Search Results (111)

Heavy metals are a major toxicological concern due to their adverse effects on human health, particularly in children exposed to contaminated areas. This study evaluated biomarkers of exposure in 253 children aged 6 to 12 from Magangue, Achi, and Arjona (Bolivar, Colombia), analyzing their relationship with neurotoxicity and hematological markers. The mean Pb concentrations at the study sites were 1.98 µg/g (Magangue) > 1.51 µg/g (Achi) > 1.24 µg/g (Arjona). A similar pattern was observed for Cd concentrations for Magangue (0.39 µg/g) > Achi (0.36 µg/g) > Arjona (0.14 µg/g). In contrast, Se concentrations followed a different trend for Arjona (0.29 µg/g) > Magangue (0.21 µg/g) > Achi (0.16 µg/g). The proportion of Se/Pb molar ratios > 1 was higher in Arjona (3.8%) than in Magangue (0.9%) and Achi (2.0%). For Se/Cd ratios, values > 1 were also more frequent in Arjona (70.7%), exceeding 20% in the other two locations. Significant differences were found among locations in red and white blood cell parameters and platelet indices. Neurotransmitter-related biomarkers, including serotonin, monoamine oxidase A (MAO-A), and acetylcholinesterase levels, also varied by location. Principal component analysis showed that Pb and Cd had high loadings on the same component as PLT, WBC, and RDW, and while Se loaded together with HGB, PDW, MCHC, MCH, and MCV, suggesting distinct hematological patterns associated with each element. Multiple linear regression analysis demonstrated a statistically significant inverse association between hair Pb levels and serotonin concentrations. Although MAO-A and Cd showed negative β coefficients, these associations were not statistically significant after adjustment. These findings highlight the potential impact of toxic element exposure on key hematological and neurochemical parameters in children, suggesting early biological alterations that may compromise health and neurodevelopment. Full article

Background: Butylated hydroxyanisole (BHA) has been extensively used in several commercial industries as a preservative. It causes severe cellular and neurological damage affecting the developing fetus and might induce attention deficit hyperactivity disorder (ADHD). Methods: Zebrafish embryos were subjected to five distinct doses of BHA—0.5, 1, 2, 4, and 8 ppb up to 96 h post fertilization (hpf). Hatching rate, heart rate, and body malformations were assessed at 48 hpf, 72 hpf, and 48–96 hpf, respectively. After exposure, apoptotic activity, neurobehavioral evaluation, neurotransmitter assay, and antioxidant activity were assessed at 96 hpf. At 120 hpf, the expression of genes DRD4, COMT, 5-HTR1aa, and BDNF was evaluated by real-time PCR. Results: BHA exposure showed a delay in the hatching rate and a decrease in the heart rate of the embryo when compared with the control. Larvae exhibited developmental deformities such as bent spine, yolk sac, and pericardial edema. A higher density of apoptotic cells was observed in BHA-exposed larvae at 96 hpf. There was a decline in catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST), and superoxide dismutase (SOD) activity, indicating oxidative stress. There was a significant decrease in Acetylcholinesterase (AChE) activity and serotonin levels with an increase in concentration of BHA, leading to a dose-responsive increase in anxiety and impairment in memory. A significant decrease in gene expression was also observed for DRD4, COMT, 5-HTR1aa, and BDNF. Conclusions: Even at lower concentrations of BHA, zebrafish embryos suffered from developmental toxicity, anxiety, and impaired memory due to a decrease in AChE activity and serotonin levels and altered the expression of the mentioned genes. Full article

Contamination of the soil with cadmium (Cd) presents serious hazards to plant growth, ecosystem harmony, and human health. Plants have evolved various mechanisms to address Cd toxicity, such as sequestration, chelation, and antioxidant defense systems. Knowledge of these mechanisms is an important requisite for the development of strategies to relieve Cd stress in plants. More recent studies also implicate the role of the neurotransmitter 5-hydroxytryptamine (serotonin) in enabling Cd mitigation behavior in plants. Beyond its well-known role in animals, serotonin has emerged as a vital signaling molecule in plants, contributing to stress responses and regulatory pathways. This review focuses on the different Cd tolerance mechanisms in plants and describes the role of serotonin in protection against Cd toxicity. Moreover, it investigates how serotonin interacts with other signaling molecules to coordinate Cd stress responses. Understanding the intricate network of Cd tolerance mechanisms and the involvement of serotonin is essential for developing effective strategies to combat Cd stress in plants and improve environmental quality. Full article

