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Nature Jul 2022Strychnine is a natural product that, through isolation, structural elucidation and synthetic efforts, shaped the field of organic chemistry. Currently, strychnine is...
Strychnine is a natural product that, through isolation, structural elucidation and synthetic efforts, shaped the field of organic chemistry. Currently, strychnine is used as a pesticide to control rodents because of its potent neurotoxicity. The polycyclic architecture of strychnine has inspired chemists to develop new synthetic transformations and strategies to access this molecular scaffold, yet it is still unknown how plants create this complex structure. Here we report the biosynthetic pathway of strychnine, along with the related molecules brucine and diaboline. Moreover, we successfully recapitulate strychnine, brucine and diaboline biosynthesis in Nicotiana benthamiana from an upstream intermediate, thus demonstrating that this complex, pharmacologically active class of compounds can now be harnessed through metabolic engineering approaches.
Topics: Biosynthetic Pathways; Metabolic Engineering; Strychnine; Nicotiana
PubMed: 35794473
DOI: 10.1038/s41586-022-04950-4 -
Acta Pharmacologica Sinica Oct 2021Ferroptotic cell death is characterized by iron-dependent lipid peroxidation that is initiated by ferrous iron and HO via Fenton reaction, in which the role of...
Ferroptotic cell death is characterized by iron-dependent lipid peroxidation that is initiated by ferrous iron and HO via Fenton reaction, in which the role of activating transcription factor 3 (ATF3) remains elusive. Brucine is a weak alkaline indole alkaloid extracted from the seeds of Strychnos nux-vomica, which has shown potent antitumor activity against various tumors, including glioma. In this study, we showed that brucine inhibited glioma cell growth in vitro and in vivo, which was paralleled by nuclear translocation of ATF3, lipid peroxidation, and increases of iron and HO. Furthermore, brucine-induced lipid peroxidation was inhibited or exacerbated when intracellular iron was chelated by deferoxamine (500 μM) or improved by ferric ammonium citrate (500 μM). Suppression of lipid peroxidation with lipophilic antioxidants ferrostatin-1 (50 μM) or liproxstatin-1 (30 μM) rescued brucine-induced glioma cell death. Moreover, knockdown of ATF3 prevented brucine-induced accumulation of iron and HO and glioma cell death. We revealed that brucine induced ATF3 upregulation and translocation into nuclei via activation of ER stress. ATF3 promoted brucine-induced HO accumulation via upregulating NOX4 and SOD1 to generate HO on one hand, and downregulating catalase and xCT to prevent HO degradation on the other hand. HO then contributed to brucine-triggered iron increase and transferrin receptor upregulation, as well as lipid peroxidation. This was further verified by treating glioma cells with exogenous HO alone. Moreover, HO reversely exacerbated brucine-induced ER stress. Taken together, ATF3 contributes to brucine-induced glioma cell ferroptosis via increasing HO and iron.
Topics: Activating Transcription Factor 3; Amino Acid Transport System y+; Animals; Antineoplastic Agents; Catalase; Cell Line, Tumor; Endoplasmic Reticulum Stress; Ferroptosis; Humans; Hydrogen Peroxide; Iron; Mice, Inbred BALB C; Mice, Nude; NADPH Oxidase 4; Neoplasms; Strychnine; Superoxide Dismutase-1; Up-Regulation; Xenograft Model Antitumor Assays; Mice
PubMed: 34112960
DOI: 10.1038/s41401-021-00700-w -
Nature Communications Mar 2023Glycine Receptors (GlyRs) provide inhibitory neuronal input in the spinal cord and brainstem, which is critical for muscle coordination and sensory perception. Synaptic...
Glycine Receptors (GlyRs) provide inhibitory neuronal input in the spinal cord and brainstem, which is critical for muscle coordination and sensory perception. Synaptic GlyRs are a heteromeric assembly of α and β subunits. Here we present cryo-EM structures of full-length zebrafish α1βGlyR in the presence of an antagonist (strychnine), agonist (glycine), or agonist with a positive allosteric modulator (glycine/ivermectin). Each structure shows a distinct pore conformation with varying degrees of asymmetry. Molecular dynamic simulations found the structures were in a closed (strychnine) and desensitized states (glycine and glycine/ivermectin). Ivermectin binds at all five interfaces, but in a distinct binding pose at the β-α interface. Subunit-specific features were sufficient to solve structures without a fiduciary marker and to confirm the 4α:1β stoichiometry recently observed. We also report features of the extracellular and intracellular domains. Together, our results show distinct compositional and conformational properties of αβGlyR and provide a framework for further study of this physiologically important channel.
