Geniposidic Acid Research Articles

Effect of Pruning Treatment on Growth Characteristics and Metabolites in Eucommia ulmoides Oliver (E. ulmoides)

The effect of pruning treatments on growth, photosynthesis characteristics, and metabolites were was studied in Eucommia ulmoides Oliver (E. ulmoides). The experiment was carried out from March–August 2019. Three treatments were used: non-pruned trees (CK), a height of 20 cm above the top edge of the flowerpot (T1), and a height of 10 cm above the top edge of the flowerpot (T2). The results showed that the branches branch number, leaves leaf number, and stem diameter increased significantly (p < 0.05) in pruning treatments compared with CK. Similarly, the net photosynthetic rate (Pn), stomatal conductance (Gs), transpiration rate (Tr), maximum photosynthetic efficiency (Fv/Fm), and non-photochemical quenching coefficient (NPQ) increased significantly in pruning treatments (p < 0.05). Interestingly, the contents of Chl a, Chl b, Chl, Car, and the rate between the Chl a content and the Chl b content increased significantly (p < 0.05) in T2, respectively. These verified that it was a better way to enhance the plants growth of E. ulmoides for pruning treatments. The GC-MS analysis showed that 36 different primary metabolites were identified, including 11 sugars, 13 acids, 5 alcohols, and 7 other compounds, the relative content of their metabolites were was higher in the T2 treatment than that in the T1 treatment, which was mainly concentrated in four main enrichment pathways (Galactose metabolism; Citrate cycle; Glyoxylate and dicarboxylate metabolism; and starch and sucrose metabolism) via KEGG analysis. Meanwhile, correlation analysis showed there were was a positive correlation between the accumulation of D-Galactose, D-Mannose, Succinic acid, and photosynthetic pigment content, and the rate of photosynthesis in T2 treatment (p < 0.05). The pruning height above the top edge of the flowerpot changed the accumulation of primary metabolites and promoted plant regeneration ability in E. ulmoides. Finally, the yield of main secondary metabolites from leaves (Genipin, Geniposide, Geniposidic acid, and Pinoresinol diglucoside) were was increased in pruning treatments by UPLC analysis. It provided a reference for the directional ecological cultivation of E. ulmoides.

Rapid multi-indicator quality evaluation of Eucommia ulmoides by near-infrared spectroscopy combined with chemometrics

ObjectiveUsing near-infrared spectroscopy and chemometrics, to establish a method for determination of multiple indicators in Eucommia ulmoides (EU) to achieve its rapid quality evaluation. Method83 batches of EU decoction slices were collected, and the content of pinoresinol diglucoside, chlorogenic acid and geniposidic acid in them was determined by high-performance liquid chromatography, the content of total flavonoids was determined by UV–Vis spectrophotometry, while the antioxidant activity of EU was measured by methods of DPPH, ABTS and FRAP, respectively. The near-infrared spectra of EU were acquired in diffuse reflectance mode, which were subjected to multivariate statistical analysis in relation with the above measured values. In order to achieve good model performance, various methods for spectra pretreatment and wavelength selection were explored. Especially, with the help of four wavelength selection methods based on swarm intelligence optimization, such as genetic algorithm (GA), gray wolf algorithm (GWO), improved global flower pollination algorithm (mgFPA), and improved sine and cosine optimization algorithm (ISCA), the partial least squares regression models were improved prominently. The model quality was evaluated by calculating the coefficient of determination (R2), root mean square error (RMSE) and residual prediction deviation (RPD) in the sets of calibration and prediction. ResultsRegardless of which indicator in EU, the model performance was fairly good, especially after the wavelength selection by GA and other three methods, where R2 > 0.9, RPD > 3 in both calibration and prediction, indicating that the models had good prediction accuracy. Based on the overall algorithmic efficiency and model results, we have the following ranking: GA > GWO > mgFPA > ISCA. ConclusionThe present models provide a novel method for rapid and comprehensive quality evaluation of EU, which may be of great significance for quality evaluation and quality control of EU.

