Search Results (33)

Stress-related psychiatric disorders are frequently associated with impaired mitochondrial function, altered neuronal energy metabolism, and reduced neuroplasticity. Intracellular pathways such as PI3K/Akt and mTOR play central roles in regulating mitochondrial bioenergetics and neuronal structural adaptation. Gelsemium is traditionally used in integrative and homeopathic practice; however, the cellular effects of prolonged exposure to high serial dilutions remain insufficiently characterized. This study aimed to examine the effects of chronic exposure to Gelsemium preparations on mitochondrial function and neuronal plasticity in vitro. Human SH-SY5Y neuroblastoma cells were treated for 14 days with different Gelsemium preparations 9C, 15C, 30C. Mitochondrial bioenergetics, reactive oxygen species (ROS) production, cell viability, neurite outgrowth, and phosphorylation of Akt and mTOR were assessed using complementary biochemical, imaging, and signaling analyses. Chronic exposure to Gelsemium preparations was associated with increased ATP production, increased mitochondrial respiration and glycolytic activity, reduced oxidative stress, improved cell viability, and increased neurite outgrowth compared with untreated controls. These changes were accompanied by increased phosphorylation of Akt and mTOR. The convergence of bioenergetic, redox, morphological, and signaling readouts suggests a coordinated cellular response under prolonged exposure conditions. These findings indicate that chronic exposure to Gelsemium preparations (9C, 15C, 30C) is associated with coordinated changes in mitochondrial bioenergetics, redox balance, and Akt/mTOR signaling in neuronal cells under in vitro conditions. Full article

Background: Koumine is a bioactive alkaloid derived from the traditional medicinal plant Gelsemium elegans. Although it has demonstrated anti-tumor effects in various cancers, its specific role and mechanism in hepatocellular carcinoma (HCC) remain unclear. This study aims to investigate the anti-HCC effects of Koumine and elucidate the underlying molecular mechanisms. Methods: A network pharmacology approach was employed to predict potential targets and pathways of Koumine against HCC. The binding affinities between Koumine and core targets were validated using molecular docking. In vitro, the effects of Koumine on the proliferation, migration, and invasion of HCC cells were assessed, and the expression levels of key proteins were examined. In vivo, the anti-tumor efficacy and toxicity of Koumine were evaluated using a murine xenograft model. Results: Network pharmacology analysis identified 124 potential targets of Koumine against HCC, with 10 core targets (e.g., P38, JAK1, JAK2, GRB2) and key pathways involving MAP2K1, P38, JAK1, and MET being implicated. Molecular docking confirmed strong binding affinities between Koumine and these core targets. In vitro experiments demonstrated that Koumine dose-dependently inhibited the proliferation, migration, and invasion of HCC cells and modulated the expression and phosphorylation of P38. In vivo results showed that Koumine significantly suppressed tumor growth without causing notable toxicity. Conclusions: This study systematically reveals that Koumine exerts its anti-HCC effects by targeting the MAP2K1, P38, JAK1, JAK2, and MET signaling pathways. These findings highlight the potential of Koumine as a novel and safe therapeutic agent for the treatment of hepatocellular carcinoma. Full article

Gelsemium elegans is a traditionally utilized medicinal plant in China, renowned for its well-documented therapeutic properties and substantial economic potential. The primary bioactive components in this plant are indole alkaloids. It is used clinically to treat conditions including rheumatoid arthritis, neuropathic pain, and some cancers. Additionally, the whole plant can be processed into livestock feed. Climate change is anticipated to substantially impact the future suitable habitat of this species. Utilizing the Biomod2 ensemble model and 18 environmental variables (bio01, bio03, bio04, bio05, bio06, bio09, bio11, bio17, hf, elev, aspect, slope, gm_lc, gm_ve, ph_water, usda, d1_swr, annual_mean_uv-b) this study projected the geographical distribution of G. elegans under current and future climate scenarios; the periods of the 2050s, 2070s, and 2090s were analyzed using SSP1-2.6, SSP2-4.5, and SSP5-8.5. Current ecological niche modeling predicts that G. elegans is predominantly distributed in southern China, with its climatically and edaphically most suitable habitats concentrated in Guangxi, Guangdong, Fujian, and Hainan provinces. Across the three future time periods under various scenarios, the overall extent of suitable habitat is projected to increase, with a northward expansion of the suitable distribution range. Key environmental factors shaping the distribution of G. elegans include Isothermality (bio03), Max Temperature of Warmest Month (bio05), Min Temperature of Coldest Month (bio06), Precipitation of Driest Quarter (bio17), and Annual Average UV Radiation. The study aims to develop a scientifically grounded theoretical framework to support the conservation-oriented management and climate-resilient utilization of G. elegans resources under ongoing climate change. Full article

