted from the traditional antimigraine Chinese medicinal combination of Gastrodia and Uncaria, respectively. In this study, using high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) technology, we performed pharmacokinetic and lipidomic study on migraine model rats after administration of PI. For the detection of the compounds in plasma, AB Sciex Triple Quad™ 4500 was applied for quantitative analysis, and the COSMOSIL C18 column (2.1 × 100 mm, 2.6 μm) was used for separation. Isorhynchophylline (ISO: m/z 384.8–241.2) and its main metabolite rhynchophylline (RHY: m/z 384.8–160.2) were simultaneously detected under positive ion modes. Besides, parishin A (PA: m/z 995.1–726.9) and its main metabolite gastrodin (GAS: m/z 331.1–123.0) were simultaneously detected with negative ion modes. For the analysis of endogenous lipid components, Dionex Ultimate 3000 (UHPLC) Thermo Orbitrap Elite was applied for the detection, and the Waters UPLCRBEH C18 column (1.7 μm 100 ∗ 2.1 mm) was used for separation. Chloroform/methanol (2 : 1, v : v) was used for extraction. The results demonstrated that PI exists significant difference in metabolism between single- and coadministration and can regulate lipid levels associated with migraine.
... Sampling and weighing were carried out at 45 and 180 min, thus allowing us to calculate the mass of the solution perfused and collected. In situ single-pass intestinal perfusion was implemented in accordance with the literatures with some modifications (Li et al., 2012;Zhou et al., 2012;Jang et al., 2013;Wang and Li, 2018;Xu et al., 2019). At the end of the experiment, the corresponding intestinal segments (duodenum, jejunum, and ileum) were dissected and their length (L) and perimeter (s) were measured. ...
Background
Amomi fructus is a famous traditional Chinese medicine (TCM) that can exert beneficial effects during the treatment of gastrointestinal diseases and is used widely in China and other countries in Southeast Asia. However, the nonvolatile active ingredients that are present in the water extractions from A. fructus used to treat gastrointestinal diseases have yet to be elucidated. The goal of this study was to identify the nonvolatile active ingredients of A. fructus.
Methods
We used an in situ single-pass intestinal perfusion (SPIP) model to identify the active ingredients of A. fructus that play significant roles in gastrointestinal absorption. In addition, we developed a high-performance liquid chromatography (HPLC) method to identify key fractions in intestinal outflow perfusate.
Results
Nineteen components were identified in a water extraction from A. fructus; these exhibited different absorption capabilities in different intestinal segments. Of these, six components were determined by the newly developed HPLC method: catechin, vanillic acid, epicatechin, polydatin, isoquercitrin, and quercitrin.
Conclusions
The current study aimed to identify the active ingredients present in water extractions prepared from A. fructus in a single-intestinal perfusate from rats. Our findings provide an experimental basis to explain the pharmacodynamic actions of A. fructus.
Background
: Chronic migraine (CM) is a highly disabling and burdensome disease. Wuzhuyu decoction (WZYD), a clinical used formula to treat and prevent episodic migraine and CM, has been reported to relieve the hyperalgesia of CM and increase brainstem and blood serotonin (5-hydroxytryptamine, 5-HT) in migraine model rats in previous studies; yet the mechanism is unclear.
Purpose
: This study aimed to observe the hyperalgesia relief effect of WZYD and investigate the mechanistic association with the regulation on central and peripheral 5-HT.
Methods
: WZYD with different doses (3.372, 1.686 and 0.843 g/kg•d) and the positive drug - sumatriptan (5.83 mg/kg•3d) were intragastrically administered in inflammatory soup (IS)-induced CM model rats, respectively. Hyperalgesia was assessed by facial mechanical withdrawal threshold and tail-flick latency. 5-HT was determined by ELISA. Western blot analysis, immunohistochemistry and immunofluorescence determination, and 16S rRNA gene sequencing were performed.
Results
: WZYD significantly relieved the hyperalgesia by elevating the facial mechanical withdrawal threshold and tail-flick latency. In WZYD groups, increased 5-HT and decreased calcitonin gene-related peptide in both the brainstem and plasma, downregulated TNF-α, IL-1β, and c-fos expression in the brainstem were observed in dose-dependent manner. Interestingly, 5-HT in colon tissues were also observed, which is associated with upregulating tryptophan hydroxylase, serotonin transporter and Piezo1 expression and increasing 5-HT and chromogranin A in enterochromaffin cells. Disorder of the microbiota, function and metabolism was correlated with 5-HT synthesis. WZYD could regulate the abundance of Anaerostipes and Acidifaciens.
Conclusion
: WZYD has the pharmacological effect on relieving hyperalgesia in CM model rats, possibly by affecting central and peripheral 5-HT.
