Search Results (211)

Insomnia is increasingly recognized as a manifestation of multisystem dysregulation characterized by sustained physiological hyperarousal. This review situates insomnia within a framework of reciprocal disturbances across neuroendocrine, inflammatory, and autonomic pathways. It examines the potential roles of cannabidiol (CBD), polyunsaturated fatty acids (PUFAs) derived from hemp seed oil (HSO), and lignans from black sesame oil (BSO) as modulators of upstream biological processes relevant to sleep regulation. Rather than acting as direct hypnotics, these compounds are considered for their capacity to influence convergent mechanisms involved in sleep–wake stability. Preclinical evidence suggests that CBD modulates endocannabinoid and serotonergic signaling, potentially contributing to the regulation of physiological processes associated with hyperarousal. Concurrently, HSO-derived fatty acids support mitochondrial function and lipid-mediated resolution. Sesame lignans further contribute through antioxidant properties linked to redox balance, neurometabolic stability, and modulation of neural excitability. However, the current evidence base is predominantly preclinical, and definitive conclusions regarding therapeutic efficacy or optimal dosing in humans remain limited. Future research should prioritize integrative clinical studies that link these specific biological modulations to standardized sleep outcomes to determine their real-world applicability. Nevertheless, the pathways discussed align with biological domains consistently implicated in established insomnia phenotypes. This review integrates these compounds within a shared hyperarousal framework to highlight convergent upstream mechanisms that extend beyond their individual effects. Full article

CDKL5 Deficiency Disorder (CDD) is a severe neurodevelopmental encephalopathy characterized by early disruptions of synaptic maturation and network stability, leading to persistent motor, cognitive, and behavioral impairments. Given the role of the endocannabinoid system in synaptic development, neuroinflammation, and neuronal resilience, we investigated whether the sustained enhancement of endogenous 2-arachidonoylglycerol (2-AG) signaling via monoacylglycerol lipase (MAGL) inhibition could mitigate key pathological features in adult Cdkl5 knockout (KO) mice. Using an intermittent 6-week treatment, the MAGL inhibitor JZL184 robustly increased plasma 2-AG levels, reduced MAGL protein levels, and activated CB1-AKT signaling without evidence of receptor desensitization. Despite this clear pharmacodynamic efficacy, behavioral effects were domain-specific: neither dose ameliorated core behavioral deficits, although the higher dose selectively reduced stereotypic jumping and modestly improved cue-dependent associative memory. At the cellular level, JZL184 induced biologically meaningful effects, partially restoring dendritic spine maturation in the primary somatosensory cortex and increasing neuronal survival in the vulnerable CA1 hippocampal region. In contrast, microglial responses were dose-dependent and divergent, with the lower dose exerting anti-inflammatory effects, while the higher dose increased cortical microglial density and Allograft Inflammatory Factor-1 (AIF-1) expression, suggesting engagement of compensatory or off-target mechanisms. Overall, these findings show that MAGL inhibition activates neuroprotective pathways and ameliorates select structural deficits in adult Cdkl5 KO mice, but is insufficient to produce broad behavioral recovery, highlighting the domain-specific effects of selective 2-AG enhancement via MAGL inhibition and the need for developmentally informed or multimodal therapeutic strategies in CDD. Full article

Background: SARS-CoV-2 infection during pregnancy has been associated with systemic inflammatory responses and placental pathology; however, the molecular mechanisms underlying placental involvement remain incompletely understood. The endocannabinoid system plays a critical role in placental development, immune regulation, and vascular homeostasis. Materials and Methods: Placental tissues were obtained from 20 healthy pregnant women and 20 women with confirmed SARS-CoV-2 infection who had recovered by the time of delivery. Demographic and laboratory parameters were recorded. Histopathological evaluation was performed using hematoxylin and eosin staining. Immunohistochemical analysis of cannabinoid receptor 1 (CNR1) and cannabinoid receptor 2 (CNR2) expression was conducted, supported by quantitative digital image analysis using QuPath. Network-based protein–protein interaction and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to explore potential molecular mechanisms. Results: COVID-19-positive placentas exhibited prominent histopathological alterations, including increased fibrinoid deposition, syncytial knot formation, vascular congestion, and intervillous inflammatory cell infiltration. Systemic inflammatory and coagulation markers, particularly neutrophil percentage, C-reactive protein, D-dimer, and fibrinogen levels, were significantly elevated in the COVID-19 group. CNR1 and CNR2 expressions were markedly increased across multiple placental compartments, including decidual cells, trophoblastic layers, syncytial knots, and Hofbauer cells. Quantitative digital analysis confirmed significant upregulation of both receptors. Bioinformatic analysis revealed enrichment of endocannabinoid signaling, cAMP-related pathways, and inflammatory mediator regulation of TRP channels. Conclusions: The findings indicate that SARS-CoV-2 infection is associated with coordinated inflammatory, structural, and molecular alterations in the placenta. Upregulation of CB1 and CB2 suggests an active involvement of the endocannabinoid system in placental immune and vascular responses to COVID-19, highlighting its potential relevance for understanding placental pathology associated with maternal viral infections Full article

