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Chronic ketamine exposure results in psychotic and cognitive symptoms that resemble those found in patients with schizophrenia. Emerging evidence suggests that patients with schizophrenia exhibit gut microbiota dysbiosis and decreased levels of short-chain fatty acids (SCFAs) and BDNF, which are related to the severity of psychotic and cognitive symptoms. Dietary inulin can regulate gut microbiota, SCFAs, and BDNF. However, the role of gut microbiota, SCFAs, and BDNF in chronic ketamine-induced schizophrenia-like behaviors is unclear. In this study, we found that chronic ketamine exposure for 28 days caused gut microbiota dysregulation, reduced the expression of SCFAs in serum, hippocampus, and feces, elevated gut permeability, downregulated the BDNF-TrkB-ERK1/2-CREB signaling pathway, caused neuronal damage, and decreased the expression of synaptic proteins Syn and PSD-95, which may lead to anxiety-like behaviors, prepulse inhibition (PPI) deficits, and spatial learning and memory deficits. In addition, inulin intervention reversed gut microbiota dysbiosis by decreasing the abundance of Show less

Stress plays a pivotal role in anxiety-like disorders and cognitive decline. The present study investigated the potential effects of prior royal jelly supplementation and environmental enrichment against stress-induced anxiety-like behaviors, serum corticosterone, hippocampal brain-derived neurotrophic factor (BDNF) levels, and cognitive performance deficits in stressed rats. Male Wistar rats were randomly devised into 8 experimental groups. Rats were subjected to royal jelly (200 mg/kg) via oral gavage, standard environmental enrichment, or combination all for 14 days and control rats received saline in the same period of time. Stress induction was done on the 7th day of treatments by exposure to the restrainer under 10°C. Then open field, elevated plus maze, and inhibitory passive avoidance memory tests were used to explore emotional-cognitive behaviour. Also, corticosterone levels, and hippocampal BDNF expression were measured. Stress resulted in an increase in the serum corticosterone levels, anxiety-like behaviors, and decreased hippocampal BDNF expression which reversed by environmental enrichment and royal jelly treatments. Remarkably, the combined treatment exerts a more pronounced effect on the aforementioned outcomes. Our study strongly proposes a novel emerging therapeutic approach through nutritional interventions, emphasizing the potential of these treatments to mitigate stress-induced anxiety and memory impairments prior to stress exposure. Show less

Neuropsychiatric dysfunction is increasingly being acknowledged as a disabling complication of non-alcoholic steatohepatitis (NASH), but there are no therapeutic approaches. We investigated in the present study the neuroprotective effectiveness of naringenin, a citrus flavonoid with known anti-inflammatory and neurotrophic effects, in a murine NASH model induced by an 8-week methionine-choline-deficient (MCD) diet. Male C57BL/6 mice (n = 8/group) were treated with naringenin (50 mg/kg/day, i.p.) during the final 4 weeks. In behavioral tests, naringenin counteracted cognitive impairment in novel object recognition, reduced anxiety in both open field and elevated plus maze paradigms, and decreased immobility in the forced swim test, indicating antidepressant-like activity. Mechanistically, naringenin restored hippocampal apoptotic balance, normalizing the MCD diet-induced Show less

Yiqi Yangxin Anshen Oral Liquid (YQYX) is a multi-herbs compound derived from the ancient Chinese formulae Suanzaoren Decoction and Guipi Tang. It has been clinically used to treat insomnia and anxiety for nearly three decades. To evaluate the efficacy of YQYX and to elucidate its therapeutic mechanisms in mitigating pathological changes induced by sleep deprivation (SD). Chemical constituents and serum-absorbed components were characterized using UHPLC-Orbitrap-MS/MS. Network pharmacology was employed to predicted therapeutic targets. PCPA-induced SD rats underwent pentobarbital-induced sleep test, Morris water maze, and open field test. Serum inflammatory cytokines were measured by ELISA, and hypothalamic neurotransmitters were quantified using a validated UHPLC-QQQ-MS/MS method. Hippocampal damage was evaluated by H&E and NeuN immunofluorescence, and cAMP/PKA/CREB/BDNF pathway was studied by Western blot and immunofluorescence. LC-MS identified 102 chemical constituents and 49 serum-absorbed components in YQYX. Network pharmacology analysis based on the serum-absorbed components predicted the cAMP signaling pathway as a key therapeutic target. YQYX significantly ameliorated SD-induced sleeplessness effects, spatial learning-memory impairments, and anxiety-like behaviors. It also reduced serum levels of IL-1β, TNF-α, and IL-6. Notably, YQYX restored hypothalamic neurotransmitters homeostasis (serotonin, dopamine, histamine, and acetylcholine). Histological analysis showed that YQYX prevented SD-induced hippocampal damage. Moreover, YQYX upregulated the cAMP/PKA/CREB/BDNF signaling pathway. YQYX exhibits multi-target therapeutic effects by maintaining neurotransmitter homeostasis, protecting hippocampal neurons, and activating neuroplasticity pathways, thereby validating its ethnopharmacological basis for treating sleep disorders. Show less

