Search Results (188)

Fungal infections remain a major threat to human health, with non-albicans Candida (NAC) species causing more than half of all clinical cases and many strains gaining resistance to current treatments rapidly. Previously, N-arachidonoyl ethanolamine (anandamide, AEA) has been studied and shown to possess antibacterial and antifungal properties against various bacteria and Candida albicans. Given the previous findings, we aim here to expand the current preliminary research on AEA to investigate its antifungal activities against clinically relevant NAC species in vitro: Candida glabrata, Candida parapsilosis, and Candidaozyma auris. The minimum inhibitory concentration (MIC) and growth curve analysis determined planktonic inhibition. MTT metabolic assay and ATP production via BacTiter-Glo luminescence assay evaluated biofilm formation. Membrane fluidity, polarization and efflux pump activity were examined using fluorescence probes Laurdan, DiS-C3(3), and Rhodamine 6G, respectively. Reactive oxygen species (ROS) were assessed using DCFH-DA. Biofilm architecture and cell viability were analyzed by spinning disk confocal microscopy (SDCM). AEA reduced MIC values and slowed planktonic growth, while MTT and ATP assays demonstrated a pronounced dose-dependent reduction in biofilm metabolic activity. Membrane-targeted effects revealed increased fluidity and permeability at 125 µg/mL. Notably, AEA rapidly impaired efflux pump activity and induced intracellular ROS production. This effect was accompanied by reduced cell viability, increased proportions of PI-positive cells, and enhanced intracellular dye retention, as confirmed by SDCM. Together, these findings demonstrate that AEA exerts antifungal activity by disrupting membrane integrity and associated cellular functions and provide the first comparative characterization of species-specific membrane and oxidative stress responses to AEA across three major clinically relevant multidrug-resistant NAC species. Full article

Cannabis sativa contains more than 120 phytocannabinoids, with Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) being the best characterized. This review synthesizes preclinical and clinical evidence on hemp-derived extracts, cannabinoids, and active compounds. THC primarily acts as a partial agonist at cannabinoid receptor type 1 (CB1) and type 2 (CB2), producing psychoactive, appetite-stimulating, antiemetic, and analgesic effects. CBD is non-intoxicating and has a multimodal profile involving CB1 negative allosteric modulation, CB2 inverse agonism or antagonism, inhibition of anandamide inactivation, and activity at 5-HT1A receptors, transient receptor potential channels, GPR55, and peroxisome proliferator-activated receptor gamma. Preclinical models of Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, epilepsy, and pain support anti-inflammatory, antioxidant, anti-excitotoxic, and glial-modulating mechanisms, but clinical translation remains uneven. The strongest evidence supports FDA-approved cannabidiol for Lennox–Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex, and THC-based agents for refractory chemotherapy-induced nausea and vomiting and AIDS-related anorexia. Moderate-certainty evidence supports nabiximols for multiple sclerosis spasticity and small benefits in selected chronic neuropathic pain populations. Evidence remains insufficient or negative for acute pain, insomnia, most psychiatric disorders, and many promoted indications. Key risks include cannabis use disorder, cognitive and psychiatric effects, cardiovascular events, sedation, high-dose CBD hepatotoxicity, and drug interactions. Rigorous, long-term, product-standardized trials are needed. Full article

