Search Results (34)

Members of the broad family of Strychnos alkaloids have been the favorite molecules for the development and evaluation of new NMR methods for many years, including the establishment of the ¹H-¹⁵N two-dimensional NMR methods. The present study is an effort to computationally evaluate the ¹⁵N chemical shift behavior of eight members of this structurally diverse group of indole alkaloids. The molecules range from relatively “simple” strychnine and brucine and their respective N-oxides to molecules as complex as vinorelbine, a synthetic analog used in cancer chemotherapy, and sungucine, a naturally occurring complex dimeric member of the family. The 20 ¹⁵N chemical shifts in this study afforded a CMAE of 2.96 ppm and an RMSD of 3.50 ppm, with the data affording a correlation coefficient, r = 0.997. Full article

Background: Epilepsy is a chronic, non-communicable brain disorder characterized by recurrent seizures. Some derivatives of 1,2,3,4-tetrahydroisoquinolines have demonstrated anticonvulsant effects. This study aims to investigate the effects of 33 derivatives of 1-aryl-1,2,3,4-tetrahydroisoquinoline on seizures induced by nicotine and strychnine. Methods: The anticonvulsant effects of 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives were evaluated in white male mice. Convulsant agents were administered subcutaneously at doses of 10.0 mg/kg for nicotine and 1.5 mg/kg for strychnine, 60 min after the oral administration of the test compounds at doses ranging from 0.1 to 10 mg/kg. The onset time, duration of tremors and seizures, and survival rate of the animals were recorded. The docking studies were conducted for 32 tested compounds targeting the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (PDB ID: 1FTL). Furthermore, a predictive ADMET study was conducted to evaluate the pharmacokinetic and toxicity profiles of the compounds. Results: Compounds 20 and 25 exhibited the highest activity against strychnine-induced seizures. When evaluating the effects of 1-aryl-1,2,3,4-tetrahydroisoquinolines and reference drugs on the tremorogenic and convulsive actions of nicotine at doses of 0.1–5 mg/kg, compounds 3, 6, 8, 14, 16, 25, 27, 29, 30, 31, and 34 demonstrated comparable activity to the reference drugs. The docking results targeting AMPA (PDB ID: 1FTL) revealed comparable binding interactions for most of the compounds, with a (−)C-Docker interaction energy range of 33.82–45.41 Kcal/mol, compared to that of the ligand (41.60 Kcal/mol). The structural requirements of the studied scaffold were analyzed to identify the essential pharmacophoric features for anticonvulsant activity. Furthermore, a predictive ADMET study was conducted to evaluate the pharmacokinetic and toxicity profiles of the compounds. Conclusions: Certain derivatives of 1,2,3,4-tetrahydroisoquinolines may serve as potential anticonvulsant agents for epilepsy. Full article

Objectives: This research aims to explore the therapeutic potential of Bi-Qi capsules in the treatment of gout by identifying crucial drug targets through a multidimensional data analysis strategy. Methods: Bi-Qi capsule drug targets and differentially expressed genes (DEGs) of gout were derived from public databases, such as Swiss Target Prediction, STITCH, and the GEO database. Subsequently, the overlapped targets were analyzed to elucidate the potential therapeutic mechanism and to identify candidate targets of Bi-Qi capsules against gout. Next, Mendelian randomization (MR) analysis was employed to screen and explore the causal relationship between candidate targets and gout. Finally, single-cell RNA sequencing (scRNA-seq), gene set enrichment analysis (GSEA), transcription factor and ceRNA regulatory networks, and molecular docking were performed to validate the role of the crucial targets of Bi-Qi capsules in the treatment of gout. Results: A total of 46 candidate targets were identified, in which KCNA5, PTGS2, and TNF exhibited significant causal relationships with gout (p < 0.05) and were regarded as the crucial targets. Through scRNA-seq and gene labeling, crucial targets were found to be expressed in eighteen cell clusters and eight cell types, which are closely associated with carbohydrate metabolism, nerve conduction, and the innate immunity process. Bi-Qi capsule active compounds such as tanshinone IIA, strychnine, tanshinaldehyde, cryptotanshinone, tumulosic acid, and glycyrrhetic acid exhibit a better binding ability to crucial targets. Conclusions: The results not only elucidate the anti-gout mechanism of Bi-Qi capsules but also provide an insight into multi-target natural medication for metabolic disease treatment, which contributes to guiding the clinical application of Bi-Qi capsules in the future. Full article

