Search Results (95)

Neuro-oncology focuses on the diagnosis and treatment of brain tumors, which, despite their rarity, are associated with high mortality due to their invasiveness and limited treatment options. Emerging evidence suggests that dopamine (DA), a neurotransmitter crucial for cognitive and emotional processes, and its receptors may influence tumor growth and the tumor microenvironment. This study aimed to evaluate the potential anticancer effects of repurposed antipsychotic dopamine-targeting drugs (Clozapine, CLZ; Pimozide, PIM; Olanzapine, OLZ; and Risperidone, RIS) and antiemetic drugs (Domperidone, DOM; Droperidol, DRO) on neuroblastoma (SH-SY5Y) and glioblastoma (A172) cell lines, and to assess whether their efficacy is modulated by oxidative stress and DA synthesis. The drugs were first tested individually, followed by co-treatment with tyrosine (Tyr), a dopamine precursor, and hydrogen peroxide (H₂O₂), an inducer of oxidative stress. Additionally, drug activity was evaluated in the simultaneous presence of H₂O₂ and Tyr. CLZ exhibited the highest cytotoxicity in both cell lines, suggesting strong anticancer potential and also synergism among the different combinations, particularly in SH-SY5Y. Liquid chromatography of the extracellular medium showed greater Tyr consumption in SH-SY5Y compared to A172 cells, indicating a higher dependence on extracellular Tyr to mitigate drug- and/or stress-induced cytotoxicity. In summary, several of the repurposed antipsychotics demonstrated cytotoxic effects on central nervous system tumor cells, with CLZ showing the most promising activity, even under oxidative stress conditions. These findings support further investigation into dopamine-targeting drugs as potential therapeutic agents in neuro-oncology. Full article

Dopamine (DA) is a neurotransmitter responsible for important functions in mammals’ bodies, including mood, movement and motivation. High or low dopamine levels are associated mainly with mental illnesses such as schizophrenia and depression. Therefore, contributing to the development of electrochemical devices to precisely determine the DA levels in urine samples, a simple and low-cost sensor is proposed in this work. The proposed sensor design is based on crosslinked chitosan films combining carbon black (CB) and deep eutectic solvents (DESs), incorporated onto the surface of a glassy carbon electrode (GCE). Fourier Transform Infrared Spectroscopy (FT-IR) was applied to characterize the produced DESs and their precursors, while the films were characterized by scanning electron microscopy (SEM), electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV). The sensor modified with CB and DES–ethaline (DES (ETHA)-CB/GCE) showed a significantly enhanced analytical signal for DA using differential pulse voltammetry under the optimized working conditions. Moreover, a better heterogeneous electron transfer rate constant (k⁰) was obtained, about 45 times higher than that of the bare GCE. The proposed sensor achieved a linear response range of 0.498 to 26.8 µmol L⁻¹ and limits of detection and quantification of 80.7 and 269 nmol L⁻¹, respectively. Moreover, the sensor was successfully applied in the quantification of DA in the synthetic urine samples, with recovery results close to 100%. Furthermore, the sensor presented good precision, as shown from the repeatability tests. The presented method to electrochemically detect DA has proven to be efficient and simple compared to the conventional methods commonly reported. Full article

Medulloblastoma (MB) is the most common malignant brain tumor in children and typically arises in the cerebellum, likely due to disruptions in neuronal precursor development. The primary inhibitory neurotransmitter in the central nervous system (CNS), γ-aminobutyric acid (GABA), exerts its effects through GABA_A, GABA_B, and GABA_C receptors. GABA receptor activity regulates the development and function of cerebellar neurons, including glutamatergic cerebellar granule cells (CGCs). Beyond the nervous system, GABA is also a common metabolite in non-neuronal cell types. An increasing body of evidence indicates that GABA can influence cell proliferation, differentiation, and migration in several types of adult solid tumors, including brain cancers. GABA and GABA_A receptor agonists can impair the viability and survival of MB cells, primarily acting on GABA_A receptors containing the α5 subunit. A marked expression of the gene encoding the α5 subunit is found across all MB tumor molecular subgroups, particularly Group 3 MB, which has a poor prognosis. Importantly, high levels of the γ-aminobutyric acid type A receptor subunit α5 (GABRA5) gene are associated with shorter patient overall survival in Group 3 and Group 4 MB. In contrast, high γ-aminobutyric acid type A receptor subunit β1 (GABRB1) gene expression is related to longer survival in all MB subgroups. The GABAergic system may, therefore, regulate MB cell function and tumor progression and influence patient prognosis, and is worthy of further investigation as a biomarker and therapeutic target in MB. Full article

