An effective method for preventing cholestatic liver injury of Aucklandiae Radix and Vladimiriae Radix: Inflammation suppression and regulate the expression of bile acid receptors.

ETHNOPHARMACOLOGICAL RELEVANCE: Aucklandiae Radix (AR) and Vladimiriae Radix (VR) were used to treat gastrointestinal, liver and gallbladder diseases at practice. In most conditions, VR was used to be a substitute of AR or a local habit may attribute to the same main active ingredients Costunolide and Dehydrocostus lactone, which presented many similar pharmacological activities. However, other different lactone compounds in AR and VR also play a role in disease treatment, so the difference in therapeutic effects of AR and VR in related diseases needs to be further studied. AIMS OF THE STUDY: Revealing the differences between the chemical compounds of the total lactone extracts of AR and VR (TLE of AR and VR) and the differences in the protective effects of cholestatic liver injury to ensure rational use of AR and VR. STUDY DESIGN AND METHODS: The macroporous adsorption resin was used to purify and enrich the lactone compounds to obtain the total lactone extracts of AR and VR. HPLC-PDA was used to obtain the data to establish chemical fingerprint and chemometric analysis to compare similarities and differences between TLE of AR and VR. The pharmacodynamic experiment revealed how TLE of AR and VR to show protect effects on cholestatic liver injury. RESULTS: Similarity analysis results showed TLE of AR and VR had a high similarity (>0.9). Nevertheless, difference analysis results showed 4 compounds, Costunolide, Dehydrocostus lactone, 3ß-acetoxy-11ß-guaia-4 (15), 10 (14)-diene-12,6α-olide and vladinol F may contribute to the differences between them. The pharmacodynamics experiments results showed the TLE of AR and VR affected the different liver cholate-associated transporters mRNA expression (TLE of AR up-regulated CYP7A1, TLE of VR down-regulated FXR and BSEP), the TLE of AR and VR had an effect to regulate biochemical indicators (AST, ALT, ALP, TBA) of liver function, and TLE of VR was better than TLE of AR in reducing the expression of inflammatory factors (IL-6 and IL-1ß). CONCLUSION: The liver protection of AR and VR have been confirmed, but the differences of material basis and mechanism of drug efficacy needed further study to guarantee formulation research and provide theoretical references for clinical rational applications of AR and VR.

Sequential loading of inclusion complex/nanoparticles improves the gastric retention of Vladimiriae Radix essential oil to promote the protection of acute gastric mucosal injury.

The essential oil from Vladimiriae Radix (VEO) is a medicinal natural product with anti-ulcer activity. A novel gastroretentive drug delivery system was developed by preparing the hydroxypropyl-ß-cyclodextrin (HP-ß-CD) inclusion complex incorporated into chitosan nanoparticles (V-CD/NPs), to improve the bioavailability of VEO and its protective effect on gastric mucosa. The optimum preparation process of V-CD/NPs was obtained by Plackett-Burman and Box-Behnken response surface methodology. The resulting V-CD/NPs gained a suitable positive potential and small particle size, and showed stability in simulated gastric fluid, whose morphology and in vitro drug release profiles had a pH-sensitivity. Besides, V-CD/NPs was proved to strongly bind with mucin, and in vivo imaging revealed that it could be retained in the stomach for more than 8 h. The results of drug concentration in gastric tissues showed that the sequential loading of inclusion complex/nanoparticles promoted the local absorption of VEO in gastric tissues, which was favorable to reach the effective therapeutic concentration in the lesioned mucosa area. In comparison to VEO and V-CD, the callback effect of V-CD/NPs on 1L-1ß, 1L-6, TNF-α, NF-κB, MDA and SOD was comparable to cimetidine, and V-CD/NPs outperformed in gastric mucosal protection. Therefore, the gastroretentive drug delivery system developed in our study effectively enhanced the anti-ulcer activity of VEO, which could be a promising strategy for the prevention and treatment of the acute gastric mucosal injury.

A comprehensive chemical and pharmacological review of three confusable Chinese herbal medicine-Aucklandiae radix, Vladimiriae radix, and Inulae radix.

