Search Results (74)

Background/Objectives: The incorporation of bioactive molecules into mesoporous carriers is a promising strategy to improve stability, solubility, and therapeutic efficacy. In this study, we report for the first time the encapsulation of the synthetic chalcone 4-Cl into KIT-6 mesoporous silica and evaluate its cytotoxicity, toxicological profile, and pharmacological activities (antinociceptive, anti-inflammatory, and anxiolytic) using an in vivo zebrafish (Danio rerio) model. Methods: Zebrafish were orally dosed with 4-Cl, 4-Cl/KIT-6, or KIT-6 (4, 20, 40 mg/kg) and mortality was recorded for 96 h. For analgesia, zebrafish pretreated with 4-Cl, 4-Cl/KIT-6, KIT-6, or morphine received a tail stimulus (0.1% formalin). Locomotor activity (quadrant crossings) was monitored for 30 min to assess analgesia (neurogenic: 0–5 min; inflammatory: 15–30 min). For inflammation, abdominal edema and weight gain were assessed 4 h after intraperitoneal carrageenan (1.5%). Zebrafish (n = 6/group) received 4-Cl, 4-Cl/KIT-6, or KIT-6 (4, 20, 40 mg/kg, p.o.). Controls received ibuprofen (100 mg/kg, p.o.) or 3% DMSO. Weight was measured hourly for 4 h post-carrageenan (difference between baseline and hourly weights). Results: Physicochemical characterizations confirmed successful encapsulation without compromising the ordered structure of KIT-6, as evidenced by a significant reduction in surface area and pore volume, indicating efficient drug incorporation. In vivo assays demonstrated that the 4-Cl/KIT-6 formulation maintained the pharmacological activities of the free chalcone, reduced toxicity, and, notably, revealed a significant anxiolytic effect for the first time. Conclusions: These findings highlight KIT-6 as a promising platform for chalcone delivery systems and provide a solid basis for future preclinical investigations. Full article

Background: Cardiovascular diseases, particularly hypertension, and gastrointestinal disorders represent major public health concerns in Mexico. Although a range of pharmacological treatments exists, their use is associated with adverse effects, highlighting the need for safer therapeutic alternatives. Species of the Ipomoea genus are widely employed in Mexican traditional medicine (MTM) for their purgative, anti-inflammatory, analgesic, and sedative properties. Particularly, Ipomoea purpurea is traditionally used as a diuretic and purgative; its leaves and stems are applied topically for their anti-inflammatory and soothing effects. This study aimed to determine their phytochemical composition and to evaluate the associated vasodilatory activity, modulatory effects on intestinal smooth-muscle motility, and toxicological effects of the methanolic (ME-Ip) and dichloromethane (DE-Ip) extracts obtained from the aerial parts of I. purpurea. Methods: The phytochemical composition of the ME-Ip and DE-Ip extracts of I. purpurea was assessed using UPLC-QTOF-MS and GC-MS, respectively. For both extracts, the vasodilatory activity and effects on intestinal smooth muscle were investigated using ex vivo models incorporating isolated rat aorta and ileum, respectively, whereas acute toxicity was evaluated in vivo. Results: Phytochemical analysis revealed, for the first time, the presence of two glycosylated flavonoids within the Ipomoea genus; likewise, constituents with potential anti-inflammatory activity were detected. The identified compounds in I. purpurea extracts may contribute to the vasodilatory, biphasic, and purgative effects observed in this species. The EC₅₀ values for the vasodilatory effects of the methanolic (ME-Ip) and dichloromethane (DE-Ip) extracts were 0.80 and 0.72 mg/mL, respectively. In the initial phase of the experiments on isolated ileal tissues, both extracts induced a spasmodic (contractile) effect on basal motility, with ME-Ip exhibiting higher potency (EC₅₀ = 27.11 μg/mL) compared to DE-Ip (EC₅₀ = 1765 μg/mL). In contrast, during the final phase of the experiments, both extracts demonstrated a spasmolytic effect, with EC₅₀ values of 0.43 mg/mL for ME-Ip and 0.34 mg/mL for DE-Ip. In addition, both extracts exhibited low levels of acute toxicity. Conclusions: The phytochemical profile and the vasodilatory and biphasic effects of the I. purpurea extracts explain, in part, the use of I. purpurea in MTM. The absence of acute toxic effects constitutes a preliminary step in the toxicological safety assessment of I. purpurea extracts and demonstrates their potential for the development of phytopharmaceutic agents as adjuvants for the treatment of cardiovascular and gastrointestinal disorders. Full article