Background/Objectives: The gut–brain axis and systemic metabolic dysregulation are increasingly implicated in Alzheimer’s disease (AD) pathogenesis. This study aimed to characterize gut microbiota and plasma metabolomic profiles associated with amyloid pathology and cognitive impairment in patients with mild cognitive impairment (MCI). Methods: A cross-sectional multi-omics baseline analysis was performed in 47 MCI patients enrolled in a randomized, double-blind, crossover dietary intervention trial (NCT05029765). Gut microbiota composition was assessed by 16S rRNA sequencing (n = 47), and plasma metabolomics by untargeted LC-MS/MS (n = 45 after exclusion of two PCA-defined metabolomic outliers). Patients were stratified according to plasma amyloid-beta 42/40 ratio (BA42/40) and ADAScog11 score, representing complementary biomarkers of amyloid burden and cognitive impairment, respectively. Results: Higher amyloid burden and worse cognitive performance were associated with significant gut microbiota alterations, including increased alpha diversity and distinct beta diversity profiles. Differential abundance analyses consistently showed enrichment of Bacteroides-associated taxa and Akkermansia, alongside depletion of short-chain fatty acid-producing genera such as Faecalibacterium, Blautia, and Phascolarctobacterium. Plasma metabolomics identified a coherent signature associated with elevated BA42/40, characterized by accumulation of secondary bile acid sulfates and depletion of sphingolipids, neuroactive steroids, and anti-inflammatory lipid mediators, including pregnenolone sulfate, resolvin E1, and anandamide. A valid OPLS-DA discriminant model was obtained for BA42/40, whereas no predictive model was achieved for ADAScog11. Critically, this dissociation, characterized by significant microbiota differences but no metabolomic separation for ADAScog11, is itself an informative finding, suggesting that gut microbiota dysbiosis and plasma metabolomic alterations are not equally coupled to both dimensions of MCI pathophysiology. Conclusions: MCI patients with greater amyloid pathology and cognitive impairment exhibited gut microbiota dysbiosis. However, metabolic associations were observed only for BA42/40, but not for ADAScog11. These findings provide a mechanistic framework for evaluating the impact of Mediterranean diet and probiotic interventions in the longitudinal phase of the trial. Full article

Background: The endocannabinoid system (ECS) and the Kisspeptin system (KS) play crucial roles in the central and peripheral regulation of male reproduction. The KS comprises Kisspeptins, the cleavage product of the Kiss1 protein, and its receptor Kiss1R; it is a critical central regulatory factor of the Gonadotropin Releasing Hormone (GnRH), but its role in the testis in sustaining spermatogenesis is not fully understood. Similarly, in addition to the brain, the ECS is widely expressed in the testis, where it regulates spermatogenesis, steroidogenesis, and the production of high-quality gametes. Since the possible crosstalk between KS and ECS at the gonadal level is poorly understood, this study investigates the possible mutual modulation between ECS and KS in rat testis. Methods: Experiment 1: Testis pieces collected from adult rats were treated ex vivo for 1 h with the endocannabinoid anandamide (AEA, 10⁻⁸ M) ± SR141716A (10⁻⁷ M, a cannabinoid receptor (CB) 1 antagonist), or with SR141716A alone. Experiment 2: Testis pieces were treated for 4 h with decreasing doses of Kisspeptin-10 (Kp10, 10⁻⁶–10⁻⁹ M) ± Kp234 (a Kiss1R antagonist). Proteins extracted from the treated tissues were analyzed by Western blot for Kiss1R, Kiss1, CB1, CB2, AEA-hydrolyzing enzyme Fatty Acid Amide Hydrolase (FAAH), and AEA-biosynthetic enzyme N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD) proteins. Results: AEA treatment, via CB1, reduced Kiss1R protein in testis. Kp10 treatment increased the expression of CBs and NAPE-PLD at all doses and increased FAAH at 10⁻⁹ M dose only. Pre-incubation with Kp234 abolished Kp10 effects on CB1, NAPE-PLD, and FAAH, suggesting a direct Kp10-dependent modulation; on the other hand, pre-incubation with Kp234 did not abolish Kp10’s effects on CB2, suggesting an indirect action of Kp10 on CB2. Conclusions: Mutual modulation between ECS and KS exists in the testis: AEA, via CB1, suppresses Kisspeptin signaling, while Kisspeptin regulates the ECS through both Kiss1R-dependent and independent mechanisms. These local interactions identify new potential mechanisms in the intratesticular communications sustaining spermatogenesis via ECS and suggest that KS might be a new therapeutic target to rescue ECS impairment in male reproductive dysfunction. Full article

