Search Results (142)

It has been demonstrated that prolonged exposure to stress engenders a plethora of neuropsychiatric, immune and metabolic disorders. However, its pathophysiology transcends the conventional hypothalamic–pituitary–adrenal (HPA) axis. This review addresses the central question of how integrated neural and microbial pathways regulate stress responses and resilience. We present a model in which the parasympathetic nervous system (particularly the vagus nerve) and the gut microbiota interact to form a bidirectional neuroimmune network that modulates the HPA axis, immune function, neurotransmitter balance, and metabolic adaptation. Key molecular pathways include nitric oxide synthesis via the classical nitric oxide synthase (NOS)-dependent and microbiota-mediated nitrate–nitrite routes, inducible nitric oxide synthase (iNOS) regulation, nuclear factor erythroid 2-related factor 2 (Nrf2) signalling, lysosomal function, autophagy and the cholinergic anti-inflammatory reflex. Other pathways include the gamma-aminobutyric acid (GABA) and serotonin (5-HT) systems, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signalling, polyamine metabolism and peroxisome proliferator-activated receptor gamma (PPARγ). Intermittent hypoxia training (IHT) enhances mitochondrial function, oxidative stress responses, autonomic balance and gut microbiota composition. This promotes parasympathetic activity and stress resilience that is tailored to the individual. These adaptations support the concept of personalised stress response profiles based on hypoxic adaptability. Clinical implications include combining IHT with vagus nerve stimulation, probiotics, dietary strategies, and stress reduction techniques. Monitoring vagal tone and microbiota composition could also serve as predictive biomarkers for personalised interventions in stress-related disorders. This integrative framework highlights the therapeutic potential of targeting the parasympathetic system and the gut microbiota to modulate stress. Full article

Background/Objectives: Thermoregulation is essential for survival, with the hypothalamic preoptic area integrating peripheral signals to maintain core body temperature. While fever enhances immune responses, excessive hyperthermia causes cellular damage. Previous work has shown that central glucagon-like peptide-1 (GLP-1) receptor antagonism intensifies lipopolysaccharide (LPS)-induced fever, suggesting a role for GLP-1 signaling in temperature regulation. However, the direct effects of GLP-1 receptor agonists on fever remained unexplored. This study investigated the effects of liraglutide (LIRA), a GLP-1 analog used to treat diabetes and obesity, on temperature regulation and fever in rats, with a focus on sex-dependent mechanisms. Methods: Male and female Wistar rats received lipopolysaccharide (LPS, i.p.) to induce fever, followed by LIRA treatment (0.3 mg/kg, i.p.) one hour later. Body temperature was monitored for up to six hours post-LPS injection. Results: LIRA reduced body temperature in both euthermic and febrile rats of both sexes. LPS increased PGE₂ concentration in both sexes, with males showing a twofold increase compared to females. LIRA treatment reduced PGE₂ levels in LPS-challenged males (62%, p < 0.01) but not in female rats. LPS elevated interleukin (IL)-6 levels in both sexes, while LIRA treatment decreased IL-6 only in females (45%, p < 0.05). In males, LPS reduced hypothalamic serotonin (5-HT) levels, and LIRA further decreased 5-HT in saline-treated animals. In females, LIRA increased 5-HT levels (84%, p < 0.01) in LPS-challenged animals. Additionally, LIRA exhibited sex-specific effects on hypothalamic JNK phosphorylation, increasing activation in LPS-treated males and reducing it in LPS-treated females. Conclusions: LIRA demonstrates antipyretic properties through distinct, sex-specific mechanisms. In males, temperature reduction correlates with decreased hypothalamic PGE₂, whereas in females, antipyretic effects are associated with reduced IL-6, decreased JNK phosphorylation, and increased 5-HT. These findings reveal sexually dimorphic GLP-1R-mediated thermoregulatory pathways during inflammation. However, the causal relationships between these molecular changes and temperature regulation require further investigation, particularly regarding whether observed biochemical alterations represent primary mechanisms or secondary consequences of temperature modulation. Future studies should investigate the functional significance of the apparent contradiction in serotonergic responses between sexes. Full article