Dynamic changes of endophytic bacteria in the bark and leaves of medicinal plant Eucommia ulmoides in different seasons

The bark and leaves of the Eucommia ulmoides Oliv. (E. ulmoides) have good medicinal value. Studies show endophytes play important roles in host medicinal plant secondary metabolite synthesis, with season being a key influencing factor. Therefore, we used 16 S rRNA to detect endophytic bacteria (EB) in E. ulmoides bark and leaves collected in winter, spring, summer, and autumn, and analyzed the contents of major active components respectively. The results showed that the species diversity and richness of EB of the E. ulmoides bark were higher than those of leaves in all seasons except fall. Among them, the higher species diversity and richness were found in the E. ulmoides bark in winter and spring. EB community structure differed significantly between medicinal tissues and seasons. Concurrently, the bark and leaves of E. ulmoides showed abundant characteristic EB across seasons. For active components, geniposidic acid showed a significant positive correlation with EB diversity and richness, while the opposite was true for aucubin. Additionally, some dominant EB exhibited close correlations with the accumulation of active components. Delftia, enriched in autumn, correlated significantly positively with aucubin. Notably, the impact of the same EB genera on active components differed across medicinal tissues. For example, Sphingomonas, enriched in summer, correlated significantly positively with pinoresinol diglucoside (PDG) in the bark, but with aucubin in the leaves. In summary, EB of E. ulmoides was demonstrated high seasonal dynamics and tissue specificity, with seasonal characteristic EB like Delftia and Sphingomonas correlating with the accumulation of active components in medicinal tissues.

Effects of Yinzhihuang on Alleviating Cyclosporine A-Induced Cholestatic Liver Injury via Farnesoid X Receptor-Mediated Regulation of Transporters and Enzymes in Vitro and in Vivo.

Yinzhihuang (YZH), a traditional Chinese medicine prescription, was widely used to treat cholestasis. Cholestatic liver injury limited the use of the immunosuppressive drug cyclosporine A (CsA) in preventing organ rejection after solid organ transplantation. Clinical evidences suggested that YZH could enhance bile acids and bilirubin clearance, providing a potential therapeutic strategy against CsA-induced cholestasis. Nevertheless, it remains unclear whether YZH can effectively alleviate CsA-induced cholestatic liver injury, as well as the molecular mechanisms responsible for its hepatoprotective effects. The purpose of the present study was to investigate the hepatoprotective effects of YZH on CsA-induced cholestatic liver injury and explore its molecular mechanisms in vivo and vitro. The results demonstrated that YZH significantly improved the CsA-induced cholestatic liver injury and reduced the level of liver function markers in serum of Sprague-Dawley (SD) rats. Targeted protein and gene analysis indicated that YZH increased bile acids and bilirubin efflux into bile through the regulation of multidrug resistance-associated protein 2 (Mrp2), bile salt export pump (Bsep), sodium taurocholate cotransporting polypeptide (Ntcp) and organic anion transporting polypeptide 2 (Oatp2) transport systems, as well as upstream nuclear receptors farnesoid X receptor (Fxr). Moreover, YZH modulated enzymes involved in bile acids synthesis and bilirubin metabolism including Cyp family 7 subfamily A member 1 (Cyp7a1) and uridine 5'-diphosphate (UDP) glucuronosyltransferase family 1 member A1 (Ugt1a1). Furthermore, the active components geniposidic acid, baicalin and chlorogenic acid exerted regulated metabolic enzymes and transporters in LO2 cells. In conclusion, YZH may prevent CsA-induced cholestasis by regulating the transport systems, metabolic enzymes, and upstream nuclear receptors Fxr to restore bile acid and bilirubin homeostasis. These findings highlight the potential of YZH as a therapeutic intervention for CsA-induced cholestasis and open avenues for further research into its clinical applications.

Effects of lactic acid bacteria on antioxidant activity in vitro and aroma component of Eucommia ulmoides tea.

Eucommia ulmoides tea is a popular functional health drink in Asian countries, but its unique herbal aroma is difficult for consumers to accept. The effects of four lactic acid bacteria strains (Lactobacillus plantarium, Lactobacillus bulgaricus, Lactobacillus acidophilus and Streptococcus thermophilus) fermentation on the physicochemical property, antioxidant activity in vitro and aroma component of E. ulmoides leaves were studied. Within the four strains, the sample by L. bulgaricus fermentation showed the higher concentrations of chlorogenic acid, geniposidic acid and stronger antioxidant activity in vitro. Moreover, the sample by L. bulgaricus fermentation produced a stronger fruity and floral flavor. These results suggested that L. bulgaricus was the best strain for fermentation E. ulmoides tea. The differences between different strains should be considered when selecting lactic acid bacteria for raw material fermentation of fruits and vegetables.