Range limits are often hypothesized to arise from reduced reproductive success at distributional margins, yet direct tests integrating pollination and post-pollination processes remain uncommon. Whether reproductive failure constrains the distylous Gelsemium sempervirens at its western range edge in eastern Texas was investigated by quantifying flowering phenology, floral visitation, pollinator effectiveness, and seed fate over two flowering seasons. Flowering timing differed markedly between years due to freeze events, but flowering effort and morph synchrony remained high. Although multiple floral visitors were recorded, fruit set was overwhelmingly associated with the southeastern blueberry bee (Habropoda laboriosa), which dominated visitation and remained active throughout the flowering period. No evidence of autonomous self-pollination or breakdown of functional distyly was detected. Seed set in unattacked fruits was high and comparable to values reported from central-range populations. In contrast, post-pollination seed loss due to cryptic fruit herbivory substantially reduced seed survival, though herbivory patterns did not differ qualitatively from those documented elsewhere in the species’ range. Together, these results indicate that reproductive failure does not explain the abrupt western range limit of G. sempervirens and instead suggest that ecological transitions associated with the forest–prairie ecotone, rather than pollination or early seed development, may play a more important role in shaping the species’ distribution. Full article

Glycine receptors (GlyRs) are essential for inhibitory neurotransmission in the central nervous system (CNS) and represent promising targets against neurological disorders. Several indole alkaloids from Gelsemium species have been shown to modulate GlyRs. Notably, the anxiolytic and analgesic properties of certain Gelsemium alkaloids appear to depend on GlyR modulation. However, prior studies have focused on only a few indole alkaloids, leaving the activity of other Gelsemium compound classes unexplored. This study employed an integrative in silico approach to investigate the interactions between GlyR α1 and α3 subtypes and 162 structurally diverse Gelsemium compounds. Physicochemical, pharmacokinetic, and toxicological analyses identified compounds with favorable bioavailability in the CNS. Molecular docking revealed that indolic alkaloids bind the GlyR orthosteric site with profiles comparable to the reference Gelsemium compound, gelsemine. Molecular dynamics simulations confirmed the stability and conformational integrity of selected ligand-receptor complexes. Overall, novel potential GlyR modulators were identified, with several compounds showing a promising selectivity profile towards GlyR α1 and α3 subtypes. These findings further support the therapeutic potential of Gelsemium alkaloids and provide a foundation for further pharmacological and toxicological validation. Full article

Gelsemine, a naturally occurring indole alkaloid derived from plants of the Gelsemium species of the Gelsemiaceae family, has been extensively investigated for its neuroprotective and anti-inflammatory properties. Recent studies have demonstrated that gelsemine exerts neuroprotective effects against beta-amyloid (Aβ) oligomers, a key neurotoxic peptide implicated in the pathogenesis of Alzheimer’s disease (AD). However, despite these beneficial effects, the precise molecular targets underlying gelsemine’s neuroprotective actions in AD remain unidentified. Here, we employed a combination of bioinformatic, biochemical, and functional assays in neuronal models to investigate the mechanism of gelsemine’s action in AD cellular models. Our findings indicate that gelsemine inhibits the activity of transglutaminase 2 (TG2), an enzyme involved in protein cross-linking with emerging roles in Aβ aggregation and neurotoxicity. Molecular modeling and biochemical analyses reveal that gelsemine interacts with the TG2 catalytic site, leading to its inhibition. Furthermore, gelsemine modulates the TG2-mediated Aβ aggregation process, thereby attenuating Aβ-induced neurotoxicity and preserving neuronal function. These findings establish TG2 as a previously unrecognized molecular target of gelsemine and underscore the potential of Gelsemium-derived alkaloids as neuroprotective agents. The modulation of TG2 activity by natural alkaloids may provide a novel therapeutic approach for mitigating Aβ toxicity and preserving neuronal function in AD. Full article