Serotonin (5-HT) is a vital intercellular messenger with diverse signaling functions throughout the human body. We have characterized and implemented a novel, in vitro fluorescence-based method of measuring 5-HT binding to gain a fuller understanding of the interactions between 5-HT and its receptors. This method involves expression of 5-HT receptor proteins in cultured cells with the fluorescent, non-canonical amino acid l-3-(6-acetylnaphthalen-2-ylamino)-2-aminopropanoic acid (ANAP) incorporated into the ligand binding site. ANAP fluorescence was quenched in solution by both 5-HT and dopamine. Time-resolved photoluminescence and transient absorption spectroscopy confirmed that ANAP quenching by 5-HT occurs via a charge-transfer process that recovers through back-electron transfer on the nanosecond timescale. Supported by density functional theory calculations, this process likely involved an ANAP reduction by 5-HT. To test this method on intact receptors in a cellular context, we expressed 5-HT_3A receptors (5-HT-gated ion channels) in HEK293T cells with ANAP inserted co-translationally into the transmitter binding site. Fluorescently labeled 5-HT_3A receptors were functional and activated by 5-HT, as assessed by whole-cell patch clamp. Addition of 5-HT caused a concentration-dependent quenching of fluorescence from ANAP-tagged channels in intact cells and unroofed plasma membranes, demonstrating the utility of this method for measuring 5-HT binding to its receptors. Collectively, these results delineate a technique for measuring transmitter binding that can be widely adopted to explore 5-HT binding not only to 5-HT₃ receptors, but to any 5-HT receptor, transporter, or binding protein in heterologous expression systems. Full article

Background: Burning Mouth Syndrome (BMS) is a nociplastic pain condition characterized by altered central nervous system pain processing, significantly impacting patient quality of life. Pharmacological management often involves amitriptyline (monotherapy) and aripiprazole (for refractory cases) in Japan. However, the therapeutic efficacy of these drugs in BMS frequently exhibits a non-sigmoid (U-shaped or bell-shaped) dose–response relationship, indicating a clinically effective dose that is often considerably lower than those used for their primary indications and challenging conventional pharmacological assumptions. Method: This paper synthesizes existing pharmacological knowledge to elucidate the mechanisms underlying the non-dose-dependent actions of amitriptyline and aripiprazole in BMS. It focuses on their specific interactions with key neurotransmitter systems and receptors, particularly N-methyl-D-aspartate (NMDA) receptors and dopamine D2 receptors, to explain the observed non-linear dose–response and the importance of identifying a personalized therapeutic window. Result: Amitriptyline demonstrates efficacy in BMS at low doses (e.g., 25 mg), primarily through its action as an NMDA receptor antagonist via calcium-dependent desensitization and open-channel block, addressing central sensitization. Its effects are distinct from its antidepressant actions, and the “serotonin paradox” highlights the complexity of serotonin’s role in pain. Aripiprazole, utilized for refractory BMS, acts as a dopamine D2 receptor partial agonist, leading to a non-linear dose–response where sustained therapeutic effect is observed at specific low doses (e.g., 1.7–1.8 mg/day). This non-linearity is attributed to partial agonism, alongside interactions with serotonin 5-HT1A and 5-HT2A receptors. The general non-dose-dependency for both drugs is further explained by phenomena such as multiple binding sites with differing affinities, receptor desensitization/downregulation, activation of counter-regulatory mechanisms, and hormesis. Discussion: The observed non-linear dose–response curves for amitriptyline and aripiprazole in BMS underscore the inadequacy of a “one-size-fits-all” treatment approach. This necessitates a shift towards personalized medicine, which considers individual patient factors including pharmacogenomics, comorbidities, age, organ function, and psychological/social profiles. The true “personalized therapeutic window” is a balance between achieving significant pain relief and minimizing adverse effects, emphasizing careful titration and patient-centered care. Conclusions: The pharmacological actions of amitriptyline and aripiprazole in BMS are not linearly dose-dependent, but rather exhibit a personalized therapeutic window driven by complex interactions with NMDA and D2 receptors and adaptive physiological responses. This intricate pharmacological landscape mandates a personalized medicine approach to optimize treatment outcomes, improve patient adherence, and enhance the quality of life for individuals suffering from this challenging nociplastic pain condition. Full article