Aucklandiae radix (AR, Muxiang), vladimiriae radix (VR, Chuanmuxiang), and inulae radix (IR, Tumuxiang) are widely used in clinical or folk medicine in China. Their Chinese names all have the Chinese character "Muxiang," which makes it confusable in usage, especially AR and VR, because VR was used as a substitute for AR during a historical period. The National Health Commission of the People's Republic of China has approved AR as a functional food. However, VR and IR are not listed. Many research articles on three kinds of "Muxiang" have been published. However, no review was appeared to compare similarities and differences among the three kinds of "Muxiang." Here, the morphological characterization, phytochemistry, and pharmaceutical effects of AR, VR, and IR were reviewed. We found that only six compounds were common in the three species. Twenty-six compounds were common to AR and VR. Twenty-two compounds were common to AR and IR. Only seven compounds were common to VR and IR. The extracts of AR, VR, and IR were all reported with antiinflammatory effects, which is the most important activity of "Muxiang" species. The volatile oil of AR, VR, and IR had antibacterial activities. Extracts of AR and VR showed anti-gastric ulcers and anti-diarrhea effects. Extracts of AR and IR exhibited anticancer effects. In addition, AR extract had liver protective effect. It is worth mentioning that costunolide and dehydrocostus lactone, which were the common representative compounds of "Muxiang" species, showed antiinflammatory, anticancer, anti-gastric ulcers, and liver protective effects. This review will be a benefit reference for correct understanding and application of the three "Muxiang" species.

Aucklandiae Radix and Vladimiriae Radix: A systematic review in ethnopharmacology, phytochemistry and pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Aucklandiae Radix (AR) and Vladimiriae Radix (VR), as commonly used traditional Chinese herbal medicine, were widely used in the treatment of gastrointestinal diseases. The two herbal medicines were warm, pungent and bitter. They entered the spleen, stomach, large intestine and gallbladder meridians, and had the effect of promoting qi circulation to relieve pain. It is usually used for chest and hypochondrium, abdominal fullness and pain, tenesmus, indigestion, and warming the middle to harmonize the stomach in clinically. AIM OF THIS REVIEW: To provide a reference for the identification of traditional use, the material basis of efficacy and preclinical research between AR and VR, this review systematically summarized the similarities and differences in ethnopharmacology, phytochemistry and modern pharmacology. MATERIALS AND METHODS: The literature information was collected systematically from the electronic scientific databases, including PubMed, Science Direct, Google Scholar, Web of Science, Geen Medical, China National Knowledge Infrastructure, as well as other literature sources, such as classic books of herbal medicine, master's thesis, doctoral thesis. RESULTS: In the plateau areas of Sichuan Province, VR used to be regarded as substitute or local habit for AR, which is regularly used for chest, abdominal fullness and pain, diarrhea, and other related diseases. In Chinese Pharmacopoeia (ChP) 2020 edition, 145 prescription preparations with AR were collected, such as Xianglian Wan, Muxiang Shunqi Wan, Liuwei Muxiang San. However, only one prescription preparation (Jiuxiang Zhitong Wan) contained VR. Additionally, 237 and 254 chemical components were separately isolated and identified from AR and VR, 69 kinds of compounds were common among them, and the significant differences were presented in sesquiterpene lactones, monoterpenoids, triterpenoids and phenylpropanoids. Moreover, Costunolide (COS) and Dehydrocostus lactone (DEH), two main research objects of modern pharmacology, showed multiple pharmacological activities. Not only could they inhibit the activity of some cancer cells (such as breast cancer and leukemia cells), but they regulated the levels of various inflammatory factors (including TNF-α, NF-κB, IL-1ß, IL-6) and repressed the growth and reproduction of various microorganisms (like Helicobacter pylori, Staphylococcus aureus). CONCLUSION: COS and DEH as the common active components, provide a certain basis for local medicine about the substitution of VR for AR in Sichuan province of China in the past. In addition, the sesquiterpenoids are the main common compounds in AR and VR by collecting and collating a large number of literature and various data websites. Furthermore, AR and VR have significant differences in ethnopharmacology and phytochemistry, especially in sesquiterpene lactones, monoterpenoids, triterpenoids and phenylpropanoids, and are probably viewed as reference of a separate list of AR and VR in Chinese Pharmacopoeia.

Study of the therapeutic effect of raw and processed Vladimiriae Radix on ulcerative colitis based on intestinal flora, metabolomics and tissue distribution analysis.

