Search Results (930)

The ‘miracle tree’ Moringa oleifera from the Moringaceae family is recognized for its rich nutritional value and therapeutic properties. This study aimed to evaluate the phytopharmaceutical compound Moringa isothiocyanate-1 (MIC-1) isolated from hydroalcoholic extract of M. oleifera seeds for the treatment of seizures and anxiety in adult zebrafish. MIC-1 (up to 0.5 mg/mL) did not show any acute toxic effects over a 96-h period. Moreover, MIC-1 (0.005 and 0.05 mg/mL) delayed the onset of seizures induced by pentylenetetrazol, indicating anticonvulsant activity. The anticonvulsant effects of MIC-1 (0.05 mg/mL) were reversed by flumazenil, suggesting a mechanism involving the GABA_A receptor. Furthermore, MIC-1 (0.05 mg/mL) has anxiolytic effects, with involvement of the serotonergic and GABAergic systems. In silico assays confirmed the interaction of MIC-1 with the GABA_A, 5-HT_1B, 5-HT_2A/C, and 5-HT_3A/B receptors. Additionally, MIC-1 was effective in treating anxiety related to alcohol withdrawal in zebrafish. These findings suggest the pharmacological potential of MIC-1 for the development of new treatments for seizures and anxiety. Full article

Rising drug resistance undermines current anti-influenza virus therapies. Although targeting the hemagglutinin (HA)–sialic acid receptor interaction is a promising strategy, progress is impeded by the lack of subtype-independent screening models. Herein, we established a fluorescence-based cell high-throughput model using fluorescein isothiocyanate-conjugated Sambucus Nigra Lectin (FITC-SNA) as a stable HA surrogate and α-2,6-sialyltransferase (ST6GAL1)-overexpressing MDCK cells to mimic the HA–receptor interface. This platform was designed to serve as an efficient primary screening tool to rapidly filter large compound libraries for potential binders to the receptor-binding interface. Screening 10,000 compounds identified Obatoclax Mesylate and Ethylparaben as primary hits. Both exhibited broad-spectrum HA inhibition activity, validating the model’s capability to identify compounds interfering with viral attachment. Further cellular antiviral assays revealed cytotoxicity for both compounds, resulting in low selectivity indexes (SIs), indicating that while these molecules effectively target the interaction site, they require substantial structural optimization for therapeutic use. Molecular docking confirmed their binding to type A H1N1, H3N2, and B/Victoria HA proteins, while ADMET predictions highlighted specific structural optimization needs to mitigate toxicity. In conclusion, this subtype-independent, highly specific high-throughput screening (HTS) model provides an efficient and reliable platform for early-stage influenza drug discovery and lead compound development. Full article

Background/Objectives: α-Phellandrene (α-PHEL) is a monoterpene found in essential oils and is known for its antinociceptive and anti-inflammatory properties. This study investigated the antinociceptive effects of free α-PHEL and β-cyclodextrin-associated α-PHEL (α-PHEL/β-CD) in a Complete Freund’s adjuvant (CFA)-induced model of chronic inflammatory pain. Methods: Mechanical allodynia and hyperalgesia were evaluated in female Wistar rats using the von Frey and Randall–Selitto tests, respectively. Locomotor activity and motor performance were evaluated in male Swiss mice. Animals received α-PHEL (6.25–100 mg/kg) and α-PHEL/β-CD (3.12–12.5 mg/kg), as well as vehicle (2% Tween 80/0.9% saline) and dexamethasone (0.5 mg/kg, p.o.), with evaluations conducted in the von Frey test at intervals of 1 to 24 h. The antihyperalgesic effect was evaluated using α-PHEL, α-PHEL/β-CD, vehicle, and diclofenac (5 mg/kg, p.o.), with assessments in the Randall–Selitto test from 1 to 6 h. Over 10 days, the animals were treated and evaluated daily to determine the effect during repeated treatment. The involvement of the opioid pathway was assessed using naloxone, whereas the serotonergic pathway was investigated using PCPA and ketanserin in the von Frey test. Motor coordination was tested in the rotarod, and exploratory behavior was assessed in the open field. Results: α-PHEL reduced CFA-induced hyperalgesia and allodynia in both acute and chronic phases. The α-PHEL/β-CD preparation produced significant antinociceptive effects at all tested doses during repeated administration. Naloxone and 5-HT₂A receptor blockade reduced the antinociceptive effect of α-PHEL, while α-PHEL and the α-PHEL/β-CD preparation did not alter locomotor activity or motor coordination. Conclusions: The α-PHEL/β-CD preparation exhibits antinociceptive activity in inflammatory pain without affecting locomotor activity or motor coordination. The findings with free α-PHEL suggest the possible contribution of opioid and serotonergic pathways to its antinociceptive effect. Full article

