摘要：
BACKGROUND: Gelsemium elegans (G. elegans) is a flowering plant of the Loganiaceae family, which had been used in traditional Chinese herb medicine for many years for the treatment of rheumatoid pain, neuropathic pain, spasticity, skin ulcers, anxiety and cancer. Acute toxicity of the plant severely limits the application and development of G. elegans; however, long-term toxicity of exposure to G. elegans has not been illuminated. PURPOSE: This study is a comprehensive observation of the effects of long-term exposure (21 days at 70 mg/kg) to G. elegans in rats. METHODS AND RESULTS: The histopathological examination showed only a mild glial cell proliferation in the brain, and no lesions were observed in other organs. No abnormal changes in the biochemical parameters were observed that would have significant effects. The identification and analysis of absorbed natural ingredients showed that the active ingredients of the G. elegans could distribute to various tissues, and six compounds were identified in the brain, suggesting that they could cross the blood-brain barrier. Based on the intestinal content metabolomics, the tryptophan (Trp) biosynthesis, bile acid synthesis and bile secretion pathways have attracted our attention. Plasma metabolomic results showed that uric acid (UA) was significantly increased. The results of the brain metabolomic tests showed that the level of pyridoxal (PL) was decreased; considering the expression levels of the related enzymes, it was hypothesized that the level of pyridoxal 5'-phosphate (PLP) was decreased. PLP was important for the regulation of the neuronal γ-aminobutyric acid (GABA)/glutamate (Glu) interconversion and therefore neuronal excitability. The data of the study suggested that toxic reaction caused by G. elegans was due to a disruption of the balance of the neurotransmitter GABA/Glu transformation. CONCLUSIONS: Overall, G. elegans did not cause significant toxic reaction in the rats after long-term exposure. The results were significant for the future clinical applications of G. elegans and suggested that G. elegans could be potentially developed as a drug. The study provided a scientific basis for investigation of the mechanisms of toxicity and detoxification.
作者机构：
[Wu, Yong; Sun, Zhi-Liang; Liu, Zhao-Ying; Zhao, Na-Jiao; Wang, Li-li; Liu, Lei; Wang, Qin] Hunan Engineering Research Center of Veterinary Drug, College of Veterinary Medicine, Hunan Agricultural University, Changsha, People's Republic of China
通讯机构：
[Yong Wu] H;Hunan Engineering Research Center of Veterinary Drug, College of Veterinary Medicine, Hunan Agricultural University, Changsha, People’s Republic of China
摘要：
The objective of this study was to investigate the single- and multiple-dose pharmacokinetics of chelerythrine (CHE) and its metabolite, dihydrochelerythrine (DHCHE), after oral and IM administrations in pigs.Six crossbreed (Landrace × Large White) female pigs (7-8 weeks old; 24.1 ± 2.6 kg bw) administered oral and IM CHE at a dose of 0.1 mg/kg orally and intramuscularly in a cross-over design. Multiple oral administration was performed at 0.1 mg/kg a time, three times a day at 8-h intervals for three consecutive days. Blood samples were collected from the anterior vena cava and placed into heparinized centrifuge tubes before dosing (time 0 h) and at different times after oral and IM administrations. Pre-treatment plasma was analysed by high-performance liquid chromatography-tandem mass spectrometry.After IM administration, CHE and DHCHE rapidly reached peak concentrations (C(max), 69.79 ± 15.41 and 3.47 ± 1.23 ng/mL) at 0.42 ± 0.13 and 0.33 ± 0.13 h, respectively. After single oral administration, CHE and DHCHE rapidly increased to reach C(max) of 5.04 ± 1.00 and 1.21 ± 0.35 ng/mL at 1.83 ± 0.26 and 1.67 ± 0.26 h, respectively. The half-life (T(1/2)) was 2.03 ± 0.26 and 2.56 ± 1.00 h for CHE and DHCHE, respectively. After multiple oral administration, the average steady-state concentrations (C(ss)) of CHE and DHCHE were 2.51 ± 0.40 and 0.6 ± 0.06 ng/mL, respectively.CHE is metabolized rapidly after a single oral administration, multiple daily doses and long-term use of CHE are recommended.