The rapid pace of modern life has contributed to a significant decline in sleep quality, which has become an urgent global public health issue. Melatonin, an endogenous hormone that regulates circadian rhythms, is vital in maintaining normal sleep cycles. While oral melatonin supplementation is widely used, transdermal delivery systems present advantages that include the avoidance of first-pass metabolism effects and enhanced bioavailability. In this study, a novel melatonin transdermal delivery system was successfully developed using a thermosensitive poly(N-vinylcaprolactam) [p(NVCL)]-based carrier. The p(NVCL) polymer was synthesized through free radical polymerization and characterized for its structural properties and phase transition temperature, in alignment with skin surface conditions. Orthogonal optimization experiments identified 3% azone, 3% menthol, and 4% borneol as the optimal enhancer combination for enhanced transdermal absorption. The formulation demonstrated exceptional melatonin loading characteristics with high encapsulation efficiency and stable physicochemical properties, including an appropriate pH and optimal moisture content. Comprehensive in vivo evaluation using normal mouse models revealed significant sleep quality improvements, specifically a shortened sleep latency and extended non-rapid eye movement sleep duration, with elevated serum melatonin and serotonin levels. Safety assessments including histopathological examination, biochemical analysis, and 28-day continuous administration studies confirmed excellent biocompatibility with no adverse reactions or systemic toxicity. Near-infrared fluorescence imaging provided direct evidence of enhanced transdermal absorption and superior biodistribution compared to oral administration. These findings indicate that the p(NVCL)-based melatonin transdermal gel system offers a safe, effective and convenient non-prescription option for sleep regulation, with promising potential for clinical translation as a consumer sleep aid. Full article

Antidepressants are emerging contaminants that have raised global concern due to their abuse. Venlafaxine (VFX), a serotonin and norepinephrine reuptake inhibitor, can cause adverse and potentially toxic effects on aquatic organisms. Electrochemical advanced oxidation processes (EAOPs) are gaining attention as promising degradation techniques for a variety of drugs. EAOP methods proposed for VFX degradation mainly utilize boron-doped diamond (BDD) electrodes, characterized by low background current and high oxygen overpotential. However, challenges arise, including delamination from the substrate, difficulties in scaling up, and limited service life. In this study, platinum was employed as an anode for the galvanostatic degradation of VFX, due to its stability and well-established surface cleaning procedure, which ensured high reproducibility. A 0.1 M Na₂SO₄ solution at pH 9 was used as the supporting electrolyte, and a current density of 25 mA/cm² was applied. After 7 h, a degradation efficiency of 94% was achieved for a 25 ppm VFX solution. The hydroxyl and sulfate radicals generated in the electrochemical system were the active species responsible for VFX degradation, which followed a first-order kinetic model with a rate constant of 0.0084 min⁻¹. The main degradation intermediates were identified through LC-MS, including two isomers with a nominal m/z of 276 and three isomers with a nominal m/z of 294. The toxicity of the VFX degradation products was assessed by an in silico prediction model. This evaluation confirmed the sustainability of the developed method. Full article