We aimed to simulate tau abnormalities—specifically hyperphosphorylation and aggregation—that are hallmarks of tauopathies, including Alzheimer’s disease, to evaluate tau-targeting therapies. To model pathological p-tau accumulation at early disease stages, we exposed mouse cortical cultures to redox-active iron from hemin (Hm), a breakdown product of hemoglobin, or challenged them with the excitatory neurotransmitter glutamate. Using the AT8 phospho-specific antibody, we demonstrate that a subtoxic concentration of Hm (3 µM) promotes pathological p-tau accumulation in a subpopulation of cultured cortical neurons and their proximal neurites. Uric acid (UA; 0.1–200 µM), the metabolic end-product of purines in humans, prevented p-tau build-up. Neither xanthine, the immediate precursor of UA, nor allantoin, its oxidized product, reproduced this effect. Live cell imaging studies revealed that UA operates by repressing iron-driven lipid peroxidation. DOT (3 µM), a brain-permeant tetracycline (TC) without antibiotic activity, mimicked UA’s anti-tau and antioxidant effects. Interestingly, both UA and DOT remained effective in preventing p-tau accumulation induced by glutamate (10 µM). To simulate tau aggregation at more advanced disease stages, we conducted a Thioflavin-T aggregation assay. Our findings revealed that UA and DOT prevented tau aggregation seeded by heparin. However, only DOT remained effective when heparin-assembled tau fibrils were used as the seeding material. In summary, our results indicate that UA-elevating agents may hold therapeutic utility for tauopathies. The non-purine compound DOT could serve as an effective alternative to UA-related therapies. Full article

Background/Objectives: Canine intervertebral disc herniation (IVDH) is an important musculoskeletal pathology. Unlike in humans, IVDH mechanisms in dogs are underinvestigated from a system-level integrative omics point of view. The aim of this study was to identify key serum molecular players in canine IVDH. Methods: An integrative multi-omics approach combining high-resolution LC-MS-based untargeted metabolomics and tandem mass tag (TMT)-based proteomics was applied. Additionally, serum zinc concentration was determined by spectrophotometry. Results: Nineteen serum metabolites were differentially abundant in IVDH dogs. Metabolite analysis highlighted dysregulation in lipoic acid and branched-chain amino acid (BCAA) metabolism, with elevated levels of valine, leucine, and isoleucine in IVDH. These findings suggest disrupted energy, nitrogen, and neurotransmitter metabolism, potentially contributing to the IVDH pathophysiology. Additionally, lower serum uridine, possibly influenced by BCAA accumulation, was observed, indicating altered neuroinflammatory responses. ELISA validation confirmed elevated serum levels of zinc-α2-glycoprotein (ZAG), alpha-1-microglobulin/bikunin precursor (AMBP), and vitronectin (VTN) in IVDH, supporting immune modulation and neuroprotective mechanisms. Serum prekallikrein (KLKB1) and Protein C inhibitor (SERPINA5), involved in fibrin cloth formation, were found to be lowered in IVDH patients. Pathway enrichment revealed disturbances in aromatic amino acid biosynthesis, with elevated phenylalanine, tyrosine, and tryptophan influencing neurotransmission and inflammation. In addition, elevated serum Zn concentration emphasized its antioxidant importance in immune response, wound healing, and neuropathic pain signaling. Conclusions: Integration with our prior CSF multi-omics data reinforced the relevance of identified molecules in IVDH-associated neurodegeneration, inflammation, and repair processes. This study offers insight into potential diagnostic biomarkers and therapeutic targets for canine IVDH through serum-based molecular profiling. Full article

