Search Results (1,449)

Background/Objectives: Parkinson’s disease (PD) is a progressive neurodegenerative disorder that poses a substantial threat to global human health. Yam (Dioscorea opposita Thunb.) is a traditional medicinal and edible plant that has long been used in Asia, Africa, and the Caribbean. Its major bioactive components, such as dioscin and polysaccharides, have been reported to exhibit neuroprotective effects; however, the impact of dietary yam on PD progression remains to be elucidated. Therefore, we sought to evaluate its neuroprotective potential and the underlying mechanisms in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced PD mice. Methods: Mice received six-week dietary yam supplementation. Behavioral, histological, and neurochemical analyses were performed to assess motor function, dopaminergic neuron integrity, and dopamine levels. Gut microbiota and metabolic profiles were analyzed using 16S rRNA gene sequencing and non-targeted metabolomics. Transcriptomic sequencing and Western blot analysis of the substantia nigra pars compacta (SNc) were conducted to investigate molecular mechanisms, and integrative multi-omics analysis was applied to explore microbiota–metabolite–host interactions. Results: Yam supplementation improved motor function, preserved nigrostriatal dopaminergic neurons, and restored striatal dopamine levels in PD mice. Notably, yam was associated with the maintenance of intestinal homeostasis by strengthening barrier integrity and enriching beneficial taxa, including Ileibacterium, Lachnospiraceae NK4A136 group, and Blautia. Consistently, yam also elevated neuroprotective purines and amino acids, including inosine, xanthine, and succinic acid. At the molecular level, yam treatment modulated mitochondrial oxidative phosphorylation by increasing PGC-1α and COX7c expression, and reduced inflammasome-related neuroinflammatory signaling. Integrative modeling showed significant associations between yam-modulated genes and PD-related indices with microbiota and metabolites. Conclusion: These findings suggest that yam may represent a potential dietary strategy for alleviating PD-related neurodegeneration by modulating the microbiota–gut–brain axis. Full article

Background: Gut microbiome-derived metabolites, particularly short-chain fatty acids (SCFA) and tryptophan derivatives, are central mediators of the gut–brain axis. This ex vivo study assessed how nutritional interventions impact such metabolites during early life, a critical period for neurodevelopment. Methods: The effects of galacto-oligosaccharides (GOS), nutrient blends (vitamins, minerals and amino acids) and their combinations were evaluated in the gut microbiomes of infants (2–4 months, n = 6) and young children (2–3 years old, n = 6) using the ex vivo SIFR^® technology. Results: Baseline microbiome composition was age-dependent, with infants displaying lower α-diversity and greater interpersonal variability. After ex vivo incubation, nutrient blends increased the propionate/butyrate ratio and branched-chain fatty acids in young children and elevated several B-vitamins and amino acid-derived metabolites, including indole-3-carboxaldehyde, imidazoleacetic acid and pipecolinic acid. Combining nutrient blends with GOS exhibited potential synergistic effects on propionate (infants) and 2-hydroxyisocaproic acid (HICA, both age groups). GOS strongly stimulated Bifidobacteriaceae and increased metabolites linked to bifidobacterial metabolism like acetate, HICA, N-acetylated amino acids, aromatic lactic acids and acetylagmatine; in young children, butyrate and γ-aminobutyric acid (GABA) also increased. Conclusions: Combinations of GOS with nutrient blends impacted microbiome-derived metabolites associated with the gut–brain axis, with potential synergistic increases of metabolites with emerging roles in neurodevelopment, including GABA, acetylagmatine and HICA. Despite shared bifidogenic effects, differences between age groups indicate that microbiome maturity may influence responses to nutritional intervention. Future clinical studies are needed to determine whether these metabolite changes translate into neurodevelopmental benefits in vivo. Full article