A multi-strategy platform for Q-markers screening and quality control of Wuzi Yanzong Wan based on fingerprint and network pharmacology

Wuzi Yanzong Wan (WZYZW) is a classic formula for tonifying the kidneys in Traditional chinese medicine (TCM) and is widely used clinically in diseases of the reproductive system, immune system and nervous system. Therefore, the quality control and prediction quality markers (Q-markers) of WZYZW is of positive significance.In this study, We first established the fingerprints, calibrated 28 common peaks, identified 12 common peaks of gallic acid, geniposidic acid, chlorogenic acid, ellagic acid, rutin, hyperoside, verbascoside, astragalin, kaempferol, schisandrol A, schisandrol B and schisandrin B, and the similarity was greater than 0.9 of 10 batches.Then, withing network pharmacology, we screened 41 core targets such as PIK3CA, AKT1, PIK3CB, potential pathways such as pathways in cancer and PI3K-Akt signalling pathway of 12 components. The results showed that they were tightly connected to predicated targets and pathways. Finally, by using the hyperoside as internal reference standard, a Quantitative analysis of multi-components (QAMS) for WZYZW was established to determine the contents of WZYZW. The percent difference(%) showed that there was no significant difference between the quantitative results of external standard method (ESM) and QAMS method. Contents of the 11 components above were 0.0091 ∼ 0.0185 %, 0.1019 ∼ 0.1361 %, 0.0518 ∼ 0.0718 %, 0.0130 ∼ 0.0320 %, 0.0084 ∼ 0.0190 %, 0.0621 ∼ 0.1192 %, 0.0127 ∼ 0.0419 %, 0.0006 ∼ 0.0089 %, 0.0212 ∼ 0.0261 %, 0.0061 ∼ 0.0400 %, 0.0084 ∼ 0.0103 %, respectively. Overall, the method developed was applied to the quality evaluation and Q-markers research of WZYZW as well as provided guiding significance for the Q-marker research of TCM.

Optimization of extraction process for classic prescription Yihuang Decoction based on Box-Behnken design-response surface methodology, standard relation, and analytic hierarchy process combined with entropy weight method

Based on the concept of quality by design(QbD), the Box-Behnken design-response surface methodology combined with standard relation(SR) and analytic hierarchy process(AHP)-entropy weight method(EWM) was applied to optimize the extraction process of the classic prescription Yihuang Decoction. The content of geniposidic acid, phellodendrine hydrochloride, and berberine hydrochloride in Yihuang Decoction, the extract yield, and fingerprint similarity were used as the critical quality attributes(CQAs) of the extraction process. The extraction time, water addition, and extraction times were used as the critical process parameters(CPPs). After determining the levels of each factor and level through single-factor experiments, response surface experiments were designed according to the Box-Behnken principle, and the experimental results were analyzed. The SR between each sample and the reference sample under various evaluation indicators of different extraction parameters was calculated. The weights of the five evaluation indicators were determined using AHP-EWM, followed by comprehensive evaluation. A function model between CPPs and CQAs characterized by comprehensive scores was established to predict the optimal extraction process parameters. In the final comprehensive weight coefficients, the yield rate accounted for 43.1%, and the content of berberine hydrochloride, phellodendrine hydrochloride, and geniposidic acid accounted for 35.1%, 6.3%, and 15.5%, respectively. After comprehensive score analysis with SR, the established second-order polynomial model was statistically significant(P<0.01, and the lack of fit was not significant). The predicted optimal extraction conditions for Yihuang Decoction were determined as follows: 8-fold volume of water, extraction time of 1.5 h, and extraction once. The mean comprehensive score of the validation experiment was 85.77, with an RSD of 0.99%, and it met the quality control stan-dards for the reference sample of Yihuang Decoction. The results indicate that the optimized extraction process for Yihuang Decoction is stable and reliable, and the water extract is close in quality attributes to the reference sample. This can serve as a foundation for the research and development of granules in the future. Box-Behnken design-response surface methodology combined with SR and AHP-EWM can provide references for the modern extraction process research of other classic prescriptions.

Identification of pancreatic lipase inhibitors from Eucommia ulmoides tea by affinity-ultrafiltration combined UPLC-Orbitrap MS and in vitro validation.