A naive Bayesian classifier (NBC) combined with principal component analysis (PCA) effectively differentiates the dose-dependent effects of certain groups of psychoactive drugs based on their impact on the amplitude–spectral characteristics of electrocorticograms (ECoG) in rats. This approach has been shown to be useful for pharmacological screening of agents with unknown or poorly understood activity. Despite previously obtained optimistic results, classification determination for some drugs was inaccurate, necessitating the search for possible ways to improve the predictive effectiveness of the proposed algorithm. One possible approach would be to use as input quantitative data not only the impact of the psychoactive drugs studied on the amplitude–spectral characteristics of ECoG but also connectivity changes, including the average coherence power of different pairs of leads. The aim of this study was to compare the accuracy of NBC in classifying the pharmacological mechanism of action of agents with well-known mechanisms (test set) using pharmaco-EEG data on changes in the amplitude–spectral characteristics of ECoG, coherence, and the combined use of two data sets. Materials and methods. Experiments were performed on Wistar rats with chronically implanted ECoG electrodes. The training set, relative to which the effects of the pharmacological agents from the test set were classified, were the matrices of effects of 12 pharmacological agents: the NMDA antagonist dizocilpine, the D2/D3 antagonists haloperidol and sulpiride, the M-anticholinergic tropicamide, the H1/5HT2A receptor blocker hydroxyzine, the acetylcholinesterase inhibitor galantamine, the alpha-2 adrenergic agonist dexmedetomidine, the alpha-2 adrenergic antagonist atipamezole, the adenosine receptor blocker caffeine and the GABA-mimetics aminophenylbutyric acid (phenibut), bromdihydrochlorophenylbenzodiazepine (phenazepam) and 5-ethyl-5-phenyl-2,4,6(1H,3H,5H)-pyrimidinetrione. The test set included various drugs with tropism for the targets of the training set drugs: dopamine receptor antagonists chlorpromazine, droperidol, tiapride and raclopride, H1-histamine blockers diphenhydramine and promethazine, 5-HT2-receptor blockers ritanserin and glemenserin, acetylcholinesterase inhibitor ipidacrine, alpha2-adrenergic receptor antagonist yohimbine, alpha2-adrenergic agonists medetomidine and xylazine, GABA-mimetics 5-ethyl-5-(1-methylbutyl)-2,4,6(1H,3H,5H)-pyrimidinetrione and chloral hydrate. The analysis of the ECoG signal included the calculation of 132 amplitude–spectral characteristics and 75 coherence indicators, which, using the PCA, led to new integrative indicators used for further classification of the NBC. Results and discussion. For each drug in the test set, the median similarity probability with a particular group from the training set was calculated, which was used to assess the classification quality. It was found that, when using the amplitude–spectral characteristics of ECoG, the proposed methodological approach allows for the identification of the ECoG effects of several groups of psychoactive drugs, including D2/D3-dopamine, M-cholinergic, H1-histamine, and 5-HT2-serotonin receptor blockers, AChE inhibitors, GABA-mimetics, and alpha-2-adrenergic receptor agonists and antagonists. This approach enabled the correct classification of 18 of 24 groups in the test set. When using changes in coherence indices as the initial data, the classification accuracy also amounted to 18 of 24 groups. When combining the two data sets, the number of correctly identified NBC groups was 20 of 24 groups. When comparing the classification during training (confusion matrix), it was found that coherence data or adding coherence data to the data based on changes in amplitude–spectral characteristics leads to a statistically significant (p < 0.01 in both cases) increase in accuracy. Conclusions. The obtained data demonstrated high accuracy in classifying the pharmacological activity of the test sample drugs using any of the three compared approaches. Despite the lack of statistically significant differences between them, classification based on the combined dataset demonstrated a higher number of “correct” similarities. This allows us to recommend the approach based on combined data of drug effects on amplitude–spectral characteristics and coherence as the most promising for further studies using pharmaco-EEG screening. Full article