Background: Natural compounds, including ellagic acid (ELG), are promising anticancer agents with low adverse effects. In this paper, we test in vitro the effectiveness of mesoporous silica nanoparticles (MSN) as an ELG carrier against colon cancer. Methods: We produced MSNs functionalized with triptycene (TRP) and loaded with ELG, further called MSNTRPELG nanoformulation. The nanoformulation contained over 11 wt.% TRP and approximately 25 wt.% ELG in the mesoporous structure and on the surface of particles. It was assessed for anticancer effects against two colon cancer cells: HCT-116 and HT-29 for treatment with up to 200 µM. Results: Comparing to free ELG, we have shown a three times higher cancer inhibition. The lowest IC50 values were for HCT-116 (88.1 ± 0.1 µM) and HT-29 (77.6 ± 0.1 µM). When treated with free ELG, the values were 187.1 ± 0.1 µM and 300.0 ± 0.1 µM, respectively. MSNTRPELG enhanced apoptosis primarily by activating caspase-3, p53, and Bax while downregulating Bcl-2 in HCT-116 and HT-29 cells. It also inhibited receptor tyrosine kinases (HER2 and VEGFR2). Preliminary Western blot observations suggest suppression of B-RAF, C-RAF, and K-RAS oncogenes, with stronger inhibition by the nanoformulation than by free ELG. Conclusions: This work highlights the potential of MSNs to enhance the efficacy of natural prodrugs, particularly ELG, in cancer therapy. Full article

Background: Patients with sepsis-associated encephalopathy (SAE) present with cognitive impairments. Serotonergic neurotransmission plays a critical role in regulating cognitive processes, and its dysfunction may contribute to SAE-related deficits. However, the effect of 5-hydroxytryptophan (5-HTP), a direct serotonin precursor, on SAE has not been investigated. We hypothesized that 5-HTP could alleviate cognitive dysfunction in SAE. Methods: The SAE mouse model was induced via intraperitoneal administration of lipopolysaccharide (LPS, 10 mg/kg). Cognitive function and locomotor activity were assessed using the Barnes maze, novel object recognition test, and open-field test to evaluate the effects of 5-hydroxytryptophan (5-HTP). Additionally, WAY100635, a selective 5-HT1A receptor antagonist, was co-administered with 5-HTP to investigate the potential mechanisms underlying its effects on SAE-related cognitive dysfunction. The effects of 5-HTP and WAY100635 on cognition and motor activity were also investigated in healthy mice. Results: LPS-induced sepsis caused a learning deficit. A dose of 10 mg/kg 5-HTP improved cognitive dysfunction, whereas doses of 25 and 100 mg/kg worsened cognitive dysfunction. Moreover, 100 mg/kg 5-HTP increased mortality in SAE mouse models. Neither 5-HTP (10 mg/kg) nor WAY100635 (1 mg/kg) alone exerted a significant impact on the locomotor activity or cognitive function of healthy mice. The cognition-enhancing effect of 5-HTP (10 mg/kg) was reversed by WAY100635 (1 mg/kg). Conclusions: improvement in cognitive dysfunction by 5-HTP suggests that serotonergic transmission plays a role in the pathophysiology of SAE, and 5-HTP, an over-the-counter supplement approved for human use, may hold clinical potential for the prevention and treatment of SAE. Full article