Cancer remains a significant challenge, prompting the exploration of new therapies. Breast cancer is the most prevalent among women, and current medications often have serious side effects. Additionally, there is limited research on natural resources that have historically provided bioactive compounds with potential anti-cancer properties. This study examines two such resources—Cannabis sativa and Datura metel L.—both known for their pharmacological diversity and traditional medicinal use. Cannabis sativa, with its major constituents Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), has garnered considerable interest. Datura metel L., despite its toxicity, contains alkaloids like scopolamine and withametelin, which have shown cytotoxic properties against cancer cells. This study selected five breast cancer-related receptors, docking them against various phytoconstituents in both plants to identify potent cytotoxic entities. Target proteins were extracted from the PDB database, and docking studies were performed using AutoDock software. The docking scores of the phytochemicals were then compared with one another. The docking studies on Cannabis sativa revealed that apigenin (−8.15), β-caryophyllene oxide (−8.35), THCA (−8.84), epicatechin (−8.18), and vitexin (−9.58) showed good interaction with the PARP receptor (PDB ID: 5DS3), while cannabidiol (−8.38) and cannabichromene (−8.36) showed strong interactions with CDK4/6 (PDB ID: 6GS7). Additionally, strychnine (−9.99), naringin (−9.19), and luteolin (−8) demonstrated good interactions with the estrogen receptor (PDB ID: 3ERT). In the case of Datura metel L., withametelin (−10.69) and dinoxin B (−10.72) showed good interactions with the estrogen receptor (PDB ID: 3ERT), and scopolamine (−8.24) with CDK4/6 (PDB ID: 6GS7). These findings suggest that these phytoconstituents possess anti-cancer activities. Full article

Although post-distillation side-streams of basil (Ocimum basilicum L.) pose significant economic and environmental challenges, they also bring forth new opportunities in the flavor industry. Thus, the objective of the current study was to assess the phenolic profile of basil side-stream extracts to identify key compounds and to evaluate their taste properties, using liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis, flavor prediction tools and molecular docking. In particular, 52 phytoconstituents, mainly phenolic acids, salvianolic acids, flavonoids and fatty acids derivatives, were elucidated in the side-streams of two different basil varieties (Minimum and Genovese) harvested and distilled in early and late autumn, highlighting the effect of pre-harvest factors on basil’s phenolic fingerprint. Furthermore, the results of tests undertaken using taste prediction tools showed that most of the identified compounds were very likely to taste bitter, while six of them (caffeoylferuloyltartaric acid, isoquercetin, lithospermic acid A, sagerinic acid, salvianolic acids C and F) presented a high bitterant capacity (70–90%). Moreover, according to molecular docking studies, these compounds exhibited a stronger binding affinity to the hTAS2R46 bitter receptor compared to its known agonist, strychnine. This outcome and consequently their bitterness were mainly attributed to interactions with Glu265, Thr180 and/or Trp88 through the formation of direct hydrogen bonds. Therefore, the present results provide insights into the taste profiles of basil side-streams, leading to more sustainable and innovative uses of aromatic herbs residues. Full article

Bacterial infection is a common complication in bone defect surgery, in which infection by clinically resistant bacteria has been a challenge for the medical community. Given this emerging problem, the discovery of novel natural-type inhibitors of drug-resistant bacteria has become imperative. Brucine, present in the traditional Chinese herb Strychnine semen, is reported to exert analgesic and anti-inflammatory effects. Brucine’s clinical application was limited because of its water solubility. We extracted high-purity BS by employing reflux extraction and crystallization, greatly improved its solubility, and evaluated its antimicrobial activity against E. coli and S. aureus. Importantly, we found that BS inhibited the drug-resistant strains significantly better than standard strains and achieved sterilization by disrupting the bacterial cell wall. Considering the safety concerns associated with the narrow therapeutic window of BS, a 3D BS-PLLA/PGA bone scaffold system was constructed with SLS technology and tested for its performance, bacteriostatic behaviors, and biocompatibility. The results have shown that the drug-loaded bone scaffolds had not only long-term, slow-controlled release with good cytocompatibility but also demonstrated significant antimicrobial activity in antimicrobial testing. The above results indicated that BS may be a potential drug candidate for the treatment of antibiotic-resistant bacterial infections and that scaffolds with enhanced antibacterial activity and mechanical properties may have potential applications in bone tissue engineering. Full article