Clinical trials and naturalistic studies describe psychedelics under markedly different exposure conditions. This narrative review searched PubMed/MEDLINE, the Cochrane Library, ClinicalTrials.gov, and regulatory sources through 15 July 2026, and examined safety and outcomes across four dimensions of exposure: dose, frequency, person, and context. In screened adults receiving one to three supervised doses, transient headache, nausea, anxiety, and cardiovascular activation are common; serious reactions are uncommon but include persistent anxiety, suicidality signals, and a recent case of hallucinogen persisting perception disorder. Evidence supports MDMA (3,4-Methylenedioxymethamphetamine) -assisted therapy for post-traumatic stress disorder and psilocybin-based interventions for depression, although functional unblinding, selected samples, inconsistent comparators, and a recent negative primary trial constrain certainty. Naturalistic studies suggest that vulnerability and context modify outcomes, but frequency is inconsistently measured and rarely linked to cumulative exposure or long-term health. Short-term microdosing trials show limited benefit, whereas long-term cardiac and psychiatric safety remains unresolved. Exposure-defined cohorts, prospective registries, echocardiographic surveillance, and blinding-aware comparative trials are priorities. Full article

Background/Objectives: Psilocybin-assisted therapy has progressed from early proof-of-concept work to a substantially expanded evidence base, with four pivotal studies published in 2025–2026 that were not incorporated into earlier reviews. This review synthesizes the pharmacological and neurobiological foundations of psilocybin and appraises clinical evidence across major depressive disorder (MDD), treatment-resistant depression (TRD), post-traumatic stress disorder (PTSD), cancer-related distress, and substance use disorders, emphasizing long-term durability, expanding indications, and methodological limitations. Methods: A narrative review was conducted using a targeted search of PubMed/MEDLINE, Embase, Scopus, and Web of Science (January 2000–April 2026), emphasizing 2025–2026 publications. Predefined eligibility principles prioritized randomized controlled trials, long-term follow-up studies, and systematic reviews; formal PRISMA procedures were not applied, consistent with the narrative design. Results: Four 2025–2026 studies extend the evidence base: a 52-week follow-up confirming dose-dependent maintenance of antidepressant benefit after a single 25 mg psilocybin session; the first pilot study in Veterans with severe TRD, reporting a 60% response rate at three weeks; the first safety trial in PTSD, where symptom improvement tracked self-transcendent experience intensity but worsened with session anxiety; and a living review of 15 randomized trials confirming a meaningful antidepressant effect while identifying functional unblinding as a substantial threat to effect estimates. Conclusions: Evidence supports psilocybin-assisted therapy as mechanistically distinct and clinically promising, most strongly in MDD and TRD, with preliminary support in PTSD and Veterans. Functional unblinding, small open-label designs, narrow safety populations, and absent SSRI-integration protocols constrain the current conclusions. Full article