Alzheimer’s disease (AD) is characterized by oxidative stress, amyloid-beta (Aβ) deposition, and tau hyperphosphorylation. While polysaccharides have demonstrated anti-AD effects, the properties of Cremastra appendiculata polysaccharides (CAPs) remain underexplored. This study evaluates the physicochemical properties, antioxidant activity, anti-AD effects, and underlying mechanisms of CAP in vitro and in Caenorhabditis elegans (C. elegans) AD models. CAP, containing 22.37% uronic acid, is stable below 270 °C and adopts a triple helix structure. Scanning electron microscopy (SEM) reveals an irregular layered architecture. In vitro, CAP exhibits significant antioxidant activity, protecting PC12 cells from Aβ-induced cytotoxicity. In C. elegans, CAP extends the lifespan in a concentration-dependent manner without affecting growth, alleviating tau-induced locomotor defects, reducing Aβ-induced paralysis and serotonin hypersensitivity, and decreasing Aβ deposition by 79.96% at 2.0 mg/mL. CAP enhances antioxidant capacity and heat resistance by reducing reactive oxygen species (ROS) levels and increasing glutathione S-transferase 4 (GST-4) and glutathione peroxidase (GSH-Px) activities. Additionally, CAP upregulates key genes in the insulin/insulin-like growth factor signaling pathway, including daf-16 and skn-1, along with their downstream targets (sod-3, ctl-1, gst-4, hsp-70). These findings suggest that CAP has potent antioxidant and anti-AD effects, alleviating Aβ- and tau-induced toxicity, and may serve as a promising therapeutic agent for Alzheimer’s disease. Full article

Background/Objectives: Montelukast (MLK), a leukotriene receptor antagonist, has been associated with neuropsychiatric side effects. This study aimed to rationally modify MLK’s structure to reduce these risks by optimizing its interactions with dopamine D2 (DRD2) and serotonin 5-HT1A receptors using computational molecular simulation techniques. Methods: A library of MLK derivatives was designed and screened using structural similarity analysis, molecular docking, molecular dynamics (MD) simulations, MM/PBSA binding free energy calculations, and ADME-Tox predictions. Structural similarity analysis, based on Tanimoto coefficient fingerprinting, compared MLK derivatives to known neuropsychiatric drugs. Docking was performed to assess initial receptor binding, followed by 100 ns MD simulations to evaluate binding stability. MM/PBSA calculations quantified binding affinities, while ADME-Tox profiling predicted pharmacokinetic and toxicity risks. Results: Several MLK derivatives showed enhanced DRD2 and 5-HT1A binding. MLK_MOD-42 and MLK_MOD-43 emerged as the most promising candidates, exhibiting MM/PBSA binding free energies of −31.92 ± 2.54 kcal/mol and −27.37 ± 2.22 kcal/mol for DRD2 and −30.22 ± 2.29 kcal/mol and −28.19 ± 2.14 kcal/mol for 5-HT1A, respectively. Structural similarity analysis confirmed that these derivatives share key pharmacophoric features with atypical antipsychotics and anxiolytics. However, off-target interactions were not assessed, which may influence their overall safety profile. ADME-Tox analysis predicted improved oral bioavailability and lower neurotoxicity risks. Conclusions: MLK_MOD-42 and MLK_MOD-43 exhibit optimized receptor interactions and enhanced pharmacokinetics, suggesting potential neuropsychiatric applications. However, their safety and efficacy remain to be validated through in vitro and in vivo studies. Until such validation is performed, these derivatives should be considered as promising candidates with optimized receptor binding rather than confirmed safer alternatives. Full article

Background/Objectives: The purpose of this research was to investigate the effects of bisphenol A (BPA) exposure on neurobehavioral testing in young Wistar rats and to evaluate the therapeutic potential of Thymus ciliatus (TEO) essential oil to attenuate the damage induced by this chemical toxin. Methods: The essential oil was extracted by hydro-distillation (yield of 2.26%), and the characterization by GC-MS indicates that the major components of Thymus ciliatus oil are thymol (63.33%), p-cymene (13.4%), and σ-terpinene (6.69%). Acute BPA intoxication was induced with a dose of 50 mg/kg orally for 60 days. The neurobehavioral evaluation, performed using a comprehensive set of tests including the forced swim test, dark/light box, Morris water maze, open field test, and sucrose preference test, clearly demonstrated that bisphenol A (BPA) exposure induced significant neurobehavioral impairments. Results: These impairments included reduced exploratory behavior indicative of heightened stress, anxiety, and depressive-like states, as well as deficits in memory and learning. Furthermore, BPA intoxication was associated with metabolic disturbances such as hyperglycemia along with histopathological evidence of brain tissue damage. However, TEO treatment attenuated these adverse effects by restoring neurobehavioral function. Molecular docking analysis revealed an affinity between the major essential oils identified in T. ciliatus, BPA, and the 5HT2C receptor and the MAO, AChE, and BChE enzymes, suggesting a potential mechanism underlying BPA’s effects on behavior and memory. In addition, TEO also showed an interaction with these molecules, suggesting a therapeutic potential against BPA. These findings underscore the promising role of TEO in mitigating the poisonous effects of BPA and pave the way for additional research into the molecular mechanisms and therapeutic uses of natural bioactive compounds for the prevention and treatment of toxic diseases. Thymol, the major compound in TEO, exhibited activity related to the dopamine and serotonin pathways, so it could have potential antidepressant properties. Conclusions: Thymol might be a promising candidate for the treatment of neurodegenerative and neurological disorders such as depression, Parkinson’s disease, and Alzheimer’s disease while also preventing histological damage in the brain. Full article