BACKGROUND: The intestinal flora imbalance and metabolic disorders are closely related to the pathogenesis of ulcerative colitis (UC). As a commonly used herb for the treatment of gastrointestinal diseases, Vladimiriae Radix (VR) has been used for hundreds of years, and its main active ingredients are costunolide (COS) and dehydrocostus lactone (DEH). Clinical usage habits and previous studies have shown that the processed Vladimiriae Radix (pVR) seems to be more suitable for treating bowel disease than the raw Vladimiriae Radix (rVR), but there is still no relevant comparative study. PURPOSE: To investigate the therapeutic effect of rVR and pVR on UC by analyzing the intestinal flora, metabolomics and tissue distribution. METHODS: UC rat models were established to investigate the anti-inflammatory activities of rVR and pVR by enzyme-linked immunosorbent assay (ELISA), and to study their regulation of intestinal flora and metabolism by 16s rRNA gene analysis and Ultra Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS). Moreover, the distribution of COS and DEH in UC mouse tissues were also observed by High Performance Liquid Chromatography Mass Spectrometry (HPLC-MS). RESULTS: rVR and pVR reduced tissue damage and the levels of TNF-α, IL-6, IL-1ß, IL-10, TGF-ß and MPO, especially pVR. 16s rRNA gene analysis showed that rVR superior in ameliorating species evenness and restoring the abundance of Lachnospiraceae and Ruminococcaceae, while pVR is better at increasing the richness and the abundance of Prevotellaceae. Metabolomics analysis suggested that rVR regulates the ß-alanine, pantothenic acid and coenzyme A biosynthesis, but pVR regulates more abundant metabolic pathways. The tissue distribution data indicated the accumulation of COS and DEH in the gastrointestinal tract. CONCLUSION: rVR and pVR had obvious therapeutic effect on UC. The potential mechanisms might be regulating abnormal metabolism, affecting the diversity and structure of intestinal flora, and accumulation of COS and DEH in colon.

Comparative study of raw and processed Vladimiriae Radix on pharmacokinetic and anti-acute gastritis effect through anti-oxidation and anti-inflammation.

BACKGROUND: Vladimiriae Radix (VR) is the dry root of Vladimiria souliei (Franch.) Ling or Vladimiria souliei (Franch.) Ling var. cinerea Ling. Costunolide (CO) and dehydrocostus lactone (DE) are the two most effective active ingredients of VR. Raw Vladimiriae radix (rVR) and processed Vladimiriae radix (pVR) are the two most common forms. They have been used for hundreds of years to treat gastritis, gastric ulcer and gastrointestinal pain, but their protective effects on gastric mucosa have been widely considered to be different, and the mechanism is not clear. PURPOSE: A comparative study of in vivo process and efficacy difference of raw and processed Vladimiriae Radix was carried out to explore the treatment mechanism and to provide reference for the rationality of clinical usage. METHODS: In this study, multi-batch rVR and pVR were used to establish the characteristic chromatograms through high performance liquid chromatography (HPLC) to control the qualities of their extracts. A rapid and accurate ultra-high performance liquid chromatography - mass spectrometry (UPLC-MS) method was established and verified, and the concentrations of CO and DE in plasma of rats after oral administration were determined to analyze the pharmacokinetics. The anti-inflammatory and antioxidant activities of ethanol-induced acute gastric mucosa injury (AGMI) in rats were quantitatively analyzed by ELISA and Westernblot methods. RESULTS: Characteristic chromatograms study showed that there were 9 common characteristic peaks between the chromatograms of rVR and pVR, and there was a high level (> 0.90) of the similarity between batches (only one batch less than 0.90). The increased levels of Tmax, T1/2 and MRT were found in rats treated with the pVR. Animal model studies indicated that both the two forms of VR could relieve AGMI, but pVR could more effectively reduce the content of ethanol in blood and lower the levels of TNF-α, IL-6, IL-1ß, NO, iNOS and MDA, and increase the level of SOD. Results of Westernblot proved that pVR also could inhibit the expression of NF-κB p65, IκBα and up-regulate the expression of HO-1 and NRF2 more operatively to protect gastric mucosa through anti-inflammatory and antioxidant stress mechanisms. CONCLUSION: Compared with rVR, pVR has an accelerated absorption in vivo and its effect time was prolonged, and the observed improvement of anti-AGMI effect was achieved through anti-oxidation and anti-inflammation regulation.