Background: Minor phytocannabinoids engage CB₁ and CB₂ receptors, as well as broader receptors and ion-channel targets. However, fragmented evidence limits translation into central nervous system (CNS) therapeutics. This review introduces pharmacological switching, defined as a dose-, state-, or model-dependent shift in the dominant determinant of a compound’s net effect that reverses the direction, rather than merely the magnitude, of that effect on a defined functional endpoint, as a framework for compound–indication matching. Unlike biased agonism, which redistributes downstream coupling without reversing direction, switching requires directional reversal between or within receptor systems. Methods: This narrative review integrates receptor pharmacology, preclinical CNS disease-model data, early-phase clinical evidence, and pharmacokinetics identified through a structured literature search. Results: Three mechanistic axes recurred: PPARγ/CB₂/Nrf2-linked neuroinflammatory modulation; TRP/GABA_A/5-HT₁A-linked control of neuronal excitability; and low-efficacy CB₁ antagonism with 5-HT₁A potentiation. Their expression was context-dependent: tetrahydrocannabivarin is reported to shift from CB₁ antagonism toward partial agonism as receptor occupancy rises, cannabidiolic acid shows stress-conditional anxiolytic and antiemetic activity, and cannabigerolic acid displays seizure-model-dependent bidirectionality. No instance yet meets all five defining criteria; each is graded provisional or proposed pending systematic testing. Human evidence remains limited: inconclusive cannabidivarin efficacy in epilepsy and neuropathic pain, proof-of-mechanism neuroimaging in autism, and early tetrahydrocannabivarin safety data. Conclusions: Minor phytocannabinoids are pharmacologically diverse but clinically underdeveloped. A tiered, biomarker-guided framework is proposed to match compound–indication pairs to the doses, formulations, and subgroups most likely to express their therapeutic pharmacology. Full article

Colorectal cancer (CRC) remains a major cause of cancer mortality worldwide, highlighting the need for novel molecular targets and alternative therapeutic strategies. TYRO3, a member of the TAM receptor tyrosine kinase family, has been associated with tumor progression and poor prognosis in CRC. In this study, the effects of the natural compounds Meleagrin and Cucurbitacin B on TYRO3 expression and CRC cell behavior were investigated in HCT-116 and HT-29 cells. Cell proliferation, apoptosis, migration, and TYRO3 expression were evaluated using functional and expression-based analyses. Both compounds modulated TYRO3 expression and suppressed proliferation and wound closure dynamics in CRC cells. Cucurbitacin B exerted more pronounced antiproliferative and pro-apoptotic effects, whereas Meleagrin demonstrated antiproliferative activity with comparatively lower effects on normal colon epithelial cells (CCD 841 CoN), suggesting a potentially more favorable selectivity profile. Collectively, these findings support further mechanistic investigation of TYRO3-modulating natural compounds as potential therapeutic candidates for CRC. Full article

Serotonin (5-hydroxytryptamine, 5-HT) is traditionally considered a neurotransmitter, but most of the body’s serotonin is peripheral and participates in vascular, hemostatic, inflammatory, and immune processes. This review summarizes current evidence on the role of peripheral serotonin in innate and adaptive immunity and evaluates its clinical relevance in inflammatory and immune-mediated diseases. The article synthesizes experimental and clinical data on serotonin sources, 5-HT receptors, SERT, serotonylation, and 5-HT-dependent regulation of neutrophils, monocytes/macrophages, mast cells, dendritic cells, T cells, and B cells. The reviewed data indicate that serotonin modulates leukocyte recruitment, platelet–immune interactions, NETosis, macrophage polarization, dendritic cell–T-cell communication, lymphocyte activation, vascular permeability, and tissue remodeling. Clinically, serotonergic mechanisms are implicated in sepsis, inflammatory bowel disease, autoimmune disorders, cardiovascular inflammation, thromboinflammation, and the tumor microenvironment. However, the direction of 5-HT effects is not uniform and depends on receptor subtype, cell type, local mediator concentration, disease stage, and tissue context. Serotonin should therefore be regarded as a context-dependent immunoregulatory mediator rather than an exclusively pro- or anti-inflammatory factor. Further studies are needed to standardize clinical measurements of serotonin and its metabolites and to define therapeutically relevant serotonergic targets. Full article