Background/Objectives: The growing diversity of novel nanoparticle synthesis methods, particularly for silver nanoparticles (AgNP), coupled with their significant biological activity and wide range of applications across various medical fields, necessitates a comprehensive investigation into the consequences of particle-induced cellular damage. This study aimed to investigate AgNP-induced damage to macrophage plasma membranes, focusing on concentration, temperature, incubation time, and the role of pro- and antioxidant factors, using model systems based on mouse peritoneal macrophages. Methods: Mouse peritoneal macrophages were incubated with AgNP (0.1–10 μg/mL) at temperatures ranging from 4 °C to 37 °C. Membrane integrity was assessed via microfluorimetric analysis. The influence of prooxidant (UV-B) and antioxidant (serotonin) factors was also examined. A mathematical model was developed to describe the interaction between AgNP and macrophages. Results: The diameter of our synthesized silver nanoparticles, assessed via dynamic light scattering (DLS), ranged from 5 to 170 nm, with a predominant size distribution peak at 70 nm. AgNP caused dose- and temperature-dependent membrane damage, which was more pronounced at 4 °C and 37 °C than at 22 °C and increased with incubation time. UV-B enhanced membrane damage, while serotonin mitigated it. The mathematical model correlated strongly with the experimental data, emphasizing the role of ROS in membrane disruption. AgNP also dose-dependently increased ROS generation by macrophages. Conclusions: AgNP, in doses of 0.1–10 μg/mL, induces dose-dependent membrane damage in macrophages. The developed model is a useful tool for predicting nanoparticle toxicity. Together with the experimental findings, it highlights the critical role of ROS, lipid peroxidation, the lipid bilayer state, and antioxidant defenses in AgNP-induced membrane damage. Full article

Cyclodextrin (CD)-based drug delivery systems have emerged as a promising strategy to overcome limitations commonly encountered in antidepressant therapy, including low bioavailability, poor solubility, and suboptimal penetration of the blood–brain barrier. This review synthesizes current evidence demonstrating that complexing various classes of antidepressants—such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and atypical antidepressants—with β-CD or its derivatives significantly enhances drug solubility and stability. In addition, encapsulation with CDs can diminish systemic toxicity and improve pharmacokinetics, thereby helping to optimize dosage regimens and reduce adverse effects. Analysis of published in vitro and in vivo studies indicates that CD formulations not only boost therapeutic efficacy but also enable sustained or targeted release, which is critical for drugs requiring precise plasma and tissue concentrations. When compared to other carriers (e.g., liposomes, polymeric nanoparticles, dendrimers), CD-based systems often stand out for their ease of formulation, biocompatibility, and cost-effectiveness, although limited drug-loading capacity can be a drawback. We recommend expanding in vivo trials to substantiate the clinical benefits of CD–antidepressant complexes, particularly for treatment-resistant cases or specific subpopulations (e.g., elderly and pediatric patients). Additional investigations should also explore hybrid systems—combining CDs with advanced nano- or macroparticles—to amplify their advantages and address any limitations. Ultimately, integrating CDs into antidepressant regimens holds substantial potential to refine therapy outcomes, reduce adverse events, and pave the way for more personalized, effective interventions for depression. Full article