Gelsemium has a long history of medicinal use but is also a poisonous plant. Some low-toxicity alkaloids in Gelsemium exhibit anxiolytic, anti-inflammatory, analgesic, and other pharmacological effects; however, certain alkaloids in Gelsemium are highly toxic. Nevertheless, the molecular targets underlying the biological effects of Gelsemium alkaloids remain poorly understood. We employed electrophysiological techniques and molecular modeling to examine the modulatory effects of Gelsemium alkaloids on inhibitory neurotransmitter receptors, as well as to elucidate the mechanisms underlying their molecular interactions. Our findings indicate that low-toxicity alkaloids primarily exert their pharmacological effects through actions on glycine receptors, with the binding site located at the orthosteric site between two α-subunits. Both highly toxic and low-toxicity alkaloids target GABAA receptors, using the β+/α− interface transmembrane structural domains as common binding sites. These results identify the targets through which Gelsemium alkaloids affect the central nervous system and predict the binding modes and key amino acids involved from a computational modeling perspective. However, further experimental validation through mutational studies is necessary to strengthen these findings. Full article

Gelsemium sempervirens (L.) J.St.-Hil. is an evergreen shrub occurring naturally in North and Middle America. So far, more than 120 alkaloids have been identified in this plant in addition to steroids, coumarins and iridoids, and its use in traditional medicine has been traced back to these compound classes. However, a comprehensive phytochemical investigation of the plant with a special focus on further compound classes has not yet been performed. Therefore, the present study aimed at an extensive HPLC-MSⁿ characterization of secondary metabolites and, for the first time, reports the occurrence of various depsides and phenolic glycerides in G. sempervirens roots and rhizomes, consisting of benzoic and cinnamic acid derivatives as well as dicarboxylic acids. Furthermore, mono- and disaccharides were assigned by GC-MS. Applying the Folin–Ciocalteu assay, the phenolic content of extracts obtained with different solvents was estimated to range from 30 to 50% calculated as chlorogenic acid equivalents per g dry weight and was related to the DPPH radical scavenging activity of the respective extracts. Upon lactic acid fermentation of aqueous G. sempervirens extracts, degradation of phenolic esters was observed going along with the formation of low-molecular volatile metabolites. Full article

Indole alkaloids are the main bioactive molecules of the Gelsemium genus plants. Diverse reports have shown the beneficial actions of Gelsemium alkaloids on the pathological states of the central nervous system (CNS). Nevertheless, Gelsemium alkaloids are toxic for mammals. To date, the molecular targets underlying the biological actions of Gelsemium alkaloids at the CNS remain poorly defined. Functional studies have determined that gelsemine is a modulator of glycine receptors (GlyRs) and GABA_A receptors (GABA_ARs), which are ligand-gated ion channels of the CNS. The molecular and physicochemical determinants involved in the interactions between Gelsemium 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 (IC₅₀ 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, GABA_ARs 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 Gelsemium indole alkaloids on inhibitory receptors, expanding our knowledge regarding the interaction of these types of compounds with protein targets of the CNS. Full article

Reverse transcription quantitative polymerase chain reaction (RT-qPCR) is an accurate method for quantifying gene expression levels. Choosing appropriate reference genes to normalize the data is essential for reducing errors. Gelsemium elegans is a highly poisonous but important medicinal plant used for analgesic and anti-swelling purposes. Gelsenicine is one of the vital active ingredients, and its biosynthesis pathway remains to be determined. In this study, G. elegans leaf tissue with and without the application of one of four hormones (SA, MeJA, ETH, and ABA) known to affect gelsenicine synthesis, was analyzed using ten candidate reference genes. The gene stability was evaluated using GeNorm, NormFinder, BestKeeper, ∆CT, and RefFinder. The results showed that the optimal stable reference genes varied among the different treatments and that at least two reference genes were required for accurate quantification. The expression patterns of 15 genes related to the gelsenicine upstream biosynthesis pathway was determined by RT-qPCR using the relevant reference genes identified. Three genes 8-HGO, LAMT, and STR, were found to have a strong correlation with the amount of gelsenicine measured in the different samples. This research is the first study to examine the reference genes of G. elegans under different hormone treatments and will be useful for future molecular analyses of this medically important plant species. Full article