Obesity and excessive weight gain have emerged as significant global health concerns in recent years and are often comorbid with numerous contemporary diseases, including cardiovascular disorders, diabetes, and cognitive impairments. L-carnitine, a vital cofactor in mitochondrial energy metabolism, possesses potent antioxidant and anti-inflammatory properties that merit investigation for mitigating obesity-associated neuronal damage. Consequently, this study investigated the potential neuroprotective effects of L-carnitine on anxiety- and depression-like behaviors in adolescent rats subjected to neonatal monosodium glutamate (MSG) exposure, a model known to induce obesity and associated neurobehavioral alterations. Neonatal rats received MSG (4 g/kg, s.c.) on alternate postnatal days (PND) 2-10. Subsequently, L-carnitine (200 mg/kg) was administered via oral gavage daily from PND 60 to 81 (subchronic treatment). Anxiety- and depression-like behaviors were assessed using the Forced Swim Test (FST), Elevated Plus Maze (EPM), and Open Field Test (OFT). All molecular and histological analyses were conducted in the prefrontal cortex (PFC), a region selected for its susceptibility to excitotoxicity and critical role in emotional regulation. Oxidative stress was evaluated through measurements of total oxidant and antioxidant levels. To elucidate the underlying molecular mechanisms, gene expression analyses focused on neuronal survival and apoptosis (BDNF, Bax, Bcl-2), while immunohistochemical evaluations targeted neuroinflammation and cell death pathways (TNF-α, Caspase-3, IL-1β, and Bcl-2). The findings reveal that neonatal MSG exposure leads to pronounced anxiety- and depression-like behaviors, accompanied by metabolic dysregulation, oxidative stress, neuroinflammation, and apoptosis. Although L-carnitine treatment did not reverse obesity-related metabolic alterations, it exhibited notable sustained anxiolytic effects. The neuroprotective potential of L-carnitine was further supported by its ability to reduce cortical neuroinflammation and neurodegerenative damage through suppression of proinflammatory cytokines and restoration of antioxidant balance. Overall, this study offers valuable insights into the cognitive, genetic, and histological outcomes associated with obesity-related mood disturbances and contributes to understanding the complex biological mechanisms underlying these conditions. Show less

As a complex physiological and psychological phenomenon, pain has a wide impact on the quality of life of patients. Chronic pain represents one of the most challenging public health issues, and ensuring effective pain management is not only a fundamental right of individuals but also a sacred duty of healthcare providers. This review focuses on recent advancements (within the past five years) in understanding how electroacupuncture (EA) alleviates pain-related affective disorders, such as anxiety and depression. By integrating findings from clinical trials and mechanistic studies, we highlight three key mechanisms: (1)Brain functional regulation: EA modulates brain regions (e.g., prefrontal cortex, insula, thalamus) and networks (default mode network, salience network) via functional magnetic resonance imaging (fMRI)-observed functional connectivity changes. (2)Neurotransmitter and receptor modulation: EA regulates pain and emotions by altering BDNF, β-endorphin, TRPV1, NMDARs, and P2Y12 receptor signaling, supported by studies on chronic pain and depression models. (3)Immune factor adjustment: EA reduces neuroinflammation by targeting TLR4/NF-κB pathways and pro-inflammatory cytokines (IL-1β, TNF-α), improving pain-related affective disorders. Clinical and preclinical evidence demonstrates EA's safety, efficacy, and multi-target effects, however, optimal treatment parameters and individualized strategies require further investigation. Future research should combine multi-omics, large-scale multi-center clinical studies , and precision medicine approaches to deepen understanding of EA's mechanisms and clinical applications. Show less

Quercetin is a flavonoid bioactive compound with potential anti-depression effect. Dietary advanced glycation end products (AGEs) might be critically associated with depression. We aimed to explore whether quercetin ameliorates dietary AGEs-induced anxiety and depression-like behaviors in female mice, with a focus on hypothalamic-pituitary-adrenal axis (HPA) regulation and gut microbiota composition. Mice were divided into three groups: control, dietary AGEs, and AGEs plus quercetin. Dietary AGEs induced anxiety and depression-like behavioral effects, reduced BDNF, P-CREB, PSD95, doublecortin, and synaptophysin protein expression. Dietary AGEs induced HPA axis overactivation has been confirmed by decreased hippocampal GR, P-GR S211, and arginase-1, and elevated FKBP51, NLRP3, caspase-1, and p65 protein expression. Dietary AGEs resulted in gut microbiota disorder and correlation analysis revealed significant associations between Proteobacteria, the [Eubacterium] coprostanoligenes group, Klebsiella and Lachnospiraceae_NK4A136_group with behavioral parameters. Quercetin intervention improved dietary AGEs associated anxiety and depression-like behavioral effects via restoring HPA axis and gut microbiota. Show less

This study investigated an intranasal nose-to-brain delivery strategy to repurpose ondansetron (OND) for anxiety management using PLGA nanoparticles co-loaded with superparamagnetic iron oxide nanoparticles (SPIONs) and incorporated into a Carbopol 940 mucoadhesive gel. Nanoparticles were optimized using an I-optimal experimental design evaluating PLGA concentration and surfactant type. The optimized SPION/OND-PLGA nanoparticles showed a small particle size (141.547 ± 1.31 nm), narrow distribution (PDI = 0.235 ± 0.002), relatively high zeta potential (-34.307 ± 0.53 mV), and satisfactory encapsulation efficiency (42.09 ± 1.34%). The developed nanogel exhibited acceptable organoleptic properties, shear-thinning behavior, sustained drug release, and enhanced ex vivo nasal permeability, with OND permeation values of 996.96 ± 6.53 μg, 621.92 ± 7.54 μg, and 317.87 ± 2.88 μg per cm Show less