Acrylamide (ACR), utilized as a precursor for producing polyacrylamide for water purification, has demonstrated neurotoxic properties. However, the mechanisms underlying its neurotoxicity remain inadequately understood. In this investigation, Caenorhabditis elegans were exposed to ACR at concentrations ranging from 250 to 1000 μg/mL and then their locomotor behavior, neuronal development, neurotransmitter concentrations, and gene expression profiles were assessed. Exposure to 250–1000 μg/mL ACR resulted in observable behaviors such as head swiveling and body bending, accompanied by a significant reduction in body size. Furthermore, ACR exposure caused damage to serotonergic, cholinergic, dopaminergic, and glutamatergic neuronal structures. In this context, elevated levels of serotonin, dopamine, acetylcholine, and glutamate were detected, along with notable upregulation of the expression of genes associated with neurotransmitters, including tph-1, cat-4, mod-1, mod-5, cat-1, ser-1, dat-1, dop-1, dop-3, unc-17, cho-1, eat-4, and glr-2. Moreover, ACR exposure elevated reactive oxygen species (ROS), O₂, and H₂O₂ levels while concurrently depleting glutathione (GSH), thereby compromising the antioxidant defense system. This led to a significant upsurge in the expression of genes involved in the nematode ACR detoxification pathway, specifically daf-16, skn-1, mlt-1, sod-3, gst-4, gcs-1, hsf-1, and hsp-16.2. Additionally, Spearman correlation analysis revealed a significant inverse relationship between certain neurotransmitter and antioxidant genes and locomotor activities, highlighting the role of these genes in mediating ACR-induced neurotoxicity in C. elegans. Collectively, this research enhances the understanding of the mechanisms related to ACR neurotoxicity. Full article

Tryptophan (Trp) is an important essential amino acid that plays a variety of physiological functions in the human body, including being a precursor of neurotransmitter and participating in immune regulation. Currently, more and more studies show that some pollutants in the environment can affect the metabolism of Trp and consequently affect human health. The present paper offers a comprehensive overview of prior research investigating the impact of environmental pollutants, including inorganic and organic contaminants, microplastics, and nanoplastics on the nervous system, immune system, digestive system, and maternal–fetal pregnancy, revealing their detrimental effects on Trp metabolism and human well-being. Full article

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a progressive degeneration in the neurons of the frontal cortex, spinal cord, and brainstem, altering the correct release of neurotransmitters. The disease affects every muscle in the body and could cause death three to five years after symptoms first occur. There is currently no efficient treatment to stop the disease’s progression. The lack of identification of potential therapeutic strategies is a consequence of the delayed diagnosis due to the absence of accurate ALS early biomarkers. Indeed, neurotransmitters altered in ALS are not measurable in body fluids at quantities that allow for testing, making their use as diagnostic tools a challenge. Contrarily, neuroproteins and neuropeptides are chemical messengers produced and released by neurons, and most of them have the potential to enter bodily fluids. To find out new possible ALS biomarkers, the research of neuropeptides and proteins is intensified using mass spectrometry and biochemical-based assays. Neuropeptides derived from the proVGF precursor protein act as signaling molecules within neurons. ProVGF and its derived peptides are expressed in the nervous and endocrine systems but are also widely distributed in body fluids such as blood, urine, and cerebrospinal fluid, making them viable options as disease biomarkers. To highlight the proVGF and its derived peptides’ major roles as ALS diagnostic biomarkers, this review provides an overview of the VGF peptide alterations in spinal cord and body fluids and outlines the limitations of the reported investigations. Full article