Nanoplastics (NPs) represent a major challenge in environmental contamination resulting from the physical, chemical, and biological degradation of plastics. Their characterization requires advanced and expensive methods, which limit routine analyses. The biological effects of NPs depend on their chemical and physical properties, which influence toxicity and interactions with biological systems. Studies in animal models, such as Daphnia magna and Danio rerio, show that NPs induce oxidative stress, inflammation, DNA damage, and metabolic alterations, often related to charge and particle size. NPs affect endocrine functions by acting as endocrine disruptors, interfering with thyroid and sex hormones and showing potential transgenerational effects through epigenetic modifications, including DNA hyper- and hypomethylation. Behavioral and neurofunctional alterations have been observed in Danio rerio and mouse models, suggesting a link between NP exposure and neurotransmitters such as dopamine and serotonin. Despite limited human studies, the presence of NPs in breast milk and placenta underscores the need for further investigation of health effects. Research focusing on genetic and epigenetic markers is encouraged to elucidate the molecular mechanisms and potential risks associated with chronic exposure. Full article

The increasing presence of antimicrobial agents and pesticides in aquatic environments raises concerns about their potential impacts on non-target organisms. Among these chemicals, deltamethrin (DM), a widely used pesticide, and sulfamethoxazole (SMX), an antimicrobial commonly detected in water bodies, pose significant ecological risks. This study investigates the acute toxicity, neurotoxic effects, oxidative stress responses, immune-related gene expression, and feeding behavior of adult zebrafish exposed to DM and SMX. The 96 h LC₅₀ for DM was 4.84 µg/L, indicating significant acute toxicity, while the LC₅₀ for the DM + SMX mixture was 11.32 µg/L, suggesting that SMX may mitigate the toxicity of DM. Neurotransmitter alterations, including reduced levels of γ-aminobutyric acid (γ-GABA), serotonin (5-HT), and acetylcholinesterase (AChE), were observed, with the combination of DM and SMX showing partial restoration of AChE activity. Oxidative stress markers revealed significant changes in antioxidant enzyme activities, with DM exposure increasing superoxide dismutase (SOD) and glutathione-S-transferase (GST) activities, while decreasing catalase (CAT) and glutathione peroxidase (GPX) activities. Immune-related gene expression demonstrated suppressed IgM, IgD, and IgZ levels, along with altered inflammatory responses, with both DM and DM + SMX exposure inducing pro-inflammatory cytokines. Finally, feeding behavior was significantly impaired in the DM group at the 3 min mark, while the DM + SMX group showed partial mitigation of this effect. These findings highlight the neurotoxic, immunotoxic, and behavioral effects of DM and SMX, and underscore the potential for chemical interactions to modulate toxicity in aquatic organisms. Full article

Background: Pain is a complex condition influenced by peripheral, central, immune, and psychological factors. Multitarget approaches offer a more effective and safer alternative to single-target analgesics by enhancing efficacy, reducing side effects, and minimizing tolerance. This study aimed to identify a novel multitarget analgesic with improved pharmacological properties. Methods: An in vivo-guided screening approach was used to discover a new analgesic compound. Compound 29, derived from a novel scaffold inspired by opiranserin and vilazodone pharmacophores, was identified through analog screening in the formalin test. Its efficacy was further evaluated in the spinal nerve ligation (SNL) model of neuropathic pain. Mechanistic studies explored its interaction with neurotransmitter transporters and receptors, while pharmacokinetic and safety assessments were conducted to determine its stability, brain penetration, and potential toxicity. Results: Compound 29 demonstrated high potency in the formalin test, with an ED50 of 0.78 mg/kg in the second phase and a concentration-dependent effect in the first phase. In the SNL model, it produced dose-dependent analgesic effects, increasing withdrawal thresholds by 24% and 45% maximum possible effect (MPE) at 50 and 100 mg/kg, respectively. Mechanistic studies revealed strong triple uptake inhibition, particularly at dopamine (DAT) and serotonin (SERT) transporters, alongside high-affinity 5-HT2A receptor antagonism. Pharmacokinetic analysis indicated enhanced stability and blood–brain barrier permeability. In vitro studies confirmed its nontoxicity to HT-22 cells but revealed potential hERG inhibition and strong CYP3A4 inhibition. Conclusions: Compound 29 is a promising multitarget analgesic with potent efficacy and favorable pharmacokinetics. Ongoing optimization efforts aim to mitigate side effects and enhance its therapeutic profile for clinical application. Full article