Depression and anxiety during pregnancy are major public health concerns with lasting consequences for mother and child. Although the gut microbiome contributes to stress and mood regulation, its role in preconceptional stress and transgenerational outcomes remains unclear. Here, we examined behavioral, microbial, and thalamic transcriptional effects of preconceptional social isolation rearing (SIR) in female mice and tested whether maternal probiotic supplementation mitigates these alterations. SIR females displayed increased anxiety-like and social-avoidant behavior, reduced gut microbial diversity, depletion of Odoribacter, Tuzzerella, and Alloprevotella, and enrichment of Bacteroides and Lachnospiraceae. A multispecies probiotic (Lactobacillus rhamnosus HN001, L. acidophilus La-14, Bifidobacterium lactis HN019) reversed these behavioral and microbial changes. Adult offspring of SIR dams showed sex-dependent behavioral deficits and microbial alterations partly reflecting maternal patterns. Prenatal SIR was associated with reduced thalamic Bdnf expression in offspring and altered Grin2a/2b selectively in males. In contrast, prenatal probiotic exposure exerted broader transcriptional effects and restored Bdnf levels in SIR offspring. SIR-induced increases in Lachnospiraceae were transmitted to offspring, whereas reductions in Ruminococcaceae were normalized by maternal probiotic treatment. Predicted functional profiling indicated sex-dependent modulation of microbial pathways related to tryptophan and central carbon metabolism. These findings demonstrate enduring transgenerational effects of preconceptional stress on the gut-brain axis and support maternal probiotic supplementation as a potential strategy to mitigate stress-induced dysregulation. Show less

Premature ejaculation (PE) accompanied by anxiety or depression is a complex clinical condition at the intersection of male reproductive dysfunction and emotional disorders. Increasing evidence suggests that serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) play central and interrelated roles in its pathogenesis. In this review we examine the bidirectional functions of 5-HT and BDNF in both the reproductive and nervous systems, highlighting their importance in regulating ejaculation, emotional stability, and synaptic plasticity. A comprehensive literature search (2010-2025) was conducted across multiple databases using relevant Medical Subject Headings (MeSH) terms, including pertinent original research and review articles, to synthesize the roles and regulatory pathways of 5-HT and BDNF in PE with comorbid anxiety or depression. We summarize the shared and distinct roles of 5-HT and BDNF in maintaining physiological balance across these systems and focus on their involvement in the major pathological processes underlying PE with anxiety or depression, including neurotransmitter imbalance, neuroendocrine dysregulation, inflammation, and oxidative stress. Furthermore, we outline the related signaling pathways through which 5-HT and BDNF exert their effects and interact. We also evaluate current pharmacological and non-pharmacological interventions targeting these molecules, demonstrating their potential to improve both ejaculatory control and emotional symptoms, and critically appraise selective serotonin reuptake inhibitor (SSRI)-related risks and highlighted the need for individualized dosing and monitoring. Emerging evidence suggests that Traditional Chinese Medicine formulations can extend intravaginal ejaculatory latency and mitigate mood symptoms and may serve as stand-alone or adjunctive options to reduce reliance on selective serotonin reuptake inhibitors (SSRIs). Overall, 5-HT and BDNF are not only deeply involved in the biological mechanisms of PE with comorbid psychological disorders, but also represent promising biomarkers and therapeutic targets, and their integrative neuro-reproductive regulatory functions provide new insights into the diagnosis and treatment of this multifaceted condition. Show less

Post-traumatic stress disorder (PTSD) causes debilitating nightmares, flashbacks and anxiety stemming from a catastrophic, often life-threatening traumatic event. Originally described in soldiers exposed to the horrors of battle, PTSD is now recognized in civilian victims of assault, natural disasters and mass casualty events. Most people experiencing trauma do not develop PTSD, so understanding neurobiological mechanisms is crucial to predicting risk and developing targeted treatments. There have been many studies seeking to find biomarkers for PTSD, and their results have converged on several brain regions, molecular pathways and neuropsychological functions. In this review, we focus on selected findings about the glucocorticoid receptor (GR), the chaperone protein FKBP51 (FK506 binding protein 51), BDNF (brain-derived neurotrophic factor), fear memory reconsolidation and epigenetic regulation of gene expression in the hypothalamic-pituitary-adrenal (HPA) axis, amygdala and hippocampus. Together, these disparate aspects of brain function provide an emerging model for understanding the etiology and pathophysiology of PTSD. Avoidance of lethal threats is fundamental for survival, and this stringent evolutionary requirement has conserved many components of fear memory storage and behavioural response to danger. PTSD research can therefore rely on non-human animal model systems with better face and construct validity than most other psychiatric disorders. With this advantage, advances in PTSD biomarker identification are likely closer to clinical translation than in other mental illnesses. We attempt to highlight the most promising biomarkers that could be targeted by novel treatments and propose a map for future research work. Show less