Background/Objectives: Postoperative delirium (POD) is a common postoperative complication, especially in the elderly, and is associated with a worsening prognosis, prolonged hospitalization and reduced quality of life of patients. A growing body of research indicates that disorders of the composition of the gut microbiota and dysfunction of the gut–brain axis may play a key role in the pathogenesis of POD. Methods: The aim of this review was to assess the association between the gut microbiota and the occurrence of POD. This review was carried out in accordance with the JBI and PRISMA-ScR guidelines, searching for publications in six databases and selecting them according to PCC criteria. Finally, seven works were included in the analysis after an independent assessment. Conclusions: The available studies indicate that disorders of the gut microbiota and related metabolic and immune changes may significantly increase the risk of POD. It has been shown that certain bacteria and metabolites, such as SCFAs or indoles, can perform both protective and conducive functions for the development of POD. Understanding these mechanisms opens up the prospect of developing new preventive and therapeutic strategies based on the modulation of the gut microbiota. Full article

Background: Scientific interest has grown in naturally derived compounds capable of supporting or enhancing cognitive performance. Tanacetum vulgare L. is an abundant source of secondary metabolites and has been associated with a broad range of biological activities; however, its potential influence on cognitive function remains largely unexplored. Methods: The present study explored the effects of T. vulgare essential oil (EO) on cognitive performance, hippocampal brain-derived neurotrophic factor (BDNF) expression, and histomorphological alterations in a rat model. Animals were administered T. vulgare EO at doses of 0.5 and 1.5 mL/kg for 28 days and were subjected to a series of behavioral tests after one week of pretreatment. Results: Both doses of EO facilitated the formation of short- and long-term memory traces in the inhibitory avoidance tasks, with a more pronounced effect observed at the lower dose, whereas improvement in passive learning was evident only at the higher dose. Spatial and recognition memory were enhanced at both doses. EO treatment significantly increased hippocampal BDNF expression without inducing pathological alterations. Conclusions: These findings suggest that T. vulgare EO may improve specific hippocampal-dependent cognitive functions, with upregulation of hippocampal BDNF representing a potential underlying mechanism. Full article

Diagnosis of atypical parkinsonian syndromes (APS), including progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), rely on clinical criteria that often result in misclassification or delayed confirmation. Cerebrospinal fluid (CSF) metabolomics offers the potential to identify disease-specific biochemical “fingerprints”. The aim of the study is to identify CSF metabolomic biomarkers that distinguish PSP and MSA from each other and from non-neurodegenerative controls. Targeted mass spectrometry-based metabolomics was performed on CSF samples from 30 patients with MSA, 41 with PSP, and 30 age- and sex-matched non-neurodegenerative controls. Global metabolomic profiles showed no clear group separation. Both PSP and MSA showed elevated gut-derived metabolites p-cresyl sulfate and deoxycholic acid versus controls. In PSP, decreased cortisone and increased hexosylceramide d18:1/24:1 were observed, whereas in MSA, dihydroxyphenylalanine was elevated alongside homoarginine and creatinine. In the direct comparison of APS, levels of α-aminoadipic acid were increased in PSP compared to MSA. Pathway analysis highlighted disrupted glycerophospholipid metabolism in both APS disorders. Distinct metabolite panels mainly combining membrane-associated lipids, gut-derived and neurotransmitter-related metabolites demonstrated high diagnostic accuracy for distinguishing PSP and MSA from control groups (AUC = 0.95 for PSP and AUC = 0.98 for MSA), while a separate panel showed moderate performance in differentiating PSP from MSA (AUC = 0.85). Distinct but partially overlapping CSF metabolomic profiles characterize PSP and MSA. These metabolomic fingerprints highlight gut–brain axis involvement, alterations in cell membrane-related lipid metabolism, and disease-specific changes in neurotransmitter-related metabolites. Further, a panel of these metabolites showed strong potential as diagnostic biomarkers. Full article