Topics: Animals; Receptors, Glycine; Strychnine; Zebrafish; Ivermectin; Glycine
PubMed: 36914669
DOI: 10.1038/s41467-023-37106-7 -
Molecules (Basel, Switzerland) Mar 2022Strychnine (STN) and its major metabolite Strychnine N-Oxide (SNO) were examined electrochemically. Both parent compounds and its major metabolite showed electroactivity...
Strychnine (STN) and its major metabolite Strychnine N-Oxide (SNO) were examined electrochemically. Both parent compounds and its major metabolite showed electroactivity on glassy carbon electrodes using CV and DPV techniques. One oxidation peak at 1008 mV was observed for STN with the optimum peak intensity at pH 7. SNO produced two oxidation peaks, at 617 mV and 797 mV, at pH 5. The peaks demonstrated irreversible behaviour and the irreversibility of the system was confirmed at different scan rates. A calibration curve was produced for both CV and DPV measurements and the sensitivity of the proposed EC method was good compared with previous electrochemical and non-electrochemical methods. The precision of oxidation peak of STN using the STN-MIP method produced a maximum value of 11.5% and 2.32% for inter-day and intraday %RSD, respectively. The average% recovery was around 92%. The electrochemical method has been successfully applied to the determination of STN in spiked plasma and urine samples. For SNO, both anodic peaks of SNO demonstrated irreversible behaviour. A different sweep rate was used for calculating the number of ‘transfer electrons’ in the system; based on this, the mechanism of oxidation reaction was proposed. Calibration curves for both oxidative peaks were produced using DPV measurements. The second anodic peak demonstrated high linearity and precision with %RSD < 1.96%.
Topics: Cyclic N-Oxides; Electrochemistry; Electrodes; Hydrogen-Ion Concentration; Strychnine
PubMed: 35335189
DOI: 10.3390/molecules27061826 -
BMC Complementary Medicine and Therapies Oct 2022Improper use of strychnine can cause death. The aim of this study was to identify and evaluate toxic mechanisms of action associated with active compounds in strychnine...
BACKGROUND
Improper use of strychnine can cause death. The aim of this study was to identify and evaluate toxic mechanisms of action associated with active compounds in strychnine using a network toxicology approach, and explore potential pathogenic targets.
METHODS
In the present study, strychnine target and central nervous system-related gene set were established using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and four disease gene databases (Genecards, OMIM, PharmGkb, TTD). An "ingredient-target" interactive active network map was constructed using Cytoscape software (version 3.8.0). Functional enrichment analysis was performed based on the hub genes. A protein-protein interaction network was constructed using STRING database. The pharmacokinetics (ADMET) properties of strychnine were evaluated using SwissADME tool. Molecular docking was performed using Autodock Vina to explore the interactions between the active compounds and the target protein.
RESULTS
Five strychnine toxicity-related components and a gene set of 40 genes were obtained. GO and KEGG analyses showed that Strychnine acts on the central nervous system through G protein-coupled receptor signaling pathway. Analysis of "ADMET" related parameters showed a high gastrointestinal tract absorption of (S)-stylopine and isobrucine and the compounds could cross the blood brain barrier. CHRM1 was selected as a key gene in strychnine toxicity. Molecular docking results showed that the co-crystalized ligands did not form hydrogen bond with CHRM1. (S)-stylopine had the highest binding affinity (binding energy = - 8.5 kcal/mol) compared with the other two compounds.
CONCLUSION
Network toxicology and molecular docking reveal the toxicity mechanisms of strychnine active compounds. The findings showed that CHRM1 is a potential neurotoxic target. (S)-stylopine showed stronger neurotoxic effect compared with the other ligands.
Topics: Drugs, Chinese Herbal; Medicine, Chinese Traditional; Molecular Docking Simulation; Protein Interaction Maps; Strychnine
PubMed: 36244968
DOI: 10.1186/s12906-022-03753-4 -
Journal of Traditional Chinese Medicine... Aug 2020To investigate the antagonistic effect of the extract of Baizhu (Rhizoma Atractylodis Macrocephalae) (RAM) on the intestinal absorption of brucine and strychnine in...
OBJECTIVE
To investigate the antagonistic effect of the extract of Baizhu (Rhizoma Atractylodis Macrocephalae) (RAM) on the intestinal absorption of brucine and strychnine in Strychnos nux-vomica (NUX) and propose the mechanism of these effects.
METHODS
The apparent permeability value (Papp) and absorption rate constant (Ka) were chosen as indices. The everted intestinal sac model and in situ single-pass intestinal perfusion model were used to study the effects of the RAM extract on the absorption of brucine and strychnine. To confirm the results, the brucine and strychnine concentrations in hepatic portal venous blood were determined. Western blotting was used to study P-glycoprotein (P-gp) expression in the Caco-2 cell line.