Background/Objectives: Substance use disorders, particularly opioid addiction, continue to pose a major global health and toxicological challenge. Morphine dependence represents a significant problem in both clinical practice and preclinical research, particularly in modeling the pharmacodynamics of withdrawal. Rodent models remain indispensable for investigating the neurotoxicological effects of chronic opioid exposure and withdrawal. However, conventional behavioral assessments rely on manual observation, limiting objectivity, reproducibility, and scalability—critical constraints in modern drug toxicity evaluation. This study introduces MWB_Analyzer, an automated and high-throughput system designed to quantitatively and objectively assess morphine withdrawal behaviors in rats. The goal is to enhance toxicological assessments of CNS-active substances through robust, scalable behavioral phenotyping. Methods: MWB_Analyzer integrates optimized multi-angle video capture, real-time signal processing, and machine learning-driven behavioral classification. An improved YOLO-based architecture was developed for the accurate detection and categorization of withdrawal-associated behaviors in video frames, while a parallel pipeline processed audio signals. The system incorporates behavior-specific duration thresholds to isolate pharmacologically and toxicologically relevant behavioral events. Experimental animals were assigned to high-dose, low-dose, and control groups. Withdrawal was induced and monitored under standardized toxicological protocols. Results: MWB_Analyzer achieved over 95% reduction in redundant frame processing, markedly improving computational efficiency. It demonstrated high classification accuracy: >94% for video-based behaviors (93% on edge devices) and >92% for audio-based events. The use of behavioral thresholds enabled sensitive differentiation between dosage groups, revealing clear dose–response relationships and supporting its application in neuropharmacological and neurotoxicological profiling. Conclusions: MWB_Analyzer offers a robust, reproducible, and objective platform for the automated evaluation of opioid withdrawal syndromes in rodent models. It enhances throughput, precision, and standardization in addiction research. Importantly, this tool supports toxicological investigations of CNS drug effects, preclinical pharmacokinetic and pharmacodynamic evaluations, drug safety profiling, and regulatory assessment of novel opioid and CNS-active therapeutics. Full article

Background/Objectives: The administration of human monoclonal antibodies (mAb) in preclinical pharmacokinetics and toxicology studies often triggers an immune response, leading to the formation of anti-drug antibodies (ADA). To mitigate this effect, we have recently performed and reported on studies using short-term immunosuppressive regimens to induce prolonged immune tolerance towards a human mAb, erenumab, in rats. Here, we report on the development of a semi-mechanistic modeling approach that quantitatively integrates pharmacokinetic and immunogenicity assessments from immune tolerance induction studies to provide a framework for the simulation-based evaluation of different immune induction scenarios for the maintenance of prolonged immune tolerance towards human mAbs. Methods: The integrated pharmacokinetic/pharmacodynamic (PK/PD) modeling approach combined a semi-mechanistic model of the adaptive immune system to predict ADA formation kinetics with a population pharmacokinetic model to assess the impact of the time course of the ADA magnitude on the PK of erenumab in rats. Model-derived erenumab concentration–time profiles served as input for a quantitative system pharmacology-style semi-mechanistic model of the adaptive immune system to conceptualize the ADA response as a function of the kinetics of CD4⁺ T helper cells and T regulatory cells. Results: The model adequately described the observed ADA magnitude–time profiles in all treatment groups and reasonably simulated the kinetics of selected immune cells responsible for ADA formation. It also successfully captured the impact of tacrolimus/sirolimus immunomodulation on ADA formation, demonstrating that the regimen effectively suppressed ADA formations and induced immune tolerance. Conclusions: This work demonstrates the utility of modeling approaches to integrate pharmacokinetic and immunogenicity assessment data for the prospective planning of long-term toxicology studies to support the preclinical development of mAbs. Full article