Thyroid hormones (THs) and estrogen (E2) play essential roles in neuronal differentiation and plasticity during brain development. S-equol, a plant-derived isoflavone metabolite, is a selective E2 receptor (ER) ligand that exhibits neurotrophic effects; however, its interaction with TH receptor (TR) signaling remains unclear. In this study, we investigated the effects of S-equol on TRβ-associated transcriptional activity and neuronal morphogenesis in mouse neuroblastoma-derived Neuro-2a cells or rat C6 glioma cells. Luciferase reporter assays demonstrated that S-equol significantly enhanced T3-induced TRβ transcriptional activity in a concentration- and time-dependent manner. Additionally, exposure to S-equol or T3 alone promoted neurite outgrowth and wound closure, whereas co-exposure to both compounds resulted in a more significant enhancement of these processes. Furthermore, mRNA expression levels of synapse-related genes (Dlg4, Syn1, Syp, Camk2b, and Bdnf) were significantly increased by S-equol co-exposure in the presence of T3. In silico docking analysis revealed that S-equol exhibited moderate to high binding affinity for TRβ (−8.7 kcal/mol), ERα, and ERβ, suggesting a structural basis for TR–ER crosstalk. Collectively, these findings indicate that S-equol functions as a dual-acting modulator that may modulate T3 signaling involving TR–ER interaction. Although S-equol may exert beneficial effects on neurodevelopment, it may also act as an endogenous endocrine modulator that alters the fine regulation of TH action during development, warranting careful evaluation from physiological and toxicological perspectives. Full article

Insomnia is one of the most common sleep disorders. Traditionally, its pathophysiology has been interpreted mainly from the perspective of the central nervous system (CNS). However, accumulating evidence suggests that the microbiota–gut–brain axis (MGBA), a bidirectional communication network linking the gut and the CNS, may play an important role in the development, maintenance, and treatment of insomnia. This review summarizes the major signaling pathways of the MGBA and discusses its potential mechanisms in insomnia. Current evidence indicates that gut microbiota and their metabolites may influence sleep–wake homeostasis through neural, immune, endocrine, and circadian pathways. At the same time, insomnia-related stress responses, immune imbalance, and lifestyle disturbances may in turn affect the gut microbiota, thereby forming a bidirectional regulatory network. Animal and clinical studies further support a close association between gut microbial dysbiosis and insomnia. In addition, this review systematically summarizes factors that may affect the MGBA, including diet, lifestyle, psychosocial stress, medications, and medical exposures. On this basis, MGBA-targeted interventions, such as dietary modification, prebiotics and probiotics, lifestyle interventions, fecal microbiota transplantation, and natural medicines, may provide promising new strategies for the prevention and treatment of insomnia. Nevertheless, the current evidence still relies largely on animal studies and cross-sectional research, and further longitudinal studies and high-quality interventional trials are needed to clarify causality, long-term efficacy, and standardized therapeutic approaches. Full article

Background/Objectives: Neurodegenerative diseases like Alzheimer’s, Parkinson’s, and Amyotrophic lateral sclerosis (ALS) share common molecular pathways, including neuroinflammation and oxidative stress, which complicate the effectiveness of single-target treatments. Garcinia mangostana L. (mangosteen) has shown neuroprotective properties, but previous studies focused on lipophilic xanthones, which have poor bioavailability and uncertain blood–brain barrier permeability. Methods: In the current study, polar metabolites from G. mangostana peel aqueous extract (GMPE) were assessed for potential multi-target interactions via UHPLC-QTOF-MS-based metabolomics, systems pharmacology, and molecular docking analysis. Further, in silico ADMET screening and network-based analyses assessed for overlap between GMPE compounds and genes associated with neurodegeneration (AD, PD, ALS). Results: Analysis of genes linked to AD, PD, and ALS revealed 121 common molecular targets influenced by GMPE metabolites. Network and enrichment analyses indicated that the compounds derived from GMPE may be involved in common pathways related to oxidative stress, neuroinflammation, and neuronal survival. Molecular docking analyses suggest that selected metabolites are likely to exhibit moderate binding affinities to their respective protein targets. Conclusions: The results presented in this study provide evidence that GMPE may possess potential multi-target interactions within common neurodegenerative pathways. However, since the data are based on computational and predictive approaches, these results should be considered hypothesis-generating and warrant further experimental validation. Full article