摘要：
<jats:title>Abstract</jats:title><jats:p>Xuefu Zhuyu Decoction (XFZYD) is a traditional Chinese medicine prescription used for the clinical treatment of traumatic brain injury (TBI). The purpose of this work was to develop a sensitive and rapid UHPLC–MS/MS method to simultaneously study the pharmacokinetics of nimodipine and eight components of XFZYD, namely, amygdalin, hydroxysafflor yellow A, rutin, liquiritin, narirutin, naringin, neohesperidin and saikosaponin A, in rats with and without TBI. Multiple reaction monitoring was highly selective in the detection of nine analytes and the internal standard without obvious interference. The calibration curves displayed good linearity (<jats:italic>r</jats:italic> > 0.99) over a wide concentration range. The mean absolute recoveries of the nine analytes were 85–106%, and all matrix effects were in the range 80–120%. The intra‐ and inter‐day precision and accuracy were acceptable (RSD, <15%; RE%, ±20%). The validated method was successfully applied to compare the pharmacokinetics in four experimental groups, including control rats orally administered XFZYD and TBI model rats orally administered XFZYD, XFZYD and nimodipine, or nimodipine alone. The results showed that herb–drug interactions occurred between XFZYD and nimodipine in the treatment of TBI, nimodipine affected the pharmacokinetics of XFZYD, and XFZYD affected the absorption, distribution and excretion of nimodipine <jats:italic>in vivo.</jats:italic></jats:p>
期刊：
Journal of Veterinary Pharmacology and Therapeutics,2020年43(2):208-214 ISSN：0140-7783
通讯作者：
Liu, Zhao-Ying;Sun, Zhi-Liang
作者机构：
[Wu, Yong; Cao, Yan; Sun, Zhuo; Sun, Zhi-Liang; Liu, Zhao-Ying; Zhao, Na-Jiao; Wang, Qin] Hunan Agr Univ, Coll Vet Med, Hunan Engn Technol Res Ctr Vet Drugs, Changsha, Peoples R China.;[Liu, Zhao-Ying; Sun, ZL] Hunan Agr Univ, Coll Vet Med, Changsha, Hunan, Peoples R China.
通讯机构：
[Liu, ZY; Sun, ZL] H;Hunan Agr Univ, Coll Vet Med, Changsha, Hunan, Peoples R China.
关键词：
dihydrosanguinarine;drug metabolite;sanguinarine;unclassified drug;benzophenanthridine derivative;isoquinoline derivative;sanguinarine;animal cell;animal experiment;animal tissue;area under the curve;Article;controlled study;cytosol;drug accumulation;drug clearance;drug half life;drug metabolism;elimination half-life;female;in vitro study;in vivo study;intestine flora;intestine mucosa;maximum concentration;mean residence time;microsome;nonhuman;pharmacokinetics;priority journal;single drug dose;steady state;time to maximum plasma concentration;animal;half life time;intramuscular drug administration;metabolism;oral drug administration;pig;Administration, Oral;Animals;Area Under Curve;Benzophenanthridines;Half-Life;Injections, Intramuscular;Isoquinolines;Swine
通讯机构：
[Liu, Zhao-Ying] H;Hunan Agr Univ, Coll Vet Med, Changsha 410128, Hunan, Peoples R China.
