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1.
J Enzyme Inhib Med Chem ; 38(1): 2155639, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36629436

RESUMO

Monoterpenoid indole alkaloids (MIAs) represent a major class of active ingredients from the plants of the genus Gelsemium. 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.


Assuntos
Gelsemium , Alcaloides de Triptamina e Secologanina , Alcaloides de Triptamina e Secologanina/farmacologia , Alcaloides de Triptamina e Secologanina/química , Gelsemium/química , Alcaloides Indólicos/farmacologia , Alcaloides Indólicos/química , Extratos Vegetais , Dor
2.
Molecules ; 27(8)2022 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-35458803

RESUMO

Gelsemium elegans (Gardn. & Champ.) Benth is a toxic flowering plant in the family Loganiaceae used to treat skin diseases, neuralgia and acute pain. The high toxicity of G. elegans restricts its development and clinical applications, but in veterinary applications, G. elegans has been fed to pigs as a feed additive without poisoning. However, until now, the in vivo processes of the multiple components of G. elegans have not been studied. This study investigates the excretion, metabolism and tissue distribution of the multiple components of G. elegans after feeding it to pigs in medicated feed. Pigs were fed 2% G. elegans 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 G. elegans were excreted in the urine. However, ten natural products and four metabolites were detected in bile samples, which suggested that G. elegans 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 G. elegans is widely distributed in tissues and can cross the blood-brain barrier. Among the characterized compounds, a highly toxic gelsedine-type alkaloid from G. elegans 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 G. elegans in pigs. These data can provide an important reference to explain the efficacy and toxicity of G. elegans. Additionally, the results of the tissue distribution of G. elegans are of great value for further residue depletion studies and safety evaluations of products of animals fed G. elegans.


Assuntos
Alcaloides , Gelsemium , Alcaloides/química , Animais , Cromatografia Líquida de Alta Pressão , Gelsemium/química , Masculino , Extratos Vegetais , Suínos , Distribuição Tecidual
3.
J Pept Sci ; 28(9): e3410, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35307909

RESUMO

Four novel Gelsemium elegans cyclic peptides (GEPs) were isolated in an antihuman cervical carcinoma activity tracking method, and their amino acid sequences were identified. The GEP-1 cyclic-(Trp-Leu-His-Val)-peptide inhibited HeLa cell proliferation in a dose- and time-dependent manner. GEP-1 induced intracellular reactive oxygen species (ROS) overproduction and induced HeLa cells apoptosis in a caspase-dependent manner. GEP-1 also induced collapse of the mitochondrial membrane potential and promoted the mitochondrial release of cytochrome c (cyt c), apoptosis-inducing factor (AIF), and endonuclease G (Endo G) in HeLa cells. Furthermore, GEP-1 triggered the extrinsic death receptor-dependent pathway, which was characterized by activating Fas and FADD. Notably, GEP-1 is a potential antihuman cervical carcinoma peptide.


Assuntos
Carcinoma , Gelsemium , Apoptose , Linhagem Celular Tumoral , Gelsemium/metabolismo , Células HeLa , Humanos , Potencial da Membrana Mitocondrial , Peptídeos Cíclicos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
4.
Rapid Commun Mass Spectrom ; 36(12): e9302, 2022 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-35344234

RESUMO

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.


Assuntos
Alcaloides , Antineoplásicos , Gelsemium , Alcaloides/metabolismo , Animais , Cromatografia Líquida de Alta Pressão/métodos , Indóis , Microssomos Hepáticos/metabolismo , Ratos , Suínos , Espectrometria de Massas em Tandem/métodos
5.
Hum Exp Toxicol ; 41: 9603271211062857, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35018838