Background: Chronic pain is a multifactorial condition for which interdisciplinary multimodal rehabilitation is guideline-recommended, yet the biological mechanisms underlying treatment response remain incompletely understood and validated predictive biomarkers have not been established. Objective: This exploratory prospective cohort study examined clinical outcomes and circulating biomarker changes, encompassing the endocannabinoid system (ECS), inflammatory mediators, stress-regulatory markers, and metabolic parameters, in 410 patients with chronic pain of predominantly musculoskeletal etiology undergoing a standardized five-week rehabilitation program. Materials and Methods: Pain intensity and affective pain were assessed at baseline and end of rehabilitation; global performance of treatment (GPT) was additionally recorded. Serum analyses included anandamide (AEA), 2-arachidonoylglycerol (2-AG), IL-6, cortisol, IGF-1, BDNF, and leptin. Biomarker-outcome associations were examined via multiple regression analyses adjusted for demographics and biological and clinical confounders. Results: Statistically significant reductions were observed in pain intensity (−0.785 points, NRS; p < 0.001) and affective pain (−0.750 points; p < 0.001). IL-6 was associated with pain outcomes across time points. Higher baseline 2-AG independently predicted lower end-of-rehabilitation pain intensity, affective pain, and more favorable GPT. Greater AEA reductions were associated with favorable GPT. Conclusions: Baseline 2-AG emerges as a candidate predictor of treatment response, with lower pre-treatment levels potentially reflecting reduced stress-adaptive capacity, supporting inclusion of ECS markers in future controlled biomarker studies. Full article

Peripherally restricted (‘second-generation’) cannabinoid CB₁ receptor (CB₁R) antagonists have been suggested to have therapeutic potential in numerous diseases. However, their effects on the cardiovascular system require further research. The peripheral CB₁R antagonist AM6545 failed to modify the decrease in blood pressure (BP) elicited by inhibition of anandamide degradation in spontaneously hypertensive rats. The aims of the present study were to examine the effect of AM6545 on BP and its interaction with endocannabinoid-evoked effects in deoxycorticosterone acetate (DOCA)-salt rats. For this purpose, we applied methanandamide (MethAEA), a stable analogue of anandamide, and URB597, an inhibitor of its degradation, in urethane-anesthetized animals. AM6545 did not affect BP by itself. MethAEA elicited a biphasic effect (a rise in BP, followed by its fall); both phases were antagonized by AM6545. URB597 induced a monophasic hypotensive effect, which was abolished by AM6545 in DOCA-salt rats but further enhanced in control animals. AM6545 also unmasked an additional increase in BP after URB597 in both groups of rats. In conclusion, AM6545 modifies the cardiovascular effects of endocannabinoids in hypertension in a model-dependent manner. The cardiovascular effects of CB₁R antagonists should be carefully evaluated when assessing their potential therapeutic significance, as they may unmask an increase in BP. Full article

The endocannabinoid system is a complex regulatory network whose functioning is associated with maintaining homeostasis and regulating immune response. The aim of this study was to evaluate the relationship between endocannabinoid system activity, inflammation, and the progression of chronic kidney disease (CKD) in patients with autosomal dominant polycystic kidney disease (ADPKD). The study included 105 participants: 60 individuals with ADPKD and 45 healthy volunteers. From a single venous blood draw, concentrations of anandamide (AEA), 2-arachidonoylglycerol (2-AG), tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6) were measured in EDTA plasma. Basic laboratory parameters were also assessed, including complete blood count, iron metabolism indices, electrolyte panel, and azotemia parameters. There were statistically significant differences in the concentrations of both endocannabinoids, with higher mean values observed in the control group (p < 0.001). IL-6 concentrations were significantly higher in the ADPKD group compared with controls (p < 0.001). Although TNF-α concentrations were higher in the ADPKD group than in the control group, these differences did not reach statistical significance. Statistically significant correlations were also identified between inflammatory markers, endocannabinoid concentrations, and indices of renal function. Patients with ADPKD exhibit an altered endocannabinoid profile characterized by reduced AEA and 2-AG concentrations, which correlates with disease progression and poorer kidney function. The endocannabinoid system may modulate inflammation in ADPKD. Full article