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder marked by abdominal pain and irregular bowel habits. Recently, more and more evidence supports gut microbiota imbalance in IBS and highlights the potential of probiotics in restoring gut health and reducing symptoms. In this study, we explored the effects of Lactococcus cremoris PS133 (PS133) on an IBS-like condition in rats triggered by 5-hydroxytryptophan (5-HTP), a serotonin precursor. Eight-week-old Sprague Dawley rats received either PS133 or saline for 14 days, followed by 5-HTP to induce IBS-like symptoms. Colorectal distension tests showed that PS133 reduced visceral hypersensitivity. PS133 also protected intestinal mucin against 5-HTP-induced degradation, as seen in alcian blue staining, and increased the levels of tight junction proteins (occludin and zonula occludens-1) in the colon, indicating improved gut barrier integrity. Additionally, PS133 normalized the levels of substance P (a neuropeptide) in the spinal cord and altered 5-hydroxyindoleacetic acid (a serotonin metabolite) in the brain. Gut microbiota analysis revealed PS133 regulated specific bacterial groups, including [Eubacterium]_coprostanoligenes_group and Lactococcus. Overall, PS133 improved gut function, reduced IBS-like symptoms, and modulated gut microbiota, neurotransmitters, and intestinal barrier health in this IBS model. Full article

Monoamine neurotransmitters play a critical role in the development and function of the nervous system. In this study, we investigated the impact of parental serotonin (5-HT) modulation on the monoamine balance in the identified apical neurons of Lymnaea stagnalis embryos and its influence on embryonic locomotor activity. Using immunocytochemical and pharmacological approaches, we detected serotonin in the apical neurons of veliger-stage embryos, observing that the relative 5-HT level within these neurons varied with seasonal conditions. Pharmacological elevation of parental 5-HT levels significantly increased the relative 5-HT level in the oocytes and subsequently in the apical neurons of their offspring. Notably, while the relative dopamine (DA) levels in these neurons remained stable, the increase in the relative 5-HT level significantly enhanced the embryos’ rotational locomotion. The expression of tryptophan hydroxylase (TPH), a key enzyme in serotonin synthesis, is a prerequisite for the elevation of the relative 5-HT level in apical neurons and is detected as early as the gastrula stage. Importantly, neither a reduction of 5-HT in the maternal organism by chlorpromazine application nor its pharmacological elevation via serotonin precursor (5-HTP) application at the cleavage stage affected the monoamine balance in apical neurons. These findings provide novel insights into how the parental 5-HT level selectively alters the monoamine phenotype of the identified neurons, offering a model for studying environmentally induced neural plasticity in early development. Full article

Background: Alzheimer’s disease is a central nervous system degenerative disease closely related to age with a complex pathogenesis. As a natural medicinal plant, forest-grown ginseng (GSF) contains abundant ginsenosides and offers significant neuroprotective effects. Methods: In this study, we comprehensively investigated the effect of GSF on the cell viability of PC12 cells in an AD model alongside metabolic changes in the serum and brains of mice, combined with an efficacy evaluation of PC12 cells in vitro and UHPLC-MS-based metabolomics in vivo. The goal of this study is to clarify the potential mechanism of GSF in treating AD. Results: The PC12 cell results showed that GSF can promote the proliferation of PC12 cells, reduce the content of IL-8, increase the activity of SOD, and alleviate the inflammation and oxidative stress induced by Aβ25~35. The immunohistochemical results for the mouse brain tissue also showed that GSF could reduce the inflammatory response of mouse brain tissue by reducing the overexpression of IBa1. AD was alleviated by reducing Aβ protein deposition in the mouse brain tissue. An untargeted metabolomics analysis was performed using UHPLC-Q-Exactive MS and principal component analysis (PCA) to identify the differentially expressed metabolites in the serum and brain tissue of AD mice after treatment. Twenty and seventeen different metabolites were identified in the serum and brain tissue, respectively. The pathway enrichment analysis of differential metabolites showed that GSF could treat AD by up-regulating succinic acid semialdehyde, carbamoyl phosphate, Sphingosine 1-phosphate, L-cystathionine, 2-ketobutyric acid, Vanillylmandelic acid, and D-Ribose to regulate sphingomyelin metabolism, the synthesis and metabolism of neurotransmitters and precursors, and energy metabolism. Conclusions: GSF can reduce neuroinflammation and alleviate Alzheimer’s disease by regulating the metabolic disorders of amino acids, sphingolipids, unsaturated fatty acids, and arachidonic acid in mice serum and brain tissue metabolites. These results suggest a link between metabolite imbalance and AD, and reveal the basis for the mechanism of ginsenosides in AD treatment. Full article