RESUMO

BACKGROUND: Gelsenicine, one of the most toxic alkaloids of Gelsemium elegans Benth (G. elegans), causes severe respiratory depression. However, its toxicity mechanisms are yet to be elucidated and no effective antidotes are available. OBJECTIVE: This study aimed to analyse the toxicity characteristics of gelsenicine. METHODS: Both acute and sub-acute toxicities were evaluated. Gelsenicine distribution and elimination in the central nervous system (CNS) and blood were observed. Effective antidotes for gelsenicine poisoning were screened. RESULTS: In the acute toxicity study, gelsenicine was highly toxic, and female rats exhibited greater sensitivity to gelsenicine than male rats (LD50 0.520 mg/kg vs 0.996 mg/kg, respectively). Death was primarily caused by respiratory failure. However, in the sub-acute toxicity study, no significant organ damage was observed. Gelsenicine was easily absorbed from the gastrointestinal tract and penetrated the blood-brain barrier, reaching peak concentrations in the CNS within 15 min and rapidly decreasing thereafter. Flumazenil or diazepam combined with epinephrine reversed gelsenicine toxicity and significantly improved survival rate in mice. CONCLUSIONS: Gelsenicine is a highly toxic substance that affects nerve conduction without causing damage; the potential toxic mechanism is possibly associated with GABAA receptors. Our findings provide insights into the clinical treatment of gelsenicine-related poisoning and its toxicity mechanisms.


Assuntos
Antídotos/uso terapêutico , Gelsemium/química , Alcaloides Indólicos/toxicidade , Neurotoxinas/toxicidade , Extratos Vegetais/toxicidade , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/tratamento farmacológico , Animais , Modelos Animais de Doenças , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Insuficiência Respiratória/mortalidade , Fatores Sexuais
6.
Nat Prod Res ; 36(10): 2630-2636, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-33908330

RESUMO

A new alkaloid 14-hydroxygelseziridine (1), along with four known oxindoles (2-5), was isolated and characterized from the well-known toxic medicine Gelsemium elegans. Their structures were elucidated by means of spectroscopic techniques and quantum chemistry calculations. Structurally, new compound 1 has a three membered oxygen ring at N-4/C-20. All compounds were tested for osteoclast (MOC-1) inhibitory activity in vitro. Compound 2 exhibited the selective osteoclast inhibitory activity. Flow cytometry revealed that the apoptosis of osteoclasts induced by 2. Furthermore, the PCR bioassay suggested that compound 2 may activate the apoptotic pathway of osteoclasts by reducing the expression of IL-6 and c-Jun, and increasing caspase 9. This work provided the evidence for the rationality as the traditional treatment for bone related diseases of G. elegans, and shed a new light on its further research.


Assuntos
Alcaloides , Gelsemium , Alcaloides/química , Alcaloides/farmacologia , Gelsemium/química , Osteoclastos , Oxindóis/farmacologia
7.
Homeopathy ; 111(2): 97-104, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34715718

RESUMO

INTRODUCTION: There is some evidence that homeopathic treatment has been used successfully in previous epidemics, and currently some countries are testing homeoprophylaxis for the coronavirus disease 2019 (COVID-19) pandemic. There is a strong tradition of homeopathic treatment in India: therefore, we decided to compare three different homeopathic medicines against placebo in prevention of COVID-19 infections. METHODS: In this double-blind, cluster-randomized, placebo-controlled, four parallel arms, community-based, clinical trial, a 20,000-person sample of the population residing in Ward Number 57 of the Tangra area, Kolkata, was randomized in a 1:1:1:1 ratio of clusters to receive one of three homeopathic medicines (Bryonia alba 30cH, Gelsemium sempervirens 30cH, Phosphorus 30cH) or identical-looking placebo, for 3 (children) or 6 (adults) days. All the participants, who were aged 5 to 75 years, received ascorbic acid (vitamin C) tablets of 500 mg, once per day for 6 days. In addition, instructions on healthy diet and general hygienic measures, including hand washing, social distancing and proper use of mask and gloves, were given to all the participants. RESULTS: No new confirmed COVID-19 cases were diagnosed in the target population during the follow-up timeframe of 1 month-December 20, 2020 to January 19, 2021-thus making the trial inconclusive. The Phosphorus group had the least exposure to COVID-19 compared with the other groups. In comparison with placebo, the occurrence of unconfirmed COVID-19 cases was significantly less in the Phosphorus group (week 1: odds ratio [OR], 0.1; 95% confidence interval [CI], 0.06 to 0.16; week 2: OR, 0.004; 95% CI, 0.0002 to 0.06; week 3: OR, 0.007; 95% CI, 0.0004 to 0.11; week 4: OR, 0.009; 95% CI, 0.0006 to 0.14), but not in the Bryonia or Gelsemium groups. CONCLUSION: Overall, the trial was inconclusive. The possible effect exerted by Phosphorus necessitates further investigation. TRIAL REGISTRATION: CTRI/2020/11/029265.