摘要：
<jats:sec><jats:title>Rationale</jats:title><jats:p><jats:italic>Gelsemium elegans</jats:italic> (<jats:styled-content style="fixed-case"><jats:italic>G. elegans</jats:italic></jats:styled-content>) is highly toxic to humans and rats but has insecticidal and growth‐promoting effects on pigs and goats. However, the mechanisms behind the toxicity differences of <jats:styled-content style="fixed-case"><jats:italic>G. elegans</jats:italic></jats:styled-content> are unclear. Gelsenicine, isolated from <jats:styled-content style="fixed-case"><jats:italic>G. elegans</jats:italic>,</jats:styled-content> has been reported to be a toxic alkaloid.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>In this study, the <jats:italic>in vitro</jats:italic> metabolism of gelsenicine was investigated and compared for the first time using human (HLM), pig (PLM), goat (GLM) and rat (RLM) liver microsomes and high‐performance liquid chromatography/mass spectrometry (HPLC/MS).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>In total, eight metabolites (<jats:bold>M1</jats:bold>–<jats:bold>M8</jats:bold>) were identified by using high‐performance liquid chromatography/quadrupole‐time‐of‐flight mass spectrometry (HPLC/QqTOF‐MS). Two main metabolic pathways were found in the liver microsomes of the four species: demethylation at the methoxy group on the indole nitrogen (<jats:bold>M1</jats:bold>) and oxidation at different positions (<jats:bold>M2</jats:bold>–<jats:bold>M8</jats:bold>). <jats:bold>M8</jats:bold> was identified only in the GLM. The degradation ratio of gelsenicine and the relative percentage of metabolites produced during metabolism were determined by high‐performance liquid chromatography/tandem mass spectrometry (HPLC/QqQ‐MS/MS). The degradation ratio of gelsenicine in liver microsomes decreased in the following order: PLM ≥ GLM > HLM > RLM. The production of <jats:bold>M1</jats:bold> decreased in the order of GLM > PLM > RLM > HLM, the production of <jats:bold>M2</jats:bold> was similar among the four species, and the production of <jats:bold>M3</jats:bold> was higher in the HLM than in the liver microsomes of the other three species.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Based on these results, demethylation was speculated to be the main gelsenicine detoxification pathway, providing vital information to better understand the metabolism and toxicity differences of <jats:styled-content style="fixed-case"><jats:italic>G. elegans</jats:italic></jats:styled-content> among different species.</jats:p></jats:sec>
通讯机构：
[Liu, Zhao-Ying] H;Hunan Agr Univ, Coll Vet Med, 1 Nongda Rd, Changsha 410128, Hunan, Peoples R China.;Hunan Agr Univ, Hunan Engn Technol Res Ctr Vet Drugs, 1 Nongda Rd, Changsha 410128, Hunan, Peoples R China.
关键词：
alkaloid;Chinese drug;gelsemine;Gelsemium elegans extract;humantenmine;koumine;plant extract;unclassified drug;alkaloid;indole alkaloid;plant extract;animal experiment;area under the curve;Article;Gelsemium;Gelsemium elegans;goat;limit of detection;limit of quantitation;male;maximum plasma concentration;nonhuman;quantitative analysis;tandem mass spectrometry;time to maximum plasma concentration;ultra performance liquid chromatography;animal;goat;human;liquid chromatography;metabolism;pig;tandem mass spectrometry;Alkaloids;Animals;Chromatography, Liquid;Gelsemium;Goats;Humans;Indole Alkaloids;Plant Extracts;Swine;Tandem Mass Spectrometry
摘要：
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 T-max, T-1/2 and MRT0-t of the three alkaloids were similar between the two methods. In addition, the values of C-max and AUC(0-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.
摘要：
<jats:p> Gelsemium elegans Benth. (G. elegans), a traditional Chinese medicine, has great potential as an effective growth promoter in animals, however, the mechanism of its actin remains unclear. Here, we evaluated the protective effects of koumine extract from G. elegans against lipopolysaccharide (LPS)-induced intestinal barrier dysfunction in IPEC-J2 cells through alleviation of inflammation and oxidative stress. MTT and LDH assays revealed that koumine significantly reduced LPS cytotoxicity. Transepithelial electrical resistance (TEER) and cell monolayer permeability assays showed that koumine treatment attenuated the LPS-induced intestinal barrier dysfunction with no particularly different effects in tight junction proteins such as ZO-1, claudin-1, and occludin. LPS-triggered inflammatory response was also suppressed by koumine, as evidenced by the downregulated inflammatory factors, including TNF-[Formula: see text], IL-6, IL-1[Formula: see text], NO, iNOS, and COX-2, which was closely connected with the inhibition of NF-[Formula: see text]B pathway for the decrease of phosphorylation of I[Formula: see text]B[Formula: see text] and NF-[Formula: see text]B and nuclear translocation of p-p65. Amount of reactive oxygen species (ROS) and MDA induced by LPS was also reduced by koumine through activation of Nrf2 pathway, and increased in the levels of Nrf2 and HO-1 degradation of keap-1 to promote anti-oxidants, including superoxide dismutase (SOD) and catalase (CAT). To summarize, koumine-reduced the oxidative stress and inflammatory reaction triggered by LPS through regulation of the Nrf2/NF-[Formula: see text]B signaling pathway and preventing intestinal barrier dysfunction. </jats:p>
摘要：
RATIONALE: Macleaya microcarpa (Maxim.) Fedde is a genus of Macleaya belonging to papaveraceae family. Benzylisoquinoline alkaloids are considered the main bioactive constituents of M. microcarpa. METHODS: Using HPLC-Q/TOF-MS/MS we identified the benzylisoquinoline alkaloids in the aerial parts of M. microcarpa at early flowering stage. Target profiling and identification of benzylisoquinoline alkloids in the extracted samples from fresh aerial parts of M. microcarpa were exclusively based on a personal accurate mass database of known compounds combined with the mass spectral fragmentation behavior of Macleaya alkaloids. RESULTS: Ninety-seven alkaloids including seven benzyltetrahydroisoquinolines, one aporphine, nine tetraprotoberberines, three protoberberines, two N-methyltetrahydroprotoberberines, four protopines, forty-seven dihydrobenzophenanthridines, and twenty-four benzophenanthridines were identified from the fresh aerial parts of M. microcarpa, and seventy-seven of them were detected for the first time in M. microcarpa. In addition, some of the screened alkaloids were related to the biosynthetic pathways of sanguinarine and chelerythrine. CONCLUSIONS: The integrated method is sensitive and reliable for screening and identifying trace or ultra trace isoquinoline alkaloids and contributed to a better understanding of benzylisoquinoline alkaloids in fresh aerial parts of M. microcarpa.