The G-protein-coupled receptor cannabinoid receptor 2 (CB₂R) initiates a key signaling pathway in mammalian physiology and pathophysiology. CB₂R signaling holds significant therapeutic potential in ameliorating many pathologies, particularly in inflammatory conditions, neurodegenerative disorders, fibroproliferative and ocular diseases. CB2 modulators have been studied for their anti-inflammatory and tissue protective effects in preclinical animal models of cardiovascular, gastrointestinal, liver, kidney, lung and neurodegenerative disorders with numerous compounds undergoing clinical evaluation. Existing ligands can be classified as endocannabinoids, cannabinoid-like natural products and synthetic CB₂R ligands. A genetically encoded G-protein-coupled receptor activation-based (GRAB) sensor for CB₁R—GRAB_eCB2.0 was developed recently. This current study extends the sensor’s development to allow for a GPCR activation-based sensor for CB₂R. The sensor, GRAB-CB2, will facilitate the evaluation of pharmacological characteristics and responses of various functionally selective and indiscriminate cannabinoid ligands acting on CB2. Full article

The endocannabinoid system is a ubiquitous neuromodulatory network that links internal physiological state to neural circuit function across the brain. While its roles in memory, reward, pain, and motor control are well established, its contribution to olfactory processing has only recently gained attention. This review synthesizes the current knowledge on the anatomical, cellular, and functional interactions between the endocannabinoid system and the olfactory pathway, from the olfactory epithelium and main olfactory bulb to higher order cortical targets. We highlight how endocannabinoid signaling, primarily via cannabinoid receptor type 1 (CB1), shapes synaptic transmission within olfactory bulb microcircuits, modulates centrifugal feedback, and adjusts sensory gain in a state-dependent manner, particularly in relation to hunger, feeding behavior, stress, and reward. In addition, we review evidence that the endocannabinoid system regulates olfactory neurodevelopment and adult neurogenesis by influencing neural stem cell proliferation, migration, and integration into existing circuits. Emerging links between endocannabinoid signaling, olfactory dysfunction, neuropsychiatric disease, metabolic disorders, and neurodegeneration underscore the translational relevance of this system. We also discuss methodological challenges inherent to studying endocannabinoid signaling and outline future directions, including circuit-specific targeting and intranasal delivery strategies. Together, these findings position the olfactory system as a powerful and accessible model for understanding how endocannabinoids couple internal state to perception and behavior, with important implications for therapeutic development. Full article

Background: Metamizol (dipyrone) is a widely used analgesic and antipyretic drug in several European countries, particularly for postoperative pain management in both adult and pediatric populations. Methods: A narrative literature review was conducted to evaluate the efficacy, safety, and pharmacological mechanisms of metamizol in postoperative pain management. A comprehensive search of PubMed, Scopus, and the Cochrane Library was performed, and included articles published up to 2024. Search terms included metamizol, dipyrone and children. Results: The available evidence indicates that metamizol provides effective postoperative analgesia, with an efficacy comparable to that of other non-steroidal anti-inflammatory drugs and paracetamol. Pediatric studies similarly support its effectiveness in postoperative settings. Regarding safety, short-term use of metamizol appears to be well tolerated, with a low incidence of serious adverse events. Mechanistic studies suggest that metamizol exerts analgesic effects through a multimodal pathway, involving not only cyclo-oxygenase inhibition but also modulation of opioid and endocannabinoid systems. Conclusions: Metamizol represents an effective and generally well-tolerated option for short-term postoperative pain management in both adults and children when used under appropriate clinical monitoring. Current evidence supports a favorable benefit-to-risk balance for short-term use while highlighting the need for caution during prolonged therapy. Further large-scale, prospective studies are warranted to better define rare adverse events, clarify interindividual risk factors, and refine the understanding of their non-classical mechanisms of action. Full article