The endocannabinoid system (ECS) is a fundamental regulator of brain and body homeostasis, integrating neural, immune, and stress-related signaling pathways. Dysregulation of ECS components, including cannabinoid receptors (CB1 and CB2), endocannabinoids such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes (FAAH and MAGL), has been increasingly implicated in the pathophysiology of neuropsychiatric disorders, including mood, anxiety, psychotic, stress-related, and eating disorders. Altered endocannabinoid signaling contributes to maladaptive stress responses, emotional dysregulation, and impaired synaptic plasticity, highlighting the role of the ECS as a core integrative mechanism. Therapeutic strategies targeting ECS, particularly through FAAH inhibition and the use of plant-derived cannabinoids, such as cannabidiol (CBD), show promise in restoring endogenous homeostasis while minimizing the adverse cognitive and affective effects associated with direct CB1 activation. ECS function and treatment response are further influenced by genetic polymorphisms in CNR1, CNR2, FAAH, and MGLL, as well as epigenetic mechanisms, including DNA methylation, histone modifications, and microRNA regulation. Despite these advances, clinical translation remains limited by interindividual variability, the complexity of ECS interactions, and the relatively small size of existing clinical studies. Future research integrating longitudinal clinical trials with multi-omics approaches is essential to support the development of evidence-based, personalized interventions. Overall, understanding ECS mechanisms and dysregulation provides a valuable framework for the development of targeted therapies in neuropsychiatric disorders. Full article

Headache disorders, including migraine, tension-type headache, trigeminal autonomic cephalalgias, post-traumatic headache and medication overuse headache, represent a major global health burden and remain difficult to treat despite therapeutic advances. The endocannabinoid system (ECS) has emerged as a key regulator of neural, vascular, and immune processes central to headache pathophysiology. Through coordinated actions of CB1 and CB2 receptors, the endogenous ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes, the ECS modulates trigeminovascular activity, descending pain control, cortical excitability, and neuroimmune sensitization. Preclinical studies demonstrate that ECS activation suppresses trigeminal firing, reduces calcitonin gene-related peptide (CGRP) release, attenuates neurogenic inflammation, stabilizes cortical susceptibility to spreading depression, and limits glial activation following traumatic brain injury. Conversely, ECS dysregulation contributes to central sensitization and impaired descending inhibition underlying medication overuse headache and other headache disorders. Pharmacological strategies targeting endocannabinoid degradation, such as inhibition of FAAH, MAGL, and COX-2, enhance endogenous cannabinoid tone and consistently reduce headache-like behaviors across diverse models. Importantly, sex differences shape ECS function, with females exhibiting distinct hormonal regulation, receptor expression, and glial activation that influence responsiveness to ECS-targeted interventions. Collectively, mechanistic and translational evidence highlights the ECS as a promising therapeutic target across primary and secondary headache disorders. Future clinical studies should incorporate sex-informed designs, integrate biomarkers of trigeminovascular and neuroimmune activity, and evaluate peripherally restricted ECS modulators and cannabinoid-based formulations as candidates for individualized headache therapy. Full article

Fatty acid amide hydrolase (FAAH) is a central component of the endocannabinoid system (ECS), where it primarily regulates intracellular levels of anandamide (AEA) through enzymatic hydrolysis. Although FAAH has been extensively studied in neural and immune contexts, its involvement in female reproductive physiology is receiving increasing attention. Accumulating evidence indicates that FAAH participates in several important ovarian processes, including follicular development, steroid hormone synthesis, ovulation, and luteal function. In this review, we outline the biochemical properties of FAAH and its spatial distribution in ovarian tissues, with a particular focus on how FAAH-mediated AEA metabolism contributes to intraovarian signaling. Furthermore, we highlight the potential implications of altered FAAH activity in ovarian disorders such as polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), and infertility. By integrating molecular observations with clinical findings, this work provides updated perspectives on FAAH as both a physiological regulator and a potential therapeutic target in reproductive medicine. 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

The study investigated the effects of intracerebroventricular (ICV) administration of the endocannabinoid anandamide (AEA) on suppression of gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) secretion during lipopolysaccharide (LPS)-induced inflammation in ewes at the follicular phase of the estrous cycle. Animals were divided into three groups: control, LPS (intravenous, IV; 400 ng/kg), and LPS + AEA (ICV; 100 µM/animal). In LPS-treated ewes, AEA increased GnRH concentration in the preoptic area (POA) and upregulated GnRH mRNA expression in the POA and anterior hypothalamus (AHA). Central administration of AEA decreased the circulating concentration of cortisol in LPS-treated ewes. Moreover, AEA lowered proinflammatory interleukin (IL)-1β and increased anti-inflammatory IL-10 protein expressions in the hypothalamus of LPS-treated ewes. However, ICV AEA did not reverse the inflammation-associated reduction in LH secretion. These findings show that acute central administration of AEA abolishes the inhibitory effect of inflammation on GnRH synthesis in the POA and even stimulates it, likely through attenuation of central inflammation, as reflected by IL-1β and IL-10 changes in the POA. Nevertheless, short-term AEA administration was insufficient to counteract the inflammation-mediated suppression of LH secretion. Further studies are needed to explore the role of endocannabinoids (ECBs) in modulating GnRH/LH secretion under inflammatory conditions, particularly with prolonged exposure. Full article