Chronic pain is a complex disorder of central nervous system maladaptation, perpetuated not only by ascending nociceptive transmission but also by entrenched prior expectations. Conventional analgesics typically fail to reverse this cognitive rigidity and the ensuing pathological cycles. Classic psychedelics, however, are emerging as a promising avenue to help address this therapeutic impasse. This narrative review provides a comprehensive overview of the emerging science of psychedelics, encompassing their biological binding targets, potential neural mechanisms and clinical applications, in the context of chronic pain. We synthesize the therapeutic potential of classic psychedelics and critically examine the discrepancies between clinical outcomes and foundational mechanistic research. Furthermore, we evaluate key translational barriers, particularly compromised blinding and expectancy bias, and highlight the necessity for developing novel validation strategies. Ultimately, these new insights compel a fundamental rethinking of how biological neuroplasticity and subjective psychological experiences independently or synergistically drive analgesia, thereby offering a paradigm-shifting perspective for the translation of psychedelics into evidence-based analgesic therapeutics. Full article

Cannabis sativa contains more than 120 phytocannabinoids, with Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) being the best characterized. This review synthesizes preclinical and clinical evidence on hemp-derived extracts, cannabinoids, and active compounds. THC primarily acts as a partial agonist at cannabinoid receptor type 1 (CB1) and type 2 (CB2), producing psychoactive, appetite-stimulating, antiemetic, and analgesic effects. CBD is non-intoxicating and has a multimodal profile involving CB1 negative allosteric modulation, CB2 inverse agonism or antagonism, inhibition of anandamide inactivation, and activity at 5-HT1A receptors, transient receptor potential channels, GPR55, and peroxisome proliferator-activated receptor gamma. Preclinical models of Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, epilepsy, and pain support anti-inflammatory, antioxidant, anti-excitotoxic, and glial-modulating mechanisms, but clinical translation remains uneven. The strongest evidence supports FDA-approved cannabidiol for Lennox–Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex, and THC-based agents for refractory chemotherapy-induced nausea and vomiting and AIDS-related anorexia. Moderate-certainty evidence supports nabiximols for multiple sclerosis spasticity and small benefits in selected chronic neuropathic pain populations. Evidence remains insufficient or negative for acute pain, insomnia, most psychiatric disorders, and many promoted indications. Key risks include cannabis use disorder, cognitive and psychiatric effects, cardiovascular events, sedation, high-dose CBD hepatotoxicity, and drug interactions. Rigorous, long-term, product-standardized trials are needed. Full article

Background: Recent evidence suggests that the antidepressant vortioxetine (Vx) inhibits the growth of glioblastoma (GBM), the most aggressive primary malignant tumor of the CNS. We used five patient-derived GBM cell lines to confirm the anti-GBM effect of Vx and explore its mechanism(s) of action. Methods: We performed in silico analysis, PCR, TUNEL assay, colony assay, and proliferation assay. Results: Vx potently inhibited GBM cell growth, and showed efficacy at concentrations of 0.1 μM that roughly correspond to therapeutic concentrations of Vx in major depression. Other antidepressants, i.e., fluoxetine and duloxetine, inhibited GBM cell growth only at high concentrations. Computational analysis showed that at least three receptor targets of Vx (5-HT₇, 5-HT_1D, and 5-HT_1B) were expressed at moderate/high levels in GBM. The 5-HT_1B receptor transcript was found in all GBM cell lines and was the only detectable Vx target in three of the five cell lines. Blocking 5-HT_1B with SB224289 abolished the anti-GBM effect of Vx, even in cells expressing other Vx. Conclusions: These findings demonstrate that therapeutic concentrations of Vx inhibit GBM cell proliferation and suggest that this action may be mediated, at least in part, by 5-HT_1B receptor activation. Full article