The discovery of the glymphatic system (GS) transformed understanding of central nervous system homeostasis by revealing a brain-wide network that facilitates cerebrospinal and interstitial fluid exchange along perivascular pathways. This system clears metabolic waste and maintains the precise ionic environment required for neuronal function through the coordinated action of astrocytic aquaporin-4 channels and intact perivascular architecture. Glioblastoma multiforme (GBM), the most aggressive primary brain tumor in adults, alters physiological barriers through pathological angiogenesis, compression of perivascular spaces, depolarization of aquaporin-4 at astrocytic endfeet, and obstruction of venous and lymphatic drainage. This narrative review synthesizes current experimental and clinical literature identified through targeted searches of PubMed and Scopus to examine interactions between glioblastoma, glymphatic system dysfunction, and tumor microenvironmental changes. To minimize selection bias, studies were categorized according to evidence source and experimental design. Evidence from rodent models and advanced imaging demonstrates as tumor growth impairs glymphatic function, the resulting dysfunction promotes tumor progression by enabling accumulation of pro-tumorigenic growth factors, inflammatory mediators, and acidic metabolites, while elevated interstitial fluid pressure limits drug delivery. Impaired antigen drainage further diminishes immune surveillance, contributing to the immunosuppressive microenvironment that limits immunotherapy efficacy. A critical evaluation of these mechanisms highlights how the glymphatic system influences disease progression and suggests novel avenues for diagnostic imaging and therapeutic intervention. Although significant challenges remain in modeling human fluid dynamics, understanding these hidden networks offers a promising frontier for strategies aimed at restoring cerebral clearance and improving clinical outcomes. Full article

The relationship between epilepsy, obesity, and metabolic syndrome (MetS) has emerged as a rapidly evolving area of neurobiology inquiry. Emerging evidence suggests that epilepsy extends beyond neuronal hyperexcitability, reframing it as a systemic condition characterized by significant metabolic dysregulation. Converging supports a bidirectional relationship while seizures, antiseizure medications (ASM), and neuroinflammation induce exacerbate potentiate epileptogenesis through shared molecular pathways. At the cellular level, chronic epileptic activity induces oxidative stress, mitochondrial dysfunction, and the activation of microglia and astrocytes. This, in turn, leads to the release of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6. These mediators traverse the blood-brain barrier (BBB), subsequently modifying insulin signaling, and disrupting glucose homeostasis, which collectively fosters a pro-inflammatory and insulin-resistant environment. Furthermore, antiseizure medications such as valproate can exacerbate these effects by directly impairing insulin receptor signaling and altering adipokine production, ultimately contributing to weight gain and systemic metabolic dysregulation. Obesity and MetS induce neuroinflammatory and excitotoxic states that promote seizure onset via leptin resistance, reduced adiponectin levels, and compromised AMP-activated protein kinase (AMPK) signaling. Emerging evidence emphasizes the gut-brain axis as a crucial regulator in this reciprocal interaction. Dysbiosis, altered microbial metabolites (e.g., short-chain fatty acids), and heightened intestinal permeability facilitate systemic inflammation and BBB disruption, enhancing neuronal excitability. Insulin resistance in the brain disrupts synaptic transmission, impairs mitochondrial biogenesis, and compromises redox equilibrium, perpetuating a pathological cycle linking metabolic stress to epileptic activity. This review synthesizes the cellular, molecular, and systemic pathways connecting epilepsy, obesity, and MetS, and proposes that epilepsy be reconceptualized as a neuro-metabolic disorder. Insights into these convergent pathways provide a rationale for novel therapeutic strategies that simultaneously target seizure control and metabolic regulation, encompassing microbiota modulation, antioxidant therapy, and insulin-sensitizing interventions with the overarching aim of restoring neuro-metabolic homeostasis. Full article