The endocannabinoid system (ECS) is a primary regulatory system in human physiology that serves to help maintain homeostasis throughout the nervous system, immune system, and gastrointestinal system. This review has the goal of evaluating the unique opportunity for the ECS to provide a regulatory axis within the microbiota–gut–brain axis, particularly with regard to neurodevelopment, immune tolerance, and gut health. Cannabinoid receptors CB1 and CB2 and endogenous ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG have the ability to provide a variety of signaling pathways that can regulate cognitive resilience, emotional tuning, and immune regulation. Because the ECS has the ability to regulate multiple neurochemicals, alter immune cell functions, and maintain gut barriers, the ECS exists at the crossroads of many physiological systems, which also have a predictive role in neurodegenerative disease, chronic inflammation, and mental illness. Our goal is to present the latest and best recent advances in the ECS literature and establish evidence that there exists some modest potential for the therapeutic modulation of the ECS to improve pathological manifestations of cross-system dysregulation. In addition to cellular signaling pathways, the ECS affects other homeostatic processes, such as synaptic plasticity and the level of neuroprotection in the CNS, immune-related homeostasis, and coordinating the composition of gut microbiota. We argue that the ECS represents a suitable new therapeutic target that could modulate dysregulation across these systems more inclusively. This paper aims to emphasize the proposed potential of the ECS’s position in this axis and propose advanced cannabinoid-based interventions as a novel mechanism for developing personalized medicine and health systems through multi-system integration. Full article

Truffles are edible symbiotic hypogeal fungi and highly prized worldwide for their unique aroma and rich nutritional profile. Belonging to the order Pezizales and family Tuberaceae, with the genus Tuber being the most notable, truffles contain a diverse array of bioactive compounds including phenols, terpenoids, polysaccharides, anandamide, fatty acids, and ergosterols. These compounds contribute to a wide range of biological activities such as antioxidant, antibacterial, anti-inflammatory, hepatoprotective, and anticancer effects. This review comprehensively summarizes current scientific evidence on the biochemical composition, nutritional and aromatic properties, and biological activities of truffles, with special emphasis on their antioxidant and anti-tumor potential. Additionally, factors influencing truffle productivity and quality as well as advanced extraction and storage techniques to preserve bioactivity are discussed, highlighting their potential as valuable functional foods and sources of natural antioxidants. Full article

Atherosclerosis, the principal pathology underlying cardiovascular diseases, is now recognized as a chronic inflammatory disorder of the arterial wall. This review focuses on the central role of oxylipins, a diverse family of bioactive lipids derived from polyunsaturated fatty acids (PUFAs), in the inflammatory processes driving atherosclerosis. We synthesize evidence that oxylipins produced via cyclooxygenase (COX), lipoxygenase (LOX), cytochrome P450 (CYP), anandamide (AEA) pathways and non-enzymatic transformations of PUFAs are pivotal modulators of vascular function, immune cell recruitment, and plaque stability. The balance between pro-inflammatory mediators and specialized pro-resolving mediators (SPMs) is critical; a shift towards inflammation underlies disease progression. Advances in lipidomics now enable comprehensive oxylipin profiling, revealing distinct signatures with significant diagnostic and prognostic potential for assessing coronary artery disease severity and predicting future cardiovascular events. Therapeutically, while current anti-inflammatory strategies target downstream pathways, this review highlights emerging approaches that modulate the oxylipin system directly. These include promoting SPMs synthesis through omega-3 supplementation, inhibiting pro-inflammatory leukotriene production, and preserving cardioprotective epoxyeicosatrienoic acids (EETs) via soluble epoxide hydrolase (sEH) inhibition. A deeper understanding of these complex oxylipin networks promises to yield novel biomarkers and targeted therapies designed to restore inflammatory homeostasis and combat atherosclerotic cardiovascular disease. Full article