Strychnine (STCN) has demonstrated an exceptional anticancer effect against various cancers. However, the STCN clinical utility has been hampered by its low water solubility, restricted therapeutic window, short half-life, and significant toxicity. The objective of this investigation was to design and optimize a formulation of strychnine-loaded transliposomes (STCN–TLs) for dermal administration of STCN to treat skin cancer. The formulations of STCN–TL were examined in terms of vesicle size (VS), polydispersity index (PDI), entrapment efficiency (EE), and in vitro delivery. The improved STCN–TL formulation exhibited VS, PDI, EE, and in vitro delivery of 101.5 ± 2.14 nm, 0.218 ± 0.12, 81.74 ± 1.43%, and 85.39 ± 2.33%, respectively. In an ex vivo penetration, the created STCN–TL formulation demonstrated a 2.5-fold increase in permeability compared to the STCN solution. CLSM pictures of skin (rat) revealed that the rhodamine B-loaded transliposome preparation penetrated deeper than the rhodamine B hydroalcoholic mixture. Additionally, rat skin managed with STCN–TL nanogel exhibited a significant increase in C_{skin max} and AUC_0-8 compared to rat skin treated with traditional STCN gel. The findings demonstrated that the transliposome preparation might be a suitable nanocarrier for the cutaneous distribution of STCN in the amelioration of skin cancer. Full article

To determine the origin of oscillatory potentials (OPs), binocular electroretinogram (ERG) recordings were performed under light and dark adaptation on adult healthy C57BL/6J mice. In the experimental group, 1 μL of PBS was injected into the left eye, while the right eye was injected with 1 μL of PBS containing different agents: APB, GABA, Bicuculline, TPMPA, Glutamate, DNQX, Glycine, Strychnine, or HEPES. The OP response depends on the type of photoreceptors involved, showing their maximum response amplitude in the ERG induced by mixed rod/cone stimulation. The oscillatory components of the OPs were affected by the injected agents, with some drugs inducing the complete abolition of oscillations (APB, GABA, Glutamate, or DNQX), whereas other drugs merely reduced the oscillatory amplitudes (Bicuculline, Glycine, Strychnine, or HEPES) or did not even affect the oscillations (TPMPA). Assuming that rod bipolar cells (RBC) express metabotropic Glutamate receptors, GABA_A, GABA_C, and Glycine receptors and that they release glutamate mainly on Glycinergic AII amacrine cells and GABAergic A17 amacrine cells, which are differently affected by the mentioned drugs, we propose that RBC-AII/A17 reciprocal synapses are responsible for the OP generation in the ERG recordings in the mice. We conclude that the reciprocal synapses between RBC and AII/A17 are the basis of the ERG OP oscillations of the light response, and this fact must be taken into consideration in any ERG test that shows a decrease in the OPs’ amplitude. Full article

NeuroAid II, a folk Chinese Medicine, is currently used in Asia for the treatment of stroke. An experimental study demonstrated that NeuroAid enables neuronal cells to be more resistant to glutamate toxicity. This research was constructed to evaluate the efficacy of NeuroAid in the prevention of epilepsy (EP). Forty healthy adult male mice were used and divided into four groups (10 mice/group): normal control group; positive control group; NeuroAid-treated group (10 mg/kg); topiramate-treated group (10 mg/kg). The treatment continued for 7 days, and on the last day, EP was induced using strychnine at a dose of 2 mg/kg via intraperitoneal (ip) administration. Seizure severity, latency to the seizure onset, the number of seizures, and the duration of each seizure episode were observed for one hour. The death and protection rates over the next twenty-four hours were recorded. Brain specimens from surviving animals were extracted and examined pathologically for quantification of glutamate receptor (GluR) gene expression in the isolated hippocampus employing real-time PCR analysis. Treatment with NeuroAid resulted in a significant reduction in seizure severity, prolonged the onset of seizures, decreased the number and duration of episodes, reduced brain insult, and decreased mortality rate. Reductions in the gene expression of GluRs in the hippocampus with minor histopathological changes were observed in the NeruoAid- and topiramate-treated groups. It is concluded that NeuroAid has a potential antiepileptic effect (EP) with the ability to prevent convulsion through its effect on the glutamate receptor. Full article

