Characterization of gelsevirine metabolites in rat liver S9 by accurate mass measurements using high-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry.
Zhang Hua-Hai,Huang Ya-Jun,Liu Yan-Chun,Jiang Xu-Yan,Zhang Shuo-Xin,Liu Zhao-Ying
Rapid communications in mass spectrometry : RCM
RATIONALE:Gelsemium elegans Benth. belongs to the family Loganiaceae and is widely distributed in northern America, east Asia, and southeast Asia. It has attracted wide attention for its diverse biological effects and complex architectures. Gelsevirine is one of the major components in G. elegans. Compared with other alkaloids from G. elegans, gelsevirine exhibits equally potent anxiolytic effects but with less toxicity. However, the metabolism of gelsevirine has not been clearly elucidated. METHODS:The metabolism of gelsevirine was investigated using liver S9 fractions derived from rat liver homogenates by centrifugation at 9000 g. A rapid and accurate high-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (HPLC/QqTOF-MS) method was applied to characterize the gelsevirine metabolites. RESULTS:We discovered a total number of four metabolites of gelsevirine. The metabolic pathways of gelsevirine consisted of hydrogenation, N-demethylenation and oxidation in rat liver S9. CONCLUSIONS:This is the first study on the metabolism of gelsevirine. We proposed possible metabolic pathways of gelsevirine. These findings may warrant future studies of the in vivo metabolism of gelsemine in animals.
10.1002/rcm.8457
Orally Administered Koumine Persists Longer in the Plasma of Aged Rats Than That of Adult Rats as Assessed by Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry.
Ye Li-Xiang,Xu Ying,Zhang Shui-Hua,Cao Da-Xuan,Chen Ling-Fan,Su Yan-Ping,Huang Hui-Hui,Yu Chang-Xi
Frontiers in pharmacology
Aging leads to changes in nearly all pharmacokinetic phases. Koumine (KM), an alkaloid derived from Benth., is effective against age-associated chronic diseases, but its dose proportionality following oral administration in aged individuals remains unknown. Herein, we established and validated a simple method that requires low sample volumes to determine KM concentration in rats using ultra-performance liquid chromatography-tandem mass spectrometry. The maximum plasma concentration (C) of 7 mg·kg KM was ~12-fold and ~24-fold higher than that of 0.28 mg·kg KM in adult and aged rats, respectively ( < 0.01). Time to reach C (T) for 7 mg·kg KM was 4-fold longer in aged rats ( < 0.05). The area under the curve (AUC) of 7 mg·kg KM was >17-fold and >43-fold higher than those of 0.28 mg·kg KM in adult and aged rats, respectively ( < 0.01). The half-life (t) of 7 mg·kg KM was over 4-fold longer than that of 0.28 mg·kg KM in adult rats ( < 0.01). The t of 1.4 and 7 mg·kg KM were 1.5~2-fold longer, than that of 0.28 mg·kg KM in aged rats ( < 0.05). The clearance rate of 7 mg·kg KM was significantly lower in aged than in adult rats ( < 0.05). For 7.0 mg·kg KM, the C in aged rats was higher than in adult rats during the T period ( < 0.05). In aged rats, the AUC for KM was >2.5-fold higher ( < 0.05) and the t was >60% longer than in adult rats ( < 0.05). These results help interpret the pharmacokinetics of KM in aging-associated diseases.
10.3389/fphar.2020.01113
Pharmacokinetic Study of Multiple Components of Gelsemium elegans in Goats by Ultra-Performance Liquid Chromatography Coupled to Tandem Mass Spectrometry.
Cao Jun-Jie,Yang Kun,Huang Chong-Yin,Li Yu-Juan,Yu Hui,Wu Yong,Sun Zhi-Liang,Liu Zhao-Ying
Journal of analytical toxicology
Gelsemium elegans (G. elegans) has been used in traditional Chinese medicine. This plant is highly toxic to humans, but can promote the growth of pigs and goats in the veterinary clinic. It is a very complex mixture containing tens or hundreds of different components. Therefore, multiple-component pharmacokinetic studies of G. elegans are a major challenge due to the lack of authentic standards of the components. The purpose of this study was to investigate the plasma pharmacokinetics of multiple components after a single oral dose of G. elegans in goat using a sensitive ultra-performance liquid chromatography coupled to tandem mass spectrometry method for the simultaneous semiquantification of multiple alkaloids without standards. The method was validated in terms of the specificity, LOD, LOQ, linearity, accuracy, precision and matrix effects. To validate the global pharmacokinetic characteristics, the results obtained from the semiquantitative analysis of three authentic compounds (gelsemine, koumine and humantenmine) were compared with the absolute quantification from our recently published method. The results showed that the two methods had similar analytical results, and the obtained values of Tmax, T1/2 and MRT0-t of the three alkaloids were similar between the two methods. In addition, the values of Cmax and AUC0-t of the three alkaloids after normalization were close to the real values, which indicated that this semiquantitative method could be used in the pharmacokinetic study of multiplecomponents. Then the pharmacokinetic parameters of 23 other G. elegans alkaloids in goats were obtained. The results suggested that the gelsedine-type alkaloids were the major active ingredients that predict and explain the efficacy and toxicity of G. elegans.
10.1093/jat/bkz100
An analytical strategy to explore the multicomponent pharmacokinetics of herbal medicine independently of standards: Application in Gelsemium elegans extracts.
Yang Kun,Long Xue-Ming,Cao Jun-Jie,Li Yu-Juan,Wu Yong,Bai Xia,Sun Zhi-Liang,Liu Zhao-Ying
Journal of pharmaceutical and biomedical analysis
The multicomponent pharmacokinetic study of herbal medicine is a great challenge due to the low plasma concentrations, large range of concentration scales, lack of authentic standards and uncertain interactions of the components. The aim of this work was to explore the in vivo pharmacokinetics of herbal medicine independently of authentic standards using an integrated analytical strategy. First, ion pairs of multiple components were tuned and selected, and then major parameters were optimized for derivative multiple reaction monitoring (DeMRM) by LC-MS/MS, which was combined with characterization of the chemical profiles of the herbal medicine by LC-QqTOF/MS. Second, different concentrations of herbal extracts were employed instead of authentic standards to construct calibration curves for the semiquantitative determination of multiple components in plasma. Taking Gelsemium elegans as an example, in addition to the fully validated and sufficient methodological results, a total of 27 alkaloid components, major bioactive constituents of Gelsemium elegans, were simultaneously monitored in pig plasma. The concentration-time profiles and pharmacokinetic properties of these 27 components were characterized. The absolute quantification of three components was compared with the results obtained using authentic standards, and the method showed very similar analytical characteristics, such as linearity, precision, accuracy, and the values of the pharmacokinetic parameters T, Vd, Cl and MRT. This analytical strategy was found to be capable of assessing herbal pharmacokinetics independently of specific authentic compounds for each component. This study was the first attempt to systematically reveal the in vivo pharmacokinetics of Gelsemium elegans. This strategy and methodology will find widespread use in the quantitative pharmacokinetic analysis of multiple components independently of standards for herbal medicine, among other applications.