Cyflumetofen (CYF) and its main metabolite, trifluoromethyl benzoic acid (B-1), both of which contain a trifluoromethyl group, are increasingly used in agriculture due to their high stability and efficacy. Structurally, these molecules share several physicochemical features with per- and polyfluoroalkyl substances (PFASs), including endocrine disruption and reproductive toxicity. This study aims to evaluate the reproductive toxicity effects of CYF and its metabolites using adult zebrafish as a model organism. The results indicate that exposure to CYF and B-1 at environmentally relevant concentrations for 21 days causes hormonal disruption and abnormal gonadal development in fish; moreover, as the concentrations increase, CYF and B-1 significantly impair the reproductive capacity of zebrafish and lead to developmental abnormalities in their offspring. Based on the ratio of E2/T and the alteration of key genes in the HPG axis, such as cyp17a2 and cyp11c1, it is hypothesized that CYF and B-1 disrupt hormonal homeostasis via the HPG axis. Notably, male fish were more susceptible when exposed to CYF or B-1, exhibiting sex-specific differences. RNA-seq analysis revealed that CYF/B-1 promotes Ca²⁺ release from the zebrafish brain and induces steroid hormone dysregulation based on the HPG axis via genes such as hsd17a and gnrh. In summary, this study provides key insights into the reproductive toxicity of CYF and its major metabolite, highlighting their risks to the environment and human health. Full article

Diet is a key modulator of the gut microbiota, thereby influencing host physiology. Microbial colonization begins early in life, influenced by maternal sources, mode of birth, diet, and environmental exposures, and stabilizes into an adult-like microbiome during early childhood. This maturation yields a microbial ecosystem dominated by Firmicutes and Bacteroidetes that contributes to host physiological homeostasis. Gut microorganisms function as an integrated metabolic system that transforms dietary substrates into bioactive metabolites, including short-chain fatty acids (SCFAs), amino acid-derived compounds, and microbial lipids. These metabolites regulate glucose and lipid metabolism, intestinal barrier integrity, and immune modulation. Although many metabolic functions are conserved, their activity is shaped by diet, microbial cross-feeding, and local intestinal conditions, enabling functional specialization within the gut. Disruption of this system, known as dysbiosis, is associated with alterations in microbial diversity and metabolic output that have been linked to metabolic diseases, including obesity and related disorders. Evidence from experimental models and observational studies suggests that these associations may involve interconnected inflammatory and metabolic mechanisms, such as impaired intestinal barrier function, low-grade inflammation, and altered dietary energy harvest; however, causal relationships in humans remain incompletely understood. Beyond peripheral effects, the gut microbiome influences host metabolism via the gut–brain axis, a bidirectional network that integrates neural, endocrine, immune, and metabolic signaling. Microbiota-derived metabolites and gut hormone modulation contribute to appetite regulation, energy balance, and glucose homeostasis, while central neuroendocrine signaling can reciprocally shape the intestinal microbial niche. Collectively, these findings highlight the gut microbiome as a central regulator of host metabolism, whose disruption may contribute to the development of metabolic disease. Full article