Erica species native to the Mediterranean basin are the principal Ericas that have found use in traditional medicine. Examples include treatments for urinary tract disorders, inflammatory conditions, gastrointestinal ailments and weight loss. This review critically evaluates the ethnobotanical usage, phytochemical profiles and pharmacological potential of the Mediterranean Erica species, including Erica arborea L., Erica multiflora L. and Erica manipuliflora Salisb. A wide spectrum of bioactive secondary metabolites has been identified across these species, notably pentacyclic triterpenes (e.g., lupeol, ursolic acid and oleanolic acid) and polyphenolics (e.g., myricetin and quercetin glycosides). Extracts of these species have demonstrated antioxidant, anti-inflammatory, analgesic, antimicrobial and diuretic activities in vitro and/or in vivo, providing pharmacological support for traditional uses. Phytochemical profiles vary by species, plant part, geography and extraction technique. Filsuvez^®, comprising pentacyclic triterpenes from birch bark, has clinical approval for the treatment of partial thickness wounds associated with dystrophic and junctional epidermolysis bullosa. The undoubted reservoir of pentacyclic triterpenes and flavonoid glycosides in Mediterranean Erica species warrants further comprehensive mechanistic studies, toxicological evaluations and clinical validation. Full article

Salvia divinorum is a psychoactive plant presenting a complex pharmacological profile, attracting significant scientific interest due to its potential therapeutic applications and associated health risks. This review provides a comprehensive analysis of the toxic and therapeutic effects of S. divinorum, evaluating its potential medical applications while highlighting the risks associated with its consumption. Additionally, the review examines the plant’s recreational use, global consumption trends, and legal status. By synthesising current research, this article aims to clarify the implications of S. divinorum use and inform future studies on its pharmacological potential and regulatory considerations. Full article

Combretum micranthum G. Don (kinkeliba) is a medicinal plant traditionally employed in West Africa for its diuretic and gastrointestinal therapeutic properties. Despite its extensive ethnomedicinal use, comprehensive toxicological assessments are still lacking. This study aimed to characterize the phenolic composition of C. micranthum ethanolic leaf extract using HPLC-DAD-ESI-MS and evaluate its acute and subacute oral toxicity in BALB/c mice, per OECD Guideline 420. Female mice received oral doses of 50, 300, and 2000 mg/kg of extract for acute toxicity assessment for 14 days. In the subacute study, both sexes were administered daily doses at the same concentrations over 28 days. Clinical signs, body weight, and food and water consumption were regularly monitored throughout both protocols. At the end of each study, hematological, biochemical, and histopathological parameters were analyzed. Phenolic profiling revealed nine major compounds with a total of 293.54 mg/g extract. No mortality or significant clinical manifestations were observed at any dose. However, significant variations in platelet counts and amylase activity were noted in the acute phase. In the subacute model, slight, non-critical alterations in hepatic and renal biomarkers were observed, without signs of systemic toxicity. Histopathological examination revealed similar lesions in both acute and subacute phases, including multifocal inflammatory infiltrates (lymphocytes and neutrophils) in the periportal area of the liver, minimal bacterial overgrowth in the superficial layer of the gastric mucosa, minimal medullary mineralization and inflammatory infiltrates with lymphocytes in the kidneys, and minimal to moderate vacuolization in the pancreatic acini. These results indicate that C. micranthum ethanolic extract is relatively safe at the tested doses, reinforcing its traditional use and supporting further research into its pharmacological potential. Full article