Insomnia is a common and complex disorder, rooted in the dysregulation of circadian rhythms, impaired neurotransmitter function, and disturbances in sleep–wake homeostasis. While conventional hypnotics such as benzodiazepines and Z-drugs are effective in the short term, their use is limited by a high potential for dependence, cognitive side effects, and withdrawal symptoms. In contrast, melatonergic receptor agonists—melatonin, ramelteon, tasimelteon, and agomelatine—represent a pharmacologically targeted alternative that modulates MT1 and MT2 receptors, which are pivotal to the regulation of circadian timing and sleep initiation. Clinical evidence supports the efficacy of these agents in reducing sleep onset latency, extending total sleep duration, and re-aligning disrupted circadian rhythms, particularly among older individuals and patients with non-24 h sleep–wake disorders. Notably, agomelatine offers additional antidepressant properties through selective antagonism of the 5-HT_2C receptor in micromolar concentrations. In contrast, its agonistic activity at melatonergic receptors is observed in the low sub-nanomolar range, which illustrates the complexity of this drug’s interactions with the human body. All compounds reviewed demonstrate a generally favorable safety and tolerability profile. Accumulating evidence highlights that selected medicinal plants, such as chamomilla, lemon balm, black cumin, valeriana, passionflower and lavender, may exert relevant hypnotic or anxiolytic effects, thus complementing melatonergic strategies in the management of insomnia. This structured narrative review presents a comprehensive analysis of the molecular pharmacology, receptor affinity, signaling pathways, and clinical outcomes associated with melatonergic agents. It also examines their functional interplay with serotonergic, GABAergic, dopaminergic, and orexinergic systems involved in arousal and sleep regulation. Through comparative synthesis of pharmacokinetics and neurochemical mechanisms, this work aims to inform the development of evidence-based strategies for the treatment of insomnia and circadian rhythm sleep–wake disorders. Full article

We report the synthesis and characterization of folic acid (FA)-conjugated human serum albumin nanoparticles, (HSA-FA):Ru NPs, as targeted carriers for rutin (Ru), a flavonoid with known anticancer activity. Nanoparticles were fabricated via a desolvation method, and their surface was functionalized with folic acid to promote selective uptake by cancer cells overexpressing folate receptors. Morphological and dimensional analyses performed by atomic force microscopy (AFM), scanning electron microscopy (SEM), and fluorescence microscopy confirmed that all nanoparticles were below 100 nm and exhibited good colloidal stability. Voltametric measurements confirmed the successful incorporation of both rutin and folic acid within the (HSA-FA):Ru nanoparticle formulation. Biological evaluation was conducted on healthy L929 fibroblasts and HT-29 colon adenocarcinoma cells. MTS colorimetric assays revealed that (HSA-FA):Ru NPs significantly reduced the viability of HT-29 cells, while maintaining higher compatibility with L929 cells. Fluorescence and electron microscopy further confirmed preferential nanoparticle uptake and surface accumulation in HT-29 cells, supporting the role of folic acid in enhancing targeted delivery. The study demonstrates that HSA-based nanoparticles functionalized with FA and loaded with Ru offer a biocompatible and efficient strategy for selective intracellular drug delivery in colorectal cancer. These findings support the use of albumin-based nanocarriers in the development of targeted therapeutic platforms for cancer treatment. Full article

5-HT4 receptors play an important role in the regulation of synaptic plasticity. However, the effect of 5-HT4Rs on neural network activity and intercellular calcium signaling remains enigmatic. Using calcium imaging and original software, we determined the network-level characteristics of calcium dynamics within primary hippocampal cultures. We found that the single activation of 5-HT4 receptors by BIMU8 significantly reduced the correlation of activity within neuron–glial networks of primary cultures, without altering the proportion of active cells or the frequency of calcium events. In contrast, chronic stimulation of 5-HT4Rs promoted greater cell involvement in Ca²⁺ signal generation and increased the frequency of calcium events, while maintaining the connectivity level of the neuron–glial network. Moreover, our immunocytochemical labeling results indicated that chronic stimulation of 5-HT4Rs increased the size of both presynaptic and postsynaptic terminals. The acute blockade of 5-HT4Rs by RS23597-190 exerted a marked inhibitory effect on calcium activity in primary hippocampal cultures. Network connectivity and correlation of calcium activity were disrupted, and the number of functional connections among cells sharply declined. Our study showed that 5-HT4 receptors exhibit diverse effects based on the type and duration of activation, mediating several key functions in regulating neural network calcium activity. Full article