10.1016/j.jpba.2019.112833
Development and in-house validation of a sensitive LC-MS/MS method for simultaneous quantification of gelsemine, koumine and humantenmine in porcine plasma.
Yang Kun,Long Xue-Ming,Liu Yan-Chun,Chen Fu-Hua,Liu Xiao-Feng,Sun Zhi-Liang,Liu Zhao-Ying
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
Three monomers of G. elegans indole alkaloids (gelsemine, koumine and humantenmine) were simultaneously detected in porcine plasma for the first time with the development and validation of a sensitive and reliable LC-ESI-MS/MS method. Using a gradient mobile phase at a constant flow rate of 0.2 mL/min via electrospray ionization (positive ion mode) in a multiple reaction monitoring (MRM) scan, gelsemine, koumine and humantenmine were eluted, separated and detected at an appropriate retention time. The porcine plasma was prepared using protein precipitation with 1% formic acid-acetonitrile: methanol (2:1, v/v). Using matrix-matched calibration curves and weighted least squares linear regression, a good linearity (r > 0.99) was achieved with a concentration range of 0.1-200 μg/L for gelsemine, koumine and humantenmine; estimated LOD and LOQ values were 0.10 μg/L and 0.2 μg/L, respectively. The mean of the recoveries was in the range of 82.68-100.35% of porcine plasma at four different levels, and the intra-day and inter-day precision (CV) were lower than 15% with a range of 2.46-8.76% and 2.73-10.83%, respectively. The proposed method has proved to be suitable for accurate, quantitative determination of gelsemine, koumine and humantenmine in porcine plasma.
10.1016/j.jchromb.2018.01.019
Identification of gelsemine metabolites in rat liver S9 by high-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry.
Yang Kun,Huang Ya-Jun,Xiao Sa,Liu Yan-Chun,Sun Zhi-Liang,Liu Yi-Song,Tang Qi,Liu Zhao-Ying
Rapid communications in mass spectrometry : RCM
RATIONALE:Gelsemine has been extensively studied because of its anti-tumor, immunomodulatory, insecticidal itching and other significant effects. However, limited information on the pharmacokinetics and metabolism of gelsemine has been reported. Therefore, the purpose of the present study was to investigate the in vitro metabolism of gelsemine in rat liver S9 by using rapid and accurate high-performance liquid chromatography/ quadrupole-time-of-flight mass spectrometry (HPLC/QqTOF-MS). METHODS:The incubation mixture was processed with 15% trichloroacetic acid. Multiple scans of gelsemine metabolites and accurate mass measurements were automatically performed simultaneously through data-dependent acquisition in only 30 min. The structural elucidations of these metabolites were performed by comparing their changes in accurate molecular masses and product ions with those of the parent drug. RESULTS:Five metabolites of gelsemine were identified in rat liver S9. Of these, four metabolites of gelsemine were identified for the first time. The present results showed that the metabolic pathways of gelsemine are oxidation, demethylation, and dehydrogenation in rat liver S9. CONCLUSIONS:In this study, metabolites of gelsemine in liver S9 were identified and elucidated firstly using the HPLC/QqTOF-MS method. The proposed metabolic pathways of gelsemine in liver S9 will provide a basis for further studies of the in vivo metabolism of gelsemine in animals and humans.
10.1002/rcm.8012
An integrated strategy toward comprehensive characterization and quantification of multiple components from herbal medicine: An application study in .
Chinese herbal medicines
Objective:To develop a powerful integrated strategy based on liquid chromatography coupled with mass spectrometry (LC-MS) systems for the comprehensive characterization and quantification of multiple components of herbal medicines. Methods:Firstly, different mobile phase additives, analysis time, and MS acquisition modes were orthogonally tested with liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (LC-QTOF/MS) in order to detect as many components of as possible with high peak intensity. Secondly, several data mining strategies, including database searching, diagnostic ion filtering and neutral loss filtering, were utilized to perform chemical profiling. Subsequently, this study focused on the quantification and validation of the performance of a liquid chromatography-triple mass spectrometry (LC-QqQ/MS) assay based on derivative multiple reaction monitoring (DeMRM). Results:A total of 147 components from were characterized, among them 116 nontarget components were reported for the first time. A sensitive and reproducible LC-QqQ/MS method was successfully developed and validated for the simultaneous relative quantification of 41 components of . This LC-QqQ/MS method was then applied to compare the contents of components in the roots, stems and leaves. Conclusion:The present integrated strategy would significantly contribute to chemical studies on herbal medicine, and its utility could be extended to other research fields, such as metabolomics, quality control, and pharmacokinetics.
10.1016/j.chmed.2020.06.002
In vitro Metabolism of Humantenine in Liver Microsomes from Human, Pig, Goat and Rat.
Huang Si-Juan,Zuo Meng-Ting,Qi Xue-Jia,Ma Xiao,Wang Zi-Yuan,Liu Zhao-Ying
Current drug metabolism
BACKGROUND:Gelsemium elegans Benth (G. elegans) is a well-known toxic plant. Alkaloids are the main active components of G. elegans. Currently, the metabolism of several alkaloids, such as gelsenicine, koumine, and gelsemine, has been widely studied. However, as one of the most important alkaloids in G. elegans, the metabolism of humantenine has not been studied yet. METHODS:In order to elaborate on the in vitro metabolism of humantenine, a comparative analysis of its metabolic profile in human, pig, goat and rat liver microsomes was carried out using high performance chromatography/ quadrupole time-of-flight mass spectrometry (HPLC/QqTOF-MS) for the first time. RESULTS:Totally, ten metabolites of humantenine were identified in liver microsomes from human (HLMs), pig (PLMs), goat (GLMs) and rat (RLMs) based on the accurate MS/MS spectra. Five metabolic pathways of humantenine, including demethylation, dehydrogenation, oxidation, dehydrogenation and oxidation, and demethylation and oxidation, were proposed in this study. There were qualitative and quantitative species differences in the metabolism of humantenine among the four species. CONCLUSION:The in vitro metabolism of humantenine in HLMs, PLMs, GLMs and RLMs was studied by a sensitive and specific detection method based on HPLC/QqTOF-MS. The results indicated that there were species-related differences in the metabolism of humantenine. This work might be of great significance for the further research and explanation of species differences in terms of toxicological effects of G. elegans.
10.2174/1389200222666210901113530
Sex Differences in the In Vivo Exposure Process of Multiple Components of in Rats.