To study the flexibility of strychnine, we performed molecular dynamics simulations with orientational tensorial constraints (MDOC). Tensorial constraints are derived from nuclear magnetic resonance (NMR) interaction tensors, for instance, from residual dipolar couplings (RDCs). Used as orientational constraints, they rotate the whole molecule and molecular parts with low rotational barriers. Since the NMR parameters are measured at ambient temperatures, orientational constraints generate conformers that populate the whole landscape of Gibbs free energy. In MDOC, structures are populated that are not only controlled by energy but by the entropy term TΔS of the Gibbs free energy. In the case of strychnine, it is shown that ring conformers are populated, which has not been discussed in former investigations. These conformer populations are not only in accordance with RDCs but fulfill nuclear Overhauser effect (NOE)-derived distance constraints and ³J_HH couplings as well. Full article

This study aimed to assess the potential of Lactuca serriola (Asteraceae) seed n-hexane, chloroform, methanol, and aqueous extracts as anticonvulsant, sedative, anticonvulsant and antiepileptic agents in Swiss albino mice. Different doses of each extract were evaluated for the anxiolytic potential using the hole-board, the elevated plus maze and the light/dark test. A phenobarbitone-induced sleep test was employed for the evaluation of sedative potential. Acute anticonvulsant activity was evaluated by picrotoxin and strychnine-induced convulsion models. All extracts significantly reduced the number of head dips where n-hexane extract (400 mg/kg) showed 96.34% reduction in the tendency of head dipping when compared with the control. Mice treated with extracts preferred elevated plus maze open arms and were shown to lack open arms evasion, especially n-hexane extract (400 mg/kg)—which showed 456.14%—increased the duration of open arm stay with the respective control group. By reducing sleep latency and greatly lengthening sleep duration, L. serriola enhanced the effects of barbiturate-induced sleep. A significant increase in convulsion latency and decrease in convulsions induced by picrotoxin and strychnine duration was observed in all extract-treated groups. All the extracts exhibited anti-epileptogenic potential as the seizure score in pentylenetetrazol (PTZ)-induced kindling in mice was reduced significantly. Maximum protection was afforded by chloroform extract that reduced the seizure score by 79.93% compared with the PTZ group. Chloroform executed antioxidant effect by elevating super oxide dismutase (SOD) by 126%, catalase (CAT) by 83.53%, total glutathione (tGSH) by 149%, and reducing malondialdhyde (MDA) levels by 36.49% in the brain tissues that is further consolidated by histopathological examination. Metabolic profiling of the most active chloroform extract using Gas chromatography coupled with mass showed the presence of 16 compounds. This anti-epileptic activity was further confirmed via in silico molecular modelling studies in the active site Gamma-aminobutyric acid aminotransferase (GABA-AT) where all of the tested metabolites illustrated a potent inhibitory potential towards GABA-AT with hexadecanoic acid, 15-methyl-, methyl ester followed by octadecanoic acid, methyl ester showed the best fitting. The results indicated the possible anxiolytic and anti-epileptogenic potential of the plant and further consolidated the ethnopharmacological use of L. serriola seeds. Full article

The decoction turns into a complex multiphase system following exposure to high temperature and a complex chemical environment. However, the differences in the concentration of key active ingredients in different phase states and the release of drugs in sedimentary phase have yet to be elucidated. A simple ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the simultaneous quantitative determination of brucine, strychnine, liquiritin, isoliquiritin, isoliquiritigenin and glycyrrhizic acid concentrations and it was applied to compare the content of different phases and measure the release characteristics of the sedimentary phase in “Glycyrrhiza glabra-Nux vomica” decoction (NGD). The results show that the method’s selectivity, precision (intraday and interday ≤ 2%), matrix effect (101–108%), recovery and stability results were acceptable according to the guidelines. The method is sensitive and reliable. The content determination results show that the most toxic strychnine in the sedimentary phase accounted for 75.70% of the total components. The different components exhibited differential release in different media, and its components were released in the artificial intestinal fluid up to 81.02% in 12 h. Several components conformed to the primary kinetic model and the Ritger–Peppas model, and the most toxic compound exhibited slow release, thus conforming to the Ritger–Peppas model. This study provides a standard of reference for studies investigating reduction in toxicity of the combination of Glycyrrhiza glabra (Glycyrrhiza glabra L.) and Nux vomica (Strychnos nux-vomica L.). Full article