Assuntos
Bryonia , COVID-19 , Gelsemium , Homeopatia , Materia Medica , Adulto , COVID-19/prevenção & controle , Criança , Método Duplo-Cego , Humanos , Materia Medica/uso terapêutico , Pandemias/prevenção & controle , Fósforo , SARS-CoV-2 , Resultado do Tratamento
8.
Eur J Pharmacol ; 914: 174690, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34890543

RESUMO

Dysregulated activation of polyclonal B cells and production of pathogenic antibodies are involved in the development of rheumatoid arthritis (RA). Therefore, targeted B cell therapy is effective against RA. Gelsemium elegans (Gardn. & Champ.) Benth., a toxic plant widely distributed in Southeast Asia, has been used for treating rheumatoid pain, neuropathic pain, spasticity, skin ulcers, and cancers for many years in traditional Chinese medicine. Koumine, an alkaloid monomer from Gelsemium elegans Benth., exerts therapeutic effects against RA. However, whether koumine affects B cells remains unknown. In this study, the effect of koumine on B cells under T cell-independent (TI) and T cell-dependent (TD) immune responses is investigated in vitro and in vivo. Mouse primary B cells were obtained by immunomagnetic bead sorting, and immunomodulatory effects of koumine on the activation, proliferation, and differentiation of B cells were determined in TI and TD models induced by lipopolysaccharide (LPS) and anti-CD40 antibodies in vitro, respectively. The humoral immune responses of TI and TD were established using NP-AECM-FICOLL and NP-CGG in C57BL/6J mice, respectively. We found that koumine inhibited B cell differentiation in the TI model and inhibited B cell activation and proliferation in the TD model in vitro. Koumine also inhibited antibody secretion in TI immune response, TD initial immune response, and in TD secondary immune response. Our results reveal that koumine has a direct and indirect immune regulatory effect on B cells, showing that it can directly inhibit the differentiation and secretion of autoantibodies after abnormal activation of B cells, and indirectly inhibit the activation and proliferation of TD B cells to reduce the secretion of antibodies. It may be an important mechanism for its anti-RA effect in mice, providing a rationale and laboratory data support for the application of koumine in anti-human RA therapy.


Assuntos
Artrite Reumatoide , Linfócitos B , Gelsemium , Alcaloides Indólicos/farmacologia , Linfócitos T/imunologia , Animais , Formação de Anticorpos/efeitos dos fármacos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Diferenciação Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/imunologia , Agentes de Imunomodulação/farmacologia , Cooperação Linfocítica/imunologia , Medicina Tradicional Chinesa , Camundongos
9.
Curr Mol Pharmacol ; 15(5): 794-801, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34886788

RESUMO

BACKGROUND: Gelsemium elegans (G. elegans) has been shown to have strong pharmacological and pharmacodynamic effects in relevant studies both in China and USA. G. elegans has been used as a traditional medicine to treat a variety of diseases and even has the potential to be an alternative to laboratory synthesized drugs. However, its toxicity severely limited its application and development. At present, there is little attention paid to protein changes in toxicity. AIM: This study investigated the toxicity effects after long-term exposure of G. elegans of the rat brain through proteomic. METHODS: 11 differential abundance proteins were detected, among which 8 proteins were higher in the G. elegans- exposure group than in the control group, including Ig-like domain-containing protein (N/A), receptor-type tyrosine-protein phosphatase C (Ptprc), disheveled segment polarity protein 3 (Dvl3), trafficking protein particle complex 12 (Trappc12), seizure-related 6 homologlike (Sez6l), transmembrane 9 superfamily member 4 (Tm9sf4), DENN domain-containing protein 5A (Dennd5a) and Tle4, whereas the other 3 proteins do the opposite including Golgi to ER traffic protein 4 (Get4), vacuolar protein sorting 4 homolog B (Vps4b) and cadherin-related 23 (CDH23). Furthermore, we performed validation of WB analysis on the key protein CDH23. RESULTS: Finally, only fewer proteins and related metabolic pathways were affected, indicating that there was no accumulative toxicity of G. elegans. G. elegans has the potential to develop and utilize of its pharmacological activity. CHD23, however, is a protein associated with hearing. CONCLUSION: Whether the hearing impairment is a sequela after G. elegans exposure remains to be further studied.