Scorzonera undulata (S. undulata) is a medicinal plant that is traditionally used to treat various health conditions, including diabetes, constipation, diarrhea, and other digestive issues. However, comprehensive analysis of its traditional uses, phytochemistry, and pharmacological applications is still lacking. This review aims to systematically consolidate available information on the ethnopharmacological relevance, chemical profiles, and pharmacological activities of S. undulata. A comprehensive literature review of S. undulata was conducted across multiple scientific databases. Based on predefined inclusion criteria (full-text English publications providing relevant data on S. undulata) and exclusion criteria (abstracts only, studies on other species), 29 relevant studies were selected. This review systematically integrated traditional ethnobotanical knowledge with modern scientific insights, analyzing phytochemical compositions, biological activities, and pharmacological potential through a methodology designed to ensure unbiased selection from diverse sources. Traditional uses of S. undulata include treatments for diabetes, gastrointestinal disorders, snake bites, dehydration, and burns. Phytochemical studies revealed a wealth of polyphenols, flavonoids, tannins, glycosides, terpenoids, and sesquiterpenoids. In vitro and in vivo assays showed antibacterial, antifungal, anti-inflammatory, antidiabetic, antihypertensive, cytotoxic, and antioxidant properties. There are insufficient toxicity studies to assess the safety of this species. However, pharmacological research on this species remains limited. This review is the first to synthesize the traditional uses, phytochemistry, and biological activities of S. undulata, highlighting its pharmacological potential. However, further comprehensive research, including clinical trials, toxicological evaluations, and mechanistic studies, is necessary to fully identify active compounds and confirm their therapeutic applications, thus warranting additional investigation into this medicinal herb’s complete benefits. Full article

Background/Objectives: Solanum macrocarpon L. has been studied for its neuroprotective potential and memory-enhancing properties. Research suggests that bioactive compounds, including flavonoids, alkaloids, and phenolics, contribute to its cognitive benefits. These compounds may help protect against oxidative stress, neuroinflammation, and cholinergic dysfunction factors in memory impairment. This study was undertaken to investigate the effects of S. macrocarpon ethanolic leaf extract (SMEE) on the memory, anxiety-like behavior, and brain antioxidant status of scopolamine (SCOP, 100 μM)-induced amnesic zebrafish (Danio rerio) and thus to understand its possible mechanism of action. Methods: Adult zebrafish (n = 100) were divided into two cohorts (±SCOP) of five experimental groups: (I) control; (II) galantamine (GAL, 1 mg/L), serving as a positive control for both behavioral and biochemical assessments; (III–V) three groups treated with SMEE (1, 3, and 6 mg/L); (VI) scopolamine (SCOP, 100 μM); (VII) SCOP (100 μM) combined with GAL (1 mg/L); and (VIII–X) three groups treated with SCOP (100 μM) plus SMEE (1, 3, and 6 mg/L). The treatment lasted 23 days and amnesia was induced by a single dose of SCOP (100 μM) before testing. Results: The phenolic characterization from the samples was performed by using HPLC-PDA chromatography. Following HPLC analysis, an in silico pharmacokinetic evaluation was conducted using the ADMET model to investigate the pharmacological and toxicological profiles of the identified compounds. Spatial memory was evaluated through the Y-maze and novel object recognition (NOR) tests, while anxiety-like behavior was assessed using the novel tank diving test (NTT), novel approach test (NAT), and light–dark test (LDT). The zebrafish were euthanized, and homogenates of isolated brain samples were assayed for acetylcholinesterase (AChE) activity and brain antioxidant markers. The HPLC analysis revealed that the main major compounds in the extract were chlorogenic acid and rutin, both recognized for their significant antioxidant properties. Conclusions: SMEE enhanced memory by inhibiting AChE, alleviated SCOP-induced anxiety-like behavior, and significantly decreased oxidative stress markers. These findings support the potential role of SMEE in counteracting SCOP-induced cognitive and behavioral dysfunctions, related to dementia conditions. Full article