Dopamine is a neurotransmitter which is classified as a catecholamine. It is also one of the main metabolites produced by some tumor types (such as paragangliomas and neoblastomas). As such, determining and monitoring the level of dopamine is of the utmost importance, ideally using analytical techniques that are sensitive, simple, and low in cost. Due to this, we have developed a non-enzymatic dopamine sensor that is highly sensitive, selective, and rapidly detects the presence of dopamine in the body. A hybrid material fabricated with NiO and ZnO, based on date fruit extract, was synthesized by hydrothermal methods and using NiO as a precursor material. This paper discusses the role of date fruit extracts in improving NiO’s catalytic performance with reference to ZnO and the role that they play in this process. An X-ray powder diffraction study, a scanning electron microscope study, and a Fourier transform infrared spectroscopy study were performed in order to investigate the structure of the samples. It was found that, in the composite NiO/ZnO, NiO exhibited a cubic phase and ZnO exhibited a hexagonal phase, both of which exhibited well-oriented aggregated cluster shapes in the composite. A hybrid material containing NiO and ZnO has been found to be highly electro-catalytically active in the advanced oxidation of dopamine in a phosphate buffer solution at a pH of 7.3. It has been found that this can be accomplished without the use of enzymes, and the range of oxidation used here was between 0.01 mM and 4 mM. The detection limit of non-enzymatic sensors is estimated to be 0.036 μM. Several properties of the non-enzymatic sensor presented here have been demonstrated, including its repeatability, selectivity, and reproducibility. A test was conducted on Sample 2 for the detection of banana peel and wheat grass, and the results were highly encouraging and indicated that biomass waste may be useful for the manufacture of medicines to treat chronic diseases. It is thought that date fruit extracts would prove to be valuable resources for the development of next-generation electrode materials for use in clinical settings, for energy conversion, and for energy storage. Full article

Methamphetamine (METH) abuse disrupts the homeostasis of neurotransmitter (NT) metabolism, contributing to a wide range of neurological and psychological disorders. However, the specific effects of METH on NT metabolism, particularly for the tryptophan (TRP) and tyrosine (TYR) metabolic pathways, remain poorly understood. In this study, serum samples from 78 METH abusers and 79 healthy controls were analyzed using Ultra-High-Performance Liquid Chromatography with Tandem Mass Spectrometry (UHPLC-MS/MS). A total of 41 substances, primarily from the TRP and TYR metabolic pathways, were detected and subjected to multivariate analysis. Principal Component Analysis (PCA) and Partial Least Squares Discriminant Analysis (PLS-DA) revealed a significant separation of serum metabolites between METH abusers and controls, encompassing the disturbance of serotonergic, kynurenic, and microbial metabolism. In the serotonergic pathway, METH significantly reduced melatonin (MLT) levels and impaired the conversion of serotonin (5-HT) to N-acetylserotonin (NAS), a key precursor of MLT. In the kynurenic pathway, METH promoted a shift to the toxic metabolic pathway, evidenced by elevated levels of 3-hydroxykynurenine (3-HK) and quinolinic acid (QA). Furthermore, microbial metabolic pathway-related indole and its derivatives were markedly suppressed in METH abusers. Gender-specific differences were also observed, with NT metabolism in TRP and TYR pathways showing more pronounced alterations in male or female subgroups. Therefore, the current study provides a comprehensive overview of the disturbance in TRP- and TYR-associated NT metabolism caused by METH abuse and highlights NT metabolism as a promising therapeutic target for METH-induced neural and psychiatric disorders. Full article