Prenatal stress is a significant risk factor that can lead to neurobehavioral deficits in offspring. In the present study, we examined the effects of a probiotic mixture on anxiety, memory, and underlying possible molecular pathways in prenatally stressed rats. Male offspring exposed to chronic unpredictable stress (CUS) during fetal life were received either saline (CUS+SAL) or a probiotic mixture (CUS+PRO) for 30 days post-weaning. Non-stressed controls were also given either saline (CON+SAL) or probiotics (CON+PRO). The passive avoidance test and the elevated zero maze test were used to assess avoidance memory and anxiety-like behavior, respectively. In comparison to the CON+SAL controls, the CUS+SAL group exhibited significant anxiety-like behavior and impaired avoidance memory. At a molecular level, the behavioral impairments were accompanied by increased serum levels of the oxidant, MDA, and decreased serum levels of antioxidants, TAC, GSH, and SOD, upregulation of the hippocampal serotonin receptor Htr1a gene, while downregulation of microRNAs miR-26a and miR-320-3p, reduced BDNF, and increased Bax/Bcl-2 ratio apoptosis in the duodenum. Probiotics effectively mitigated these alterations. The intervention improved behavioral functions, normalized oxidative and antioxidative stress markers, and restored the expression of Htr1a and miR-320-3p to near-normal levels, while miR-26a expression remained unaffected by the treatment. It also enhanced the Bax/Bcl-2 ratio and increased BDNF content. Interestingly, unstressed control rats were unresponsive to the probiotic treatment. Conclusively, probiotic supplementation sufficiently alleviates the adverse effects of fetal life stress, possibly by affecting the gut-brain axis, highlighting the importance of beneficial bacteria in neurobehavioral development and maintenance. Show less

To investigate the association between combined vitamin D and N-acetylcysteine (NAC) supplementation and clinical outcomes in patients with generalized anxiety disorder (GAD). This retrospective cohort study included 88 propensity-score-matched patients with GAD from Beidahuang Group Neuropsychiatric Hospital. Based on clinical records, patients were classified into an observation group (vitamin D3 + NAC + usual care) and a control group (usual care only). Anxiety symptoms and cognitive function were assessed using the Beck Anxiety Inventory (BAI), Automatic Thought Questionnaire (ATQ), and Dysfunctional Attitudes Scale (DAS). Serum levels of 25-hydroxyvitamin D [25(OH)D], inflammatory markers [high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6)], oxidative stress parameters [glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD)], and neurochemical markers [brain-derived neurotrophic factor (BDNF), dopamine (DA), Serotonin (5-HT), norepinephrine (NE)] were measured at baseline and week 8. After 8 weeks, both groups showed significant improvements in BAI, ATQ, and DAS scores, with greater reductions in the observation group (all In this retrospective cohort, combined vitamin D and NAC supplementation was associated with significantly greater improvements in anxiety symptoms, cognitive patterns, and relevant metabolic biomarkers in patients with GAD compared to usual care alone, supporting its potential as an adjunctive therapy. Show less

Post-cardiac surgery anxiety or depression (PCPAD) is a common neuropsychiatric complication following cardiovascular interventional procedures, which significantly increases the risk of adverse cardiovascular events and long-term mortality. Existing treatment strategies have limitations, and clinical needs remain unmet. The gut-brain axis (GBA) serves as a core network regulating neuroimmune and endocrine responses, and its imbalance involves key links such as intestinal flora dysbiosis and neuroimmune crosstalk disorders. It is closely related to the pathogenesis of this complication, providing a novel perspective for targeted interventions. This review aims to systematically clarify the mechanism of GBA in PCPAD, comprehensively explore therapeutic strategies targeting this axis, and focus on the intervention value and application potential of natural products. The study was designed and conducted in strict accordance with the PRISMA 2020 guidelines. Relevant literatures were searched from PubMed, Web of Science Core Collection, ScienceDirect, Embase, Cochrane Library, and CNKI databases from their inception to December 2025. Literatures focusing on GBA-related mechanisms of PCPAD or investigating the mechanisms and clinical applications of natural products targeting GBA for PCPAD treatment were included. Conference abstracts, case reports, duplicate publications, and other ineligible literatures were excluded. Through quality control strategies including double independent screening and verification, priority inclusion of high-credibility evidence, and data cross-validation, 168 eligible literatures were finally included. The composition and functions of GBA, its imbalance mechanisms, and the basic and clinical evidence of natural product-based interventions were systematically analyzed. Studies have shown that GBA imbalance is the core pathogenesis of PCPAD, among which the inflammatory cascade initiated by intestinal flora dysbiosis, abnormal activation of the neuroendocrine axis, disorder of immune-nerve crosstalk, and abnormal gene and epigenetic regulation are key pathological links. In summary, GBA imbalance, especially gut microbiota dysbiosis and neuroimmune interactions, plays a critical role in the pathogenesis of PCPAD. Natural products (including traditional Chinese medicine (TCM) monomers, TCM compound prescriptions, patented TCM drugs, and natural products from other plant sources worldwide) can exert therapeutic effects by synergistically regulating GBA homeostasis through multiple targets. Specifically, they include increasing the abundance of beneficial bacteria such as Bifidobacterium and Lactobacillus, promoting the production of anti-inflammatory metabolites such as short-chain fatty acids, repairing intestinal barrier function, inhibiting pro-inflammatory pathways such as NF-κB and NLRP3 inflammasome, and regulating the levels of neurotransmitters and neurotrophic factors such as 5-HT and BDNF. Basic and clinical studies have confirmed that these natural products have high biocompatibility and low toxic side effects, and are compatible with the safe medication needs of patients during the organ function recovery period after cardiac surgery. Several natural products have been proven to modulate GBA dysfunction, with potential for clinical therapeutic application. This review systematically elucidates a new paradigm of precise intervention for PCPAD via natural products that regulate GBA through multiple targets, addressing the limitation of traditional single-target therapies and providing a low-cost, easily promotable solution for clinical translation. Additionally, natural product-based interventions offer a novel approach for treating post-cardiac surgery complications. In the future, it is necessary to further conduct large-sample, multicenter clinical trials to clarify their mechanisms of action and standardized dosage regimens, strengthen toxicological research, facilitate the translation from basic research to clinical practice, and provide more precise therapeutic strategies for patients. Show less