Scolopendra subspinipes, commonly known as the Chinese red-headed centipede, has been utilized in traditional East Asian medicine for centuries to treat conditions such as chronic pain, inflammation, convulsions, and infections. Recent pharmacological investigations have uncovered a wide array of bioactive molecules—including peptides, alkaloids, and polysaccharide–protein complexes—from both venom and whole-body extracts. This review synthesizes findings from 45 in vitro, in vivo, and clinical studies investigating the pharmacological effects of venom-derived and whole-body-derived compounds from S. subspinipes across multiple domains, including analgesic, anti-inflammatory, antimicrobial, antifungal, antioxidant, antitumor, antithrombotic, anti-fibrotic, and neuroprotective activities, along with a brief scoping review of clinical practice guidelines. Key venom-derived compounds such as the peptide SsmTX-I, immunomodulatory antimicrobial peptide scolopendrasin IX, and antitumor peptide scolopentide exhibit strong mechanistic rationale and preclinical efficacy, positioning them as lead candidates for clinical development. Compounds derived from whole-body extracts, including alkaloids and polysaccharide–protein complexes, also demonstrate promising therapeutic potential. Mechanistic studies suggest these compounds operate via distinct pathways—such as ion-channel inhibition, NF-κB suppression, and apoptosis induction—offering potential advantages over existing therapies. However, current evidence remains primarily preclinical, and challenges such as extract variability, immunogenicity, and lack of standardized dosing must be addressed. Future research should prioritize isolation and structural optimization of key peptides, standardized formulation development, toxicological profiling, and early-phase human trials. The integration of traditional knowledge and modern pharmacological insights underscores the potential of venom- and whole-body-derived S. subspinipes agents to enrich the drug discovery, particularly for conditions with unmet therapeutic needs. Full article

Over the past decade, more than a thousand new psychoactive substances (NPSs) have emerged worldwide. This rapid proliferation of “designer drugs” poses significant challenges for drug control, forensic analysis, and public health. Artificial intelligence (AI) has increasingly been applied to address these challenges in NPS design and analysis. This review provides a comprehensive overview of AI methodologies—including deep learning, generative models, and quantitative structure–activity relationship (QSAR) modeling—and their applications in the synthesis, prediction, and identification of NPSs. We discuss how AI-driven generative models have been used to design novel psychoactive compounds and predict their pharmacological activity, how QSAR models can forecast potency and toxicological profiles, and how machine learning is enhancing analytical chemistry workflows for NPS identification. Special emphasis is placed on mass spectrometry (MS)-based techniques, where AI algorithms (e.g., for spectral prediction and pattern recognition) are revolutionizing the detection and characterization of unknown NPSs. A dedicated section examines the legal and regulatory implications of AI-generated psychoactive substances in the European Union (EU) and United States (USA), highlighting current policies, potential gaps, and the need for proactive regulatory responses. The review concludes with a discussion of the benefits and limitations of AI in this domain and outlines future directions for research at the intersection of AI, analytical chemistry, and drug policy. Full article

New therapeutic molecules for farm animals are needed to address worldwide problems in the food industry, like the rise of resistance among ruminant parasites and pathogenic microbes. Since in vivo testing would involve an excessive number of animals, with consequent ethical and economic issues, the generation of sheep intestinal organoids represents a promising close-to-reality in vitro model for veterinary drug development; however, the characterization and application of such organoids remain limited. In this study, ovine intestinal organoids were generated from adult LGR5+ stem cells from the intestinal crypts of freshly slaughtered lambs, and developed in an in vitro culture system. Morphological analysis via brightfield microscopy and immunocytochemical staining revealed a pseudostratified epithelium with multiple cell types, and distinct apical–basal polarity, while RNA sequencing validated the preservation of the physiological characteristics of the original organ. The development and characterization of a robust and reproducible protocol for culturing sheep duodenum intestinal organoids in a high-throughput screening (HTS) compatible format demonstrated reliability in HTS applications, with Z’-factor tests indicating robust assay performance. Dose–response studies using pre-identified compounds showed comparable pharmacodynamic profiles between mouse and sheep organoids. These findings establish sheep intestinal organoids as an innovative tool for veterinary pharmacology and toxicology, offering a cost-effective and sustainable platform to address challenges such as drug resistance and improve livestock health. Full article