The genus Annona is scarcely investigated for its neuropharmacological and toxicological activities, especially regarding its seeds. To explore the effects on the central nervous system (CNS) and the acute toxicity (LD₅₀) of the polar extracts and fractions obtained from the A. macroprophyllata seeds, their potential as a possible source of anxiolytic drugs was evaluated. After determining LD₅₀, one or two doses were selected to evaluate the neuronal activity using electrocorticographic (ECoG) recordings, and the anxiolytic-like behavior in mice treated with the crude extracts or some of their fractions was assessed in the experimental models of anxiety, such as the open-field, hole-board, and plus-maze tests. Phytochemical analysis was carried out to identify the most abundant constituents, whose possible mechanism of action was also evaluated by in silico analysis. Results showed CNS depressant activity associated with an anxiolytic-like behavior, in which cherimolacyclopeptide D and squamins C and D were identified. According to a docking analysis, the inhibitory receptors GABA_A and 5-HT_1A of serotonin are possible mechanisms of action involved in the anxiolytic-like effects of these cyclopeptides, which, in conclusion, might be potential molecules for anxiety therapy. Full article

Neuroblastoma is an aggressive pediatric malignancy with limited therapeutic options for high-risk disease, underscoring the need for alternative treatment strategies. Drug repurposing offers a promising approach to accelerate the identification of effective anti-cancer agents. In this study, we investigated the anti-carcinogenic effects of hydroquinidine, a class IA antiarrhythmic ion channel blocker, and spiramide, a dopamine D₂/serotonin 5-HT₂ receptor antagonist and endoplasmic reticulum stress inducer, in SH-SY5Y human neuroblastoma cells. Cells were treated with increasing concentrations of each compound and evaluated using cell viability, colony formation, wound healing, proliferation, apoptosis, and quantitative gene expression assays. Both compounds induced a dose-dependent reduction in cell viability, with spiramide exhibiting greater potency than hydroquinidine. Functional assays revealed significant suppression of clonogenic survival, cell migration, and DNA synthesis, accompanied by increased oxidative stress and cell death. Molecular analyses demonstrated coordinated transcriptional regulation of apoptosis- and cell cycle-related genes, characterized by upregulation of BAX, CDKN1A, and CDKN1B, and downregulation of BCL-2 and CCND1. Notably, spiramide consistently produced stronger cytotoxic and wound-closure inhibitory effects, suggesting a greater contribution of oxidative stress- and apoptosis-associated pathways. Collectively, these findings indicate that hydroquinidine and spiramide disrupt neuroblastoma cell growth through complementary stress- and cell cycle-associated pathways and identify them as promising candidates for further preclinical evaluation. Full article

Major depressive disorder (MDD) involves dysregulation of the hypothalamic–pituitary–adrenal axis, neuroinflammation, serotonergic dysfunction, and impaired neurotrophic signaling. Whether combining corticosterone (CORT) with chronic restraint stress (CRS) produces a more comprehensive depression-like phenotype than either model alone remains unexplored. Male C57BL/6N mice were assigned to four groups—Sham (n = 7), CORT (20 mg/kg s.c.; n = 7), CRS (3 h/day; n = 7), and CORT + CRS (C+C; n = 8)—and evaluated by behavioral tests, hippocampal qRT-PCR, Western blot, LC-MS/MS metabolomics, and immunohistochemistry. All experimental groups showed elevated immobility in tail suspension and forced swim tests without inter-group differences. Two-way ANOVA revealed a behavioral–molecular dissociation: FST immobility showed CORT and CRS main effects without a significant interaction, whereas hippocampal LC-MS/MS analytes exhibited strong CORT × CRS interactions. The C+C group showed the strongest 5-HT1A receptor (HTR1A) upregulation, the greatest reductions in Trk-b and DCX, and unique decreases in serum dopamine, glutamine, and adenosine. Representative Western blot densitometry indicated the largest p-ERK/ERK reduction in C+C (54%), while p-CREB/CREB was most suppressed in CRS (52%). BDNF and NeuN proteins were lowest in C+C (68% and 61% reductions). Combined CORT + CRS produces the most comprehensive depression-related molecular profile, integrating multiple pathological domains. Full article