The gut microbiome and the central nervous system are intricately connected through a bidirectional communication system that plays a vital role in maintaining gut homeostasis and overall health. Disruptions in this interaction are linked to gastrointestinal and neuropsychiatric disorders, including anxiety. This review aims to provide a comprehensive analysis of the gut microbiota's role in anxiety and evaluate the therapeutic potential of prebiotics. This review synthesizes recent literature from databases including PubMed, Scopus, Web of Science, and Google Scholar, focusing on the gut microbiota's role in anxiety and the therapeutic potential of prebiotics. The microbiota-gut-brain axis communicates through multiple pathways, including the vagus nerve, immune signaling, microbial metabolites, and the hypothalamic-pituitary-adrenal (HPA) axis. Prebiotics modulate these pathways by enhancing beneficial microbial populations and influencing the production of neuroactive compounds. Key molecular targets implicated in this communication include brain-derived neurotrophic factor (BDNF), glucocorticoid receptors, and shortchain fatty acids, which modulate neurotransmitters such as GABA and serotonin, and influence neuroinflammatory pathways implicated in anxiety pathophysiology. The findings highlight the immunological, neurochemical, and endocrine mechanisms through which the gut microbiota interacts with neurophysiological systems. These mechanisms underscore the pharmacological potential of prebiotics in the management of psychiatric illnesses. The interplay between the gastrointestinal microbiota and neurophysiological systems provides key pharmacological insights into the potential of prebiotics as a therapeutic approach for managing psychiatric illnesses, detailing their mechanistic pathways and translational applications in clinical practice. Show less

Facial and Emotional Recognition Systems are technologies that primarily use AI and machine learning to analyze various inputs like facial expression, speech, and physiological signals, to identify and classify human emotions and link them to a variety of epigenomic traits and states. We conducted a Meta-Meta Analysis via Pharmacogenomics (PGx) and Genome-Wide Association Studies (GWAS) across two separate manifestations, including facial physics and emotional expressions. Applying GWAS datasets, 10 GWAS datasets were included, and following multiple filtrations, a GWAS Meta-Meta analysis led to a Secondary Gene List (SGL) of 586 members. Additionally, various indepth silico analyses, such as Protein-Protein Interactions (PPIs), refined 300 genes into a unified network, then, by adding 10 GARS genes, 309 genes remained. A different analysis of PPIs uncovered 141 connected genes (Final Gene List: FGL); more precisely, we conducted a PGx-based approach on this FGL. Finally, 1,480 annotations were found, among them, 682 annotations were significant; thus, we considered the genes with at least one significant annotation and found 54 Pharmacogenes in FGL (PGx-FGL). Through this in-depth analysis, we identified strong, significant top phenotypic roles for both DRD2 and BDNF linking genes in 48,780,906 subjects. Our PGx-based GWAS meta-meta-analyses, coupled with genetic and epigenetic liability testing, connected Facial and Emotional Recognition Systems to Spectrum Disorders (Attention-Deficit Hyperactivity Disorder: ADHD and Autism), Schizophrenia, Depression, and Anxiety. We propose that these findings could have heuristic therapeutic targeting potential and, as such, require intensive further clinical support. Show less

Anxiety and depression are growing global burdens with limited drug options. Traditional Chinese medicine (TCM) offers unique advantages, including Roudoukou-Suanzaoren (RS), an ancient TCM-derived beverage with the potential for treating these conditions. This study aims to explore whether this combination improves the outcomes. The results show that the main constituents of RS include flavonoids, terpenoids, alkaloids, and phenylpropanoids. Behavioral and histopathological analyses demonstrate that RS alleviates chronic restraint stress (CRS)-induced anxiety- and depression-like behaviors and attenuates neuropathological damage in relevant brain regions; the underlying mechanism is likely mediated by the CREB/BDNF/TrkB signaling pathway. Meanwhile, RS reduces proinflammatory cytokines in tissues, decreases hippocampal microglial numbers, and increases astrocytes. Additionally, RS attenuates colonic injury, restores intestinal permeability, upregulates tight-junction proteins, and improves gut microbiota dysbiosis. This study highlights that RS exerts antianxiety and antidepression effects by modulating the gut microbiota, controlling inflammatory responses, and increasing BDNF levels through the "gut-brain axis" pathway. Show less