Cancer is a major global health issue, with rising incidence rates highlighting the urgent need for more effective treatments. Despite advances in cancer therapy, challenges such as adverse effects and limitations of existing treatments remain. Immunotherapy, which harnesses the body’s immune system to target cancer cells, offers promising solutions. Gamma delta (γδ) T cells are noteworthy due to their potent ability to kill various cancer cells without needing conventional antigen presentation. Recent studies have focused on the role of γδ T cells in α-galactosylceramide (α-GalCer)-mediated immunity, opening new possibilities for cancer immunotherapy. We engineered humanized T cell receptor (HuTCR)-T1 γδ mice by replacing mouse sequences with human counterparts. This study investigates the cytotoxic activity of humanized γδ T cells against several human cancer cell lines (A431, HT-29, K562, and Daudi) in vitro, aiming to elucidate mechanisms underlying their anticancer efficacy. Human cancer cells were co-cultured with humanized γδ T cells, with and without α-GalCer, for 24 h. The humanized γδ T cells showed enhanced cytotoxicity across all tested cancer cell lines compared to wild-type γδ T cells. Additionally, γδ T cells from HuTCR-T1 mice exhibited higher levels of anticancer cytokines (IFN-γ, TNF-α, and IL-17) and Granzyme B, indicating their potential as potent mediators of anticancer immune responses. Blocking γδ T cells’ cytotoxicity confirmed their γδ-mediated function. These findings represent a significant step in preclinical development of γδ T cell-based cancer immunotherapies, providing insights into their mechanisms of action, optimization of therapeutic strategies, and identification of predictive biomarkers for clinical application. Full article

Sleep paralysis (SP), an REM parasomnia, can be characterized as one of the symptoms of narcolepsy. The SP phenomenon involves regaining meta-consciousness by the dreamer during REM, when the physiological atonia of skeletal muscles is accompanied by visual and auditory hallucinations that are perceived as vivid and distressing nightmares. Sensory impressions include personification of an unknown presence, strong chest pressure sensation, and intense fear resulting from subjective interaction with the unfolding nightmare. While the mechanism underlying skeletal muscle atonia is known, the physiology of hallucinations remains unclear. Their complex etiology involves interactions among various membrane receptor systems and neurotransmitters, which leads to altered neuronal functionality and disruptions in sensory perception. According to current knowledge, serotonergic activation of 5-hydroxytryptamine-receptor-2A (5-HT2A)-associated pathways plays a critical role in promoting hallucinogenesis during SP. Furthermore, they share similarities with psychedelic-substance-induced ones (i.e., LSD, psilocybin, and 2,5-dimethoxy-4-iodoamphetamine). These compounds also target the 5-HT2A receptor; however, their molecular mechanism varies from serotonin-induced ones. The current review discusses the intracellular signaling pathways responsible for promoting hallucinations in SP, highlighting the critical role of β-arrestin-2. We propose that the β-arrestin-2 signaling pathway does not directly induce hallucinations but creates a state of network susceptibility that facilitates their abrupt emergence in sensory areas. Understanding the molecular basis of serotonergic hallucinations and gaining better insight into 5-HT2A-receptor-dependent pathways may prove crucial in the treatment of multifactorial neuropsychiatric disorders associated with the dysfunctional activity of serotonin receptors. Full article