Koumine is one of the most abundant alkaloids found in Gelsemium elegans, and it has a wide range of pharmacological effects including antitumor, anti-inflammatory, analgesic treatment effects, and antianxiety. However, its high toxicity and unclear mechanism of action have greatly limited the medicinal development and use of koumine. We investigated the toxic effects of koumine on the developmental toxicity and behavioral neurotoxicity of zebrafish embryos and larvae. Embryos at 6 h postfertilization (hpf) were exposed to 12.5, 25, 50, 75, and 100 mg/L of koumine until 120 hpf. Koumine affected the hatching and heartbeats of the embryos. The morphological analysis also revealed many abnormalities, such as shortened bodies, yolk sac edemas, tail malformations, and pericardial edemas. To identify the neurotoxicity of koumine, the behavior of the larvae was measured. Koumine at 50 and 100 mg/L affect the escape response. The embryos exhibited uncoordinated muscle contractions along the body axis in response to touch at 36 hpf. More importantly, we found that the neurotoxicity of koumine is mainly caused by influencing the ACh content and the activity of AChE without impairing motor neuron development. A comprehensive analysis shows that a high concentration of koumine has obvious toxic effects on zebrafish, and the safe concentration of koumine for zebrafish should be less than 25 mg/L. These results will be valuable for better understanding the toxicity of koumine and provide new insights into the application of koumine. Full article

Two new monoterpenoid indole alkaloids, gelselegandines F (1) and G (2), were isolated from the aerial parts of Gelsemium elegans. Their structures were elucidated by means of spectroscopic techniques and quantum chemical calculations. The ECD calculations were conducted at the B3LYP/6-311G(d,p) level and NMR calculations were carried out using the Gauge-Including Atomic Orbitals (GIAO) method. Structurally, the two new compounds possessed rare, cage-like, monoterpenoid indole skeletons. All isolated compounds and the total alkaloids extract were tested for cytotoxicity against four different tumor cell lines. The total alkaloids extract of G. elegans exhibited significant antitumor activity with IC₅₀ values ranging from 32.63 to 82.24 ug/mL. In order to discover anticancer leads from the active extraction, both new indole compounds (1–2) were then screened for cytotoxicity. Interestingly, compound 2 showed moderate cytotoxicity against K562 leukemia cells with an IC₅₀ value of 57.02 uM. Full article

Gelsemium 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 Gelsemium. However, the toxic mechanism of Gelsemium remains ambiguous. In this work, network pharmacology and experimental verification were combined to systematically explore the specific mechanism of Gelsemium toxicity. The alkaloid compounds and candidate targets of Gelsemium, 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 Gelsemium. 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 Gelsemium toxicity. A total of 85 alkaloids in Gelsemium associated with 214 excitotoxicity-related targets were predicted by network pharmacology. Functional analysis showed that the toxicity of Gelsemium 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_2B and NMDAR_2A. In addition, the difference of binding affinity may be the basis of toxicity differences among different alkaloids. Humantenirine showed significant sex differences, and the LD₅₀ values of female and male mice were 0.071 mg·kg⁻¹ and 0.149 mg·kg⁻¹, 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 Gelsemium. These findings provide a theoretical basis for further study of the toxic mechanism of Gelsemium and potential therapeutic strategies for Gelsemium poisoning. Full article

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. Full article

Asian Gelsemium elegans (G. elegans) has a wide range of pharmacological activities. However, its strong toxicity limits its potential development and application. Interestingly, there are significant gender differences in G. elegans toxicity in rats. This work aimed to elucidate the overall absorption, distribution, metabolism, and excretion (ADME) of whole G. elegans 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 G. elegans. This study was the first to investigate the multicomponent in vivo process of G. elegans 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 G. elegans toxicity. Full article