Glyght is a new photochromic compound described as an effective modulator of glycine receptors at heterologous expression, in brain slices and in zebrafish larvae. Glyght also caused weak inhibition of GABA_A-mediated currents in a cell line expressing α1/β2/γ2 GABA_A receptors. However, the effects of Glyght on GABAergic transmission in the brain have not been analysed, which does not allow a sufficiently comprehensive assessment of the effects of the compound on the nervous system. Therefore, in this study using whole-cell patch-clamp recording, we analysed the Glyght (100 µM) action on evoked GABAergic inhibitory postsynaptic currents (eIPSCs) in mice hippocampal slices. Two populations of cells were found: the first responded by reducing the GABAergic eIPSCs’ amplitude, whereas the second showed no sensitivity to the compound. Glyght did not affect the ionic currents’ amplitude induced by GABA application, suggesting the absence of action on postsynaptic GABA receptors. Additionally, Glyght had no impact on the paired-pulse modulation of GABAergic eIPSCs, indicating that Glyght does not modulate the neurotransmitter release mechanisms. In the presence of strychnine, an antagonist of glycine receptors, the Glyght effect on GABAergic synaptic transmission was absent. Our results suggest that Glyght can modulate GABAergic synaptic transmission via action on extrasynaptic glycine receptors. Full article

Brain control by locus coeruleus (LC) neurons involves afferent glutamate (Glu) inputs. In newborns, LC Glu receptors and responses may be sparse due to immaturity of the brain circuits providing such input. However, we reported, using newborn rat brain slices, that Glu and its ionotropic receptor (iGluR) agonist NMDA transform spontaneous local field potential (LFP) rhythm. Here, we studied whether α-amino-3-hydroxy-5-methyl-4-isoxazole propionic-acid (AMPA) and kainate (KA) iGluR subtypes also transform the LFP pattern. AMPA (0.25–0.5 µM) and KA (0.5–2.5 µM) merged ~0.2 s-lasting bell-shaped LFP events occurring at ~1 Hz into ~40% shorter and ~4-fold faster spindle-shaped and more regular sinusoidal oscillations. The AMPA/KA effects were associated with a 3.1/4.3-fold accelerated phase-locked single neuron spiking due to 4.0/4.2 mV depolarization while spike jitter decreased to 64/42% of the control, respectively. Raising extracellular K⁺ from 3 to 9 mM increased the LFP rate 1.4-fold or elicited slower multipeak events. A blockade of Cl⁻-mediated inhibition with gabazine (5 μM) plus strychnine (10 μM) affected neither the control rhythm nor AMPA/KA oscillations. GYKI-53655 (25 μM) blocked AMPA (but not KA) oscillations whereas UBP-302 (25 μM) blocked KA (but not AMPA) oscillations. Our findings revealed that AMPA and KA evoke a similar novel neural network discharge pattern transformation type by acting on pharmacologically distinct AMPAR and KA receptors. This shows that already the neonatal LC can generate oscillatory network behaviors that may be important, for example, for responses to opioids. Full article

The integrated management of a serious agricultural pest, the common vole (Microtus arvalis), should be based on modern and empirically proven approaches. The aim of this paper was to map the historical development of the monitoring and control practices of the common vole in the Czech Republic (CR) territory. Published records of vole population outbreaks and heavy crop damage have been documented in the Czech literature since the turn of the 20th century, and even in crops planted in highly fragmented and diversified agricultural landscapes. In the CR, systematic state monitoring was introduced in 1955. In the 1930’s, there were more than 100 various rodent preparations against the common vole, which were formulated as smoke generators, gases, baits, dusts, toxic mushy mass, and insecticide sprays. Currently, there are only six preparations with three active ingredients registered in the CR. Zinc phosphide is the only active ingredient that has been used from the 1940s to the present, whereas anticoagulants were banned for vole control in 2011 owing to the high environmental risks. The poisoning of nontarget animals by rodenticides is not a new phenomenon tied to synthetic pesticides; poisoning by botanical extracts (strychnine) was documented more than 100 years ago. This review may provide both historical lessons for current practice and new incentives for future research. Full article