Glioblastoma (GBM) is one of the most invasive central nervous system tumors, with rising global incidence. Therapy resistance and poor prognosis highlight the urgent need for new anticancer drugs. Plant alkaloids, a largely unexplored yet promising class of compounds, have previously contributed to oncology treatments. While past reviews provided selective insights, this review aims to collectively compare data from the last decade on (1) plant alkaloid-based anticancer drugs, (2) alkaloid transport across the blood–brain barrier (BBB) in vitro and in vivo, (3) alkaloid mechanisms of action in glioblastoma models (in vitro, in vivo, ex vivo, and in silico), and (4) cytotoxicity and safety profiles. Additionally, innovative drug delivery systems (e.g., nanoparticles and liposomes) are discussed. Focusing on preclinical studies of single plant alkaloids, this review includes 22 botanical families and 28 alkaloids that demonstrated anti-GBM activity. Most alkaloids act in a concentration-dependent manner by (1) reducing glioma cell viability, (2) suppressing proliferation, (3) inhibiting migration and invasion, (4) inducing cell death, (5) downregulating Bcl-2 and key signaling pathways, (6) exhibiting antiangiogenic effects, (7) reducing tumor weight, and (8) improving survival rates. The toxic and adverse effect analysis suggests that alkaloids such as noscapine, lycorine, capsaicin, chelerythrine, caffeine, boldine, and colchicine show favorable therapeutic potential. However, tetrandrine, nitidine, harmine, harmaline, cyclopamine, cocaine, and brucine may pose greater risks than benefits. Piperine’s toxicity and berberine’s poor bioavailability suggest the need for novel drug formulations. Several alkaloids (kukoamine A, cyclovirobuxine D, α-solanine, oxymatrine, rutaecarpine, and evodiamine) require further pharmacological and toxicological evaluation. Overall, while plant alkaloids show promise in glioblastoma therapy, progress in assessing their BBB penetration remains limited. More comprehensive studies integrating glioma research and advanced drug delivery technologies are needed. Full article

The Vatairea genus (Fabaceae family) is widespread in the Amazon rainforest. Some species of this genus are known for their ethnobotanical significance and biological potential. The present study explores the pharmacological and promising therapeutic activities, ethnobotanical profile, and phytochemical prospection of Vatairea sp., a monophyletic group of flowering plants, which includes economically and culturally important genera due to their diverse uses, including medicinal applications. V. lundellii, V. guianensis, V. erythrocarpa, V. fusca, V. heteroptera, V. paraensis, V. sericea, and V. macrocarpa are included in the Vatairea sp., also recognized for its high wood quality and potential medicinal properties. Studies show significant antibacterial activity in V. guianensis extracts against Gram-positive and Gram-negative bacteria, whereas V. macrocarpa lectin exhibits broad-spectrum antibacterial effects, including modulation of antibiotic resistance. Additionally, V. macrocarpa and V. guianensis have demonstrated antifungal properties, with compounds like Vatacarpan exhibiting potent activity against Candida sp. In vivo studies highlight the neurotoxic effects of V. macrocarpa lectin, suggesting a dual role in the central nervous system. Despite these findings, research on Vatairea’s toxicological aspects is limited, with only a few studies on V. macrocarpa and V. guianensis extracts indicating a need for further exploration of this genus’ pharmacological and therapeutic potential. Full article