Assuntos
Gelsemium , Animais , Encéfalo , Proteômica , Ratos
10.
Talanta ; 239: 123069, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-34836637

RESUMO

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.


Assuntos
Alcaloides , Gelsemium , Cromatografia Líquida de Alta Pressão , Alcaloides Indólicos , Espectrometria de Massas em Tandem
11.
J Pharm Biomed Anal ; 210: 114546, 2022 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-34972069

RESUMO

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 (R2) 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.


Assuntos
Gelsemium , Alcaloides , Cromatografia Líquida de Alta Pressão , Humanos , Alcaloides Indólicos , Espectrometria de Massas em Tandem
12.
Int J Mol Sci ; 24(1)2022 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-36613970

RESUMO

Gelsemium elegans (G. elegans) is a Chinese medicinal plant with substantial economic and feeding values. There is a lack of detailed studies on the mitochondrial genome of G. elegans. In this study, the mitochondrial genome of G. elegans was sequenced and assembled, and its substructure was investigated. The mitochondrial genome of G. elegans is represented by two circular chromosomes of 406,009 bp in length with 33 annotated protein-coding genes, 15 tRNA genes, and three rRNA genes. We detected 145 pairs of repeats and found that four pairs of repeats could mediate the homologous recombination into one major conformation and five minor conformations, and the presence of conformations was verified by PCR amplification and Sanger sequencing. A total of 124 SSRs were identified in the G. elegans mitochondrial genome. The homologous segments between the chloroplast and mitochondrial genomes accounted for 5.85% of the mitochondrial genome. We also predicted 477 RNA potential editing sites and found that the nad4 gene was edited 38 times, which was the most frequent occurrence. Taken together, the mitochondrial genome of G. elegans was assembled and annotated. We gained a more comprehensive understanding on the genome of this medicinal plant, which is vital for its effective utilization and genetic improvement, especially for cytoplasmic male sterility breeding and evolution analysis in G. elegans.


Assuntos
Gelsemium , Genoma de Cloroplastos , Genoma Mitocondrial , Melhoramento Vegetal , Citoplasma , Sequência de Bases , Filogenia
13.
Molecules ; 26(23)2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34885727

RESUMO

Gelsemium elegans Benth (GEB), also known as heartbreak grass, is a highly poisonous plant belonging to the family Loganiaceae and genus Gelsemium 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.


Assuntos
Gelsemium/química , Alcaloides Indólicos/química , Extratos Vegetais/química , Plantas Tóxicas/química , Analgésicos/química , Analgésicos/uso terapêutico , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Gelsemium/toxicidade , Humanos , Agentes de Imunomodulação/química , Agentes de Imunomodulação/uso terapêutico , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/uso terapêutico , Extratos Vegetais/uso terapêutico , Plantas Tóxicas/toxicidade
14.
Molecules ; 26(24)2021 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-34946539

RESUMO

The well-known toxic medicine Gelsemium elegans is widely and historically used to treat bone fracture and skin ulcers by the folk people of China. Two new monoterpenoid indole alkaloids, gelselegandines D and E, together with the known analogue gelegamine A were isolated from G. elegans. Their structures were elucidated by means of spectroscopic techniques and quantum chemical calculations. All isolated compounds were tested for the effects on RANKL-induced osteoclast formation. Interestingly, gelselegandine E and gelegamine A, respectively, showed significant promoting and inhibitory activities on osteoclastogenesis, while gelselegandine D had no activity under the same concentration. This work suggested the different configurations for the carbons near the C-19/20 oxygen rings of the isolated compounds may be the key active groups on osteoclast formation and provided the evidence for the rationality as the traditional treatment for bone-related diseases of G. elegans.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Gelsemium/química , Osteoclastos/metabolismo , Alcaloides de Triptamina e Secologanina , Animais , Camundongos , Células RAW 264.7 , Alcaloides de Triptamina e Secologanina/química , Alcaloides de Triptamina e Secologanina/isolamento & purificação , Alcaloides de Triptamina e Secologanina/farmacologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-34433122