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent synovitis, in which fibroblast-like synoviocytes (FLSs) serve as the primary effector cells that drive the destruction of joints. Baicalin has previously demonstrated efficacy in significantly ameliorating joint symptoms in rats with CIA. As such, this study aims to investigate its underlying molecular mechanisms and impact on the FLSs of rats with CIA through an integrated proteomics and transcriptomics analysis. A Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was conducted based on two datasets; it revealed that the retrograde endocannabinoid signaling pathway—associated with susceptibility to RA—is the only one involved in both the signaling and metabolic processes modulated by baicalin. Nineteen differentially expressed proteins (DEPs) downregulated by baicalin comprise seventeen subunits of NADH dehydrogenase and two receptors, glutamate receptor 2 (GRIA2) and γ-aminobutyric acid receptor subunit alpha-5 (GABRA5). Three differential metabolites (DMs) were also affected by baicalin: γ-aminobutyric acid (GABA) and phosphatidylcholine (PC) were upregulated and phosphatidylethanolamine (PE) was downregulated. Our findings suggest that the baicalin-mediated alleviation of joint synovitis is closely related to the upregulation of GABA and PC; downregulation of GRIA2, GABRA5, and PE; and preservation of mitochondrial homeostasis within the retrograde endocannabinoid signaling pathway in FLSs. Full article

Hepatocellular carcinoma (HCC) is the main type of liver cancer and one of the malignancies with the highest mortality rates worldwide. HCC is associated with diverse etiological factors including alcohol use, viral infections, fatty liver disease, and liver cirrhosis (a major risk factor for HCC). Unfortunately, many patients are diagnosed at advanced stages of the disease and receive palliative treatment only. Therefore, early markers of HCC and novel therapeutic approaches are urgently needed. The endocannabinoid system is involved in various physiological processes such as motor coordination, emotional control, learning and memory, neuronal development, antinociception, and immunological processes. Interestingly, endocannabinoids modulate signaling pathways involved in cell survival, proliferation, apoptosis, autophagy, and immune response. Consistently, several cannabinoids have demonstrated potential antitumor properties in experimental models. The participation of metabotropic and ionotropic cannabinoid receptors in the biological effects of cannabinoids has been extensively described. In addition, cannabinoids interact with other targets, including several ion channels. Notably, several ion channels targeted by cannabinoids are involved in inflammation, proliferation, and apoptosis in liver diseases, including HCC. In this literature review, we describe and discuss both the endocannabinoid system and exogenous phytocannabinoids, such as cannabidiol and Δ⁹-tetrahydrocannabinol, along with their canonical receptors, as well as the cannabidiol-targeted ion channels and their role in liver cancer and its preceding liver diseases. The cannabidiol-ion channel association is an extraordinary opportunity in liver cancer prevention and therapy, with potential implications for several environments that are for the benefit of cancer patients, including sociocultural, public health, and economic systems. Full article

Lipopolysaccharide (LPS)-induced damage to the intestinal epithelial barrier leads to gut inflammation, and intracellular metabolites of lactic acid bacteria may participate in regulating this process to exert probiotic effects. This study aimed to investigate the repair effects and molecular mechanisms of ultrasonic disruption-treated Enterococcus faecium F11.1G (F11.1G) on the model (primary lamb IECs + 5 μg/mL LPS for 6 h). Then, results demonstrated that 10⁸ CFU/mL F11.1G significantly suppressed the excessive secretion of pro-inflammatory factors (IL-6, IL-8, IL-1β, TNF-α) induced by LPS. Gene Ontology (GO) analysis revealed that differentially expressed genes (DEGs) were primarily enriched in cellular response to lipopolysaccharide, inflammatory response, and canonical NF-κB signaling pathways. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed enrichment in NF-κB signaling pathway and MAPK signaling pathway. PPI network identified key genes including IL-1β, TNF, IL-8, RELB, FOS, TNFAIP3, NFKBIA, and MMP9. KEGG analysis indicated differentially abundant metabolites (DAMs) enrichment in purine metabolism and the endocannabinoid system. Spearman correlation analysis revealed positive correlations between pro-inflammatory genes and endogenous protective metabolites, such as adenosine and PEA, while showing negative correlations with multiple purine metabolites. Correlational analysis indicates that F11.1G alleviates intestinal inflammatory damage primarily by suppressing NF-κB/MAPK pathway activation and may synergistically regulate purine and endocannabinoid metabolism. Full article