Metabolites
Asian () has a wide range of pharmacological activities. However, its strong toxicity limits its potential development and application. Interestingly, there are significant gender differences in toxicity in rats. This work aimed to elucidate the overall absorption, distribution, metabolism, and excretion (ADME) of whole crude extract in female and male rats using high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HPLC/QqTOF-MS), which facilitates determining the reasons for the gender differences in toxicity. A total of 25 absorbed bioactive components and 3 related produced metabolites were tentatively identified in female rats, while only 17 absorbed bioactive components and 3 related produced metabolites were identified in male rats. By comparison of peak intensities, most compounds were found to be more active in absorption, distribution and excretion in female rats than in male rats, which showed that female rats were more sensitive to . This study was the first to investigate the multicomponent in vivo process of in rats and compare the differences between sexes. It was hypothesized that differences in the absorption of gelsedine-type alkaloids were one of the main reasons for the sex differences in toxicity.
10.3390/metabo13010033
Visual Distribution of Gelsemine, Koumine, and Gelsenicine by MSI in at Different Growth Stages.
Molecules (Basel, Switzerland)
The distribution of pharmatically important alkaloids gelsemine, koumine, and gelsenicine in tissues is a hot topic attracting research attention. Regretfully, the in planta visual distribution details of these alkaloids are far from clear although several researches reported the alkaloid quantification in by LC-MS/MS. In this study, mass imaging spectrometry (MSI) was employed to visualize the visualization of gelsemine, koumine, and gelsenicine in different organs and tissues of at different growth stages, and the relative quantification of three alkaloids were performed according to the image brightness intensities captured by the desorption electrospray ionization MSI (DESI-MSI). The results indicated that these alkaloids were mainly accumulated in pith region and gradually decreased from pith to epidermis. Interestingly, three alkaloids were found to be present in higher abundance in the leaf vein. Along with the growth and development, the accumulation of these alkaloids was gradually increased in root and stem. Moreover, we employed LC-MS/MS to quantify three alkaloids and further validated the distributions. The content of koumine reached 249.2 μg/g in mature roots, 272.0 μg/g in mature leaves, and 149.1 μg/g in mature stems, respectively, which is significantly higher than that of gelsemine and gelsenicine in the same organ. This study provided an accurately visualization of gelsemine, koumine, and gelsenicine in , and would be helpful for understanding their accumulation in plant and guiding application.
10.3390/molecules27061810
A high-resolution mass spectrometric approach to a qualitative and quantitative comparative metabolism of the humantenine-type alkaloid rankinidine.
Rapid communications in mass spectrometry : RCM
RATIONALE:Rankinidine belongs to the humantenine-type alkaloids isolated from Gelsemium. Currently, the mechanism behind the toxicity differences of rankinidine has not been explained. In this study, our purpose was to elucidate the major in vitro metabolic pathways of rankinidine and to compare the formation of metabolites of rankinidine in human (HLMs), rat (RLMs), goat (GLMs) and pig (PLMs) liver microsomes. METHODS:This is the first study to compare the in vitro metabolism of rankinidine with high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (LC/QTOF). The MS/MS data and LC/MS peak area acquired in positive ion mode were used to analyze metabolite structures and compare metabolism. RESULTS:We identified 11 metabolites (M1-M11) in total and found five main metabolic pathways, consisting of demethylation (M1), reduction (M2), oxidation at different positions (M3-M5), oxidation and reduction (M6-M10) and demethylation and oxidation (M11). The metabolism of rankinidine has qualitative and quantitative species-specific differences in vitro. In PLMs and GLMs, the main metabolic pathway of rankinidine was oxidation. Notably, among the four species, the oxidation ability of rankinidine was highest in pigs and goats, and the demethylation and reduction abilities of rankinidine were highest in humans and rats. CONCLUSIONS:The interspecific metabolic differences of rankinidine in HLMs, PLMs, GLMs and RLMs were compared and studied for the first time using LC/QTOF. These findings will certainly support future studies of rankinidine metabolism in vivo and will contribute to elucidating the cause of species-specific differences behind Gelsemium toxicity.
10.1002/rcm.9302
Analysis of alkaloids in Gelsemium elegans Benth using an online heart-cutting + comprehensive RPLC×RPLC system tandem mass spectrometry.
Liu Dian,Liu Yanfang,Shen Aijin,Li Xiaolu,Yu Long,Wang Chaoran,Liang Xinmiao
Talanta
Characterization of alkaloids and new compound discovery become increasing challenging for Gelsemium elegans Benth. (G. elegans), due to the lack of an effective separation method. In this study, we developed a new online heart-cutting + comprehensive (HC) RPLC × RPLC system with pH difference, which was coupled to a mass detector to realize the separation and characterization of alkaloids from G. elegans. 18 Gelsemium standards were used to construct the RPLC × RPLC system with pH difference (pH 3 and 11), and good orthogonality (correlation coefficient 0.3) was obtained. A heart-cutting valve was introduced into the traditional online comprehensive RPLC × RPLC system to remove principal components and improve detection of minor components. The online HC RPLC × RPLC system achieved good resolving power (effective peak capacity 687) in condition of optimized practical factors, like the first- and second-dimension flow rates, modulation period and elution gradient et al. Finally, a total of 256 alkaloids were grouped and tentatively identified, among which 156 were unreported, including a new alkaloid type in G. elegans and many dimeric indole alkaloids, which was an important supplement to the study on chemical constituents of G. elegans.
10.1016/j.talanta.2021.123069
An efficient method for the preparative isolation and purification of alkaloids from by using high speed counter-current chromatography and preparative HPLC.
Preparative biochemistry & biotechnology
We established an efficient method using high-speed countercurrent chromatography (HSCCC) combined with preparative high-performance liquid chromatography (prep-HPLC) for isolating and purifying Gels () alkaloids. First, the two-phase solvent system composed of 1% triethylamine aqueous solution/-hexane/ethyl acetate/ethanol (volume ratio 4:2:3:2) was employed to separate the crude extract (350 mg) using HSCCC. Subsequently, the mixture that resulted from HSCCC was further separated by Prep-HPLC, resulting in seven pure compounds including: 14-hydroxygelsenicine (, 12.1 mg), sempervirine (, 20.8 mg), 19-(R)-hydroxydihydrogelelsevirine (, 10.1 mg), koumine (, 50.5 mg), gelsemine (, 32.2 mg), gelselvirine (, 50.5 mg), and 11-hydroxyhumanmantenine (, 12.5 mg). The purity of these seven compounds were 97.4, 98.9, 98.5, 99, 99.5, 96.8, and 85.5%, as determined by HPLC. The chemical structures of the seven compounds were analyzed and confirmed by electrospray ionization mass spectrometry (ESI-MS), 1H-nuclear magnetic resonance (1H NMR), and 13 C-nuclear magnetic resonance (13 C NMR) spectra. The results indicate that the HSCCC-prep-HPLC method can effectively separate the major alkaloids from the purified , holding promising prospects for potential applications in the separation and identification of other traditional Chinese medicines.
10.1080/10826068.2024.2336990
Toxicokinetics, in vivo metabolic profiling, and in vitro metabolism of gelsenicine in rats.