Background: Choline is an essential nutrient required for proper cell functioning. Due to its status as a precursor to acetylcholine, an important neurotransmitter connected to cognition and neuromuscular function, maintaining or enhancing choline levels is of interest. Supplementation with alpha-glycerylphosphorycholine (A-GPC) can maintain choline levels, but its ability to offer support towards cognition remains an area of ongoing research. Methods: Using a randomized, double-blind, placebo-controlled, crossover approach, 20 resistance-trained males (31.3 ± 11.0 years, 178.6 ± 7.3 cm, 84.6 ± 11.4 kg, 15.4 ± 5.6% body fat) consumed either a placebo (PL), 630 mg A-GPC (HD), or 315 mg (LD) A-GPC (GeniusPure^®, NNB Nutrition, Nanjing, China). After resting hemodynamic assessments, participants took their assigned dose and had cognitive assessments (Stroop, N-Back, and Flanker), visual analog scales, and hemodynamics evaluated 60 min after ingestion. All participants then warmed up and completed vertical jumps and bench press throws before completing a bout of lower-body resistance exercise (6 × 10 repetitions using the Smith squat at a load of 70% 1RM). Venous blood was collected 5, 15, 30, and 60 min after completion of the squat protocol to evaluate changes in growth hormones, and follow-up visual analog scales and cognitive measurements were evaluated 30 min after completing the exercise bout. Results: When compared to PL, changes in Stroop total score were statistically greater after HD (13.0 ± 8.2 vs. 5.2 ± 9.0, p = 0.013, d = 0.61) and LD (10.8 ± 7.7 vs. 5.2 ± 9.0, p = 0.046, d = 0.48) administration, in addition to significantly faster times to complete the Stroop test in the HD group when compared to PL (−0.12 ± 0.09 s vs. −0.05 ± 0.09 s, p = 0.021, d = 0.56). No significant differences between groups were found for the Flanker and N-Back assessments, while a tendency was observed for HD to have faster reaction times when compared to PL during the Flanker test. No group differences were realized for visual analog scales, physical performance, or growth hormone. Statistically significant changes in heart rate and blood pressure were observed in all groups, with all recorded values aligning with clinically accepted normative values. Conclusions: HD and LD A-GPC supplementation significantly increased cognitive performance in a group of young, healthy males as measured by changes in the Stroop Total Score and completion time of the Stroop test. These results offer unique insight into the potential for A-GPC to acutely increase cognition in a group of young, healthy males. While previous research has indicated potential for A-GPC to acutely improve cognition in clinical populations, extending these outcomes to healthy individuals can be potentially meaningful for a wide variety of populations such as athletes, race car drivers, military operators, and other non-athletic populations who desire and have a need to improve their mental performance. This study was retrospectively registered as NCT06690619 on clinicaltrials.gov. Full article

DNAJC12 deficiency is a recently described inherited metabolic disorder resulting in hyperphenylalaninemia and neurotransmitter deficiency. The effect of treatment on the prevention of neurological manifestations in this newly reported and heterogenous disorder is not fully understood, and the optimal treatment strategy remains to be elucidated. The global or regional incidence of the disease is yet to be estimated. Here, we report the first individual diagnosed with DNAJC12 deficiency in Hong Kong; the condition was picked up by newborn screening due to hyperphenylalaninemia after ruling out phenylalanine hydroxylase deficiency and other tetrahydrobiopterin related disorders. Compound heterozygous variants in the DNAJC12 gene were identified, which included a novel missense change and a nonsense pathogenic variant. Treatment with neurotransmitter precursors (tetrahydrobiopterin, levodopa, and oxitriptan) was initiated at four months of age, and dietary protein restriction was started at four years and six months of age. He remains asymptomatic at four and a half years of age, apart from having mildly impaired socio-communication and language development. In this report, we discuss the current diagnostic approach to hyperphenylalaninemia in newborn screening and the uncertainties that exist in the clinical outcome from earlier detection, treatment, and monitoring of DNAJC12-deficiency patients. Full article