Adverse childhood experiences (ACEs) increase susceptibility to depression and anxiety disorders in adulthood. This study investigated the potential mechanisms through which ACEs enhance vulnerability to depression and anxiety in adulthood, using a novel "two-hit" mouse model by combining maternal separation (MS) with 14 or 21 days of restraint stress (RS). Behavioral assessments (sucrose preference test, tail suspension test, open field test, elevated zero maze) confirmed depressive- and anxiety-like behaviors in the MS + RS 21d group mice. Neurobiological analyses revealed hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis (elevated serum corticosterone [CORT] and adrenocorticotropic hormone [ACTH]) and dysregulation, characterized by reduced levels of monoamine neurotransmitters (5-hydroxytryptamine [5-HT], 5-hydroxyindoleacetic acid, dopamine, norepinephrine), altered mRNA expression of key genes (e.g., increased ACTH, CRH, SERT; decreased GR, brain-derived neurotrophic factor [BDNF]), and corresponding protein-level changes (e.g., increased 5-HT1AR, CRHRs; decreased BDNF, TrkB). Our findings indicate that the two-hit mouse model, combining MS with a 21-day RS, stably induces depressive- and anxiety-like behaviors in mice. The underlying mechanism may be associated with HPA axis dysfunction, serotonergic system dysregulation, and aberrant BDNF signaling within the prefrontal cortex-amygdala-hypothalamus circuit. Show less

Non-small cell lung cancer (NSCLC) is characterized by high morbidity and lethality, causing a great physical and psychological burden on patients. Therefore, effective treatment of NSCLC patients is very important. This study analyzes the impact of a nursing intervention of case management combined with cognitive-behavioral therapy on anxiety and depression and quality of life in postoperative NSCLC patients. A single-center, non-randomized controlled study in which 80 NSCLC patients from the Hospital were enrolled from May 2023 to January 2024, and were categorized into case management (CM) and cognitive-behavioral therapy (CBT) groups depending on treatment modalities, with case management care in both groups, and cognitive-behavioral therapy care added to the CM combined with CBT (CC) group. The Hamilton anxiety scale (HAMA), Hamilton depression scale (HAMD), self-perception burden scale (SPBS), life qualities (QLQ-C30), neurotransmitter levels, and clinical effectiveness were primarily assessed in both groups post-treatment. Secondary outcomes included pain level (VAS score), nursing satisfaction, adverse events, and complications. After treatment, the indicators of both groups were significantly different from those of the pre-treatment. Post-treatment, the CC group demonstrated significantly lower scores than the CM group in HAMA (10.18 ± 2.10 vs. 16.04 ± 3.89), HAMD (11.94 ± 2.91 vs. 16.81 ± 3.19), and SPBS (25.52 ± 3.17 vs. 33.50 ± 5.61) (all P < 0.05). Conversely, the CC group showed significantly higher QLQ-C30 scores and levels of 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF). The nursing intervention of case management combined with cognitive behavioral therapy has a good improvement effect on the anxiety and depression status of NSCLC patients. It can improve the quality of life, which is worth promoting and using in the clinic. Show less

This study aimed to investigate changes in brain structure and function of hippocampus in aged type 2 diabetes mellitus (T2DM) rats and the effects of tea polyphenol (TP) intervention using magnetic resonance imaging (MRI) and tissue-level molecular analyses. Rats were randomly assigned to six groups: Control, Aged, Aged T2DM, Aged T2DM + TP, Aged T2DM + rosiglitazone, and Aged T2DM + piracetam intervention groups. Anxiety- and depression-like behaviors were assessed using the open field test, the forced swimming test and elevated plus maze. Brain structure, blood flow and neuro-associated metabolites were evaluated via MRI. The number of nerve cells, neurons, microglia and astrocytes, the expression of BDNF/CREB/p-CREB protein, the levels of inflammatory factors, and the integrity of the myelin sheath in the hippocampus were evaluated. Relationships between behavioral, cellular and molecular changes and MRI-derived indicators were evaluated by Pearson correlation analysis. Aged T2DM rats exhibited severe anxiety- and depression-like behaviors accompanied by brain atrophy, reduced blood flow and decreased brain metabolites. At the microstructural level, the number of hippocampal neurons in the Aged T2DM group was significantly reduced, accompanied by increased counts of microglia and astrocytes. Meanwhile, the expression levels of hippocampal p-CREB and BDNF were decreased, the concentration of the inflammatory factor IL-1β, IL-6, TNF-α was elevated, and myelin integrity was impaired. Intervention with TP alleviated anxiety- and depression-like behavior, with MRI-detected abnormalities and in vitro histopathological molecular changes improved (except for myelin integrity). TP intervention mitigated alterations in brain structure and function as well as anxiety and depression-like behaviors in aged T2DM rats. Show less