RESULTS
Papp and Ka of brucine and strychnine were significantly increased in the presence of a P-gp inhibitor, but no significant increase was noted in the presence of a tight junction regulator. The RAM extract inhibited the absorption of brucine and strychnine and enhanced P-gp expression.
CONCLUSION
The primary absorption mechanism for brucine and strychnine is passive transport, which is affected by P-gp.
Topics: Animals; Atractylodes; Caco-2 Cells; Cell Line, Tumor; Drugs, Chinese Herbal; Humans; Intestinal Absorption; Male; Rats; Rats, Sprague-Dawley; Rhizome; Strychnine; Strychnos nux-vomica
PubMed: 32744023
DOI: 10.19852/j.cnki.jtcm.2020.04.005 -
The American Journal of Emergency... Dec 2023A 48-year-old male intentionally ingested "gopher killer" containing strychnine as a, suicide attempt. He rapidly developed generalized muscle spasms with opisthotonos...
A 48-year-old male intentionally ingested "gopher killer" containing strychnine as a, suicide attempt. He rapidly developed generalized muscle spasms with opisthotonos followed by cardiovascular collapse. He was resuscitated, treated with 24 h of, neuromuscular paralysis, and was discharged on hospital day 10 without sequelae. A blood strychnine concentration obtained five hours post ingestion was 2.2 mg/L. Strychnine poisoning is exceedingly rare in the modern United States and this report contains a video recording of the classic exam findings.
Topics: Male; Humans; United States; Middle Aged; Strychnine; Spasm; Suicide, Attempted; Disease Progression; Poisoning
PubMed: 37805370
DOI: 10.1016/j.ajem.2023.09.055 -
Marine Drugs 2011Fish detect extremely low levels of marine toxins tetrodotoxin (TTX) and saxitoxin (STX) via the specialized gustatory receptor(s). Physiological and pharmacological... (Review)
Review
Fish detect extremely low levels of marine toxins tetrodotoxin (TTX) and saxitoxin (STX) via the specialized gustatory receptor(s). Physiological and pharmacological studies show that receptor(s) for TTX and STX are distinct from those which detect feeding stimulant amino acids and bile acids, and that TTX and STX do not share the same receptor populations, while interacting with quinine and strychnine in a competitive fashion suggestive of an antidotal relationship.
Topics: Animals; Fishes; Fresh Water; Quinine; Receptors, Cell Surface; Saxitoxin; Strychnine; Taste Perception; Tetrodotoxin
PubMed: 22163186
DOI: 10.3390/md9112283 -
PLoS Genetics Oct 2022Many plant secondary substances are feeding deterrents for insects and play a key role in the selection of host plants. The taste sensilla of phytophagous insects...
Many plant secondary substances are feeding deterrents for insects and play a key role in the selection of host plants. The taste sensilla of phytophagous insects contain gustatory sensory neurons sensitive to deterrents but the molecular basis of deterrent chemoreception remains unknown. We investigated the function of Gr180, the most highly expressed bitter gustatory receptor in the maxillary galea of Helicoverpa armigera larvae. Functional analyses using the Xenopus oocyte expression system and two-electrode voltage clamp revealed that the oocytes expressing Gr180 responded to coumarin. Tip recording results showed that the medial sensilla styloconica of the maxilla of fifth instar larvae exhibited electrophysiological responses to coumarin. Two-choice feeding bioassays confirmed that coumarin inhibited larval feeding. A homozygous mutant strain of H. armigera with truncated Gr180 proteins (Gr180-/-) was established using the CRISPR-Cas9 system. The responses of the medial sensilla styloconica in Gr180-/- to coumarin were almost abolished, and the responses to sinigrin and strychnine were also significantly decreased. Knockout of Gr180 alleviated the feeding deterrent effects of coumarin, sinigrin, and strychnine. Thus, we conclude that Gr180 is a receptor responding to coumarin,and also participates in sensing sinigrin and strychnine. These results enhance our understanding of the gustatory sensing mechanisms of phytophagous insects to deterrents.
Topics: Animals; Larva; Taste; Strychnine; Maxilla; Moths; Receptors, Cell Surface; Coumarins
PubMed: 36206313
DOI: 10.1371/journal.pgen.1010455 -
British Journal of Sports Medicine Dec 2005
Topics: Alcohol Drinking; History, 20th Century; Humans; Male; Running; Stimulants, Historical; Strychnine
PubMed: 16306490
DOI: No ID Found