Xiang Zheng,Qiu Jieying,He Xiaoying,Yu Xinwei
Archives of toxicology
Gelsenicine, mainly isolated from Gelsemium elegans Benth., is one of the most toxic alkaloids. The lack of information on gelsenicine leads to inaccurate risk and poisoning evaluation. In this study, the metabolic profiling and toxicokinetics of gelsenicine was studied by ultra-high performance liquid chromatography (UPLC) with quadrupole time-of-flight (Q-ToF) and tandem mass spectrometry in rats after intraperitoneal (i.p., 40 μg/kg) and intragastric (i.g., 60 μg/kg) administration. After i.p. administration, the area under the curve (AUC), the apparent volume of distribution (V), and the total body clearance (CL/F) of gelsenicine in plasma were 3.79 μg/L h, 38.47 L/kg, and 11.87 mL/h kg, respectively. After i.g. administration, the corresponding values were slightly increased (5.49 μg/L h; 53.10 mL/kg, and 12.66 mL/h kg). The toxicokinetic results indicated that the hepatic first-pass effect was predominant after i.p. administration. The UPLC-Q-ToF-MS data revealed nine metabolites in plasma, urine, and bile which were largely obtained by demethylation, hydroxylation, acetylation and glycine conjugation. Metabolites were mainly excreted through urine and bile, most of which in urine was basically eliminated in 24 h. Molecular docking and liver microsome experiments further showed that gelsenicine was metabolized by cytochrome P450 3A4 and 3A5. Summarizing, the present study provides metabolic and toxicokinetic information on gelsenicine which in turn may help in future risk assessment and forensic identification after poisonings.
10.1007/s00204-021-03209-7
Simultaneous determination of gelsemine and koumine in rat plasma by UPLC-MS/MS and application to pharmacokinetic study after oral administration of Gelsemium elegans Benth extract.
Wang Lin,Wen Yanqing,Meng Fanhao
Biomedical chromatography : BMC
A simple, rapid and sensitive method using UPLC-MS/MS was established and validated for simultaneous determination of gelsemine and koumine in rat plasma after oral administration of Gelsemium elegans Benth extract. Plasma was performed with methanol precipitation and berberine was chosen as the internal standard. Plasma samples were separated on an Acquity UPLC® BEH C column (3.0 × 50 mm, 1.7 μm) with gradient elution using acetonitrile and 0.1% formic acid aqueous solution as the mobile phase at a flow rate of 0.4 mL/min. Multiple reaction monitoring mode in positive ion mode was utilized for detection. The calibration curves were linear over the range of 0.2-100 ng/mL for gelsemine and 0.1-50 ng/mL for koumine, with the lower limits of quantification 0.2 and 0.1 ng/mL, respectively. The intra- and inter-precision and accuracy were well within the acceptable ranges. The developed method was successfully applied to an in vivo pharmacokinetic study in rat after oral administration of 10 mg/kg Gelsemium elegans Benth extract.
10.1002/bmc.4201
Characterization of absorbed and produced constituents in goat plasma urine and faeces from the herbal medicine Gelsemium elegans by using high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry.
Zuo Meng-Ting,Wang Zi-Yuan,Yang Kun,Li Yu-Juan,Huang Chong-Ying,Liu Yan-Chun,Yu Hui,Zhao Xue-Jiao,Liu Zhao-Ying
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:Herbal medicine contains hundreds of natural products, and studying their absorption, metabolism, distribution, and elimination presents great challenges. Gelsemium elegans (G. elegans) is a flowering plants in the Loganiaceae family. The plant is known to be toxic and has been used for many years as a traditional Chinese herbal medicine for the treatment of rheumatoid arthritis, neuropathic pain, spasticity, skin ulcers and cancer. It was also used as veterinary drugs for deworming, promoting animal growth, and pesticides. At present, studies on the metabolism of G. elegans have primarily focused on only a few single available reference ingredients, such as koumine, gelsemine and gelsedine. MATERIAL AND METHODS:The goal of this work is to elucidate the overall metabolism of whole G. elegans powder in goats using high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HPLC/QqTOF-MS). RESULTS:Analyses of plasma, urine and fecal samples identified or tentatively characterized a total of 44 absorbed natural products and 27 related produced metabolites. Gelsedine-type, sarpagine-type and gelsemine-type alkaloids were the compounds with the highest metabolite formation. In the present study, most natural products identified in G. elegans were metabolized through glucuronidation and oxidation. Hydrogenation, dehydrogenation and demethylation also occurred. CONCLUSION:To our knowledge, this is the first report of the metabolite profiling of the G. elegans crude extract in goats, which is of great significance for a safer and more rational application of this herbal medicine.
10.1016/j.jep.2020.112617
Offline preparative three-dimensional HPLC for systematic and efficient purification of alkaloids from Gelsemium elegans Benth.
Liu Dian,Han Yang,Zhou Han,Jin Hongli,Kang Hongjian,Huang FeiFei,Liu Yanfang,Liang Xinmiao
Journal of chromatography. A
The natural compound library is the most productive source in drug discovery and alkaloids are the most potential drug leads in natural compounds. Presently, systematic purification of alkaloids remains a substantial challenge. In this study, we developed an offline preparative three-dimensional HPLC (3D-HPLC) method to resolve the problem of systematic purification of alkaloids. Ten Gelsemium standards were used in the construction of the method to evaluate several factors, including column selectivity, column loadability and separation orthogonality. The offline 3D-HPLC method achieved great orthogonal selectivity and resolution power using different stationary phases, mobile phases at different pH, and different mobile phase additives. Application of this 3D-HPLC method to Gelsemium elegans Benth. was evaluated, and 24 indole alkaloids were finally isolated, including four new alkaloids and one first-identified in this plant. Moreover, a total of 229 compounds were estimated to be obtained in this plant, almost twice the number of known Gelsemium alkaloids. Therefore, this 3D-HPLC method will be efficient for systematic purification of alkaloids from Gelsemium elegans Benth. and has the potential for alkaloid preparation from other plants.
10.1016/j.chroma.2021.461935
Confirmation of Gelsemium elegans poisoning by UHPLC-MS/MS analysis of koumine, gelsemine, and gelsenicine in hair.
Yang Huan,Xiang Ping,Yu Miao,Zou Donghua,Fan Xianyu,Wang Xin,Liu Wei
Journal of pharmaceutical and biomedical analysis
A sensitive, accurate, simple, and rapid analytical UHPLC-MS/MS method was developed for identification and quantification of koumine, gelsemine, and gelsenicine in human hair. Approximately 10 mg of hair was extracted with methanol by cryogenic grinding. The limits of detection (LODs) ranged from 1 to 5 pg/mg, and the limits of quantitation (LOQs) ranged from 2 to 10 pg/mg. The method was linear over a concentration range from the LOQs to 1000 pg/mg, and the linear correlation (R) of the calibration curves was above 0.998 for all three analytes. The bias varied from -6.5-13.1%, while the intra- and inter-day precision relative standard deviation (RSD) values were 4.3-12.4% and 3.7-13.2%, respectively. Recoveries ranged from 79.3% to 103.5%, and matrix effects ranged from 74.3% to 105.5%. The described method was used for the quantitative determination of koumine, gelsemine, and gelsenicine in a human hair sample from a Gelsemium elegans poisoning case. The highest concentrations of koumine, gelsemine, and gelsenicine were 27.2, 18.1, and 4.2 pg/mg, respectively, and corresponded to the segment associated with the ingestion period. To our knowledge, this is the first study to describe hair analysis in a G. elegans poisoning case and to provide quantitative toxicological findings.