Pancreatic lipase inhibitors can reduce blood lipids by inactivating the catalytic activity of human pancreatic lipase, a key enzyme involved in triglyceride hydrolysis, which helps control some dyslipidemic diseases. The ability of Eucommia ulmoides tea to improve fat-related diseases is closely related to the natural inhibitory components of pancreatic lipase contained in the tea. In this study, fifteen pancreatic lipase inhibitors were screened and identified from Eucommia ulmoides tea by affinity-ultrafiltration combined UPLC-Q-Exactive Orbitrap/MS. Four representative components of geniposidic acid, quercetin-3-O-sambuboside, isochlorogenic acid A, and quercetin with high binding degrees were further verified by nanoscale differential scanning fluorimetry (nanoDSF) and enzyme inhibitory assays. The results of flow cytometry showed that they could significantly reduce the activity of pancreatic lipase in AR42J cells induced by palmitic acid in a concentration-dependent manner. Our findings suggest that Eucommia ulmoides tea may be a promising resource for pancreatic lipase inhibitors of natural origin.

Refined Qingkailing protects the in vitro neurovascular unit against oxygen–glucose deprivation and re-oxygenation-induced injury

Since the proposal of the neurovascular unit (NVU) theory, it has become almost mandatory for neuroprotective medicines against ischaemic stroke (IS) to focus on this unit. Refined Qingkailing (RQKL) is a compound composed of hyodeoxycholic acid, geniposide, baicalin and cholic acid, which has shown great potential in the treatment of IS, but its effect on NVU has not been fully studied. The purpose of this study was to investigate the potential biological pathways that underlie the protective effects of RQKL against NVU damage induced by oxygen–glucose deprivation and re-oxygenation (OGD/R). Using in vitro OGD/R models, we looked into whether RQKL protects the NVU. In order to create an in vitro NVU that resembles IS, we created an OGD/R injury model using primary cultures of brain microvascular endothelial cells, neurons, and astrocytes. Based on our results, we present evidence, for the first time, that RQKL treatment of the injury caused by OGD/R significantly (1) kept the blood brain barrier (BBB) functioning and maintained the architecture of the neurons, (2) mitigated the oxidative stress damage, inflammatory cytokine release, and neuronal death, and (3) upregulated the expression of neurotrophic factors generated from glial cells and the brain in the in vitro model. Therefore, RQKL has a variety of preventive effects against NVU damage caused by OGD/R. RQKL may be a suitable medication for treating IS in a clinical setting.

Quality control and evaluation of Xiaozhong Zhitong tincture by multi-wavelength fingerprint combined with electrochemical fingerprint

Xiaozhong Zhitong tincture (XZZTT), a prominent Traditional Chinese Medicine (TCM) formulation comprising 21 intricate herbal components, poses a challenge in terms of quality control due to its complex composition and the interplay of diverse chemical constituents. To address this issue, a comprehensive assessment strategy was devised by integrating chromatographic and electrochemical techniques to construct a multidimensional fingerprint for XZZTT samples. This study encompassed the evaluation of 42 XZZTT samples through a systematic quantitative fingerprinting method (SQFM), while also quantifying the concentrations of four specific compounds—Geniposide, Palmatine hydrochloride, Paeonol, and Chlorogenic acid. The experimental approach encompassed the establishment of fingerprints using High-Performance Liquid Chromatography (HPLC), Gas Chromatography (GC), and GC-HPLC tandem fingerprints methods. Furthermore, electrochemical fingerprints (ECFP) were established using the B-Z oscillation system, and eight characteristic parameters in the oscillation system were recorded and compared among samples. Hierarchical Clustering Analysis (HCA) was subsequently employed to classify the distinct fingerprints and compare outcomes from one-dimensional spectroscopy, GC-HPLC tandem chromatography, and the fusion fingerprints. Finally, Grey Relation Analysis (GRA) was harnessed to unravel the relationship between ECFP outcomes and peak areas in fusion fingerprints, facilitating predictions regarding the substances' reducing potency. In conclusion, the rational combination of multidimensional fingerprinting and multidimensional analysis provides a reliable and comprehensive method for the evaluation of XZZTT and its related products.