Analysis of the similarities and differences between Auclandia and Vladimirae rhizomes by chemical profiling and chemometric analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Aucklandiae Radix (AR) and Vladimiriae Radix (VR), as traditional Chinese medicine, have been included in many editions of Chinese Pharmacopoeia with similar efficacy such as promoting qi and relieving pain, which are used to treat chest, hypochondriac, abdominal fullness and pain, diarrhea and tenesmus. In most conditions, VR is used to be a substitute of AR or a local habit. However, whether VR could substitute for AR to play a same role in the formulation and clinical applications needs further study. AIM OF THE STUDY: In this study, similarities and differences between AR and VR would be assessed, and possible reasons that may influence the efficacy of the AR and VR would be explained from the perspective of chemical composition. MATERIALS AND METHODS: HPLC-PDA was used to obtain the data of 10 batches of AR and VR, and to establish chemical fingerprint and chemometric analysis. UPLC-ESI-Q-TOF-MS was used to identify the structure of chemical compounds which contributed to the differences between AR and VR. RESULTS: The chemical fingerprint analysis results showed that 20 peaks in common for AR and 26 peaks in common for VR both presented a good similarity (>0.9), and 15 peaks in common for AR and VR also showed a good similarity (>0.9). Nevertheless, chemometric showed AR was distinct from VR and three chemical compounds, which leading to their differences, were identified by UPLC-ESI-Q-TOF-MS. The three chemical compounds were 3ß-acetoxy-11ß-guaia-4 (15),10 (14)-diene-12,6α-olide, 10α,14-epoxy-11ß-guaia-4 (15)-ene-12,6α-olide and costunolide, respectively. CONCLUSION: In general, AR and VR were highly similar, but their differences were deserved to be paid attention to. This research could provide reference for quality control and set a foundation for clinical applications of AR and VR.

Quality assessment and differentiation of Aucklandiae Radix and Vladimiriae Radix based on GC-MS fingerprint and chemometrics analysis: basis for clinical application.

Vladimiriae Radix, a geo-authentic medicinal herb found in Sichuan Province in China, is highly similar in chemical composition and pharmacological activity to Aucklandiae Radix. It is often used in local practice and as a substitute for Aucklandiae Radix in the treatment of gastrointestinal tract diseases. However, Vladimiriae Radix is preferred to Aucklandiae Radix in traditional Chinese medicine in Sichuan. In order to compare the difference in quality between the two species and differentiate them according to their chemical profiles, and further to explain the rationality of using Vladimiriae Radix as a substitute and explore the reason for the medication preference in Sichuan, similarity was evaluated using gas chromatography-mass spectrometry (GC-MS) fingerprinting and chemometric analysis. Volatile compounds were identified by comparing mass spectra with spectral data from the National Institute of Standards and Technology library 14.L (NIST 14.L) and the linear retention indices (RI) with those previously reported. The results showed that the similarity between the samples from Aucklandiae Radix (>96%) was greater than that of Vladimiriae Radix (>80%). In addition, 41 and 38 compounds were identified in 10 batches of Vladimiriae Radix and Aucklandiae Radix, respectively, and 21 compounds were common to both species, of which dehydrocostus lactone and aplotaxene were abundant in both. However, γ-patchoulene, longicyclene, ß-gurjunene, humulene1,2-epoxide, and ß-patchoulene were unique to Vladimiriae Radix, while 4-terpineol, α-ionone, trans-α-bergamotene, γ-selinene, and camphene were characteristic compounds of Aucklandiae Radix. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) suggested that the two species were well differentiated with regard to the level of essential oils. Orthogonal partial least squares discriminant analysis (OPLS-DA) further showed that compounds including costol, aplotaxene, caryophyllene, humulene, and ß-eudesmol, together with the characteristic compounds of the two species, could be regarded as potential markers for differentiation, among which ß-eudesmol, which is richer in Vladimiriae Radix, and ß-patchoulene, which is unique to Vladimiriae Radix, have potential therapeutic effects on gastrointestinal diseases. The results obtained in this study distinguished Vladimiriae Radix and Aucklandiae Radix on a chemical level, and the similarity in chemical constituents may provide a basis for the rationality of Vladimiriae Radix as a substitute, while ß-patchoulene and ß-eudesmol existing in Vladimiriae Radix provide a theoretical basis for its preferential use in Sichuan. The analysis method established here has important implications for the quality control and differentiation of Vladimiriae Radix and Aucklandiae Radix, which can also serve as a reference for the identification of similar species. Graphical abstract.