10.1016/j.jpba.2021.114546
Comparative Analysis of the Gelsemium Alkaloids Metabolism in Human, Pig, Goat, and Rat Liver Microsomes.
Current drug metabolism
AIM:The aim of this study was to investigate the metabolism of in human, pig, goat and rat liver microsomes and to elucidate the metabolic pathways and cleavage patterns of the Gelsemium alkaloids among different species. METHODS:A human, goat, pig and rat liver microsomes were incubated . After incubating at 37°C for 1 hour and centrifuging, the processed samples were detected by was used to detect alcohol extract of and its metabolites. RESULTS:Forty-six natural products were characterized from alcohol extract of Gelsemium elegans and 13 metabolites were identified. These 13 metabolites belong to the gelsemine, koumine, gelsedine, humantenine, yohimbane, and sarpagine classes of alkaloids. The metabolic pathways included oxidation, demethylation and dehydrogenation. After preliminary identification, the metabolites detected in the four species were different. All 13 metabolites were detected in pig and rat microsomes, but no oxidative metabolites of Gelsedine-type alkaloids were detected in goat and human microsomes. CONCLUSION:In this study, metabolic patterns in different species are clarified and the metabolism of is investigated. It is of great significance for its clinical development and rational application.
10.2174/0113892002298633240322071126
Two-Dimensional Liquid Chromatography Method for the Determination of Alkaloids in Honey.
Foods (Basel, Switzerland)
Toxic Chinese medicine residues in honey pose a serious threat to consumer health. is one of the nine ancient poisons, making the whole plant virulent. The residue of alkaloid in honey causes poisoning from time to time. Therefore, it is very important to establish a method for the detection of alkaloids in honey. In this study, a method of solid phase extraction (SPE) with two-dimensional liquid chromatography (2D-LC) was developed for the first time for the simultaneous determination of alkaloids in honey, including gelsemine, koumine and humantenmine. First, the honey samples were purified by a PRS cation exchange column and extracted with 5% ammoniated methanol. Then, we verified the methodological indicators, which were in line with the Codex Guideline requirements. The verification results are as follows: matrix-matched calibrations indicated that the correlation coefficients were higher than 0.998. The recovery was in the range of 81%-94.2% with an intraday precision (RSD) of ≤5.0% and interday RSD of ≤3.8%. The limit of detection for the three alkaloids was 2 ng/g. The limits of quantification for gelsemine and koumine were 5 ng/g, and humantenmine was 20 ng/g. This method can be applied to the monitoring of alkaloids in honey.
10.3390/foods11182891
Molecular Pharmacology of Alkaloids on Inhibitory Receptors.
International journal of molecular sciences
Indole alkaloids are the main bioactive molecules of the genus plants. Diverse reports have shown the beneficial actions of alkaloids on the pathological states of the central nervous system (CNS). Nevertheless, alkaloids are toxic for mammals. To date, the molecular targets underlying the biological actions of alkaloids at the CNS remain poorly defined. Functional studies have determined that gelsemine is a modulator of glycine receptors (GlyRs) and GABA receptors (GABARs), which are ligand-gated ion channels of the CNS. The molecular and physicochemical determinants involved in the interactions between alkaloids and these channels are still undefined. We used electrophysiological recordings and bioinformatic approaches to determine the pharmacological profile and the molecular interactions between koumine, gelsemine, gelsevirine, and humantenmine and these ion channels. GlyRs composed of α1 subunits were inhibited by koumine and gelsevirine (IC of 31.5 ± 1.7 and 40.6 ± 8.2 μM, respectively), while humantenmine did not display any detectable activity. The examination of GlyRs composed of α2 and α3 subunits showed similar results. Likewise, GABARs were inhibited by koumine and were insensitive to humantenmine. Further assays with chimeric and mutated GlyRs showed that the extracellular domain and residues within the orthosteric site were critical for the alkaloid effects, while the pharmacophore modeling revealed the physicochemical features of the alkaloids for the functional modulation. Our study provides novel information about the molecular determinants and functional actions of four major indole alkaloids on inhibitory receptors, expanding our knowledge regarding the interaction of these types of compounds with protein targets of the CNS.
10.3390/ijms25063390
The qualitative and quantitative analyses of Gelsemium elegans.
Wang Jie,Zhang Jie,Zhang Chunni,Sun Xinguang,Liao Xiaochun,Zheng Wei,Yin Qin,Yang Jie,Mao Donghua,Wang Bei,Li Qi,Chen Xiaojuan,Ding Qianzhi,Li Jin,Ma Baiping
Journal of pharmaceutical and biomedical analysis
Gelsemium elegans is a traditional Chinese medicine that has been used to treat eczema, bruises, rheumatoid arthritis and skin ulcers for many years, and alkaloids are its major active and toxic constituents. This study aimed to comprehensively assess the quality of G. elegans samples including different plant parts and origins using ultra high-performance liquid chromatography coupled with photo-diode array and quadrupole time-of-flight mass spectrometry (UHPLC-PDA-QTOF/MS) and high-performance liquid chromatography coupled with UV detector (HPLC-UV). Firstly, the UHPLC-PDA-QTOF/MS approach was developed for the characterization of alkaloids in G. elegans and understanding the differences between multiple groups of samples. Based on the exact mass information, the fragmentation characteristics and the retention time of compounds, 38 alkaloids were identified or tentatively identified. 24 potential chemical markers for differentiating different plant parts of G. elegans were selected through PCA and OPLS/PLS-DA analysis. Secondly, a heatmap visualization was employed for clarifying the distribution of 24 selected alkaloids with high response in the UV. The roots, stems and leaves from Yunnan Province possess relatively consistent alkaloids composition, respectively. Most compounds in the root have a higher content than stems and leaves. Thirdly, a HPLC-UV approach was developed for quantitative analysis of three major alkaloids (gelsemine, koumine and gelsenicine) of G. elegans, and the results showed remarkable variation in the contents of these constituents. While, the contents of three alkaloids fluctuate relatively less in the stem. These results indicated that integrated chemical profiling and quantitative analysis of alkaloids in G. elegans from different plant parts and origins could be assessed by this method, which would establish the foundation for the application of G. elegans.
10.1016/j.jpba.2019.05.015
Gelsemium poisoning mediated by the non-toxic plant Cassytha filiformis parasitizing Gelsemium elegans.