Pharmacokinetics, anti-rheumatoid arthritis activity, and active ingredient contents of Eucommia ulmoides Oliv

Eucommia ulmoides Oliv. is a deciduous tree which contains various chemical ingredients. The main objective was to document the active chemical ingredients of Eucommia ulmoides Oliv. and their metabolic profiles in vivo, with a view to providing an experimental and theoretical basis for clarifying the mechanisms underlying the pharmacological activity of Eucommia ulmoides Oliv. against rheumatoid arthritis. Eight main active constituents of Eucommia ulmoides Oliv. bark (pinoresinol glucopyranoside, aucubin, geniposidic acid, geniposide, genipin, chlorogenic acid, quercetin and betulinic acid) were quantified using high-performance liquid chromatography (HPLC). This paper additionally identified and characterized prototype metabolites via ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) combined with the Human Metabolome Database (HMDB) and literature comparisons. Ultra pressure liquid chromatography-mass spectrometry/ mass spectrometry (UPLC-MS/MS) was subsequently employed to quantify these components in blood over time and evaluate their pharmacokinetic characteristics. The anti-rheumatoid arthritis effects of genipin, pinoresinol glucopyranoside and their combinations were assessed using in vitro cellular assays. We identified and characterized a total of 53 ingredients from Eucommia ulmoides Oliv. bark and plasma samples, among which 20 were confirmed as prototype metabolites. Meanwhile, this paper derived and analyzed the metabolic cleavage pathway of 8 index ingredients. Six of these compounds displayed rapid entry into blood, with high plasma exposure and fast elimination rates. Data from the in vitro cellular assay showed that aucubin, pinoresinol glucopyranoside, genipin, and combinations of these compounds effectively inhibit MH7A cell proliferation, reduce NO release, and decrease inflammatory factor levels.

Study on the substance basis of the efficacy of eucommiae cortex before and after salt processing for the treatment of kidney-yang deficiency syndrome based on the spectrum-effect relationship

Ethnopharmacological relevanceKidney-Yang deficiency syndrome (KYDS) is one of the common diseases of the elderly and closely related to the ageing of the body, it has a major impact on the quality of life of the patient. Eucommiae Cortex (EC) is the dried bark of Eucommia ulmoides Oliv. Which has the effect of tonifying the liver and kidneys, strengthening the muscles and bones. In Traditional Chinese Medicine clinics, EC is commonly used in the treatment of KYDS, but the material basis for the improvement of its efficacy in treating KYDS after salt processing remains unclear. Aim of the studyThis study aimed to find the main active ingredients that could improve the treatment of KYDS efficacy of EC after salt processing. Materials and methodsFirstly, the fingerprints of raw and salt-processed EC were established to determine the common components by using HPLC, and then an experimental study on the treatment of KYDS efficacy was carried out to compare the difference in the efficacy between raw and salt-processed EC. Thirdly, the spectrum-effect relationship of chemical components and pharmacodynamic indexes was established by using Grey Relational Analysis and Entropy Method. Finally, the network pharmacology and molecular docking technique was used to verify the kidney tonifying effect of the active ingredients of EC. ResultsAccording to the results of the analysis of hormonal index levels on the hypothalamic-pituitary-target gland axis and the extent of renal lesions, the therapeutic effect of EC on KYDS was mainly reflected in the regulation of the Adrenocorticotropic hormone, Corticosterone in the hypothalamic-pituitary-adrenal axis and Tri-iodothyronine, Tetra-iodothyronine in the hypothalamic-pituitary-thyroid axis, moreover the therapeutic effect of salt-processed EC was stronger than that of raw EC. The pharmacologically active ingredients that improved its treatment of KYDS efficacy after salt processing were peak 1 (geniposidic acid), peak 2 (chlorogenic acid), peak 5 (geniposide), peak 6 (genipin), peak 7 (pinoresinol diglucoside) and peak 11 (hyperoside). Meanwhile, the results of network pharmacology and molecular docking showed that the 6 active ingredients could exert kidney tonic effects through multiple signaling pathways by acting on core targets such as AKT1 and PTGS2. ConclusionAs far as we known, this was the first time to establish and compare the spectrum-effect relationship between raw and salt-processed EC, which laid the foundation for the pharmacokinetics studies of EC and provided a reference for future EC studies.

Establishing the Role of Iridoids as Potential Kirsten Rat Sarcoma Viral Oncogene Homolog G12C Inhibitors Using Molecular Docking; Molecular Docking Simulation; Molecular Mechanics Poisson-Boltzmann Surface Area; Frontier Molecular Orbital Theory; Molecular Electrostatic Potential; and Absorption, Distribution, Metabolism, Excretion, and Toxicity Analysis.