Obesity is characterized by abnormal adipose tissue expansion and energy metabolism imbalance. Browning of white adipose tissue (WAT), wherein white adipocytes acquire thermogenic properties similar to brown adipose tissue, represents a key mechanism for increasing energy expenditure. Although ginseng (Panax ginseng C.A. Meyer) is widely recognized as a health-promoting botanical, its role in WAT browning has not been fully elucidated. This review summarizes evidence that ginseng and its bioactive components regulate major thermogenic pathways, including β-adrenergic/cyclic adenosine monophosphate-protein kinase (cAMP-PKA) signaling, AMP-activated protein kinase (AMPK), and the peroxisome proliferator-activated receptor γ (PPARγ)/coactivator 1α (PGC-1α) axis, thereby upregulating key markers such as uncoupling protein 1 (UCP1), PR domain containing 16 (PRDM16) and type II iodothyronine deiodinase (DIO2). These effects promote mitochondrial function and fatty acid oxidation, reduce lipogenesis, alleviate inflammation, and improve insulin sensitivity, collectively fostering a microenvironment conducive to browning. Furthermore, fermentation has been found to enhance the bioactivity and thermogenic efficacy of ginseng. Recent evidence indicates that gut microbiota and their metabolites—such as short-chain fatty acids, unsaturated fatty acids, and bile acids—play a notable role in ginseng-induced thermogenesis via receptors including G-protein-coupled receptor 41/43 (GPR41/43), takeda G-protein-coupled receptor 5 (TGR5), and farnesoid X receptor (FXR). These multi-organ interaction networks involving the gut–fat, gut–liver, and gut–brain axes reflect the role of ginseng in integrating systemic metabolism. In summary, this review discusses the multi-level regulatory network through which ginseng promotes WAT browning, providing a mechanistic basis for its potential application in body weight and metabolic health management. Full article

Obesity is a major public health problem that puts pressure on healthcare systems globally. The purpose of this narrative review is to summarize and analyse recent research on the bidirectional link between obesity and mental health, focusing on the biological, behavioural, dietary, emotional, and metabolic mechanisms arising from gut microbiota interactions. Epidemiological association between obesity and mental health disorders, especially depression and anxiety, often occurs bidirectionally, reinforcing each other. Low-grade systemic inflammation is a condition typically found in obesity, being a fundamental element of neuropsychiatric disorders. Considered the main energy substrate for colon cells, SCFAs are synthesized in the intestine and exert important local effects by reducing both local and systemic inflammation. The intestinal microbiota maintains this homeostasis through the SCFAs it produces. The combined impact of the increased intestinal permeability, immune activation, and disrupted metabolism of SCFAs and tryptophan contributes to the onset and progression of depression and anxiety, as well as to significant cognitive dysfunction, especially in obese individuals. Understanding the mechanisms by which microbiota metabolites influence brain development, neuroplasticity, and behaviour could pave the way for new and innovative therapeutic strategies for the treatment of obesity and depression. Conclusions: The association of these pathologies is not coincidental, as they coexist through overlapping biological pathways that they partially or completely share. The main pathway involved is formed by the brain–gut axis and its mediators (SCFAs). Full article

Although the brain comprises only 2% of total body weight, it contains approximately 23% of the total cholesterol of the body. In the brain, cholesterol plays a critical role as a structural component of cell membranes and myelin sheaths. However, the blood–brain barrier restricts cholesterol influx from the systemic circulation into the brain. As a result, the brain synthesizes cholesterol de novo and regulates its metabolism independently. Desmosterol, a cholesterol precursor produced during cholesterol biosynthesis, and cholesterol metabolites, 24S-hydroxycholesterol and chenodeoxycholic acid, are sterols with structurally retained side chains. These side-chain-retaining sterols have traditionally been regarded as intermediates in the cholesterol synthesis process or as metabolites for cholesterol excretion, but accumulating evidence indicates that they also function as physiologically active signaling molecules that influence brain function via nuclear receptors, such as liver X receptors, and membrane receptors, such as NMDA receptors. Through nuclear receptors, these side-chain-retaining sterols regulate the transcription of genes involved in lipid transport, inflammation control, and amyloid clearance, while their membrane receptor action enables rapid synaptic effects. These side-chain-retaining sterols mediate metabolic crosstalk between neurons and glial cells and contribute to maintaining cholesterol balance in the developing brain. Furthermore, these side-chain-retaining sterols have been shown to affect amyloid-β clearance, α-synuclein aggregation, neuroinflammation, mitochondrial function, and remyelination. Dysregulation of these side-chain-retaining sterols is associated with neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Overall, side-chain-retaining sterols are important regulators of brain physiology. This review focuses on the current knowledge regarding the physiological functions of side-chain-retaining sterols in the brain and their roles in neurodegenerative diseases. Full article