Cheung Wing Lan,Law Chun Yiu,Lee Han Chih Hencher,Tang Chi On,Lam Ying Hoo,Ng Sau Wah,Chan Suk San,Chow Tat Chong,Pang Kuen Shum,Mak Tony Wing Lai
Toxicon : official journal of the International Society on Toxinology
INTRODUCTION:Gelsemium poisoning is caused by consumption of the deadly Gelsemium species such as Gelsemium elegans, leading to significant gastrointestinal, neurological and cardio-respiratory toxicities. In 2011 (Cluster 1) and 2012 (Cluster 2), the authors encountered two clusters of gelsemium poisoning after consumption of the non-toxic parasitic plant Cassytha filiformis. The current study aims to examine the mechanism of gelsemium poisoning mediated by a benign parasitic plant. METHODS:Qualitative analysis of toxic gelsemium alkaloids using liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed on the herbal and urine samples from both clusters to confirm exposure. Morphological examination, qualitative analysis of aporphine alkaloids using liquid chromatography-ion trap-time of flight mass spectrometry (LC-IT-TOF/MS) and Sanger sequencing were performed on the plant sample from Cluster 2 to confirm its identity. A field study was conducted in local countryside and C. filiformis was collected for histological, LC-MS/MS and LC-IT-TOF/MS analyses to study its interaction with G. elegans. RESULTS:Gelsemium alkaloids that are not naturally present in C. filiformis were detected in the patients' herbal and urine samples. Misidentification and contamination with G. elegans during the preparation process were excluded by morphological examination of the plant sample from Cluster 2. Its identity as C. filiformis was verified with LC-IT-TOF/MS and molecular analyses. Histological, LC-MS/MS and LC-IT-TOF/MS analyses of C. filiformis collected during the field study confirmed that its haustoria penetrated the vascular bundles of G. elegans and absorbed its gelsemium toxins. CONCLUSIONS:The non-toxic plant C. filiformis absorbed toxic gelsemium alkaloids from its host, G. elegans, and led to gelsemium poisoning in our patients. Our study provides new insights into the toxicology of such plants. Benign parasitic plants may lead to potentially life-threatening poisoning if it parasitizes toxic hosts and absorbs their phytotoxins. The public awareness of risks associated with the use of these medicinal parasitic plants should be raised.
10.1016/j.toxicon.2018.09.009
Toxicokinetics of 11 Alkaloids in Rats by UPLC-MS/MS.
Shen Xiuwei,Ma Jianshe,Wang Xianqin,Wen Congcong,Zhang Meiling
BioMed research international
() is a plant belonging to the (), and its main components are alkaloids. It is a Chinese traditional medicinal plant and notoriously known as a highly toxic medicine. However, a method has not yet been found for the simultaneous detection of 11 alkaloids in rat plasma, and the toxicokinetics of 11 alkaloids after intravenous administration has not been reported. In this work, we have developed a sensitive and rapid method of ultraperformance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) for the detection of 11 alkaloids in rat plasma. The toxicokinetic behavior was also investigated, so as to provide a reference of the scientific properties of and improve the efficacy and safety of drugs. Sixty-six Sprague-Dawley rats were randomly divided into 11 groups, six rats in each group. Each group was intravenously given one alkaloid (0.1 mg/kg), respectively. A Waters UPLC BEH C18 column (50 mm × 2.1 mm, 1.7 m) was used for chromatographic separation. Methanol and water (containing 0.1% formic acid) were used for the mobile phase with gradient elution. Multiple reactions were monitored, and positive electrospray ionization was used for quantitative analysis. The precision was less than 16%, and the accuracy was between 86.9% and 113.2%. The extraction efficiency was better than 75.8%, and the matrix effects ranged from 88.5% to 107.8%. The calibration curves were in the range of 0.1-200 ng/mL, with a correlation coefficient ( ) greater than 0.995. The UPLC-MS/MS method was successfully applied to the toxicokinetics of 11 alkaloids in rats after intravenous administration (0.1 mg/kg for each alkaloid). The results of the toxicokinetics provide a basis for the pharmacology and toxicology of alkaloids and scientific evidence for the clinical use of alkaloids.
10.1155/2020/8247270
Excretion, Metabolism, and Tissue Distribution of () in Pigs.
Molecules (Basel, Switzerland)
() is a toxic flowering plant in the family Loganiaceae used to treat skin diseases, neuralgia and acute pain. The high toxicity of restricts its development and clinical applications, but in veterinary applications, has been fed to pigs as a feed additive without poisoning. However, until now, the in vivo processes of the multiple components of have not been studied. This study investigates the excretion, metabolism and tissue distribution of the multiple components of after feeding it to pigs in medicated feed. Pigs were fed 2% powder in feed for 45 days. The plasma, urine, bile, feces and tissues (heart, liver, lung, spleen, brain, spinal cord, adrenal gland, testis, thigh muscle, abdominal muscle and back muscle) were collected 6 h after the last feeding and analyzed using high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. Five natural products in plasma, twelve natural products and five metabolites in urine, and three natural products in feces were characterized, suggesting that multiple components from were excreted in the urine. However, ten natural products and four metabolites were detected in bile samples, which suggested that is involved in enterohepatic circulation in pigs. A total of seven of these metabolites were characterized, and four metabolites were glucuronidated metabolites. Ten natural products and six metabolites were detected in the tissues, which indicates that is widely distributed in tissues and can cross the blood-brain barrier. Among the characterized compounds, a highly toxic gelsedine-type alkaloid from was the main compound detected in all biological samples. This is the first study of the excretion, metabolism and tissue distribution of multiple components from in pigs. These data can provide an important reference to explain the efficacy and toxicity of . Additionally, the results of the tissue distribution of are of great value for further residue depletion studies and safety evaluations of products of animals fed .
10.3390/molecules27082605
Molecular Mechanism of (Gardner and Champ.) Benth. Against Neuropathic Pain Based on Network Pharmacology and Experimental Evidence.
Que Wancai,Wu Zhaoyang,Chen Maohua,Zhang Binqing,You Chuihuai,Lin Hailing,Zhao Zhichang,Liu Maobai,Qiu Hongqiang,Cheng Yu
Frontiers in pharmacology
(Gardner and Champ.) Benth. (Gelsemiaceae (GEB) is a toxic plant indigenous to Southeast Asia especially China, and has long been used as Chinese folk medicine for the treatment of various types of pain, including neuropathic pain (NPP). Nevertheless, limited data are available on the understanding of the interactions between ingredients-targets-pathways. The present study integrated network pharmacology and experimental evidence to decipher molecular mechanisms of GEB against NPP. The candidate ingredients of GEB were collected from the published literature and online databases. Potentially active targets of GEB were predicted using the SwissTargetPrediction database. NPP-associated targets were retrieved from GeneCards, Therapeutic Target database, and DrugBank. Then the protein-protein interaction network was constructed. The DAVID database was applied to Gene Ontology and Kyoto Encyclopedia of Genes and Genome pathway enrichment analysis. Molecular docking was employed to validate the interaction between ingredients and targets. Subsequently, a 50 ns molecular dynamics simulation was performed to analyze the conformational stability of the protein-ligand complex. Furthermore, the potential anti-NPP mechanisms of GEB were evaluated in the rat chronic constriction injury model. A total of 47 alkaloids and 52 core targets were successfully identified for GEB in the treatment of NPP. Functional enrichment analysis showed that GEB was mainly involved in phosphorylation reactions and nitric oxide synthesis processes. It also participated in 73 pathways in the pathogenesis of NPP, including the neuroactive ligand-receptor interaction signaling pathway, calcium signaling pathway, and MAPK signaling pathway. Interestingly, 11-Hydroxyrankinidin well matched the active pockets of crucial targets, such as EGFR, JAK1, and AKT1. The 11-hydroxyrankinidin-EGFR complex was stable throughout the entire molecular dynamics simulation. Besides, the expression of EGFR and JAK1 could be regulated by koumine to achieve the anti-NPP action. These findings revealed the complex network relationship of GEB in the "multi-ingredient, multi-target, multi-pathway" mode, and explained the synergistic regulatory effect of each complex ingredient of GEB based on the holistic view of traditional Chinese medicine. The present study would provide a scientific approach and strategy for further studies of GEB in the treatment of NPP in the future.