The RAS gene family is one of the most frequently mutated oncogenes in human cancers. In KRAS, mutations of G12D and G12C are common. Here, 52 iridoids were selected and docked against 8AFB (KRAS G12C receptor) using Sotorasib as the standard. As per the docking interaction data, 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester (dock score: -9.9 kcal/mol), 6'-O-trans-para-coumaroyl geniposidic acid (dock score: -9.6 kcal/mol), 6-O-trans-cinnamoyl-secologanoside (dock score: -9.5 kcal/mol), Loganic acid 6'-O-beta-d-glucoside (dock score: -9.5 kcal/mol), 10-O-succinoylgeniposide (dock score: -9.4), Loganic acid (dock score: -9.4 kcal/mol), and Amphicoside (dock score: -9.2 kcal/mol) showed higher dock scores than standard Sotorasib (dock score: -9.1 kcal/mol). These common amino acid residues between iridoids and complexed ligands confirmed that all the iridoids perfectly docked within the receptor's active site. The 100 ns MD simulation data showed that RMSD, RMSF, radius of gyration, and SASA values were within range, with greater numbers of hydrogen bond donors and acceptors. MM/PBSA analysis showed maximum binding energy values of -7309 kJ/mol for 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester. FMO analysis showed that 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester was the most likely chemically reactive molecule. MEP analysis data highlighted the possible electrophilic and nucleophilic attack regions of the best-docked iridoids. Of all the best-docked iridoids, Loganic acid passed Lipinski, Pfizer, and GSK filters with a similar toxicity profile to Sotorasib. Thus, if we consider these iridoids to be KRAS G12C inhibitors, they will be a boon to mankind.

In Vitro Antiproliferative Efficacy, Antioxidant Activity and LC MS Based Metabolite Profiling of Premna Barbata Stem Bark

Premna barbata Wall. ex Schauer is used traditionally as folkloric medicines for the treatment of differentpathological conditions. The first reported constituent from the bark of the plant was an iridoid glycoside premnosidic acid having antioxidant activity. Other species of this genus i.e., Premna latifolia, Premna tomentosa has shown to have antioxidant and cytotoxic activities. Despite the ethnomedicinal uses, no scientific evidence in support of antitumor activity on the stem bark of Premna barbata is reported so far. Hence, the current work aims to assess anticancer potentiality of different extracts of P. barbata on various cancer cell lines. Different extracts i.e., Petroleum ether extract (PBPE), Chloroform extract (PBCE), Ethyl acetate extract (PBEE) and Alcoholic extract (PBAE) were prepared and on each extract in-vitro antiproliferative activity was performed by using SRB assay. The most potent extract i.e., PBEE was then evaluated for antioxidant activity. Qualitative phytochemical investigation of different extracts indicates the presence of proteins, carbohydrates, steroids/triterpenoids, alkaloids, glycosides, flavonoids, and phenolic constituents. Ethyl acetate extract of Premna barbata gives potent cytotoxic activity in all cancer cell lines but more selectively to human colon cancer cell line (COLO-205) with GI 50 44.6 μg/ml. The phenolic and flavonoid content in ethyl acetate extract was 3.43±0.09 mg GE/g and 4.28±0.18mg QE/g respectively. Nineteen compounds were observed in positive (+) ESI mode chromatograms when LC-MS analysis was carried out. The LC-MS analysis by positive ionization mode, the predicted compounds such as Geniposidic acid (synonym: Premnosidic acid) and Rutin were detected. The cytotoxicity observed on cancerous cell lines in our study may be due to the presence of observed compounds. So, it can be concluded that Premna barbata stembark has remarkable cytotoxic activity against different tumor cell lines but the effect is more on colon cell lines as compared to others.

Potential Involvement of Organic Anion Transporters in Drug Interactions with Shuganning Injection, a Traditional Chinese Patent Medicine.