RESUMO

Humantenirine is an active oxindole alkaloid extracted from Gelsemium elegans Benth (G. elegans). In the present study, the metabolites of humantenirine in liver microsomes were first identified by HPLC/QqTOF-MS. Then, the metabolic profile and tissue distribution after oral administration in rats were further investigated. A total of seven metabolites were identified in vitro, and five metabolites in vitro were found in vivo. Moreover, a Ⅱ-phase metabolite was identified first in vivo. The results indicated that humantenirine could be metabolized widely. The parent drug and its metabolites were distributed widely in various tissues and highly in the liver and pancreas. However, the parent drug and its metabolites had low peak intensities in plasma. The elimination of humantenirine occurred rapidly as well, the most unconverted forms of which were found in the kidney. Metabolic pathways, including demethylation, dehydrogenation, oxidation and glucuronidation, were proposed. The present findings may provide a basis for the study of pharmacokinetic characteristics and will contribute to the evaluation of the pharmacology and toxicity of G. elegans.


Assuntos
Alcaloides , Gelsemium/química , Metaboloma/fisiologia , Administração Oral , Alcaloides/administração & dosagem , Alcaloides/análise , Alcaloides/química , Alcaloides/farmacocinética , Animais , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Masculino , Espectrometria de Massas , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
16.
Vet Med Sci ; 7(5): 2086-2092, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33955684

RESUMO

Gelsemium is a small genus of flowering plants from the family Loganiaceae comprising five species, three of which, Gelsemium sempervirens (L.) J. St.-Hil., G. elegans Benth and G. rankinii Small, are particularly popular. Compared with other alkaloids from G. elegans, gelsemine, gelsevirine and koumine exhibit equally potent anxiolytic effects and low toxicity. Although the pharmacological activities and metabolism of koumine and gelsemine have been reported in previous studies, the species differences of gelsevirine metabolism have not been well studied. In this study, the metabolism of gelsevirine was investigated by using liver microsomes of humans, pigs, goats and rats by means of HPLC-QqTOF/MS. The results indicated that the metabolism of gelsevirine in liver microsomes had qualitative and quantitative species differences. Based on the results, the possible metabolic pathways of gelsevirine in liver microsomes were proposed. Investigation of the metabolism of gelsevirine will provide a basis for further studies of the in vivo metabolism of this drug.


Assuntos
Gelsemium , Microssomos Hepáticos , Animais , Cromatografia Líquida de Alta Pressão/veterinária , Gelsemium/metabolismo , Cabras/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Extratos Vegetais/metabolismo , Ratos , Suínos
17.
J Nat Prod ; 84(4): 1326-1334, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33826318

RESUMO

A novel triamino monoterpene indole alkaloid with an unprecedented skeleton, gelstriamine A (1), four new monoterpene indole alkaloids (2-5), and 12 known analogues (6-17) were isolated from Gelsemium elegans. The structures of 1-5 were established using extensive spectroscopic techniques, NMR calculations with iJ/dJ-DP4 and 2D C-H COSY ANNs analysis, ECD calculations, chemical methods, and single crystal X-ray diffraction analysis. Gelstriamine A (1) possesses an unprecedented 6/5/7/6/6/5 heterohexacyclic scaffold bearing a unique hexahydrooxazolo[4,5-b]pyridin-2(3H)-one motif, and a plausible biosynthetic pathway was proposed. All the isolated alkaloids 1-17 showed discernible analgesic activities in an acetic acid-induced writhing test in mice, and N-desmethoxyhumantenine N4-oxide (3) exhibited more potent analgesic activities than those of morphine at doses of 0.04 and 0.2 mg/kg.