To identify associations of polymorphic variants of the genes of Two hundred thirty-five patients with AfD and 62 patients with AR and comorbid AlD aged 18 to 65 years were examined. The severity of AfD was assessed using the Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorder Version (SIGH-SAD) and the Clinical Global Impression (CGI), and the level of anxiety was assessed using the Hamilton Anxiety Rating Scale (HARS) at baseline and on Day 28 of psychopharmacotherapy. Polymorphic variants rs6265, rs7124442, rs11030104, and rs7103411 of the In AfD patients, rs3924999* The polymorphic variants rs3924999 of the Show less

Crocetin (CRT), one of the active ingredients in saffron, exerts health-promoting effects on body systems such as neuroprotective, cardioprotective and hepatoprotective properties. In the present study, the effects of CRT and lansoprazole (LAP), as a reference drug, were investigated on indomethacin (IND)-induced gastric ulcer and related anxiety. Thirty rats were divided into five groups of six. Groups 1 and 2 received vehicle and groups 3, 4 and 5 received CRT (5 and 20 mg/kg) and LAP (30 mg/kg) for seven consecutive days. All groups were deprived of food on day 6. On day 7, group 1 was treated with vehicle and groups 2, 3, 4 and 5 received 50 mg/kg IND. Anxiety and locomotor activity were recorded, and then the animals were euthanized and stomach and hippocampus samples were taken. The effects of the aforementioned treatments were studied in 24 intact rats in four equal groups. CRT (20 mg/kg) and LAP restored IND-induced alterations in the gastric content volume and pH and ulcer index and protection and cyclooxygenases 1 and 2 and prostaglandin E2 and gastric mucosal and hippocampal superoxide dismutase, malondialdehyde, tumor necrosis factor-alpha, interleukin-1β and caspase-3 and hippocampal brain derived neurotrophic factor. Histopathological alterations in the gastric mucosa and hippocampus were improved, and anxiety was suppressed. Intact rats were not influenced. CRT and LAP caused protective effects against IND-induced gastric ulcer and by antioxidative, anti-inflammatory, anti-apoptotic and PGE Show less

Conflicting results on the association of the Using combinations of various key terms, articles in PubMed, Google Scholar, and Web of Science, written in English were collected until October 31, 2024. Data were extracted independently by two authors and analyzed using Review Manager 5.4. Fifteen studies that are compliant with the HWE, providing a total of 14,184 participants were included in this meta-analysis after applying predefined inclusion/exclusion criteria based on study design, DSM-based diagnosis, and availability of genotype counts. Most pooled models demonstrated low to moderate heterogeneity with significant associations in the recessive model only. In the subgroup analysis, a significant effect was observed in the PD-uncategorized cohort. The Our updated meta-analysis suggests that the Show less

Depression imposes significant social, economic, and health burdens worldwide. Although phlorotannin-rich extract from Ecklonia cava (PS) and its active compound dieckol (DK) exhibit various biological activities, their antidepressant- and anxiolytic-like effects and underlying mechanisms remain unclear. This study investigated the antidepressant- and anxiolytic-like potential of PS and DK in a corticosterone (CORT)-induced mouse model of depression and anxiety, focusing on glucocorticoid receptor (GR) signaling. CORT-treated mice were orally administered PS or DK, and behavioral tests were performed to assess depressive- and anxiety-like behaviors. PS composition was analyzed using LC-MS/MS. Molecular docking predicted the binding of PS components to GR. GR nuclear translocation, target gene expression, and downstream signaling were examined using behavioral, molecular, and computational approaches. PS alleviated CORT-induced depressive- and anxiety-like behaviors, accompanied by reduced GR nuclear translocation, suppression of Mkp-1, and restoration of ERK-CREB-BDNF signaling. Molecular docking analysis predicted strong binding of DK to the GR ligand-binding domain. Consistently, DK reduced GR nuclear translocation and GRE binding, downregulated GR target genes (Mkp-1, Sgk-1, Fkbp5, and Bdnf), and restored ERK-CREB-BDNF signaling. In vivo, DK also improved CORT-induced behavioral deficits and normalized HPA axis activity and neurotransmitter levels. Collectively, our results suggest that DK, a major bioactive phlorotannin from E. cava, exerts antidepressant- and anxiolytic-like effects in association with modulation antagonism of GR signaling, highlighting its therapeutic potential as a natural GR-modulating agent for stress-related mood disorders. Show less