Traditional Chinese medicine injections have been widely used in China for the treatment of various diseases. Transporter-mediated drug-drug interactions are a major contributor to adverse drug reactions. However, the research on transporter-mediated Traditional Chinese medicine injection-drug interactions is limited. Shuganning injection is a widely used Traditional Chinese medicine injection for treating various liver diseases. In this study, we investigated the inhibitory effect of Shuganning injection and its four main ingredients (baicalin, geniposide, chlorogenic acid, and oroxylin A) on 9 drug transporters. Shuganning injection strongly inhibited organic anion transporter 1 and organic anion transporter 3 with IC50 values < 0.1% (v/v), and moderately inhibited organic anion transporter 2, organic anion transporting-polypeptide 1B1, and organic anion transporting-polypeptide 1B3 with IC50 values < 1.0%. Baicalin, the most abundant bioactive ingredient in the Shuganning injection, was identified as both an inhibitor and substrate of organic anion transporter 1, organic anion transporter 3, and organic anion transporting-polypeptide 1B3. Oroxylin A had the potential to act as both an inhibitor and substrate of organic anion transporting-polypeptide 1B1 and organic anion transporting-polypeptide 1B3. In contrast, geniposide and chlorogenic acid had no significant inhibitory effect on drug transporters. Notably, Shuganning injection markedly altered the pharmacokinetics of furosemide and atorvastatin in rats. Using Shuganning injection as an example, our findings support the implementation of transporter-mediated Traditional Chinese medicine injection-drug interactions in the development of Traditional Chinese medicine injection standards.

A new iridoid glucoside from the roots of Morinda officinalis

A new iridoid glucoside, moridoside (1), and nine known compounds, asperulosidic acid (2), 6-O-epi-acetylscandoside (3), geniposidic acid (4), 2-hydroxymethylanthraquinone (5), 2-hydroxymethyl-3-hydroxyanthraquinone (6), damnacanthol (7), lucidine-ω-methyl ether (8), 2-hydroxy-1-methoxyanthraquinone (9), and 3,8-dihydroxy-1,2-dimethoxyanthraquinone (10) were isolated from the methanol extract of Morinda officinalis How. roots. Their structural identification was carried out based on the spectroscopic evidence. All compounds were evaluated for their nitric oxide (NO) production inhibitory activities in LPS-stimulated RAW264.7 macrophages. Compounds 5-7 significantly inhibited the production of NO with IC50 values of 28.4, 33.6, and 30.5 μM, respectively.

Characteristics of endophytic bacteria and active ingredients in the Eucommiae cortex from different origins.

This study aimed to explore the differences between Eucommiae cortex (EC) endophytic bacteria from different origins and their effects on the active ingredients of EC. A total of 10 samples of Eucommia ulmoides Oliv. (E. ulmoides) bark were collected from each of the following four regions, namely, Zunyi in Guizhou (GZ), Baokang in Hubei (HUB), Cili in Hunan (HUN), and Loyang in Shaanxi (SX). Subsequently, the contents of the main active ingredients of EC were determined by ultra-performance liquid chromatography (UPLC), and the endophytic bacteria of EC were detected by 16S rRNA sequencing. The relationship between the dominant endophytic bacteria and the active ingredients was investigated by correlation analysis. A total of 4,551 different operational taxonomic units (OTUs) were delineated in the four groups of samples, of which 585, 439, 957, and 684 genera were annotated from GZ, HUB, HUN, and SX, respectively. The richness and diversity of endophytic bacteria from different origins were ranked as HUN > SX > GZ or HUB. The analysis demonstrated that there was no significant correlation between the diversity and richness of endophytic bacteria in EC and its active ingredients. Nevertheless, notable variations in the community structures of endophytic bacteria were observed across different origins, and they had a considerable impact on certain active ingredients in EC. Comamonas and Cedecea were the dominant genera. Characteristic bacteria of different origins could be clearly distinguished. Simultaneous, significant correlations had been identified between some characteristic endophytic bacteria derived from different origins and active ingredients of EC. For example, Delftia, a characteristic bacterium from GZ, showed a significant positive correlation with pinoresinol diglucoside. Paenibacillus and Klebsiella, two characteristic bacteria from HUB, exhibited significant positive correlations with geniposidic acid. Thauera, a characteristic bacterium from HUN, demonstrated a significant positive correlation with geniposide. Brevundimonas, a characteristic bacterium from SX, displayed a significant positive correlation with pinoresinol diglucoside. There was a complex correlation between EC endophytic bacteria and active ingredient content, while EC endophytic bacteria from different origins had significant differences at the genus level.