Exercise training reduces metabolic dysfunction and improves neural function; however, its cortical molecular effects in diabetic–obese conditions remain unclear. Here, we aimed to identify transcriptional pathways by integrating physiological evaluation with an in silico analysis of cortical RNA-seq data from Zucker Fatty Diabetes Mellitus rats following a 12-week swimming training program. Exercise training reduced body weight and improved glucose control and blood pressure. RNA-seq analysis revealed 814 differentially expressed genes, with pathway enrichment highlighting glutamatergic synapse, retrograde endocannabinoid signaling, and oxytocin signaling pathways. These coordinated transcriptional shifts involved genes related to excitatory neurotransmission, neuromodulatory feedback, and calcium-dependent regulation. As hypothesis-generating models, these pathway-level patterns suggest that exercise training may modulate cortical signaling properties in diabetic–obese states and provide a conceptual framework for future mechanistic investigation. Full article

Teleost social behavior plays an important role in foraging, reproduction, and aquaculture management, yet its physiological basis remains poorly understood. This study investigated individual differences in sociability in the large yellow croaker (Larimichthys crocea) using behavioral assays and metabolomic profiling in the brain–intestine axis. Behavioral tests revealed that high-sociability (HS) fish spent significantly more time near conspecifics than low-sociability (LS) fish, indicating clear behavioral divergence between groups. Targeted metabolomics of brain tissue showed distinct neurotransmitter signatures between HS and LS individuals, including significant differences in acetylcholine, DOPAC, xanthurenic acid, and glutamine. Untargeted intestinal metabolomics identified 65 differential metabolites between groups. Intestinal metabolites such as LEA and CEA exhibited significant group-specific variation and were functionally associated with CB1 and CB2 cannabinoid receptors, suggesting a potential endocannabinoid-mediated contribution to sociability differences. Differential metabolites enriched in amino–sugar and nucleotide–sugar metabolic pathways. Integration of behavioral and metabolomic data suggests that neurotransmitter regulation and gut–brain metabolic signaling jointly contribute to sociability differences in large yellow croaker. These findings provide mechanistic insights into social behavior and offer potential biomarkers for welfare assessment and selective breeding in aquaculture. Full article

Prolonged Grief Disorder (PGD) is marked by enduring and disruptive grief symptoms following the death of a significant other. Although PGD has been recognized as a distinct psychopathological entity within the trauma dimension in the DSM-5-TR, its neurobiological underpinnings remain not fully defined. A systematic literature review was conducted up to September 2025 following PRISMA 2020 guidelines. PubMed, Scopus, Embase and Web of Science were searched using a comprehensive strategy combining MeSH terms and free-text keywords. Eligible studies included human participants, validated grief assessment tools and biomarker assessments. Out of 2140 initial records, 12 studies published between 1989 and 2022 met inclusion criteria. Investigated neuro–psycho–endocrine systems included the hypothalamic–pituitary–adrenal (HPA) axis, catecholamines, oxytocin, endocannabinoids and immune/inflammatory markers. Key findings in pathological grief reactions included altered cortisol rhythms, elevated oxytocin levels, increased pro-inflammatory cytokines and immune system dysregulation. Results are limited by heterogeneity in study designs, small sample sizes, inconsistent use of diagnostic criteria prior to DSM-5-TR and lack of control for psychiatric comorbidities. This review highlights emerging biological correlates of PGD, particularly those involving the stress response, reward-attachment networks and immune/inflammatory pathways. Further standardized, longitudinal research is essential to gain a more defined picture of PGD, to clarify causal mechanisms and to guide targeted therapeutic interventions. Full article