Patients with inflammatory bowel disease (IBD) commonly exhibit psychiatric symptoms, such as anxiety and depression. However, studies on drugs addressing the concurrent amelioration of these symptoms in this patient population are rare. Previous studies have suggested that dihydromyricetin (DHM) may show therapeutic potential for IBD. This study investigated the therapeutic effects of DHM on dextran sulfate sodium (DSS)-induced colitis and associated behavioral disorders in mice. The findings of the experiments indicated that DHM could ameliorate colitis symptoms, including changes in body weight, colon length, disease activity index (DAI) scores, and histopathological damage. Furthermore, DHM improved the behavioral impairments observed in colitis mouse model, as evidenced by results from the open field test, elevated plus maze test, and tail suspension test, along with hippocampal histopathological assessments. Molecular analysis revealed that DHM notably suppressed the activation of NLRP3 inflammasome and IL-1β in both the colon and the hippocampus. DHM enhanced the intestinal barrier, elevated brain-derived neurotrophic factor (BDNF) levels in the hippocampus and serum, and concurrently reduced microglia activation. DHM lowered the levels of IL-1β, tumor necrosis factor-α (TNF-α), and lipopolysaccharide (LPS) in the serum. 16S rDNA sequencing results indicated that DHM could modulate DSS-induced gut microbiota dysbiosis, enriching various beneficial metabolic and neuromodulatory pathways. Metabolomic analysis demonstrated that DHM notably elevated acetic acid, propionic acid, and butyric acid levels in intestinal feces. Network pharmacology analysis identified the central intersecting genes of DHM, ulcerative colitis (UC), and neuroinflammation. Differential gene expression analysis underscored IL-1 β as a pivotal target for the co-occurrence of UC and psychiatric conditions. These findings imply that DHM may ameliorate DSS-induced colitis and concomitant behavioral disturbances in mice, underscoring its potential as a natural therapeutic agent for IBD accompanied by psychiatric comorbidities. Show less

Insomnia and anxiety are highly comorbid, severely compromising quality of life. Efficacy of current pharmacological interventions for this dual condition remains limited. Zhi-Gan Formula (ZG), consisting of Zhi-Zi-Chi Decoction and Ganmai Dazao Decoction, two classic Traditional Chinese Medicine (TCM) formulae clinically widely used for insomnia or anxiety, holds promise as a therapeutic option for insomnia-anxiety comorbidity. This study aimed to assess ZG's sleep-promoting and anxiolytic efficacy, and investigate the novel mechanism through which pituitary adenylate cyclase-activating polypeptide (PACAP) in the medial prefrontal cortex (mPFC) modulates comorbid sleep and anxiety conditions. Mice received 4-chloro-DL-phenylalanine (PCPA) injections and were subsequently administered ZG or diazepam. Behaviors were assessed using the pentobarbital-induced sleep test, open-field test (OFT), and elevated plus-maze test (EPM). Key pathways were identified via network pharmacology analysis and validated using long-term potentiation (LTP) recordings and protein quantification. Viral-mediated PACAP knockdown vectors were transfected into the mPFC. PCPA administration induced insomnia and anxiety-like behaviors. ZG administered for 3 days significantly shortened sleep latency, prolonged sleep duration, and alleviated anxiety-like behaviors, whereas diazepam only partially improved anxiety-like behaviors. Network pharmacology analysis suggested ZG's engagement in neuropeptide-receptor interactions and synaptic transmission pathways. Assessments of synaptic plasticity showed that ZG improved mPFC LTP and the expression of synaptic proteins (PSD95, synapsin-1, BDNF) impaired in the model mice. Moreover, the expression of the neuropeptide PACAP and downstream eEF2 signaling for synaptic protein synthesis were all improved by ZG. Crucially, perfusion of a PACAP agonist in the mPFC brain slices from sleep-deprived mice rescued LTP deficits. Finally, mPFC PACAP knockdown abolished the therapeutic effects and the enhanced expressions of the synaptic proteins by ZG. ZG alleviated insomnia-anxiety comorbidity by restoring synaptic plasticity in the mPFC via the PACAP-eEF2-BDNF pathway, which may also shed light on the development of a novel therapeutic approach for the treatment of sleep-anxiety comorbidity. Show less

Chronic stress, a key contributor to neurological disorders, is mechanistically linked to hypothalamic-pituitary-adrenal (HPA) axis dysregulation, neuroinflammation, and hippocampal neuronal apoptosis. Current therapeutic approaches remain limited in efficacy and safety. Schisandrol A, a neuroactive lignan from Show less

Psilocybin-containing mushrooms, commonly known as magic mushrooms, strongly affect mood, cognition, and behavior. Psilocybe azurescens is a species of psilocybin mushrooms that contains the main active compounds psilocybin and psilocin. Psilocybin mushrooms have been used since ancient times to improve the quality of life. However, their adverse effects have been less studied. This study aimed to investigate, for the first time, the effect of oral consumption of P. azurescens on social behavior, anxiety- and depressive-like behaviors in rats. The underlying mechanisms of these behaviors were also studied. Male Wistar rats received three doses of P. azurescens (10, 100, and 250 mg/kg) by gavage every other day for 14 days. Social interaction, anxiety- and depressive-like behaviors were assessed using the three-chamber, elevated plus maze, and forced swimming tests, respectively. Protein levels of neurotrophic (BDNF and GDNF), neuroinflammatory (IL-6 and TNFα), and oxidative stress (ROS and SOD) factors were measured in the hippocampus, prefrontal cortex (PFC), and amygdala by ELISA technique. The results showed that P. azurescens significantly increased anxiety- and depressive-like behaviors and disrupted social interaction behavior in rats. These effects were accompanied by increased neuroinflammation and oxidative stress and decreased neurotrophic factors in the hippocampus, PFC, and amygdala. This study suggests that the high doses of P. azurescens can cause mood disorders by increasing inflammatory responses and oxidative stress and decreasing the expression of neurotrophic factors. Show less