Insight into mass transfer during adsorption of geniposidic acid onto a fixed-bed column by numerical simulation considering influence of operating conditions on column adsorption performance

In this work, the adsorption rate of geniposidic acid (GSA) on a fixed-bed column packed with porous adsorbents was studied, thoroughly by a Fick pore diffusion model based on numerical simulation and 3D visualization. Adsorption breakthrough curves of GSA were studied experimentally, under various operation conditions such as feeding concentrations, flow rates and packed column aspect ratio. For ion exchange adsorption of GSA onto the adsorbent used in this paper, a maximum adsorption capacity reached 637.5 mmol·L−1 at 298.5 K. Modeling method for an adsorption packed column was based on the coupling of mass transfer equations with a steady velocity field obtained from Navier-Stokes equation. A finite element method was adopted by COMSOL Multiphysics with proper mesh refinement, to solve the equation system. Moreover, the influences of operation conditions on the magnitude and direction of mass fluxes induced by convection and diffusion were analyzed in details. 3D data of Mass fluxes proved that the existence of forming period and transferring period of mass transfer zone (MTZ), which are important knowledge for comprehending the dynamics of adsorption process. The magnitude of convection flux was almost 107–108 times larger than that of pore diffusion flux. Average pore diffusion diffusivities of GSA and Cl− were fitted to be 5.19 × 10−10 and 1.71 × 10−9 m2·s−1, while their maximal mass fluxes were 9.366 × 10−3 and 3.926 × 10−3 mol m−2·s−1 in simulations, respectively. Finally, adsorption and elution recycle experiments proved the feasibility of the novel GSA adsorption technology in the future scaling-up process.

Geniposidic acid attenuates DSS-induced colitis through inhibiting inflammation and regulating gut microbiota.

Geniposidic acid (GPA) is a bioactive compound isolated from Gardenia jasminoides Ellis (Rubiaceae) that has long been used to treat arthritis, jaundice, and hypertension. However, the therapeutic effects of GPA against colitis remain underexplored. This study aimed to investigate the effect of GPA on the remission of colitis and the underlying mechanisms. A DSS-induced colitis mouse model was used to evaluate the influence of GPA on the modulation of gut microbiota and intestinal epithelial barrier function. Our results indicated that GPA improved DSS-induced mouse colitis, including loss of body weight, disease activity index (DAI), colon length, and colonic pathological damage. DSS-induced destruction of the intestinal barrier was also significantly repaired by GPA treatment. In addition, the relative levels of pro-inflammatory cytokines, such as IL-1β and TNF-α, were markedly alleviated by GPA. Furthermore, western blot analysis revealed that GPA downregulated the protein expression of the nuclear transcription factor NF-κB. Finally, we first demonstrated that GPA could alleviate gut microbiota dysbiosis in mice with colitis by bacterial 16S rRNA sequencing. In conclusion, our study demonstrates the therapeutic and protective effects of GPA on IBD and provides novel insights into the prevention of colitis by targeting gut microbiota metabolism using natural products.

Geniposide plus chlorogenic acid reverses non-alcoholic steatohepatitis via regulation of gut microbiota and bile acid signaling in a mouse model in vivo.

Background: Geniposide and chlorogenic acid are the major active ingredients in Yinchenhao Decoction and are widely used as herbal medicines in Asia. This study further assessed their effects on improvement of non-alcoholic steatohepatitis (NASH) in a mouse model and explored the underlying molecular events in vivo. Methods: Male C57BL/6 and farnesoid X receptor knockout (FXR-/-) mice were used to establish the NASH model and were treated with or without geniposide, chlorogenic acid, obeticholic acid (OCA), and antibiotics for assessment of the serum and tissue levels of various biochemical parameters, bile acid, DNA sequencing of bacterial 16S amplicon, protein expression, and histology. Results: The data showed that the combination of geniposide and chlorogenic acid (GC) reduced the levels of blood and liver lipids, serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), and the liver tissue index in NASH mice. In addition, GC treatment improved the intestinal microbial disorders in the NASH mice as well as the intestinal and serum bile acid metabolism. At the gene level, GC induced FXR signaling, i.e., increased the expression of FXR, small heterodimer partner (SHP), and bile salt export pump (BSEP) in liver tissues and fibroblast growth factor 15 (FGF15) expression in the ileal tissues of NASH mice. However, antibiotics (ampicillin, neomycin, vancomycin, and tinidazole) in drinking water (ADW) reversed the effect of GC on NASH and altered the gut microbiota in NASH mice in vivo. Furthermore, GC treatment failed to improve NASH in the FXR-/- mouse NASH model in vivo, indicating that the effectiveness of GC treatment might be through FXR signaling activation. Conclusion: GC was able to alleviate NASH by improving the gut microbiome and activating FXR signaling; its effect was better than each individual agent alone.