According to our research, the flowers from Citrus grandis ‘Tomentosa’ contain rich biologically active essential oil components, but the chemical components and relative pharmacological properties have not been systematically studied. Therefore, the study aimed to identify the essential oil components by GC-MS/MS and explore the pharmacological activity and mechanism of these essential oil components by a network pharmacology approach. Finally, GC-MS/MS analysis identified 43 essential oil components, which corresponded to 739 potential targets. GO analysis results showed that 12, 18, and 12 entries were related to biological processes, cellular components, and molecular functions, respectively. A total of 120 pathways were obtained based on KEGG analysis, of which the most important was the adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway. The “active component–target–disease” network further demonstrated these essential oil components’ potential efficacy against pain, tumors, neuropsychiatric diseases, eye diseases, and respiratory diseases, which were highly related to PPARA, GABRA1, PTGS2, and SLC6A2. Experimental validation confirmed that β-caryophyllene, a major constituent, dose-dependently inhibited the proliferation of HT29 and MCF-7 cells (0–320 μM). This study provides a reliable basis for elucidating the pharmacological activity of the essential oil components and related mechanisms, which is beneficial to the comprehensive utilization and development of Citrus grandis ‘Tomentosa’. Full article

Background: Dorsal raphe serotonin (5-hydroxytryptamine, 5-HT) neurons are spontaneously active and release 5-HT that is critical for normal brain function and regulates mood and emotion. Serotonin reuptake inhibitors (SSRIs) increase the synaptic and extracellular 5-HT level and are effective in treating depression. Treatment of two weeks or longer is often required for SSRIs to produce clinical benefits. The cellular mechanism underlying this delay is not fully understood. Methods and Results: Using whole-cell patch clamp recording in brain slices, here we show that the GABAergic inputs inhibit the spike firing of raphe 5-HT neurons. This GABAergic regulation was reduced by 5-HT; additionally, this 5-HT effect was prevented by the G-protein-activated inwardly rectifying potassium (GirK) channel inhibitor tertiapin-Q, indicating a contribution of 5-HT activation of GirK channels in GABAergic presynaptic axon terminals. Equally important, after 14 days of treatment with fluoxetine, a widely used SSRI type antidepressant, the 5-HT inhibition of GABAergic inputs was downregulated. Furthermore, chronic fluoxetine treatment downregulated the 5-HT activation of the inhibitory GirK current in 5-HT neurons. Conclusions: Taken together, our results suggest that chronic fluoxetine treatment, by blocking 5-HT reuptake and hence increasing the extracellular 5-HT level, can downregulate the function of 5-HT1B receptors on the GABAergic afferent axon terminals synapsing onto 5-HT neurons, allowing extrinsic GABAergic neurons to more effectively influence 5-HT neurons; simultaneously, chronic fluoxetine treatment also downregulated somatic 5-HT autoreceptor-activated GirK channel-mediated hyperpolarization and decrease in input resistance, rendering 5-HT neurons resistant to autoinhibition and leading to increased 5-HT neuron activity. These neuroplastic changes in raphe 5-HT neurons and their GABAergic afferents may contribute to the behavioral effect of SSRIs. 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

Serotonin (5-HT), dopamine (DA), and norepinephrine (NE) are key monoamine neurotransmitters regulating behaviors, mood, and cognition. 5-HT affects early brain development, and its dysfunction induces brain vulnerability to stress, raising the risk of depression, anxiety, and autism in adulthood. These neurotransmitters are synthesized from tryptophan and tyrosine via hydroxylation and decarboxylation, and are metabolized by monoamine oxidase (MAO). This review aims to summarize the current findings on the role of dietary phytochemicals in modulating monoamine neurotransmitter biosynthesis, metabolism, and function, with an emphasis on their potential therapeutic applications in neuropsychiatric disorders. Phytochemicals exert antioxidant, neurotrophic, and neurohormonal activities, regulate gene expression, and induce epigenetic modifications. Phytoestrogens activate the estrogen receptors or estrogen-responsive elements of the promoter of target genes, enhance transcription of tryptophan hydroxylase and tyrosine hydroxylase, while inhibiting that of MAO. These compounds also influence the interaction between genetic and environmental factors, potentially reversing dysregulated neurotransmission and the brain architecture associated with neuropsychiatric conditions. Despite promising preclinical findings, clinical applications of phytochemicals remain challenging. Advances in nanotechnology and targeted delivery systems offer potential solutions to enhance clinical efficacy. This review discusses mechanisms, challenges, and strategies, underscoring the need for further research to advance phytochemical-based interventions for neuropsychiatric diseases. Full article