关键词：
Database systems;High performance liquid chromatography;Liquids;Mass spectrometry;Metabolites;Purification;Structure (composition);Accurate-mass database;Active fraction;Albizia julibrissin;Molecular formula;Quadrupole time of flight mass spectrometry;Structural characterization;Tandem mass spectrometry;High pressure liquid chromatography;acacigenin B;adianthifolioside B;albiziasaponin B;albiziasaponin B1;albiziatrioside A;albiziatrioside A1;hehuanoside A;julibrogenin C;julibroside A1;julibroside A4;julibroside C1;julibroside J22;julibroside J26;julibroside J31;julibroside J31a;julibroside J32;proceraoside D;prosapogenin 10;prosapogenin 10a;prosapogenin 10b;prosapogenin 12;prosapogenin 12a;prosapogenin 12b;prosapogenin 9;prosapogenin 9a;prosapogenin 9b;saponin;unclassified drug;unindexed drug;zygiaoside D;zygiaoside D1;saponin;Albizia;Albizia julibrissin;Article;drug structure;high performance liquid chromatography;molecular weight;priority journal;time of flight mass spectrometry;Albizia;chemistry;conformation;isolation and purification;mass spectrometry;time factor;Albizzia;Chromatography, High Pressure Liquid;Mass Spectrometry;Molecular Conformation;Saponins;Time Factors
摘要：
The purified active fraction of Albizia julibrissin saponin was proved to be a promising adjuvant candidate for vaccine. In this study, a simple, convenient, and practical strategy was established for characterizing the saponins in this purified active fraction. The personal accurate mass database including chemical structure, molecular formula, and theoretical mass was first constructed by collecting 110 reported known saponins from genus Albizia species. The raw data was obtained by high-performance liquid chromatography coupled with quadrupole time of flight mass spectrometry. The potential compounds were extracted from raw data, and matched with the accurate mass databases. A series of saponin compounds were predicted and their chemical structures were characterized by interpreting the tandem mass spectrometry data. A total of 29 saponins including 10 new compounds and 5 first found saponins from A. julibrissin were successfully characterized in this purified active fraction using this new strategy.
摘要：
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.
摘要：
Rice (Oryza sativa L.) is a chilling-sensitive staple crop that originated in subtropical regions of Asia. Introduction of the chilling tolerance trait enables the expansion of rice cultivation to temperate regions. Here we report the cloning and characterization of HAN1, a quantitative trait locus (QTL) that confers chilling tolerance on temperate japonica rice. HAN1 encodes an oxidase that catalyzes the conversion of biologically active jasmonoyl-L-isoleucine (JA-Ile) to the inactive form 12-hydroxy-JA-Ile (12OH-JA-Ile) and fine-tunes the JA-mediated chilling response. Natural variants in HAN1 diverged between indica and japonica rice during domestication. A specific allele from temperate japonica rice, which gained a putative MYB cis-element in the promoter of HAN1 during the divergence of the two japonica ecotypes, enhances the chilling tolerance of temperate japonica rice and allows it to adapt to a temperate climate. The results of this study extend our understanding of the northward expansion of rice cultivation and provide a target gene for the improvement of chilling tolerance in rice.