Assuntos
Analgésicos/farmacologia , Gelsemium/química , Alcaloides Indólicos/farmacologia , Monoterpenos/farmacologia , Analgésicos/isolamento & purificação , Animais , China , Feminino , Alcaloides Indólicos/isolamento & purificação , Masculino , Camundongos , Estrutura Molecular , Monoterpenos/isolamento & purificação , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Caules de Planta/química
18.
Forensic Sci Int ; 321: 110745, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33676237

RESUMO

We present a case of fatal poisoning from accidental ingestion of Gelsemium elegans (G. elegans), a rarely toxic plant. A 41-year-old man was found dead, at his home, 6 h after drinking homemade herbal liqueur during lunch. Autopsy and routine toxicological analyses identified neither significant pathological findings nor routine poisons. However, a local botanist revealed that the homemade herbal liqueur contained G. elegans, a poisonous plant specific to Asia. To ascertain whether the decedent had ingested G. elegans, we performed liquid chromatography-mass spectrometry (LC-MS) and found two alkaloids (gelsemine and koumine) in his blood, gastric contents, as well as the suspected herbal liqueur. The cause of death was therefore confirmed to be G. elegans poisoning. Case reports of fatal poisoning due to ingestion of G. elegans are quite rare in English. Therefore, the present case broadens the scope on the possibility of death due to ingestion of G. elegans for forensic pathologists and toxicologists.


Assuntos
Acidentes , Gelsemium/envenenamento , Adulto , Alcaloides/análise , Bebidas , Cromatografia Líquida , Evolução Fatal , Conteúdo Gastrointestinal/química , Humanos , Alcaloides Indólicos/análise , Masculino , Espectrometria de Massas , Plantas Tóxicas
19.
BMC Complement Med Ther ; 21(1): 99, 2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33743701

RESUMO

BACKGROUND: Colorectal cancer (CRC) remains one of the leading causes of cancer-related death worldwide. Gelsemium elegans Benth (GEB) is a traditional Chinese medicine commonly used for treatment for gastrointestinal cancer, including CRC. However, the underlying active ingredients and mechanism remain unknown. This study aims to explore the active components and the functional mechanisms of GEB in treating CRC by network pharmacology-based approaches. METHODS: Candidate compounds of GEB were collected from the Traditional Chinese Medicine@Taiwan, Traditional Chinese Medicines Integrated Database, Bioinformatics Analysis Tool for Molecular mechanism of Traditional Chinese Medicine, and published literature. Potentially active targets of compounds in GEB were retrieved from SwissTargetPrediction databases. Keywords "colorectal cancer", "rectal cancer" and "colon cancer" were used as keywords to search for related targets of CRC from the GeneCards database, then the overlapped targets of compounds and CRC were further intersected with CRC related genes from the TCGA database. The Cytoscape was applied to construct a graph of visualized compound-target and pathway networks. Protein-protein interaction networks were constructed by using STRING database. The DAVID tool was applied to carry out Gene Ontology and Kyoto Encyclopedia of Genes and Genome pathway enrichment analysis of final targets. Molecular docking was employed to validate the interaction between compounds and targets. AutoDockTools was used to construct docking grid box for each target. Docking and molecular dynamics simulation were performed by Autodock Vina and Gromacs software, respectively. RESULTS: Fifty-three bioactive compounds were successfully identified, corresponding to 136 targets that were screened out for the treatment of CRC. Functional enrichment analysis suggested that GEB exerted its pharmacological effects against CRC via modulating multiple pathways, such as pathways in cancer, cell cycle, and colorectal cancer. Molecular docking analysis showed that the representative compounds had good affinity with the key targets. Molecular dynamics simulation indicated that the best hit molecules formed a stable protein-ligand complex. CONCLUSION: This network pharmacology study revealed the multiple ingredients, targets, and pathways synergistically involved in the anti-CRC effect of GEB, which will enhance our understanding of the potential molecular mechanism of GEB in treatment for CRC and lay a foundation for further experimental research.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Gelsemium/química , Bases de Dados de Produtos Farmacêuticos , Humanos , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mapas de Interação de Proteínas
20.
Biomed Pharmacother ; 137: 111284, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33561641

RESUMO

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.


Assuntos
Encéfalo/efeitos dos fármacos , Gelsemium/toxicidade , Neuroglia/efeitos dos fármacos , Extratos Vegetais/toxicidade , Testes de Toxicidade Crônica , Administração Oral , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Proliferação de Células/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Masculino , Metaboloma/efeitos dos fármacos , Metabolômica , Neuroglia/metabolismo , Neuroglia/patologia , Extratos Vegetais/administração & dosagem , Ratos Sprague-Dawley , Medição de Risco , Fatores de Tempo , Ácido gama-Aminobutírico/metabolismo
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