The endocannabinoid system (eCBS) is a versatile neuromodulatory network that orchestrates synaptic plasticity, reward processing, and neuronal homeostasis. Increasing evidence implicates eCBS dysregulation in both addiction and neurodegenerative (ND) disorders, suggesting overlapping molecular and cellular mechanisms underlying these conditions. This review synthesizes recent advances in understanding how eCBS components—cannabinoid receptors (CB1 and CB2), endogenous ligands (anandamide and 2-arachidonoylglycerol), and their metabolic enzymes—modulate dopaminergic and glutamatergic signaling within reward and reinforcement circuits. Chronic exposure to drugs of abuse, including alcohol, opioids, cocaine, and methamphetamine, perturbs eCBS homeostasis, promoting oxidative stress, neuroinflammation, excitotoxicity, mitochondrial dysfunction, and protein aggregation—pathological features common to Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis. These overlapping mechanisms disrupt neuronal integrity and contribute to progressive neurotoxicity, highlighting shared pathogenic pathways between addiction and neurodegeneration. Despite these advances, critical gaps remain in delineating how substance-induced eCBS alterations precipitate neurodegenerative cascades. Addressing these gaps will be essential for harnessing the eCBS as a therapeutic target to mitigate addiction-driven neurotoxicity and age-related cognitive decline. Full article

Background and Objectives: Neuropsychiatric disorders pose a major global health challenge, marked by high prevalence, limited diagnostic precision, and suboptimal therapeutic outcomes. Current diagnoses remain primarily clinical, lacking objective biomarkers, while many patients experience poor remission rates and frequent relapse. The endocannabinoid system (ECS), a central regulator of synaptic plasticity, neuroinflammation, and stress responses, is increasingly implicated in depression, anxiety, schizophrenia, and neurodegenerative diseases. In parallel, extracellular vesicles (EVs) have emerged as critical mediators of intercellular communication and promising biomarker sources, as they reflect the physiological or pathological status of their cells of origin. This review examines the hypothesis that interactions between ECS signaling and EV-mediated communication form a convergent pathway shaping vulnerability and resilience in neuropsychiatric disorders, with potential implications for biomarker identification and therapeutic innovation. Methods: This hypothesis-driven review was developed using a narrative approach, focusing on the interface between cannabinoids and EVs in neuropsychiatric conditions. Relevant publications were identified through PubMed, Scopus, and Web of Science searches up to September 2025. Results: Emerging evidence indicates a bidirectional relationship between ECS activity and EV biology: endocannabinoids can be loaded into EVs to facilitate intercellular signaling, while phytocannabinoids such as THC and CBD can alter EV release and cargo composition. Conclusions: We propose a hypothesis-driven framework in which the possible interplay between cannabinoids and EVs may stimulate new research and support the development of biomarker-guided, personalized therapeutic strategies for neuropsychiatric disorders. Full article

Lipid metabolism and lipid-derived signaling together ensure cellular and systemic homeostasis. Their dysregulation causes obesity, type 2 diabetes, cardiovascular disease, NAFLD/MASH, and neurodegeneration throughout life. This review integrates central pathways, such as ACC–FASN-mediated de novo lipogenesis, lipid-droplet lipolysis, and mitochondrial and peroxisomal β-oxidation, and their regulation by insulin–PI3K–Akt, glucagon–cAMP–PKA, SREBPs, PPARs, and AMPK. We emphasize the mechanisms by which bioactive lipids like diacylglycerols, ceramides, eicosanoids, and endocannabinoids serve as second messengers linking nutrient state to insulin signaling, inflammation, and stress response; pathologic accumulation of these species enhances insulin resistance and lipotoxicity. Aging disrupts these axes via diminished catecholamine-stimulated lipolysis, defective fatty-acid oxidation, mitochondrial failure, and adipose depot redistribution, facilitating ectopic fat and postprandial dyslipidemia. We suggest a pathway-to-phenotype paradigm that connects lipid species and tissue environment to clinical phenotypes, allowing for mechanism-to-intervention alignment. Therapeutic avenues range from lipid lowering for atherogenic risk to novel agents targeting ACLY, ACC, FASN, CPT1, and nuclear receptors, with precision lifestyle intervention in diet and exercise. Translation is still heterogeneous because of isoform-dependent effects, safety trade-offs, and inconsistent adherence. We prioritize harmonization of lipidomics with multi-omics for stratifying patients, enriching responders, and bridging gaps between mechanistic understanding and clinical outcome, with focus on age-sensitive prevention and treatment for lipid-mediated metabolic disease. Full article