The aim of the present study was to investigate the phenolic composition and the efficacy of an innovative formulation based on Mg, Vitamin B6, and water extracts from Vitex agnus-castus, Crocus sativus, Melissa officinalis, Betula pendula, and Betula pubescens developed as an effective tool to face neuroinflammation and depression symptoms occurring in premenstrual syndrome (PMS). The formulation was analyzed through colorimetric and liquid chromatography methods for determining the content in phenols and flavonoids. Additionally, scavenging/reducing properties were investigated via 2,2-diphenyl-1-picrylhydrazyl (DPPH,) 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and horseradish peroxidase assays. The biocompatible limits were determined via allelopathy, the brine shrimp lethality test, and Daphnia magna cardiotoxicity assay. The formulation was then assayed in an experimental model constituted by isolated mouse cortex specimens exposed to K⁺ 60 mM Krebs–Ringer buffer, a toxic depolarizing stimulus able to reproduce the burden of inflammation/oxidative stress and the increased serotonin (5-hydroxytryptamine, 5-HT) impoverishment occurring in different neurological and psychiatric conditions, including depression. The results of the phytochemical analysis showed that the formulation is rich in benzoic acids, namely gentisic acid (155.31 µg/mL) and phenylethanoid compounds, namely hydroxytyrosol (39.79 µg/mL) that support the antioxidant effects measured via DPPH (IC₅₀: 1.48 mg/mL), ABTS (IC₅₀: 0.42 mg/mL), and horseradish peroxidase (IC₅₀: 2.02 mg/mL) assays. The ecotoxicological models indicated the formulation as non-toxic, permitting the identification of a biocompatible concentration (1000 µg/mL) to be used in isolated mouse cortex exposed to K⁺ 60 mM Krebs–Ringer buffer. In this model, the gene expression of cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), estrogen receptor-1 (ESR1), prolactin receptor (PRLR), brain-derived neurotrophic factor (BDNF), and serotonin transporter (SERT) was determined by real-time PCR. In the isolated mouse cortex, the formula reduced COX-2, IL-6, SERT, ESR1, and PRLR gene expression and increased BDNF and IL-10 gene expression. Overall, the study corroborated the use of the formulation as an innovative tool to contrast inflammation, oxidative stress, and neurotransmitter impairment associated with PMS. Full article

The aim of our research was to understand the impact of ochratoxin A (OTA) exposure on various physiological and behavioral aspects in adult Wistar rats, and to evaluate the efficacy of a Syzygium aromaticum essential oil (EOC) treatment in restoring the damage caused by this toxin. The essential oils were extracted by hydrodistillation, a yield of 12.70% was obtained for EOC, and the GC-MS characterization of this essential oil revealed that its principal major components are eugenol (80.95%), eugenyl acetate (10.48%), β-caryophyllene (7.21%), and α-humulene (0.87%). Acute OTA intoxication was induced by an intraperitoneal (IP) injection of 289 µg/kg/b.w. every 48 h for 12 doses, resulting in significant reductions in the body and brain weights of exposed rats when compared with controls. The neurobehavioral analysis using several behavioral testing techniques, such as the forced swimming, the dark/light test, the Morris water maze, and the open field test, clearly revealed that OTA exposure causes neurobehavioral disorders, including decreased locomotor activity, a reduced willingness to explore the environment, reflecting a state of stress, anxiety and depression, as well as impaired memory and learning. In addition, OTA intoxication has been associated with metabolic disturbances such as hyperglycemia and hypercortisolemia. However, treatment with EOC mitigated these adverse effects by improving body and brain weights and restoring neurobehavioral function. The in silico analysis revealed significant affinities between clove oils and two tested esterase enzymes (ACh and BuChE) that were more than or similar to the four neurotransmitters “dopamine, serotonin, norepinephrine, and glutamic acid” and the co-crystallized ligands NAG, MES, and GZ5. These results highlight the therapeutic potential of EOC in combating the toxic effects of OTA and pave the way for future research into the mechanisms of action and therapeutic applications of natural compounds in the prevention and treatment of poison-induced diseases. Full article