10.3389/fphar.2021.792932
The study of the constituents and source of toxicants in poisonous honey.
Wu Huiqin,Luo Huitai,Huang Fang,Zhou Xi,Huang Xiaolan,Chen Jianghan
Analytical biochemistry
A novel method for non-target screening of toxicants in poisonous honey was established in this study. Poisonous honey and nontoxic honey were contrastive detected using liquid chromatography quadrupole-time-of-flight mass spectrometry and analyzed by Mass Profiler Professional Software. 4 poisonous alkaloids were screened out and confirmed by comparison with reference compounds. In order to investigate the source of these poisonous alkaloids, 6 poisonous alkaloids, ubiquitous in Gelsemium elegan, from honey, honeybees, pollen in honeycomb and different organs of Gelsemium elegan, were quantified by liquid chromatography triple-quadrupole tandem mass spectrometry. The results showed that alkaloids composition characteristics in honey, honeybees, and pollen were similar to those in the flower and bud of Gelsemium elegan and significant different from those in leave, stem and root. This result demonstrated that poisonous alkaloids in honey were come from the gathering honey process. This strategy provided an efficient and rapid method for non-target screening of toxicants in food.
10.1016/j.ab.2019.01.001
Gelsenicine disrupted the intestinal barrier of Caenorhabditis elegans.
Chemico-biological interactions
Gelsemium elegans Benth. (G. elegans) is a traditional medicinal herb that has anti-inflammatory, analgesic, sedative, and detumescence effects. However, it can also cause intestinal side effects such as abdominal pain and diarrhea. The toxicological mechanisms of gelsenicine are still unclear. The objective of this study was to assess enterotoxicity induced by gelsenicine in the nematodes Caenorhabditis elegans (C. elegans). The nematodes were treated with gelsenicine, and subsequently their growth, development, and locomotion behavior were evaluated. The targets of gelsenicine were predicted using PharmMapper. mRNA-seq was performed to verify the predicted targets. Intestinal permeability, ROS generation, and lipofuscin accumulation were measured. Additionally, the fluorescence intensities of GFP-labeled proteins involved in oxidative stress and unfolded protein response in endoplasmic reticulum (UPR) were quantified. As a result, the treatment of gelsenicine resulted in the inhibition of nematode lifespan, as well as reductions in body length, width, and locomotion behavior. A total of 221 targets were predicted by PharmMapper, and 731 differentially expressed genes were screened out by mRNA-seq. GO and KEGG enrichment analysis revealed involvement in redox process and transmembrane transport. The permeability assay showed leakage of blue dye from the intestinal lumen into the body cavity. Abnormal mRNAs expression of gem-4, hmp-1, fil-2, and pho-1, which regulated intestinal development, absorption and catabolism, transmembrane transport, and apical junctions, was observed. Intestinal lipofuscin and ROS were increased, while sod-2 and isp-1 expressions were decreased. Multiple proteins in SKN-1/DAF-16 pathway were found to bind stably with gelsenicine in a predictive model. There was an up-regulation in the expression of SKN-1:GFP, while the nuclear translocation of DAF-16:GFP exhibited abnormality. The UPR biomarker HSP-4:GFP was down-regulated. In conclusion, the treatment of gelsenicine resulted in the increase of nematode intestinal permeability. The toxicological mechanisms underlying this effect involved the disruption of intestinal barrier integrity, an imbalance between oxidative and antioxidant processes mediated by the SKN-1/DAF-16 pathway, and abnormal unfolded protein reaction.
10.1016/j.cbi.2024.111036
Network Pharmacology and Experimental Verification to Unveil the Mechanism of N-Methyl-D-Aspartic Acid Rescue Humantenirine-Induced Excitotoxicity.
Metabolites
is a medicinal plant that has been used to treat various diseases, but it is also well-known for its high toxicity. Complex alkaloids are considered the main poisonous components in . However, the toxic mechanism of remains ambiguous. In this work, network pharmacology and experimental verification were combined to systematically explore the specific mechanism of toxicity. The alkaloid compounds and candidate targets of , as well as related targets of excitotoxicity, were collected from public databases. The crucial targets were determined by constructing a protein-protein interaction (PPI) network. Subsequently, Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to explore the bioprocesses and signaling pathways involved in the excitotoxicity corresponding to alkaloids in . Then, the binding affinity between the main poisonous alkaloids and key targets was verified by molecular docking. Finally, animal experiments were conducted to further evaluate the potential mechanisms of toxicity. A total of 85 alkaloids in associated with 214 excitotoxicity-related targets were predicted by network pharmacology. Functional analysis showed that the toxicity of was mainly related to the protein phosphorylation reaction and plasma membrane function. There were also 164 pathways involved in the toxic mechanism, such as the calcium signaling pathway and MAPK signaling pathway. Molecular docking showed that alkaloids have high affinity with core targets, including MAPK3, SRC, MAPK1, NMDAR and NMDAR. In addition, the difference of binding affinity may be the basis of toxicity differences among different alkaloids. Humantenirine showed significant sex differences, and the LD values of female and male mice were 0.071 mg·kg and 0.149 mg·kg, respectively. Furthermore, we found that N-methyl-D-aspartic acid (NMDA), a specific NMDA receptor agonist, could significantly increase the survival rate of acute humantenirine-poisoned mice. The results also show that humantenirine could upregulate the phosphorylation level of MAPK3/1 and decrease ATP content and mitochondrial membrane potential in hippocampal tissue, while NMDA could rescue humantenirine-induced excitotoxicity by restoring the function of mitochondria. This study revealed the toxic components and potential toxic mechanism of . These findings provide a theoretical basis for further study of the toxic mechanism of and potential therapeutic strategies for poisoning.
10.3390/metabo13020195
Monoterpene indole alkaloids from .
Natural product research
Two new monoterpene indole alkaloids, Eleganine A () and Eleganine B (), along with 11 known compounds (3-13) were isolated from the stems and leaves of . Compound 1 is a gelsenicine-related monoterpenoid indole alkaloid possessing an iridoid unit. Their structures and absolute configurations of - were established by UV, IR, HR-ESI-MS, NMR spectroscopy, and electronic circular dichroism data analyses. All isolated compounds were evaluated for their anti-inflammatory and inhibiting glucose-induced mesanginal cell proliferation activities. None of them showed activity with IC far beyond 50 M.
10.1080/14786419.2023.2261070
Recent progress in chemistry and bioactivity of monoterpenoid indole alkaloids from the genus : a comprehensive review.
Journal of enzyme inhibition and medicinal chemistry
Monoterpenoid indole alkaloids (MIAs) represent a major class of active ingredients from the plants of the genus . Gelsemium MIAs with diverse chemical structures can be divided into six categories: gelsedine-, gelsemine-, humantenine-, koumine-, sarpagine- and yohimbane-type. Additionally, gelsemium MIAs exert a wide range of bioactivities, including anti-tumour, immunosuppression, anti-anxiety, analgesia, and so on. Owing to their fascinating structures and potent pharmaceutical properties, these gelsemium MIAs arouse significant organic chemists' interest to design state-of-the-art synthetic strategies for their total synthesis. In this review, we comprehensively summarised recently reported novel gelsemium MIAs, potential pharmacological activities of some active molecules, and total synthetic strategies covering the period from 2013 to 2022. It is expected that this study may open the window to timely illuminate and guide further study and development of gelsemium MIAs and their derivatives in clinical practice.
10.1080/14756366.2022.2155639
Benth: Chemical Components, Pharmacological Effects, and Toxicity Mechanisms.
Lin Hailing,Qiu Hongqiang,Cheng Yu,Liu Maobai,Chen Maohua,Que Youxiong,Que Wancai
Molecules (Basel, Switzerland)
Benth (GEB), also known as heartbreak grass, is a highly poisonous plant belonging to the family and genus that has broad application prospects in medicine. This article reviews its chemical components, pharmacological effects, toxicity mechanisms, and research progress in clinical applications in recent years. Indole alkaloids are the main active components of GEB and have a variety of pharmacological and biological functions. They have anti-tumor, anti-inflammatory, analgesic, and immunomodulation properties, with the therapeutic dose being close to the toxic dose. Application of small-dose indole alkaloids fails to work effectively, while high-dose usage is prone to poisoning, aggravating the patient's conditions. Special caution is needed, especially to observe the changes in the disease condition of the patients in clinical practice. In-depth research on the chemical components and mechanisms of GEB is essential to the development of promising lead compounds and lays the foundation for extensive clinical application and safe usage of GEB in the future.
10.3390/molecules26237145
Genus and its Endophytic Fungi - Comprehensive Review of their Traditional Uses, Phytochemistry, Pharmacology, and Toxicology.
Current topics in medicinal chemistry
BACKGROUND:The use of ethnic medicinal plants has revitalized wide popularity in Africa, Asia, and most of the world because of the energy consumption barriers increase of synthetic drugs. is a traditional genus of plants with famous cultural and medicinal significance in Southeast Asia and North America. Three species are reported from the genus , including (Gardn. & Camp.) Benth., (L.) J.St.-Hil., and Small. Among them, is well known for its toxicity and is used as a traditional remedy for skin problems, neuralgia, fractures, and cancer. The first record of the toxic medicine is the Chinese herbal medicine classically known as In the legend, the Shennong emperor was poisoned by , hence, it is also wellknown as Duan Chang Cao in China. In addition, tincture is also used in the treatment of inflammation of the spinalcolumn, and diminishes blood to the cerebrospinal centers. INTRODUCTION:This review aims to provide up-to-date information on and its endophytic fungi on their traditional uses, phytochemistry, pharmacology, and toxicology. Mechanism studies regarding the detoxification profile of are also reviewed. METHODS:For this updated review, the literature survey and search were performed on the scientific databases PubMed, ScienceDirect, Wiley, China CNKI, Web of Science, SciFinder, and Google Scholar using the relevant keywords. RESULTS:The plants of the genus are all reported as rich sources of monoterpene indole alkaloids. Previous phytochemical studies published more than 200 alkaloids from and its endophytic fungi, which have attracted considerable attention from pharmaceutists and phytochemists due to their diverse and complex structures. The bioactivities of phytoconstituents studied using various chemical methods are summarized and described herein. Considering the huge influence of regarding its traditional applications, the activities of isolated compounds were focused on the anti-tumor, anti-inflammatory, analgesic and antianxiety, immunostimulatory, and immunosuppressive properties, which provide evidence supporting the ethnopharmacological effectiveness of the genus . Unlike all previous reviews of genus , to the best of our knowledge, the recently reported natural products from its endophytic fungi are first time summarized in this review. CONCLUSION:It is clearly suggested from the literature information that the structures and biological activities of have a wide range of attraction from folk to the community of scholars. However, as a highly toxic genus, the work on the detoxification mechanism and toxicology of is urgently needed before entering clinical research. It is noteworthy that the discussion about the relationship between structural and biological activities are a valuable topic of expectation, while the structural modification for active or toxic components may shed light on toxicological breakthrough. Besides the compounds from the plants of genus , the recently reported natural products from its endophytic fungi may provide a supplement for its ethnomedicinal uses and ethnological validity.
10.2174/1568026623666230825105233
The Metabolism and Disposition of Koumine, Gelsemine and Humantenmine from Gelsemium.
Wang Zi-Yuan,Zuo Meng-Ting,Liu Zhao-Ying
Current drug metabolism
BACKGROUND:Gelsemium is a toxic flowering plant of the Gelsemiaceae family. It is used to treat skin diseases in China, and it is an important medicinal and homeopathic plant in North America. Up to now, more than 200 compounds have been isolated and reported from Gelsemium. More than 120 of these are indole alkaloids, including the main components, koumine, gelsemine and humantenmine which produce the pharmacological and toxicological effects of Gelsemium. However, their clinical application their limited by its narrow therapeutic window. Therefore, it is very important to study the metabolism and disposition of indole alkaloids from Gelsemium before their clinical application. This paper reviews all the reports on the metabolism and disposition of alkaloids isolated from Gelsemium at home and abroad. METHODS:The metabolism and disposition of alkaloids from Gelsemium were searched by the Web of Science, NCBI, PubMed and some Chinese literature databases. RESULTS:Only koumine, gelsemine and humantenmine have been reported, and few other alkaloids have been described. These studies indicated that the three indole alkaloids are absorbed rapidly, widely distributed in tissues, extensively metabolized and rapidly eliminated. There are species differences in the metabolism of these alkaloids, which is the reason for the differences in their toxicity in animals and humans. CONCLUSION:This review not only explains the pharmacokinetics of indole alkaloids from Gelsemium but also facilitates further study on their metabolism and mechanism of toxicity.
10.2174/1389200220666190614152304